Microwaves in Organic Synthesis

Microwaves in Organic Synthesis
Edited by
A. Loupy
Microwaves in Organic Synthesis. Edited by Andr Loupy

Copyright # 2002 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
ISBN: 3-527-30514-9
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Microwaves in Organic Synthesis
Edited by
Andr Loupy
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ISBN 3-527-30514-9
V
Contents
Preface XVIII
List of Authors XXI
1 Wave±Material Interactions, Microwave Technology and Equipment 1

Didier Stuerga and Michel Delmotte
1.1 Fundamentals of Microwave±Matter Interactions 1
1.1.1 Introduction 1
1.1.1.1 History 2
1.1.1.2 The Electromagnetic Spectrum 2
1.1.1.3 Energetics 3
1.1.2 The Complex Dielectric Permittivity 4
1.1.2.1 Polarization and Storage of Electromagnetic Energy 4
The physical origin of polarization 4
Orienting effect of a static electric field 6
1.1.2.2 Thermal Conversion of Electromagnetic Energy 7
Physical origin of dielectric loss 7
Relaxation times 9
Consequences of the thermal changes of the dielectric permittivity 11
Conduction losses 13
Magnetic losses 13
Parameters of the thermal conversion 14
1.1.3 Thermodynamic and other Effects of Electric Fields 15
1.1.4 The Athermal and Specific Effects of Electric Fields 17
1.1.5 Conclusions 18
1.2 Overview of Microwave Reactor Design and Laboratory and Industrial
Equipment 18
1.2.1 Microwave Ovens and Reactors ± Background 19
1.2.1.1 Applicators, Waveguides, and Cavities 19
1.2.1.2 Single-mode or Multimode? 20
1.2.1.3 Limits of Domestic Ovens 21
1.2.1.4 Temperature-measurement Limits 21
1.2.1.5 The Design Principles of Microwave Applicators 21
1.2.2 Commercial Laboratory Microwave Reactors 22

ISBN: 3-527-30514-9
VI Contents
1.2.2.1 The Prolabo Products 22

1.2.2.2 The CEM Products 23
1.2.2.3 The Milestone Products 24
1.2.2.4 The Personal Chemistry Products 25
1.2.2.5 Plazmatronika Products 26
1.2.3 Experimental Microwave Reactors 26
1.2.3.1 The RAMO System 26
1.2.3.2 The Supercritical Microwave Reactor 27
1.2.3.3 The Coconut Reactor 28
1.2.4 Industrial Equipment ± Batch or Continuous Flow? 28
1.2.4.1 The Pulsar System 29
1.2.4.2 The Thermostar System 30
References 32
2 Microwave-assisted Organic Chemistry in Pressurized Reactors 35

Christopher R. Strauss
2.1 Introduction 35
2.2 Rationale for Pressurized Microwave Reactors 36
2.2.1 The Continuous Microwave Reactor (CMR) 37
2.2.2 The Microwave Batch Reactor (MBR) 38
2.2.3 Transfer of Microwave Energy 39
2.4 Contrasts between Synthesis and Digestion 40
2.5 Advantages of the MBR and CMR 40
2.6 Applications of the MBR and CMR 41
2.6.1 Reactions with Sterically Constrained Molecules 42
2.6.2 Preparation of Thermally Labile Products 43
2.6.2.1 Depolymerization of Cellulose 43
2.6.2.2 Hofmann Elimination 43
2.6.2.3 Alkyl 2-(hydroxymethyl)acrylates 44
2.6.3 New Reactions that Require High Temperature 44
2.6.3.1 Etherification 44
2.6.3.2 Uncatalyzed Hydrogen-transfer Reduction 46
2.6.4 Reactions Known to Require High Temperatures 46
2.6.4.1 Willgerodt Reactions 46
2.6.4.2 Jacobs±Gould Reactions under Solvent-free Conditions 47
2.6.5 Viscous Reaction Mixtures 47
2.6.6 Reaction Vessels 48
2.6.7 Reactions with a Distillation Step 48
2.6.8 Miscellaneous Reactions 49
2.6.9 Kinetic Products 49
2.6.10 Gaseous Reactants and Media 50
2.7 High-temperature Water as a Medium or Solvent for
Microwave-assisted Organic Synthesis 51
2.7.1 Biomimetic Reactions 51
2.7.2 Indoles 52
Contents VII
2.7.3 Reactions in Aqueous Acid and Base 53

2.7.4 Avoiding Salt Formation 53
2.7.5 Resin-based Adsorption Processes 54
2.8 Metal-catalyzed Processes 54
2.9 Pressurized Microwave Systems Developed by Others
for Organic and Organometallic Chemistry 55
2.10 Technical Considerations and Safety 56
2.11 Conclusion 57
Acknowledgments 58
References and Footnotes 58
3 Nonthermal Effects of Microwaves in Organic Synthesis 61

Laurence Perreux and Andr Loupy
3.1 Origin of Microwave Effects 62
3.2 Specific Microwave Effects 63
3.3 Effects of the Medium 65
3.4 Effects of Reaction Mechanisms 69
3.4.1 Isopolar Transition-state Reactions 70
3.4.2 Bimolecular Reactions between Neutral Reactants Leading
to Charged Products 72
3.4.3 Anionic Bimolecular Reactions Involving Neutral Electrophiles 73
3.4.4 Unimolecular Reactions 74
3.5 Effect of the Position of the Transition State Along the
Reaction Coordinates 74
3.6 Effect on Selectivity 75
3.7 Some Illustrative Examples 76
3.7.1 Bimolecular Reactions between Neutral Reactants 76
3.7.1.1 Nucleophilic Additions to Carbonyl Compounds 76
Amines 76
Imine or enamine synthesis 76
Hydrazone synthesis 77
Amidation of carboxylic acids 78
Synthesis of 2-oxazolines 79
Synthesis of aminotoluenesulfonamides 80
Leuckart reductive amination of carbonyl compounds 81
Synthesis of 1,4-dithiocarbonyl piperazines 81
Alcohols 82
Solvent-free esterification of fusel oil 82
Synthesis of alkyl p-toluenesulfinates 82
Synthesis of aminocoumarins by the Pechmann reaction 83
Synthesis of cyclic acetals 83
3.7.1.2 Michael Additions 84
3.7.1.3 SN2 Reactions 84
Reaction of pyrazole with phenethyl bromide 84
Ring opening of an epoxide by amines 85
VIII Contents
N-alkylation of 2-halopyridines 85
Nucleophilic aromatic substitutions 86
Synthesis of phosphonium salts 86
3.7.2 Bimolecular Reactions with One Charged Reactant 87
3.7.2.1 Anionic SN2 Reactions Involving Charge-localized Anions 88
Selective dealkylation of aromatic alkoxylated compounds 88
Alkylation of dianhydrohexitols under phase-transfer
catalysis (PTC) conditions 89
The Krapcho reaction 90
Anionic b-elimination 91
3.7.2.2 Anionic SN2 Reactions Involving Charge-delocalized Anions 92
Alkylation of potassium benzoate 92
Pyrazole alkylation in basic media 93
Selective alkylation of b-naphthol in basic media 93
3.7.2.3 Nucleophilic Additions to Carbonyl Compounds 94
Saponification of hindered aromatic esters 94
PTC transesterification in basic medium 94
Ester aminolysis in basic medium 95
3.7.2.4 Reactions Involving Positively Charged Reactants 97
Friedel±Crafts acylation of aromatic ethers 97
Formylation using Vilsmeier reagent 98
SN2 reactions with tetralkylammonium salts 99
3.7.3 Unimolecular Reactions 99
3.7.3.1 Imidization Reaction of a Polyamic Acid 99
3.7.3.2 Cyclization of Monotrifluoroacetylated o-Arylenediamines 100
3.7.3.3 Intramolecular Nucleophilic Aromatic Substitution 101
3.7.3.4 Intramolecular Michael Additions 102
3.7.3.5 Deprotection of Allyl Esters 103
3.8 Illustrative Examples of the Effects of Selectivity 103
3.8.1 Benzylation of 2-Pyridone 104
3.8.2 Addition of Vinylpyrazoles to Imine Systems 104
3.8.3 Stereo Control of b-Lactam Formation 105
3.8.4 Cycloaddition to C70 Fullerene 106
3.8.5 Selective Alkylation of 1,2,4-Triazole 106
3.8.6 Rearrangement of Ammonium Ylides 108
3.9 Concerning the Absence of Microwave Effects 108
3.10 Conclusions 109
References 110
4 Organic Synthesis using Microwaves in Homogeneous Media 115

Richard N. Gedye
4.1 Introduction 115
4.2 Reactions at Elevated Pressures 116
4.3 Reactions at Atmospheric Pressure 121
Contents IX
4.4 Effect of Microwaves on the Rates of Homogeneous Reactions

in Open Vessels 123
4.4.1 Diels±Alder reactions 123
4.4.2 Reactions of Biologically Important Molecules 124
4.4.3 Other Reactions in Polar Solvents 125
4.4.4 Reactions in Nonpolar Solvents 129
4.4.5 Reactions in Homogeneous Media Showing no
MW Rate Enhancement 131
4.4.6 Reactions in Homogeneous Media Showing MW Rate Enhancement 133
4.4.7 Possible Explanations of MW Acceleration 135
4.5 Selectivity in MW-assisted Reactions 135
4.6 Comparison of Homogeneous and Heterogeneous Conditions 140
4.7 Advantages and Limitations of MW Heating in Organic Synthesis 142
References 143
5 Microwave and Phase-transfer Catalysis 147

Andr Loupy, Alain Petit, and Dariusz Bogdal
5.1 Phase-transfer Catalysis 147
5.2 Synthetic Applications of Phase-transfer Processes 150
5.2.1 O-Alkylations 150
5.2.1.1 Ester Synthesis 150
Alkyl acetates 150
Long-chain esters 151
Aromatic esters 152
5.2.1.2 Ether Synthesis 153
Aliphatic ethers 153
Furan diethers 153
Diethers from dianhydrohexitols 154
Phenolic ethers 155
Phenolic polyethers 158
5.2.2 N-Alkylations 159
5.2.2.1 Saccharin 159
5.2.2.2 Benzoxazinones and Benzothiazinones 159
5.2.2.3 Barbitone 160
5.2.2.4 Amides and Lactams 160
5.2.2.5 Aromatic Amines 161
5.2.2.6 Phenylpyrrolidino[60]fullerene 161
5.2.2.7 Five-membered Nitrogen Heterocycles 162
5.2.2.8 Pyrimidine and Purine Derivatives 162
5.2.3 C-Alkylations of Active Methylenes 163
5.2.4 Alkylations with Dihalogenoalkanes 164
5.2.4.1 O-Alkylations 164
5.2.4.2 S-Alkylations 165
5.2.5 Nucleophilic Additions to Carbonyl Compounds 166
5.2.5.1 Aldol Condensation 166
X Contents
5.2.5.2 Ester Saponification 167

5.2.5.3 Base-catalyzed Transesterifications 168
5.2.6 Deprotonations 169
5.2.6.1 Base-catalyzed Isomerization of Allylic Aromatic Compounds 169
5.2.6.2 Carbene Generation (a-Elimination) 169
5.2.6.3 b-Elimination 169
5.2.7.1 Aromatic Nucleophilic Substitution (SNAr) 170
5.2.7.2 Dealkoxycarbonylations of Activated Esters (Krapcho Reaction) 171
5.2.7.3 1,3-Dipolar Cycloaddition of Diphenylnitrilimine 172
5.2.7.4 Synthesis of b-Lactams 172
5.2.7.5 Selective Dealkylations of Aromatic Ethers 173
5.2.7.6 Synthesis of Dibenzyl Diselenides 174
5.2.7.7 Selective Hydrolysis of Nitriles to Amides 174
5.2.7.8 Synthesis of Diaryl-a-tetralones 175
5.2.7.9 Intramolecular Cyclization 175
5.2.7.10 Heck Cross-coupling Reaction 176
5.2.7.11 Oxidation Reactions 176
5.2.7.12 S-Alkylation of n-Octyl Bromide 177
5.2.7.13 Reductive Decyanation of Alkyldiphenylmethanes 177
5.3 Conclusion 177
References 178
6 Organic Synthesis Using Microwaves and Supported Reagents 181

Rajender S. Varma
6.2 Microwave-accelerated Solvent-free Organic Reactions 182
6.2.1 Protection±Deprotection Reactions 183
6.2.1.1 Formation of Acetals and Dioxolanes 183
6.2.1.2 N-Alkylation Reactions 184
6.2.1.3 Deacylation reactions 184
6.2.1.4 Cleavage of Aldehyde Diacetates 185
6.2.1.5 Debenzylation of Carboxylic Esters 185
6.2.1.6 Selective Cleavage of the N-tert-butoxycarbonyl Group 186
6.2.1.7 Desilylation Reactions 186
6.2.1.8 Dethioacetalization Reaction 186
6.2.1.9 Deoximation Reactions 186
6.2.1.10 Cleavage of Semicarbazones and Phenylhydrazones 188
6.2.1.11 Dethiocarbonylation 189
6.2.1.12 Cleavage of Methoxyphenyl Methyl (MPM) and
Tetrahydropyranyl (THP) Ethers 190
6.2.2 Condensation Reactions 191
6.2.2.1 Wittig Olefination Reactions 191
6.2.2.2 Knoevenagel Condensation Reactions ± Synthesis of Coumarins 191
6.2.2.3 Synthesis of Imines, Enamines, Nitroalkenes and N-Sulfonylimines 192
Contents XI
6.2.3 Isomerization and Rearrangement Reactions 194

6.2.3.1 Eugenol±Isoeugenol Isomerization 195
6.2.3.2 Pinacol±Pinacolone Rearrangement 195
6.2.3.3 Beckmann Rearrangement 195
6.2.4 Oxidation Reactions ± Oxidation of Alcohols and Sulfides 196
6.2.4.1 Activated Manganese Dioxide±Silica 196
6.2.4.2 Chromium Trioxide±Wet Alumina 196
6.2.4.3 Selective Solvent-free Oxidation with Clayfen 197
6.2.4.4 Oxidations with Claycop±Hydrogen Peroxide 198
6.2.4.5 Other Metallic Oxidants ± Copper Sulfate or Oxone±alumina 198
6.2.4.6 Nonmetallic Oxidants: Iodobenzene Diacetate (IBD)-impregnated
Alumina 199
6.2.4.7 Oxidation of Sulfides to Sulfoxides and Sulfones ±
Sodium Periodate±Silica 199
6.2.4.8 Oxidation of Sulfides to Sulfoxides ±
Iodobenzene Diacetate±Alumina 200
6.2.4.9 Oxidation of Arenes and Enamines ± Potassium Permanganate
(KMnO4)±Alumina 200
6.2.4.10 Other Oxidation Reactions 201
6.2.5 Reduction Reactions 201
6.2.5.1 Reduction of Carbonyl Compounds with Aluminum Alkoxides 201
6.2.5.2 Reduction of Carbonyl Compounds to Alcohols ±
Sodium Borohydride±Alumina 201
6.2.5.3 Reductive Amination of Carbonyls 202
6.2.5.4 Solid-state Cannizzaro Reaction 203
6.2.6 Synthesis of Heterocyclic Compounds 204
6.2.6.1 Flavones 204
6.2.6.2 2-Amino-substituted Isoflav-3-enes 204
6.2.6.3 Substituted Thiazoles 205
6.2.6.4 Synthesis of 2-Aroylbenzofurans 206
6.2.6.5 Synthesis of Quinolones 206
6.2.6.6 Multi-component Reactions (Imidazo[1,2-a]annulated N-heterocycles ±
Ugi reaction) 207
6.2.7.1 Transformation of Arylaldehydes to Nitriles 208
6.2.7.2 Nitration of Styrenes ± Preparation of b-Nitrostyrenes 209
6.2.7.3 Organometallic Reactions (Carbon±Carbon Bond-forming Reactions) 209
6.2.7.4 Synthesis of Radiolabeled Compounds ± Exchange Reactions 210
6.2.7.5 Enzyme-catalyzed Reactions 211
6.2.7.6 Solvent-free Synthesis of Ionic Liquids 212
6.3 Conclusions 212
References 213
XII Contents
7 Microwave-assisted Reactions on Graphite 219

Andr Laporterie, Julien Marqui, and Jacques Dubac
7.2 Graphite as a Sensitizer 220
7.2.1 Diels±Alder Reactions 221
7.2.2 Ene Reactions 225
7.2.3 Oxidation of Propan-2-ol 227
7.2.4 Thermolysis of Esters 227
7.2.5 Thermal Reactions in Heterocyclic Syntheses 229
7.2.6 Decomplexation of Metal Complexes 231
7.2.7 Redistribution Reactions between Tetraalkyl- or Tetraarylgermanes and
Germanium Tetrahalides 232
7.2.8 Pyrolysis of Urea 233
7.2.9 Esterification of Stearic Acid by n-Butanol 234
7.3 Graphite as Sensitizer and Catalyst 234
7.3.1 Analysis of Two Synthetic Commercial Graphites 235
7.3.2 Acylation of Aromatic Compounds 235
7.3.3 Acylative Cleavage of Ethers 240
7.3.4 Ketodecarboxylation of Carboxylic Diacids 241
7.4 Notes 244
7.4.1 MW Apparatus, Typical Procedures, and Safety Measures 244
7.4.2 Temperature Measurement 245
7.4.3 The Retention Mechanism of Reactants on Graphite 246
7.4.4 Graphite or Amorphous Carbon for C/MW Coupling? 246
7.5 Conclusion 247
Acknowledgments 247
References 248
8 Microwaves in Heterocyclic Chemistry 253

Jack Hamelin, Jean-Pierre Bazureau, and Franoise Texier-Boullet
8.2 Microwave-assisted Reactions in Organic Solvents 253
8.2.1 Heck, Suzuki, and Stille reactions 253
8.2.2 Aziridine Synthesis 255
8.2.3 b-Lactam Chemistry 255
8.2.4 1,2,4-Triazole, Pyrazole Synthesis 257
8.2.5 Multistep Synthesis of Polyheterocyclic Systems 258
8.2.6 Claisen Rearrangement 261
8.2.7 Hantzsch Cyclocondensations 262
8.2.8 1,3,4-Oxadiazole Synthesis 264
8.2.9 Biginelli Cyclocondensation 264
8.2.10 Condensation Reactions with Creatinine and Thiohydantoin 265
8.2.11 Deprotection of N-Cbz and N-Bn derivatives; Deuterium-labeled Aromatic
Dehalogenation 266
8.3 Solvent-free Synthesis 267
Contents XIII
8.3.1 Solvent-free Synthesis under Acidic Conditions 267

8.3.1.1 Tetraphenyl Porphyrin Synthesis 267
8.3.1.2 Acetalization of L-galactono-1,4-lactone 268
8.3.1.3 Aziridine Synthesis 268
8.3.1.4 Lactam Synthesis 269
8.3.1.5 Arylimidazole Synthesis 269
8.3.1.6 Pyridine, Pyrazine, and Pyridine Derivatives 270
8.3.1.7 Quinolines and Quinoxalines 271
8.3.1.8 Pyrroles, Indoles and Related Compounds; Imidazoles 272
8.3.1.9 Preparations of Coumarins 272
8.3.1.10 Dioxolane Synthesis 273
8.3.1.11 Carbohydrate Glycosylations 274
8.3.2 Reactions under Basic Conditions 275
8.3.2.1 Lactam Synthesis 275
8.3.2.2 Lactone Preparation 276
8.3.2.3 N-substituted Imidazoles and Imidazolines 276
8.3.2.4 Base-catalyzed Reactions of Glyoxal Monohydrazones
with Active Methylene Compounds 276
8.3.2.5 Annelated Pyridines and Dihydropyridines 277
8.3.2.6 Stereoselective Route to 3,5-Dihydroimidazol-4-one Derivatives 277
8.3.2.7 Oxidation using KMnO4 ±Al2O3 278
8.3.2.8 Synthesis of 1,8-Cineole Derivatives 278
8.3.2.9 1-Aminopyroles and Related Compounds 279
8.3.3 Enzymatic Catalysis in ªDry Mediaº 279
8.3.3.1 Regioselective Esterification of Glycopyranosides 279
8.3.3.2 Transglycosylations 280
8.3.4 Solvent-free Solid±Liquid Phase-transfer Catalysis (PTC) 280
8.3.4.1 b-Eliminations of Halogenated Acetals 280
8.3.4.2 Synthesis of Furanic Diethers 281
8.3.4.3 Synthesis of Diethers and New Diols Derived from
Dianhydrohexitols 281
8.3.4.4 Preparation of Benzo[b]furans 281
8.3.4.5 Cineole Derivatives 282
8.3.5 Solvent-free Reactions without Support or Catalyst 282
8.3.5.1 Condensation of Creatinine with Aldehydes 282
8.3.5.2 Addition of Isocyanates to 2-substituted 1H-Perimidine 282
8.3.5.3 Pyridine Derivatives 283
Synthesis of 2,3-dihydroimidazo-[1,2-c]-pyrimidines 283
Microwave-mediated Biginelli reactions 283
8.3.5.4 Phthalimide Synthesis 283
8.3.5.5 Pyrazoles and Triazoles 284
Pyrazoles 284
Phenacylation of 1,2,4-Triazole 285
8.3.5.6 Pyridines and Pyridones 285
8.3.5.7 Synthesis of 3-Aryl-4-hydroxyquinolin-2(1H)ones 286
XIV Contents
8.4 Room-temperature Ionic Liquids (RTIL) ± Synthesis and Applications in

Organic Synthesis under the Action of Microwaves 287
8.4.1 Synthesis of 1,3-Dialkylimidazoliums as RTIL 287
8.4.2 N-alkylation in RTIL 288
8.4.3 Knoevenagel Reactions on a Grafted Ionic Liquid Phase 289
8.5 Conclusions 289
References and Notes 290
9 Microwaves in Cycloadditions 295

Antonio de la Hoz, Angel DÌaz-Ortiz, and Fernando Langa
9.2 Reactions in Solution 296
9.2.1 Reactions under Pressure 296
9.2.2 Reactions under Reflux 296
9.2.3 Microwave Organic Reaction Enhancement (MORE) 297
9.3 Solvent-free Conditions 297
9.3.1 Reactions using Mineral Supports 298
9.3.2 Reactions without Support 299
9.3.3 Reactions with a Heat Captor 299
9.4 Specific Effects in Cycloaddition Reactions 301
9.5 [4+2] Cycloadditions 302
9.5.1 Diels±Alder Reactions 302
9.5.2 Retro Diels±Alder Reactions 311
9.5.3 Hetero Diels±Alder Reactions 312
9.5.3.1 Heterodienes 312
9.5.3.2 Heterodienophiles 315
9.5.4 Miscellaneous 316
9.6 1,3-Dipolar Cycloadditions 317
9.6.1 Azomethine Ylides 317
9.6.2 Nitrones 323
9.6.3 Nitrile Oxides 326
9.6.4 Nitrile Imines 331
9.6.5 Azides and Azomethine Imines 333
9.8 Conclusions 338
Acknowledgments 338
References 339
10 Microwave Catalysis in Organic Synthesis 345

Milan Hjek 345
10.1.1 Definitions 346
10.2 Preparation of Heterogeneous Catalysts 347
10.2.1 Drying and Calcination 347
10.2.2 Catalyst Activation and Reactivation (Regeneration) 350
Contents XV
10.3 Microwave Activation of Catalytic Reactions 351

10.3.1 Reactions in the Liquid Phase 351
10.3.1.1 Esterification, Transesterification 351
10.3.1.2 Hydrogenation, Hydrogenolysis 353
10.3.1.3 Miscellaneous Reactions 353
10.3.2 Reactions in the Gas Phase 357
10.3.2.1 Reactions of Methane 358
Oxidative coupling of methane to yield C2 and higher hydrocarbons 358
Direct partial oxidation of methane to produce methanol and other
oxygenates 360
10.3.2.2 Reactions of Higher Hydrocarbons 360
10.3.2.3 Miscellaneous Reactions 362
10.3.3 Mechanistic Aspects 362
Reactions accelerated by microwaves 363
Reactions not accelerated by microwaves 363
Superheating of liquid reaction mixture 364
Localized superheating in the solid phase 365
Selective heating 365
Hot spots 366
Effect of microwaves on selectivity 368
Effect of microwaves on rate enhancement 368
10.3.4 Microwave Catalytic Reactors 369
10.3.4.1 Batch Reactors 369
10.4 Industrial Applications 373
References 374
11 Transition Metal Catalysis and Microwave Flash Heating in

Organic Chemistry 379
Kristofer Olofsson, Anders Hallberg, and Mats Larhed 379
11.2 Safety 379
11.3 Metal-catalyzed Reactions 380
11.3.1 Heck Reactions 381
11.3.2 Carbonylative Couplings 387
11.3.3 Sonogashira Coupling Reactions 388
11.3.4 Cross-coupling Reactions 389
11.3.4.1 Suzuki Couplings 389
11.3.4.2 Stille Couplings 392
11.3.5 Other Palladium-catalyzed Reactions 395
11.3.6 Asymmetric Catalysis 396
11.3.7 Other Metal-catalyzed Reactions 399
11.4 Summary 401
Acknowledgment 401
References 401
XVI Contents
12 Microwave-assisted Combinatorial Chemistry 405

C. Oliver Kappe and Alexander Stadler 405
12.2 Solid-phase Organic Synthesis 407
12.3 Polymer-supported Reagents, Scavengers, and Catalysts 415
12.4 Soluble Polymer-supported Synthesis 417
12.5 Fluorous-phase Synthesis 419
12.6. Parallel Synthesis 420
12.7 Equipment for High-throughput Microwave-assisted Synthesis 424
12.8 Conclusion 430
References 430
13 Microwave-Enhanced Radiochemistry 435

John R. Jones and Shui-Yu Lu 435
13.1.1 Methods for Incorporating Tritium into Organic Compounds 436
13.1.2 Problems and Possible Solutions 436
13.1.3 The Use of Microwaves 439
13.1.4 Instrumentation 441
13.2 Microwave-enhanced Tritiation Reactions 442
13.2.1 Hydrogen Isotope Exchange 442
13.2.2 Hydrogenation 445
13.2.3 Aromatic Dehalogenation 446
13.2.4 Borohydride Reductions 447
13.2.5 Methylation Reactions 448
13.2.6 Aromatic Decarboxylation 449
13.2.7 The Development of Parallel Procedures 450
13.2.8 Combined Methodology 451
13.3 Microwave-enhanced Detritiation Reactions 453
13.4 Microwave-enhanced PET Radiochemistry 454
11
13.4.1 C-Labeled Compounds 455
18
13.4.2 F-labeled Compounds 456
13.5 Conclusion 459
Acknowledgments 459
References 459
14 Microwave Photochemistry 463

Petr Kln and VladimÌr CÌrkva 463
14.2 Ultraviolet Discharge in Electrodeless Lamps 464
14.2.1 Theoretical Aspects of the Discharge in EDL 465
14.2.2 The Fundamentals of EDL Construction and Performance 465
14.2.3 Spectral Characteristics of EDL 466
14.3 Microwave Photochemical Reactor 467
14.4 Microwave Photochemistry 472
Contents XVII
14.4.1 Interactions of Ultraviolet and Microwave Radiation with Matter 472

14.4.2 Photochemical Reactions in the Microwave Field ± Thermal Effects 474
14.4.3 Nonthermal Microwave Effects ± Intersystem Crossing in
Radical-recombination Reactions 476
14.4.4 Analytical and Environmental Applications of Microwave
Photochemistry 479
14.6 Concluding Remarks 481
Acknowledgments 482
References 482
Index 487
XIX
Preface
The domestic microwave oven is a serendipitous invention. Percy Spencer was work-
ing for Raytheon, a company heavily involved with radar during World War II, when
he noticed the heat generated by a radar antenna. In 1947 an appliance called a Ra-
darange appeared on the market for food processing. The first kitchen microwave
oven was introduced by Tappan in 1955. Sales of inexpensive domestic ovens now re-
present a multibillion-dollar (euro) annual market.
Numerous other uses of microwaves have appeared in the recent years ± essen-
tially drying of different types of material (paper, rubber, tobacco, leather ¼), treat-
ment of elastomers and vulcanization, extraction, polymerization, and many applica-
tions in the food-processing industry.
The field of microwave-assisted organic chemistry is therefore quite young. The
first two pioneering publications from the groups of R. Gedye and R.J. Giguere ap-
peared in 1986. These authors described several reactions completed within a few
minutes when conducted in sealed vessels (glass or Teflon) in domestic ovens. If the
feasibility of the procedure was thus apparent, a few explosions caused by the rapid
development of high pressure in closed systems were also reported. To prevent such
drawbacks safer techniques were developed ± reactions in open beakers or flasks or
solvent-free reactions, as developed essentially since 1987 in France ± in Caen (D. Vil-
lemin), Orsay (G. Bram and A. Loupy), and Rennes (J. Hamelin and F. Texier-Boul-
let). Combination of solvent-free procedures with microwave irradiation constitutes
an interesting and well-admitted approach within the concepts of Green Chemistry.
This coupling takes advantage both of the absence of solvent and of microwave tech-
nology under economical, efficient, and safe conditions with minimization of waste
and pollution.
The goal of this book is to focus on the different fields of application of this tech-
nology in different aspects of organic synthesis. The chapters, which complement
each other, were written by the most eminent scientists well-recognized in their own
field.
After essential revision, and description of wave±material interactions, microwave
technology, and equipment (Chapt. 1) the concepts of microwave-assisted organic
chemistry in pressurized reactors are described (Chapt. 2). Special emphasis on the
possible intervention of a specific (non-purely thermal) microwave effect is discussed
in Chapt. 3 and this is followed by up-to-date reviews of microwave-assisted organic

ISBN: 3-527-30514-9
XX Preface
synthesis in homogeneous media (Chapt. 4), under the action of phase-transfer cata-
lysis (Chapt. 5), using mineral solid supports under ªdry mediaº conditions
(Chapt. 6), and more specifically on graphite (Chapt. 7). Applications in which mi-
crowave-assisted technology has afforded spectacular results and applications are
discussed extensively in Chapt. 8 (heterocyclic chemistry) and Chapt. 9 (on cycload-
ditions). Finally, the techniques have led to fruitful advances in microwave catalysis
(Chapt. 10) and when applied to organometallic chemistry using transition metal
complexes (Chapt. 11) and new, very promising, techniques are now under develop-
ment as a result of applying microwave irradiation to combinatorial chemistry
(Chapt. 12), radiochemistry (Chapt. 13), and photochemistry (Chapt. 14).
I wish to thank sincerely all my colleagues and, nevertheless, (essentially) friends
involved in the realization of this book. I hope to express to all of them my friendly
and scientific gratitude as eminent specialists who agreed to devote their compe-
tence and time to submitting and reviewing papers to ensure the success of this
book.
Orsay, March 25th, 2002 Andr Loupy

XXI
List of Authors
Editor Dariusz Bogdal

Department of Chemistry
Prof. Dr. Andr Loupy Politechnika Krakowska
Laboratoire des Ractions Slectives sur ul. Warszawska 24
Supports 31-155 Krakow
Institut de Chimie Molculaire d'Orsay Poland
Universit Paris-Sud e-mail: [email protected]
Bt 410
91405 Orsay Cedex VladimÌr CÌrkva
France Institute of Chemical Process Fundamen-
Phone: 33-1-69-15-76-50 tals
Fax: 33-1-69-15-46-79 Academy of Sciences of the Czech
e-mail: [email protected] Republic
Rozvojova 135
165 02 Prague
List of Authors Czech Republic
Jean-Pierre Bazureau Michel Delmotte

Universit de Rennes 1 LM3/ENSAM 151
Institut de Chimie, Synth se and Electro- Bd. de l'Hopital
synth se Organiques 3 75013 Paris
UMR 6510, Bt. 10A France
Campus de Beaulieu e-mail: [email protected]
Avenue du gnral Leclerc
CS 74205 Angel DÌaz-Ortiz
35042 Rennes Cedex Departamento de QuÌmica Orgnica
France Facultad de QuÌmica
Universidad de Castilla-La Mancha
14071 Ciudad Real
Spain
Fax: 34-926295418
e-mail: [email protected]

ISBN: 3-527-30514-9
XXII List of Authors
Jacques Dubac Jack Hamelin

Universit Paul-Sabatier Universit de Rennes 1
Laboratoire Htrochimie Fondamentale Institut de Chimie, Synth se and Electro-
et Applique synth se Organiques 3
UMR-CNRS 5069 UMR 6510, Bt. 10A
118 route de Narbonne Campus de Beaulieu
31062-Toulouse Cedex Avenue du gnral Leclerc
France CS 74205
Fax: 33-561558204 35042 Rennes Cedex
e-mail: [email protected] France
e-mail:
Richard N. Gedye [email protected]
Department of Chemistry and
Biochemistry Antonio de la Hoz
Laurentian University Departamento de QuÌmica Orgnica
Sudbury Facultad de QuÌmica
Ontario Universidad de Castilla-La Mancha
Canada 14071 Ciudad Real
e-mail: [email protected] Spain
Fax: 34-926295418
Milan Hjek e-mail: [email protected]
Institute of Chemical Process
Fundamentals John R. Jones
Academy of Sciences of the Czech Department of Chemistry
Republic School of Physics and Chemistry
Rozvojov 135 University of Surrey, Guildford
165 02 Prague 6 ± Suchdol Surrey, GU2 7XH
Czech Republic United Kingdom
e-mail: [email protected] e-mail: [email protected]
Anders Hallberg C. Oliver Kappe

Department of Organic Pharmaceutical Institute of Chemistry
Chemistry Karl-Franzens-University Graz
BMC Heinrichstrasse 28
Uppsala University 8010 Graz
Box 574 Austria
751 23 Uppsala e-mail: [email protected]
Sweden
List of Authors XXIII
Petr Kln Julien Marqui

Department of Organic Chemistry Universit Paul-Sabatier
Faculty of Science Laboratoire Htrochimie Fondamentale
Masaryk University et Applique
Kotlarska 2 UMR-CNRS 5069
611 37 Brno 118 route de Narbonne
Czech Republic 31062-Toulouse Cedex
e-mail: [email protected] France
Fax: 33-561558204
Fernando Langa
Departamento de QuÌmica Orgnica Kristofer Olofsson
Facultad de Ciencias del Medio Ambiente Harvey W Peters Center
45071 Toledo Department of Chemistry
Spain Virginia Tech
Fax: 34-925268840 Blacksburg,VA 24061
e-mail: [email protected] USA
Andr Laporterie Laurence Perreux

Universit Paul-Sabatier Laboratoire des Ractions Slectives sur
Laboratoire Htrochimie Fondamentale Supports
et Applique ICMO
UMR-CNRS 5069 Universit Paris-Sud
118 route de Narbonne Bt 410
31062-Toulouse Cedex 91405 Orsay Cedex
France France
Fax: 33-561-55-8204
e-mail: [email protected] Alain Petit
Laboratoire des Ractions Slectives Sur
Mats Larhed Supports
Department of Organic Pharmaceutical ICMO
Chemistry Universit Paris-Sud
BMC Bt 410
Uppsala University 91405 Orsay
Box 574 France
751 23 Uppsala e-mail: [email protected]
Sweden
e-mail: [email protected] Alexander Stadler
Institute of Chemistry
Shui-Yu Lu Karl-Franzens-University Graz
Department of Chemistry Heinrichstrasse 28
School of Physics and Chemistry 8010 Graz
University of Surrey, Guildford Austria
Surrey, GU2 7XH
United Kingdom
XXIV List of Authors
Christopher R. Strauss Franoise Texier-Boullet

Centre for Green Chemistry Institut de Chimie, Synth se and Electro-
Monash University synth se Organiques 3
Clayton UMR 6510
3800 Victoria Universit de Rennes 1
Australia Bt. 10A
and CSIRO Molecular Science Avenue du gnral Leclerc
Private Bag 10 35042 Rennes Cedex
Clayton South France
3169 Victoria
Australia Rajender S. Varma
e-mail: [email protected] Clean Processes Branch
National Risk Management Research
Didier Stuerga Laboratory
GERM/LRRS BP 47870 U. S. Environmental Protection Agency
21078 Dijon cedex 26 West Martin Luther King Drive
France MS 443
e-mail: [email protected] Cincinnati, Ohio, 45268
USA
Fax: 1-513-569-7677
e-mail: [email protected]
1
1
Wave±Material Interactions, Microwave Technology
and Equipment
Didier Stuerga and Michel Delmotte
1.1
Fundamentals of Microwave±Matter Interactions
The objective of this first part of the book is to explain in a chemically intelligible
fashion the physical origin of microwave±matter interactions. After consideration of
the history of microwaves, and their position in the electromagnetic spectrum, we
will examine the notions of polarization and dielectric loss. The orienting effects of
the electric field, and the physical origin of dielectric loss will be analyzed, as will
transfers between rotational states and vibrational states within condensed phases. A
brief overview of thermodynamic and athermal effects will also be given.
1.1.1
Introduction
According to the famous chemistry dictionary of N. Macquer edited in 1775, ªAll the
chemistry operations could be reduced to decomposition and combination; hence, the fire
appears as an universal agent in chemistry as in natureº [1]. Heating has remained the
primary means of stimulating chemical reactions which proceed slowly under ambi-
ent conditions, although several other techniques have been used, e. g. photochemi-
cal, ultrasonic, high pressure, and plasma. In this book, we describe results obtained
with the help of microwave heating. Microwave heating or dielectric heating, an al-
ternative to conventional conductive heating, uses the property of some products
(liquids and solids) to transform electromagnetic energy into heat. This ªin situº
mode of energy conversion is very attractive for applications in chemistry and mate-
rial processing.
If the effect of the temperature on reaction rate is well known, and is very easy
to express, the problem is very different for effects of electromagnetic waves. What
can be expected from the orienting action of electromagnetic fields at molecular
levels? Are electromagnetic fields able to enhance or modify collisions between re-
agents? All these questions are raised by the use of microwaves energy in chemis-
try.

ISBN: 3-527-30514-9
2 1 Wave±Material Interactions, Microwave Technology and Equipment
1.1.1.1 History
The first announcement of a microwave oven was probably a magazine article about
a newly developed Radarange for airline use [2, 3]. This device, it was claimed, could
bake biscuits in 29 s, cook hamburgers in 35 s, and grill frankfurters in 10 s. The
first commercial microwave oven was developed by P. Spencer, of a company called
Raytheon, in 1952 [4]. There is a legend that P. Spencer, who studied high-power mi-
crowave sources for radar applications, observed the melting of a chocolate bar in his
pocket. Another story says that Spencer had some popping corn in his pocket that
began to pop as he was standing alongside a live microwave source [5]. This idea led
to the microwave oven in 1961 and the generation of the mass market. The wide-
spread domestic use of microwave ovens occurred during 1970s and 1980s as a re-
sult of Japanese technology transfer and global marketing. Curiously, industrial ap-
plications were initiated by the domestic oven.
Originally, microwaves played a leading role during the World War II, especially in
the battle of Britain which, thanks to radar, English planes won despite being out-
numbered three-to-one. The first generator of microwave power for radar, called the
magnetron, was designed by Randall and Booth at the University of Birmingham
during the 1940s. They were mass produced in the United States by companies such
as Raytheon.
1.1.1.2 The Electromagnetic Spectrum

In the electromagnetic spectrum, microwave radiation occurs in an area of transition
between infrared radiation and radiofrequency waves, as shown in Fig. 1.1. The wave-
lengths are between 1 cm and 1 m and frequencies between 30 GHz and 300 MHz.
Fig. 1.1 The electromagnetic spectrum.

The fundamental relationship between energy, E, frequency, n, wavelength, l, and

circular frequency, o, is given by Eq. (1):
hc
E ko hn 1
l
To avoid interference with telecommunications and cellular phone frequencies,

heating applications must use ISM bands (Industrial Scientific and Medical frequen-
cies) which are 27.12 915 MHz and 2.45 GHz, (wavelengths 11.05 m, 37.24 cm, and
12.24 cm, respectively). Domestic ovens and laboratory systems generally work at
2.45 GHz. At frequencies below 100 MHz, where conventional open wire circuits are
used, the technique will be referred to as radio-frequency heating. The object to be
heated is placed between the two electrodes of a condenser. At frequencies above
500 MHz, however, wired circuits cannot be used and the power is transferred to the
microwave applicator ± a metallic box in which the object to be heated is placed.
These operating conditions will be referred as microwave heating processes. In the
microwave band the wavelength is of order of the size of production and transmis-
sion elements. Elements cannot, therefore, be considered as points in comparison
with the wavelength, as is usual in circuit theory. In the same way, it is impossible to
consider them as far bigger than the wavelength, as in geometrical optics. Hence, be-
cause of the position of microwaves in the electromagnetic spectrum, we will use
both quantum mechanics (corpuscular aspect) and Maxwell equations (wavelike as-
pect). Detailed analysis of these phenomena is beyond the scope of this work.
1.1.1.3 Energetics
It is well known that g or X photons have energies suitable for excitation of inner
electrons. We can use ultraviolet and visible radiation to initiate chemical reactions
(photochemistry). Infrared radiation excites bond vibrations only whereas hyperfre-
quencies excite molecular rotation. In Tab. 1.1 the energies associated with chemical
bonds and Brownian motion are compared with the microwave photon correspond-
ing to the frequency used in microwave heating systems such as domestic and in-
dustrial ovens (2.45 GHz, 12.22 cm).
Tab. 1.1 Brownian motion and bonds energies.
Brownian motion Hydrogen bonds Covalent bonds Ionic bonds
4.51 (C±H)
Energy (eV) 0.017 (200 K) 0.04 to 0.44 7.6
3.82 (C±C)
435 (C±H)
Energy (kJ mol±1) 1.64 3.8 to 42 730
368 (C±C)
According to these values, the microwave photon is not sufficiently energetic to

break hydrogen bonds. Its energy is, furthermore, much smaller than that of Brow-
nian motion, and it obviously cannot induce chemical reactions. If no bond breaking
can occur by direct absorption of electromagnetic energy, then what can be expected
from the orienting effects of electromagnetic fields at molecular levels? Are electro-
magnetic fields able to enhance or to modify collisions between reagents? Do reac-
tions proceed with the same reaction rate with and without electromagnetic irradia-
tion at the same bulk temperature? In the following discussion the orienting effects
of the electric field, the physical origin of the dielectric loss, transfers between rota-
tional and vibrational states in condensed phases, and thermodynamic effects of
electric fields on chemical equilibrium will be analyzed.
1.1.2
The Complex Dielectric Permittivity
Insulating materials can be heated by applying high-frequency electromagnetic en-

ergy. The physical origin of this heating conversion lies with the ability of the electric
field to induce polarization of charges within the heated product. This polarization
cannot follow the extremely rapid reversals of the electric field and induce heating of
the irradiated media.
The interaction between electromagnetic waves and matter is quantified by two
complex physical quantities ± the dielectric permittivity e~ and the magnetic suscept-
~ The electric components of electromagnetic waves can induce currents of
ibility m.
free charges (electric conduction that could be of electronic or ionic origin). It can,
however, also induce local reorganization of linked charges (dipole moments) and
the magnetic component can induce structuring of magnetic moments. The local re-
organization of linked and free charges is the physical origin of polarization phe-
nomena. The storage of electromagnetic energy within the irradiated medium and
thermal conversion in relation to the frequency of the electromagnetic stimulation
appear as the two main aspects of polarization phenomena induced by the interac-
tion between electromagnetic waves and dielectric media. These two main aspects of
wave±matter interactions are expressed by the complex formula for the dielectric per-
mittivity as described by Eq. (2):
e~ e0 j e00 e0 e0r j e0 e00r 2
where e0 is the dielectric permittivity of vacuum, e' and e@ are the real and imaginary
parts of the complex dielectric permittivity, and e'r and e@r are the real and imaginary
parts of the relative complex dielectric permittivity. The storage of electromagnetic
energy is expressed by the real part whereas the thermal conversion is proportional
to the imaginary part.
1.1.2.1 Polarization and Storage of Electromagnetic Energy
The physical origin of polarization

~ which denotes the con-
Polarization phenomena are expressed by the polarization, P,
tribution by matter compared with that of vacuum. The electric field and the polari-
zation are linked by Maxwell's equations. The constitutive equation for vacuum is
given by Eq. (3):
D~ e0 E~ 3
where D~ is the electric displacement and E~ the electric field. For a dielectric medium
characterized by e~ , the constitutive equation is given by Eq. (4):
D~ e~ E~ e0 E~ P~ 4
In the global formulation of Eq. (4), we can express the term corresponding to
vacuum and given by Eq. (3). The second and complementary term then defines the
~ The higher the di-
contribution of matter to polarization processes, or polarization P.
electric permittivity of a material, the greater the polarization processes. The polari-
zation process described by P~ has its physical origin in the response of dipoles and
charges to the applied field. Depending on the frequency, electromagnetic fields put
one or more types of charge association under oscillation. In any material there is a
variety of types of charge association:
. inner electrons tightly bound to the nuclei,

. valence electrons,
. free or conduction electrons,
. bound ions in crystals,
. free ions as in electrolytes and nonstoichiometric ionic crystals (for example, ionic
dipoles such as OH ± have both ionic and dipolar characteristics), and
. finally the multipole (mainly the quadrupole or an antiparallel association of two
dipoles).
Depending on the frequency the electromagnetic field can induce one or more
types of charge association under oscillation. Each configuration has its own critical
frequency above which interaction with the field becomes vanishingly small, and the
lower the frequency and the more configurations are excited. For electrons of the in-
ner atomic shells the critical frequency is of the order of that of X-rays. Consequently
an electromagnetic field of wavelength more than 10±10 m cannot excite any vibra-
tions, but rather induces ionization of these atoms. There is no polarizing effect on
the material, which for this frequency has the same dielectric permittivity as
vacuum. For ultraviolet radiation the energy of photons is sufficient to induce transi-
tions of valence electrons. In the optical range an electromagnetic field can induce
distortion of inner and valence electronic shells. Polarization processes result from a
dipole moment induced by distortion of electron shells and are called electronic po-
larizability. In the infrared range electromagnetic fields induce atomic vibrations in
molecules and crystals and polarization processes result from the dipole moment in-
duced by distortion of nuclei positions. These polarization processes are called
atomic polarization. In all the processes mentioned so far, the charges affected by
the field can be considered to be attracted towards their central position by forces
which are proportional to their displacement by linear elastic forces. This mechani-
cal approach of electronic resonance is only an approximation, because electrons
cannot be properly treated by classical mechanics. Quantitative treatment of these
processes requires the formalism of quantum mechanics. The two types of polariza-
tion process described above can be connected in distortion polarization.
The characteristic material response times for molecular reorientation are 10±12 s.
Then, in the microwave band, electromagnetic fields lead to rotation of polar mole-
cules or charge redistribution. The corresponding polarization processes are denoted
orientation polarization.
Orienting effect of a static electric field

The general problem of the orienting effect of a static electric field (orientation of po-
lar molecules) was first considered by Debye [6, 7], Frælich [8], and more recently
Bættcher [9, 10].
We consider a collection of molecular dipoles in thermal equilibrium. It is as-
sumed that all the molecules are identical and they can take on any orientation. Be-
cause of thermal energy each molecule undergoes successive collisions with the sur-
rounding molecules. In the absence of an applied electric field, the collisions tend to
maintain a perfectly isotropic statistical orientation of the molecules. This means
that for each dipole pointing in one direction there is statistically a corresponding di-
pole pointing in the opposite direction, as described by Fig. 1.2.
~ the dipole moment, m,
In the presence of an applied electric field, E, ~ of a molecule
~
undergoes a torque, G. This torque tends to orientate the dipole moment parallel to
the electric field. The corresponding potential energy (for a permanent or induced
dipole) becomes minimal when the angle y between the dipole and the electric field
tends to zero. The dipole moment thus takes the same direction as the electric field.
This is the same phenomenon as the orientation of the compass needle in the
earthly magnetic field. For molecular dipoles, however, the thermal energy counter-
acts this tendency, and the system finally reaches a new statistical equilibrium which
is represented schematically by Fig. 1.2. In this configuration more dipoles are point-
ing along the field than before and the medium becomes slightly anisotropic.
The likelihood of the medium being frozen by the electric field is given by the Lan-
gevin function resulting from statistical theories which quantify competition be-
tween the orienting effect of electric field and disorienting effects resulting from
Fig. 1.2 A distribution of dipoles

undergoing the effect of a static elec-
tric field.
Fig. 1.3 The Langevin func-

tion.
thermal agitation. The relationship between the ratio of effective to maximum polari-
zation and the ratio of the potential interaction energy to the thermal agitation is de-
scribed by Fig. 1.3.
We can see that the Langevin function increases from 0 to 1 as the strength of the
electric field is increased and/or the temperature is reduced. The molecules tend to
align with the field direction. For high values of the field orientation dominates over
the disorientation induced by temperature, and all the dipoles tend to become paral-
lel to the applied field. The complete alignment corresponds to saturation of the in-
duced polarization. In many practical situations field strengths are well below their
saturation values. The arrow in Fig. 1.3 corresponds to the usual conditions of micro-
wave heating (temperature close to room temperature, 25 8C, and electric field
strength close to 105 V m±1). According to these results, the electric field strength
commonly used in microwave heating is not sufficient to induce a consequent freez-
ing of the media.
1.1.2.2 Thermal Conversion of Electromagnetic Energy
Physical origin of dielectric loss

The foregoing conclusions correspond to a static description, or cases for which the
polarization can perfectly follow the oscillation of the electric field. Indeed, the elec-
tric field orientation depends on time with a frequency equal to 2.45 GHz (the elec-
tric field vector switches its orientation approximately every 10±12 s). The torque exer-
cised by the electric field induces rotation of polar molecules, but they cannot always
orient at this rate. The motions of the particles will not be sufficiently rapid to build
up time-dependent polarization P~ (t) that is in equilibrium with the electric field at
any moment. This delay between electromagnetic stimulation and the molecular re-
sponse is the physical origin of dielectric loss. The polarization given by Eq. (4) be-
comes a complex quantity with the real part in phase with the excitation and an ima-
ginary part for which there is a phase lag with the excitation. The latter is the origin
of the thermal conversion of electromagnetic energy within the irradiated dielectric.
Relaxation processes are probably the most important of the interactions between
electric fields and matter. Debye [6] extended the Langevin theory of dipole orienta-
tion in a constant field to the case of a varying field. He showed that the Boltz-
mann factor of the Langevin theory becomes a time-dependent weighting factor.
When a steady electric field is applied to a dielectric the distortion polarization,
P~Distor, will be established very quickly ± we can say ªinstantaneouslyº compared
with time intervals of interest. But the remaining dipolar part of the polarization
(orientation polarization, P~Orient ) takes time to reach its equilibrium value. When
the polarization becomes complex, the permittivity must also become complex, as
shown by Eq. (5):
e s n2
e~ e0 j e00 n2 5
1 jot
where n is the refractive index and t the relaxation time. All polar substances have a
characteristic time t called the relaxation time (the characteristic time of reorienta-
tion of the dipole moments in the direction of the electric field). The refractive index
corresponding to optical frequencies or very high frequencies is given by Eq. (6):
e n2 6
whereas static permittivity, or permittivity for static fields, corresponds to es.

The real and imaginary parts of the dielectric permittivity are given by Eqs. (7) and (8):
e s n2
e 0 n2 7
1 o2 t 2
e s n2
e00 ot 8
1 o2 t2
Changes of e' and e@ with frequency are shown in Fig. 1.4. The frequency is dis-
played on a logarithmic scale. The dielectric dispersion covers a wide range of fre-
quencies.
The dielectric loss reaches a maximum given by Eq. (9):
es n2
e00max 9
2
at a frequency given by Eq. (10):

1
omax 10
t
This macroscopic theory justifies the complex nature of the dielectric permittivity
for media with dielectric loss. The real part of the dielectric permittivity expresses
the orienting effect of the electric field with the component of polarization which fol-
Fig. 1.4 Dependence of the

complex dielectric permittivity
on frequency (e is the real part
and e is the imaginary part, or
the dielectric loss).
lows the electric field, whereas the other component of the polarization undergoes
chaotic motion leading to thermal dissipation of the electromagnetic energy. This de-
scription is well adapted to gases (low particle density). In fact, for a liquid we must
take into account the effect of collisions with the surroundings and the equilibrium
distribution function is no longer applicable. The Debye theory can define a distribu-
tion function which obeys a rotational diffusion equation. Debye [6, 7] based his the-
ory of dispersion on Einstein's theory of the Brownian motion. He supposed that the
rotation of a molecule caused by an applied field is constantly interrupted by colli-
sions with neighbors, and the effect of these collisions can be described by a resistive
couple proportional to the angular velocity of the molecule. This description is well
adapted to liquids, but not to gases.
The general equation for complex dielectric permittivity is then given by Eq. (11):

e~r 1 rN m2
a 11
e~r 2 3e0 M 3kT 1 j o t
where N is Avogadro number, M is the molar mass, r the specific mass, and a the
atomic polarizability. The relaxation time, t, is a microscopic relaxation time that de-
pends on the average resistive force experienced by the individual molecules. In the
limit of low frequency the Debye expression is obtained for the static permittivity
whereas in the high frequency limit the permittivity will fall to a value which can be
written as the square of the optical index. The first term of the left side corresponds
to the distortion polarization whereas the other term corresponds to the orientation
polarization. For apolar molecules, we obtain the famous Clausius±Mosotti±Lorentz
equation.
Relaxation times
Debye [6] suggested that a spherical or nearly spherical molecule can be treated as a
sphere (radius r) rotating in a continuous viscous medium with the viscosity, Z, of
the bulk liquid. The relaxation time is given by Eq. (12):
8p Zr 3
t 12
2 kT
For a given molecular system it is, in fact, better to use a formula containing
tinter (T ), a part which depends on the temperature, and a part totally independent of
the temperature, tSteric , as described by Eq. (13):
t T tSteric tInter T 13
Relaxation times for dipole orientation at room temperature are between 10±10 s
for small dipoles diluted in a solvent of low viscosity and more than 10±4 s for large
dipoles in a viscous medium such as polymers (polyethylene), or dipole relaxation in
crystals (the relaxation associated with pairs of lattice vacancies). The relaxation time
of ordinary organic molecules are close to a few picoseconds. Thus for a frequency of
2.45 GHz these molecules can follow electric field oscillations, unlike substances
which are strongly associated, e. g. water and alcohols, and therefore are subject to
dielectric loss at 2.45 GHz. Consequently, the solvents for which dielectric loss is ob-
served are water, MeOH, EtOH, DMF, DMSO, and CH2Cl2. For nonpolar solvents
such as C6H6, CCl4, and ethers dielectric loss is negligible, although addition of
small amounts of alcohols can strongly increase dielectric loss and microwave cou-
pling of these solvents.
It is clear that for a substance with dielectric loss, e. g. water and the alcohols, the
molecules do not perfectly follow the oscillations of the electric field. For media with-
out dielectric loss, and for the same reasons as under static conditions, the strength
of the electric field cannot induce rotation of all polar molecules but, statistically, for
a small part only (less than 1%). This means that all the molecules oscillate around
an average direction (precession motion), as shown by Fig. 1.5.
The principal axis of the cone represents the component of the dipole under the
influence of the thermal agitation. The component of the dipole in the cone results
from the field that oscillates in its polarization plane. In this way, in the absence of
Brownian motion the dipole follows a conical orbit. In fact the direction of the cone
changes continuously (because of the Brownian movement) faster than the oscilla-
tion of the electric field; this leads to chaotic motion. Hence the structuring effect of
electric field is always negligible, because of the value of the electric field strength,
and even more so for lossy media.
Fig. 1.5 Precession motion of the dipole of a

distribution of molecules undergoing irradiation
by a time dependent electric field.
It is well known that in condensed phases energy transfer can occur between rota-
tional and vibrational states. Indeed, molecular rotation does not actually occur in li-
quids; rotational states turn into vibrational states because of an increase in collisions.
For liquids, the collision rate is close to 1030 collisions s±1. Microwave spectro-
scopy, which studies molecular rotation, only uses dilute gases to obtain pure rota-
tional states of sufficient lifetime. Rotational transitions are broadened by molecular
collisions, because the pressure is close to a few tenths of a bar, as shown in Fig. 1.6.
In conclusion, for condensed phases molecular rotations have quite a short life-
time, because of collisions. The eventual oscillations induced by the electric field are
then dissipated in the liquid state leading to vibration. At collision densities corre-
sponding to liquids the frequency of the collisions become comparable with the fre-
quency of a single rotation, and because the probability of a change in rotational
state on collision is high, the time a molecule exists in a given state is small. It is,
therefore, obvious that the electric field cannot induce organization in condensed
phases such as in the liquid state.
Consequences of the thermal changes of the dielectric permittivity

In contrast with Eq. (5), Eq. (11) gives the frequency behavior in relation to the mi-
croscopic properties of the studied medium (polarizability, dipole moment, tempera-
ture, frequency of the field, etc). Thus for a given change of relaxation time with tem-
perature we can determine the change with frequency and temperature of the dielec-
tric properties ± the real and imaginary parts of the dielectric permittivity.
Fig. 1.6 Absorption spectrum for water (gaseous, solution, and liquid).
Above the vapor band is Mecke's rotational analysis [11, 12].
Fig. 1.7 Effect of frequency and temperature on the complex dielectric

permittivity (e is the real part and e the imaginary part or the dielectric
loss) [12].
According to the value of the frequency of the field, and the relaxation time band
in relation to the temperature considered, one can find the three general changes
with temperature of the dielectric properties. Fig. 1.7 gives the three-dimensional
curves describing the dielectric properties in relation to frequency and temperature.
According to the value of the working frequency compared with the relaxation fre-
quency, three general cases could be found:
1. the real and imaginary parts of the dielectric permittivity decrease with tempera-
ture (working frequency lower than relaxation frequency);
2. the real and/or imaginary parts of the dielectric pass through a maximum (work-
ing frequency very close to relaxation frequency).
3. the real and imaginary parts of the dielectric permittivity increase with tempera-
ture (working frequency higher than relaxation frequency).
The two solvents most commonly used in microwave heating are ethanol and water.
Values for water are given by Kaatze [13] and those for ethanol by Chahine et al. [14].
Water is close to case 1 because both values decrease with temperature. In contrast,
for ethanol the real part increases and the dielectric loss reaches a maximum at 45 8C
(case 2). For ethanol, in fact, the working frequency is higher than relaxation fre-
quency at room temperature. Ethanol has a single relaxation frequency, close to
1 GHz at 25 8C, and, furthermore, its relaxation frequency increases fairly rapidly
with temperature (3 GHz at 65 8C). For water the working frequency is smaller than
the relaxation frequency at all temperature (17 GHz at 20 8C and 53 GHz at 80 8C).
The pioneering work of Von Hippel [15] and his coworkers, who obtained dielec-
tric data for organic and inorganic materials, still remains a solid basis. Study of di-
electric permittivity as a function of temperature is, however, less well developed,
particularly for solids.
Conduction losses
For highly conductive liquids and solids the loss term not only results from a single
relaxation term, as given by Eq. (8), but also from term resulting from ionic conduc-
tivity, s, as described by Eq. (14):
e s n2 s
e00 ot 14
1 o2 t2 o
The hydroxide ion is the typical example of ionic species with both ionic and dipo-
lar characteristics. For solutions containing large amount of ionic salts this conduc-
tive loss effect can become larger than dipolar relaxation. For solids conduction
losses are usually very slight at room temperature but can change substantially with
temperature. A typical example is alumina, for which dielectric losses are very small
(~10±3) at room temperature but which can reach fusion in several minutes in a mi-
crowave cavity [16]. This effect is because of a strong increase of conduction losses
associated with the thermal activation of the electrons which pass from the oxygen
2p valence band to the 3s3p conduction band. In solids, moreover, conduction losses
are usually enhanced by material defects which sharply reduce the energy gap be-
tween the valence and conduction bands.
Because conduction losses are high for carbon black powder it can be used as lossy
impurities or additives to induce losses within solids for which dielectric losses are
too small.
Magnetic losses
Chemical reagents are primarily concerned with dielectric liquids or solids. For me-
tal oxides such as ferrites, however, magnetic losses occur in the microwave region.
As for a dielectric material, a complex magnetic permeability is defined as given by
Eq. (16):
m~ m0 j m00 15
The real part is the magnetic permeability whereas the imaginary part is the mag-
netic loss. These losses are quite different from hysteresis or eddy current losses, be-
cause they are induced by domain wall and electron-spin resonance. These materials
should be placed at position of magnetic field maxima for optimum absorption of
microwave energy. For transition metal oxides such as iron, nickel, and cobalt mag-
netic losses are high. These powders can, therefore, be used as lossy impurities or
additives to induce losses within solids for which dielectric loss is too small.
Parameters of the thermal conversion

According to the Poynting formula, the time-averaged dissipated power density
Pdiss (r) at any position r within a lossy material is given by Eq. (15):
o e0 e00r ~ 2
PDiss r E r 16
2
where o is the angular frequency, e0 the dielectric permittivity of vacuum, e (r) the di-
electric loss, and E~ (r) the electric field amplitude. Depending on the dielectric loss
and electric field strength, the dissipation of electromagnetic energy leads to heating
of the irradiated medium. Hence estimation of dissipated power density within the
heated object depends directly on the electric field distribution within the heated ob-
ject and on the dielectric loss. Maxwell's equations can be used to describe the elec-
tromagnetic fields in a lossy medium and an energy balance can be solved to provide
the temperature profiles within the heated reactor. The specificity of microwave heat-
ing results from the thermal dependence of dielectric properties. The complex di-
electric permittivity is highly dependent on temperature and the dynamic behavior
of microwave heating is governed by this thermal change. The electric field ampli-
tude depends, moreover, on the real and imaginary parts of the dielectric permittiv-
ity, which themselves depend on temperature, as described by Eq. (17):
o e0 e00r T ~ 2
PDiss r; T E r; e00r T; e00r T 17
2
Consequently, this thermal change of dielectric properties causes changes in the

dissipated energy during heating, in contrast with conventional heating modes. De-
pending on the nature on the thermal changes this can result in thermal runaway,
occasionally, even, reduced material heating.
The author has studied the hydrodynamic behavior of water and ethanol, two clas-
sical solvents for chemistry [17±19]. Fig. 1.8 compares heating rate expected for water
and ethanol for conventional and microwave heating.
For identical energy density or conventional heating the ratio of the induced heat-
ing rate for water and ethanol does not change during heating. If no significant
changes are observed for the temperature range, a significant difference appears if
the dielectric loss effect is taken into account. In a third step, with electric field cor-
Fig. 1.8 Dependence on temperature of the crowave heating (with and without the elec-
heating expected with conventional and mi- tric field effect) for water and ethanol [19].
rection, the difference is significantly amplified. Hence, we observe for temperatures

below 50 8C that microwave heating is preponderant in water, and for temperature
above 50 8C microwave heating is preponderant in ethanol compared with water.
This clearly shows the selectivity difference between the classical heating and the mi-
crowave heating in relation to the thermal dependency of the real and imaginary
parts of the dielectric permittivity.
1.1.3
Thermodynamic and other Effects of Electric Fields
The thermodynamic effects of electric fields and are well known. Application of an
electric field to a solution can affect the chemical equilibrium. For example, in
Eq. (18) where C has a large dipole moment and B has a small dipole moment the
equilibrium is shifted toward C under the action of an electric field.
ABC 18
Typical examples are the conversion of the neutral form of an amino acid into its
zwitterionic form, the helix±coil transitions in polypeptides and polynucleotides, and
other conformational changes in biopolymers. Reactions of higher molecularity in
which reactants and products have different dipole moments are subject to the same
effect (association of the carboxylic acids to form hydrogen-bonded dimers). Equili-
brium involving ions are often more sensitive to the application of an electric field;
the field induces a shift toward producing more ions. This is known as the dissocia-
tion field effect (DFE) or the ªsecond Wien's effectª [20].
In principle the effect of an electric field on chemical equilibria can be described
by the thermodynamic relationship described by Eq. (19):
!
u ln K Eq: Dm
19
~
u jE j RT
P;T
where Keq. is the equilibrium constant, |E~ | the field strength (V m±1), and Dm the
molar change of the macroscopic electric moment or the molar polarization for non-
ionic systems. For ionic equilibria it must be pointed out that a true thermodynamic
equilibrium can never be reached, because of the field-induced flow of the ions. The
DFE theory was been developed by Onsager [21]. The most notable result is that Dm
is proportional to the field strength, E. Hence, according to Eq. (20):
ZE ZE
1
d ln K Eq: Dm dE / E 2 20
RT
0 0
which is the integration of Eq. (19), the change in equilibrium constant is propor-
tional to the square of the electric field strength and the effect on equilibrium con-
stant is noticeable only at high field strengths. In practice electric field strengths up
to 107 V m±1 are required to produce a measurable effect upon normal chemical re-
actions. For water at 25 8C, K changes by about 14 % if a field of 100 kV m±1 is ap-
plied. Smaller fields are required to achieve a comparable shift in less polar solvents.
Nonionic equilibria can also be perturbed by the DFE if they are coupled to a rapid
ionic equilibrium. A possible scheme is described by Eq. (21):
A H AH BH 21
in which the slow equilibrium is coupled with an acid±base equilibrium. This is the
same principle as coupling a temperature-independent equilibrium to a strongly de-
pendent equilibrium. Such a scheme has been studied in the helix±coil transition of
poly-a-l-glutamic acid by Yasunaga et al. [22] ± dissociation of protons from the side
chains increases the electric charge of the polypeptide, which in turn induces a tran-
sition from the helix to the coil form, in the dissociation of acetic acids by Eigen and
DeMayer [23], and in the dissociation of water by Eigen and DeMayer [24].
Hence, if thermodynamic effects of electric effect occur, the electric field strengths
necessary are too high compared with ordinary operating conditions of microwave
heating.
1.1.4
The Athermal and Specific Effects of Electric Fields
A chemical reaction is characterized by the difference between the free energy of the
reagents and products. According to thermodynamics the reaction is feasible only if
the free energy change is negative. The more negative the free energy change, the
more feasible the reaction. This free energy change for the reaction is the balance be-
tween broken and created chemical bonds. This thermodynamic condition is not,
however, sufficient to ensure the chemical reaction occurs rapidly (i. e. with a signifi-
cant rate of reaction). Kinetic conditions must also be verified to achieve the reaction.
The free energy of activation depends on the enthalpy of activation which expresses
the height of the energy barrier which must be surmounted. This energy condition
is only a necessary condition but not sufficient to ensure the transformation of the
reagents. The relative orientation of the molecules which react is crucial, and this
condition is expressed by the entropy of activation. This entropic term expresses the
need for a geometrical approach to ensure the effectiveness of collisions between re-
agents.
The essential questions raised by the assumption of ªathermalº or ªspecificº ef-
fects of microwaves are, then, the change of these characteristic terms (free energy
of reaction and of activation) of the reaction studied. Hence, in relation to previous
conclusions, five criteria or arguments (in a mathematical sense) relating to the oc-
currence of microwave athermal effects have been formulated by the author [25].
More details can be found in comprehensive papers which analyze and quantify the
likelihood of nonthermal effects of microwaves. This paper provides guidelines
which clearly define the character of nonthermal effects.
Hence, according to these five criteria there can be no doubt that an electric field
cannot have any molecular effect for solutions. First, the orienting effect of electric
field is small compared with thermal agitation, which results from the weakness of
the electric field amplitude. Even if the electric field amplitude were sufficient, the
presence of dielectric loss results in a delay between dipole moment oscillations and
electric field oscillations. Heating of the medium reveals the stochastic character of
molecular motion induced by dissipation of the electromagnetic wave. The third lim-
itation is the annihilation of molecular rotation in liquid state condensed phases. Ac-
cording to our demonstration, under normal operating conditions, it will be proved
that the frequently propounded idea that microwaves rotates dipolar groups is,
mildly speaking, misleading.
If the molecular effects of the electric field are irrelevant to microwave heating of
solutions, this assumption could be envisaged in the use of operating conditions
very far from current conditions. On one hand, it will be necessary to use an electric
field of higher amplitude, or to reduce the temperature according to the Langevin
function. This last solution is obviously antinomic with conventional chemical ki-
netics, and the first solution is, currently, technologically impossible. It will, on the
other hand, be necessary to avoid reaction media with dielectric loss. The molecular
effects of the microwave electric field could, paradoxically, be observed for a medium
which is not heated by the action of microwave irradiation.
1.1.5
Conclusions
The interaction between a dipole and an electric field is clearly interpreted by quan-
tum theory. Coupling is weaker than with magnetic fields, and when a dipole popu-
lation is subjected to an electric field there is such a demultiplication of quantum le-
vels that they are very close to each other. The interaction energy is continuous, and
we have to use Boltzmann or Langevin theories. Because of the weak coupling be-
tween the dipole and electric field, and the lack of quantified orientations, the study
of electric dipole behavior gives less information about the dipole itself than about
its surroundings. Indeed electric dipoles are associated with molecular bonds (the
electric dipole moment results from the distribution of positive and negative charges
on the studied molecule; if they are centered at different points then the molecule
has a permanent dipole and the molecule is polar). Any motion of electric dipoles in-
duced, for example, by interaction with an electric field, lead to correlative motion of
molecular bonds, whereas motion of magnetic moments is totally independent of
any molecular motion. Consequently, studies of dielectric properties must be those
of ªgroup propertiesª. Those properties cannot be modeled by a single dipole; a
group of dipoles interacting among themselves would be a key ingredient for these
models. The origin of confusion between the behavior of a single dipole and a collec-
tion of dipoles (in other words differences between dilute and condensed phases) is
the most important problem, and the source of the confusion of those who claim
that microwave effect results from orienting effect of the electric field.
In conclusion, is it necessary to obtain a microwave athermal effect to justify mi-
crowave chemistry? Obviously not ± it is not necessary to present microwaves effects
in a scientific disguise. There are many examples in which microwave heating re-
sults in specific time±temperature histories and gradients which cannot be achieved
by other means especially for solid materials. Hence, rather than claiming nonther-
mal effects it is better to claim a means or a tool which induces a specific thermal
history.
1.2
Overview of Microwave Reactor Design and Laboratory and Industrial Equipment
The objective of this section is to provide the reader with a basic knowledge of micro-
wave techniques used in the design and the construction of microwave ovens.
After some considerations relating to microwave technology, we will examine mi-
crowave ovens and reactor background. The limits of domestic ovens and tempera-
ture measurements will be analyzed, as well as design principles of microwave appli-
cators. Next, a brief overview of laboratory, experimental and industrial equipment
will be given.
1.2 Overview of Microwave Reactor Design and Laboratory and Industrial Equipment 19
1.2.1
Microwave Ovens and Reactors ± Background
This part has been designed by the authors as a practical tool for people interesting
by using laboratory or industrial equipment. An overall coverage of microwave ovens
design would require more space than is available in this chapter. An excellent cover-
age of applicator theory can be found in [5, 26] and basis of electromagnetic wave-
guides and cavities can be found elsewhere [27].
1.2.1.1 Applicators, Waveguides, and Cavities

The microwave applicator is the component of a processing system in which energy
is applied to the product to be heated. The equipment designer's objective is to in-
sure that this is accomplished in the most efficient possible manner. The reagents
packaging (powder, liquids, pellets) coupled with dielectric characteristics allow the
designer to mold literally a process in terms of applying energy where it is needed
and with the requested quantity. A wide variety of applicators are available or have
been patented to cover almost any conceivable applications of microwave power [5].
In chemistry applications, the goal is to achieve the desirable reaction or products.
High power microwaves are generated by vacuum tubes. The magnetron and kly-
stron are the most commonly used tubes for the generation of continuous waves
power for microwave processing. Power is normally launched from the microwave
tube into a transmission line or waveguide, where it travels to a load or termination
such an antenna or a microwave heating applicator.
Lumped circuits with capacitors and inductors used at lower radiofrequencies are
not usable at microwave frequencies. Open transmission lines are not used at micro-
wave frequencies because radiation would be excessive. This has led to the use of wa-
veguide as transmission media and to the use of resonant cavities as applicators. Wa-
veguides are metallic tubes with circular or rectangular cross-section. Resonant cav-
ities are metallic boxes (parallelepiped or circular). Voltage and currents are not the
fundamental concerns. In fact, power is considered to travel in the transmission line
by means of electromagnetic waves which consist of alternating electric and mag-
netic fields. When energy is launched into waveguide, many modes may be excited.
For a waveguide, an infinite number of modes or wave configurations can exist.
Only those modes above cutoff will attenuate in a short distance. Cutoff conditions
are defined by dimensions of waveguide cross section. Discontinuities within the wa-
veguide may excite higher order modes, resulting in higher energy storage at the dis-
continuity. As for waveguides, an infinite number of modes or wave configurations
can exist for microwave cavities. According to geometry and dimensions of the
boxes, single-mode or multimode cavities can be obtained. Domestic ovens belong to
this last category. The empty domestic ovens have approximately two hundred of
modes [28].
When microwaves travel along a waveguide terminated by the microwave heating
application (for example a resonant cavity loaded by the object to be heated) a re-
flected wave travels back towards the source. The wave traveling towards the termi-
nation is called the incident wave and the wave traveling back to the magnetron is
the reflected waves. The goal of microwave oven designer is to ensure that all the in-
cident power is absorbed by the load. In other words, the resonant frequency of the
loaded oven (and not the empty oven) should be close to frequency of the magnetron
(i. e. 2.45 GHz). If too much energy is reflected back to the source, the magnetron
may be damaged. That is the reason why it is not advised to run empty domestic
ovens. However, most commercial ovens are protected by a thermal automatic cutoff
in case of poor matching between magnetron and oven.
1.2.1.2 Single-mode or Multimode?

The electric field pattern produced by the standing waves within the cavity may be
extremely complex. Some areas may receive large amounts of energy while others
may receive slight energy [29±31]. In order to minimize this fact, domestic ovens use
mode stirrers or fan-shaped paddles and turntables. These devices are designed for
typical domestic loads. Consequently, the use of domestic ovens for laboratory pur-
pose with small loads, poorly lossy media can lead to bad operating conditions, spe-
cially difficult to reproduce. The use of single-mode or quasi-single-mode cavities al-
low to define precise positions within the cavities where the electric field strength is
maximum. Moreover, the electric field strength is much higher than those obtained
in multimode devices. The effective cavity power is three orders of magnitude
higher.
However, the use of single-mode cavities is more complex because of the insertion
of the lossy sample changes the frequency resonance of the device. A multimode cav-
ity is more versatile than a single-mode device because of the modes number. A mo-
vable plunger can allow a tuning of the cavity in order to ensure a good matching to
the source. As the dielectric properties of materials strongly depend on temperature,
a real-time tuning is necessary during the heating process. It was usually ensured by
a computer. The use of a circulator which directs the reflected energy into a dummy
water load is needed to avoid damage of the magnetron for poor matching situations.
Another unfavorable argument against domestic oven for reproducible operating
conditions is the problem of the variable power. The variable power of domestic
ovens is produced by periodic switching of the magnetron power. Large switching
periods are undesirable for chemistry processes because of the cooling period be-
tween switching steps.
In conclusion, the use of multimode system for laboratory purpose with reprodu-
cible operating conditions implies the same geometry, volume and position for the
samples to be heated and switching cycle smaller than characteristic time of chemi-
cal kinetic of the studied reaction. The use of single-mode cavities seems to be of par-
ticular importance for allowing an efficient application of microwave energy. One of
the mistake is to believe that single-mode cavities imply small operating volume
close to several cubic centimeters. An efficient temperature control system allowing
feedback control during heating would be an asset in case of thermal runaway and/
or exothermic reactions. The thermal runaway is induced by thermal dependency of
dielectric losses. Above a threshold value of temperature, the magnitude of heating
rate becomes very high. The typical example is the heating of alumina (see the pre-
vious part on microwave±matter interaction).
1.2.1.3 Limits of Domestic Ovens

The majority of microwave promoted organic synthesis has been performed in mul-
timode domestic ovens. In these ovens, despite the power level which commonly
fluctuates as a result of the on±off cycles and heterogeneous energy, there are other
problems dealing with safety. Heating organic solvents with open vessels can lead to
violent explosion induced by electric arcs inside cavity or sparking resulting from the
switching of magnetron. The conventional chemical reflux system could be used if
the water condenser is outside the microwave cavity. In this case, it is necessary to
connect the reaction vessel to the condenser through a port that ensures microwave
leakage to safe limit. Mingos et al. [32] has described this kind of domestic oven
modification for atmospheric pressure operating conditions.
High pressure operating conditions induced by microwave heating are very attrac-
tive for chemists. Microwave heating leads to core heating, then microwave heating
of autoclaves has advantages compared to conventional heating modes. The closed
vessel could be transparent to electromagnetic waves and can sustain the pressures
induced by vaporization of solvents. The vessel material should have very slight di-
electric losses. Moreover, this material must be chemically inert and able to accom-
modate the pressure rate induced by microwave heating. The pressure rate obtained
depends on the microwave power level and also on media heated. The Parr instru-
ment company [33] has designed this kind of vessels. They are made with Teflon and
polyetherimide and they can support pressures up to 80 atm and temperature up to
250 8C [34]. The reagents volume is close to 20 cm3. Obviously, in order to use safely
this system, a pressure release system permits to avoid strong explosion of the ves-
sels. However, for safety and reproducible operating conditions we recommend to
use pressure systems with real time monitoring of pressure.
1.2.1.4 Temperature-measurement Limits

The other limit is the problem of temperature measurements. Classical temperature
sensors could be avoided in relation to power level. Hence, temperature measure-
ments will be distorted by strong electric currents induced inside the metallic wires
insuring connection of temperature sensor. The technological solution is the optical
fiber thermometers [35±39]. However, measurements are limited below 250 8C. For
higher values, surface temperature can be estimated by infrared camera or pyrom-
eter [38, 40]. However, due to volumic character of microwave heating, surface tem-
peratures are often inferior to core temperatures.
1.2.1.5 The Design Principles of Microwave Applicators

The classical industrial design of microwave applicators and specifically the choice
of the geometrical shape is based on a simple similarity principle between the wave
propagation and spatial distribution within the empty and the loaded microwave ap-
plicator. The dielectric load is the reactor defined by chemical vessels and the reac-
tants to be transformed. This theoretical approach is approximate. The spatial distri-
bution of electromagnetic fields within applicators strongly depends on geometrical
shape and dielectric properties of the load [41±43]. Hence, this design method will
be only valid if the dielectric perturbation induced by the reactor is negligible. In
fact, the magnitude of the perturbation is proportional to reactor to applicator vo-

lume ratio. The perturbation could be negligible if this ratio is close to 10±4 and most
of laboratory and industrial devices have higher ratio [44].
Hence, it is more efficient but also more complicated to be guided by a geometri-
cal matching principle. According to this geometrical matching principle the micro-
wave applicator designer want to ensure a good match between electric field spatial
distribution and geometrical shape of the chemical vessel used. This geometrical
matching principle is easier to apply for monomodes applicators because of the
knowledge of the waves propagation directions and spatial distribution. The limit of
this design method is that it requires the knowledge of the empty applicator modes,
but also the of the loaded applicator modes.
In the following text the different laboratory, experimental and industrial devices
will be described according to the geometric shape of microwave applicators and re-
actors. Two fundamental transverse cross-section of microwave applicator will be dis-
tinguished: rectangular and circular whereas reactor geometrical shape will be cy-
lindrical or egg-shaped. The microwave applicators and chemical reactors geometri-
cal shape, and the physical nature of the reactant phases (solid, liquid or gas) are the
most important points of the following description of laboratory, experimental and
industrial microwave reactors..
First, laboratory and experimental reactors will be described. The vessel containing
reactants or their supports are made of convenient dielectric materials (cylindrical or
egg-shaped reactor). Original microwave reactors will be described. The first one is a
metallic cylindrical reactor which is also the microwave applicator. It allow to reaches
high pressures. The other one is a egg-shaped microwave reactor leading to high fo-
cusing level of microwave power.
Second, industrial microwave reactors will be described. Most of industrial appli-
cators are made of rectangular wave guides. Reactants are contained within pipe or
put on a simple conveyer belt.
1.2.2
Commercial Laboratory Microwave Reactors
Only a few microwave reactors equipped with efficient temperature control systems
for safe microwave synthesis at laboratory scale are currently available on the market.
These systems lead to reproducible operating conditions.
1.2.2.1 The Prolabo Products

This first family of laboratory equipment was no more commercial since the closing
down of the Prolabo French company. The support is made by CEM [45]. However,
we describe these system because many laboratories use these devices [46]. The
Synthewave 402 and 1000 are systems devoted to laboratory synthesis [47, 48]. They
are constituted by a closed rectangular waveguide section playing the role of cavity.
The magnitude of microwave power available is 300 W. They can use cylindrical
tubes with several diameters. A condenser could be connected to the tube. The ori-
ginality of this setup is to allow measurements of temperature by an infrared pyrom-
Fig. 1.9 General view of the Synthewave 402 (left)

and the Synthewave 1000 (right) (courtesy of A. Loupy).
eter [49]. This system allow measurements on the bottom of the heated tube. This
system was a good solution for laboratory experiments. Users should be aware of the
problem of temperature measurements. It is better to calibrate the system for each
media to be tested [50]. This setup could be associated with a computer in order to
regulate reagents temperature. The Synthewave 402 and Synthewave 1000 are de-
The Soxwave 100 is a variant which has been designed for extractions such as
Soxhlet which are laborious. The extraction tube is capped with a cooling column.
Optional temperature control during extraction was available. Maxidigest (one mi-
crowave unit 15 W to 250 W) and Microdigest (3 up to 6 independent digestions at
one time with integrated magnetic stirrers) are other variants for digestion.
1.2.2.2 The CEM Products [45, 51±53]

The MARS-S is constituted of a multimode cavity very close to domestic oven with
safety precautions (15 mL vessels up to 0.5 L round-bottomed flasks, magnetic stir-
ring, temperature control). The magnitude of microwave power available is 300 W.
The optical temperature sensor is immersed in the reaction vessel for quick response
up to 250 8C. A ceiling mounted is available in order to make connection with a con-
ventional reflux system located outside the cavity or to ensure addition of reactants.
These ports are provided with a ground choke to prevent microwave leakage. It is
also possible to use a turntable for small vessels with volumes close to 0.1 mL to
15 mL vessels (120 positions for 15 mL vessels). Pressure vessels are available (33 bar
monitored, 20 controlled).
The Discover system is a new device designed for synthesis. CEM company claims
a single-mode applicator and focused microwave. According to technical data, the ap-
plicator is constituted with two concentric cavity with aperture insuring the cou-
pling. It can operate at atmospheric conditions using open vessels and standard
glassware (1 mL to 125 mL)or at elevated pressure and temperature using sealed ves-
sels (0.5 mL to 10 mL sealed with a septum). In situ pressure control, infrared tem-
Fig. 1.10 General view of MARS-S (courtesy of

A. Loupy).
Fig. 1.11 General view of Dis-

cover (courtesy of A. Loupy and
D. Conseil).
perature control and variable speed stirring are available. The MARS-S is described
by Fig. 1.10 whereas the Discover system is described by Fig. 1.11.
The Star Systems 100 is device designed for digestions and extractions such as
Soxhlet which are laborious
1.2.2.3 The Milestone Products [54±56]

The ETHOS MR is constituted of a multimode cavity very close to domestic oven
with safety precautions. It can use standard glassware or glass (420 mL up to 2.5 bar)
and polymer reactors (375 mL up to 200 8C and 30 bar) with magnetic stirring. The
magnitude of microwave power available is 1 kW. The optical temperature sensor is
immersed in the reaction vessel for quick response up to 250 8C. An infrared sensor
is also available. A ceiling mounted is available in order to make connection with a
conventional reflux system located outside the cavity or to ensure addition of reac-
tants.
The ETHOS CFR is shown in Fig. 1.12. It is a continuous flow variant of the
ETHOS MR.
Fig. 1.12 General View of ETHOS CFR

(courtesy of A. Loupy).
1.2.2.4 The Personal Chemistry Products [57]

The SmithSynthesizer and SmithCreator are systems devoted to laboratory synth-
esis. They are constituted by a closed rectangular waveguide section playing the role
of cavity. They can use specific cylindrical tubes. Pressure and temperature sensors
allow real-time monitoring and control of operating conditions. This system was a
good solution for laboratory experiments. The SmithSynthesizer is described by
Fig. 1.13. More details about the SmithSynthesizer could be found in Sect. 12.7 in
Chapt. 12.
Fig. 1.13 General View of the SmithSynthesizer.

1.2.2.5 Plazmatronika Products [58]

Plazmatronika microwave reactor appears similar to multimodal microwave oven. It
has been equipped with strong magnetic stirrer which can mix liquids even with
some granulates. Field stirrer with metal rotating wings working was applied under-
neath the reaction vessel. Infrared thermography with fine beam focusing has been
applied to measure temperature at the bottom of the reaction chamber and feed
back loop-controlled temperature regulation is built in standard.
1.2.3
Experimental Microwave Reactors
Experimental systems are devices designed by research laboratory. Up to now, they

are not commercial devices.
1.2.3.1 The RAMO System

Since seven years, D. Stuerga have designed an original microwave reactor the
RAMO system (French acronym ± Reacteur Autoclave MicroOnde). This microwave
applicator and the reactor are original. The resonant frequency of the cavity can be
controlled by varying the position of a plunger. The effective cavity power could be
increased by three orders of magnitude. The autoclave is made with polymer materi-
als which are microwave transparent, chemically inert and sufficiently strong to ac-
commodate the pressures induced. The reactants are placed in a Teflon flask in-
serted within a polyetherimide flask. A fiber-optic thermometry system, a pressure
transducer and a manometer allow to measure simultaneously temperature and
pressure within the reactor. The system is controlled by pressure. The reactor is de-
Fig. 1.14 General view of the RAMO system

(courtesy of D. Stuerga).
The microwave power could be adjusted in order to allow constant pressure within
the vessel. A incorporated pressure release valve permits to use this experimental de-
vice routinely and safely. Furthermore, an inert gas as argon could be introduced
within the reactor to avoid sparking risk with flammable solvents. This experimental
device is able to raise temperature from ambient to 200 8C in less than 20 s (pressure
is close to 1.2 Mpa and heating rate is close to 7 8 s±1). The RAMO system has been
designed for nanoparticles growing and elaboration [59±62]. The RAMO system is a
batch system. It could be easily transpose to continuous process with industrial scale
(several hundred kilograms by seconds).
1.2.3.2 The Supercritical Microwave Reactor

For several years M. Delmotte et al. have designed a microwave reactor for high pres-
sure chemistry [63]. The microwave applicator and reactor are identical in order to
accommodate the mechanical constraints induced by high pressure within liquids.
This is the main interest of this device. The metallic cylindrical pipe is simulta-
neously a waveguide and the reactor. The device is described by Fig. 1.15.
The cylindrical reactor±applicator has steel wall with thickness close to 30 mm.
This thickness permits to reach internal pressures above 30 Mpa. These operating
pressure conditions are above the critical point of water. The internal diameter of
the reactor is 50 mm and its length is 500 mm. The system is powered simulta-
neously with two 6-kW generators placed at the both ends of the reactor. This si-
multaneous supply is necessary to overcome the penetration depth within water.
The penetration depth of waves is defined as the distance from the surface of the
material at which the power drops to 1/e from its value at the surface. The penetra-
tion depth of microwaves is equal to 15 mm for water at 20 8C. The electromagnetic
energy transfer is ensured by matched alumina windows. The propagated mode
within the reactor is theoretically the TE11 mode. The interest of this system is to
make very specific chemical reaction such as oxidation in aqueous medium under
critical conditions.
Fig. 1.15 The supercritical microwave reactor applicator The

two cones are cylindrical waveguides for microwave power supply
(courtesy of M. Delmotte).
Fig. 1.16 General view of the coconut

reactor (courtesy of D. Stuerga).
1.2.3.3 The Coconut Reactor

D. Stuerga and P. Pribetich have designed an egg-shaped microwave reactor. Its
name has been chosen in relation to its appearance (a black egg which reveals, after
opening, a white core). The coconut reactor is described by Fig. 1.16.
The origin of this project is the classical observation of egg explosion during mi-
crowave cooking. Spheroidal objects act as dielectric lenses focusing electromagnetic
energy. The difference between sphere and egg is the level of focusing. The authors
don't want to focus all the microwave power within a small area. The most important
point is to control the shape and volume of the focusing spot. This focusing spot is
named caustic in geometrical optic. The focusing effect obtained allows heating rates
five times higher than those obtained with the RAMO system (close to 35 8 s±1).
1.2.4
Industrial Equipment ± Batch or Continuous Flow?
Industrial equipment is classically divided into batch reactor and continuous flow
systems. The typical sizes of batch reactor for industrial heterogeneous or homoge-
neous reactions are close to several cubic meters of liquids reagents. The design of
microwave applicators able to heat these volumes meets scientific and technological
limits of microwave penetration within high lossy media. The penetration depth of
microwaves are beneath decimeter for classical solvents as water, alcohols, etc¼ So,
the microwave treatment of a cubic meter of solvents is generally technologically im-
possible. Moreover, several cubic meters of liquids reagents inside batch reactors
should need microwave power close to one megawatt power. This microwave power
is out of range of the classical devices of microwave technology, generally close to
one hundred kilowatts at 915 MHz or 2.45 GHz frequencies.
Consequently, we consider that the industrial scale technological management of
microwave assisted chemical reaction is no compatible with batch reactors coupled
with multimode applicators. Some typical processes with a systematic decrease of
the dielectric losses of the concerned reactant, such as filtration and drying of
mineral or pharmaceutical powders are compatible with multimode applicators. To
our knowledge, the only industrial batch microwave device is the microwave variant
of the Turbosphere (ªall in one solutionº mixer/granulator/dryer designed by Moritz
Fig. 1.17 General view of the microwave var-

iant of Turbosphere (courtesy of A. Loupy).
company) described by Fig. 1.17. This industrial equipment is sold by the Pierre
Guerin company, well known in the pharmaceutical industry [64].
In contrast, several industrial continuous flows systems are commercially avail-
able. The continuous flow systems permit the spatial localization of a small quantity
of matter (between grams and one kilogram) in front of a microwave source with
power magnitude close to several kilowatts (typically close to 2 or 6 kW). According
to the flow and heating rates expected, several modular power units should be asso-
ciated and microwave power magnitude could be typically about ten kW. The indus-
trial continuous flows systems described in the following have been designed for
food industries and drying and not specially for chemistry industry. However, these
devices could be used for chemical processes.
1.2.4.1 The Pulsar System

This first industrial device has been designed by MES company [65] for drying. It
could be used for solid state reactions with powder reactants. Consequently, the reac-
tor cannot be a classical chemical vessel or a classical chemical reactor with stirrer
and others associated technical devices but a container able to enclose a reactant
powder layer. The geometrical shape of the microwave applicator is parallelepiped
box and the reactants are supported by a dielectric conveyor belt with edges as de-
scribed by the Fig. 1.18.
This conveyor belt passes through several open parallelepiped applicators such as
oversized applicators. The geometrical structure of these waveguides is derived from
a standard waveguide adjusted to the TE01 mode at frequency equal to 2450 MHz
[66]. Each opened applicators is connected to one or two microwave generators set in
both side parts of the equipment. If the interface matching of the matter layer is con-
veniently performed, each opened parallelepiped applicator transfers the electromag-
netic power supplied by generators inside reactive bed. The power is dissipated in
heat and the temperature of reactant gradually increases.
Fig. 1.18 General view of the Pulsar system. Each applicator is

connected to one or two microwave generators set in both side
parts of the equipment (courtesy of MES company).
This equipment could be used for chemical reactions based on a strong solid±gas
interaction with gas adsorbed on powder such as limited air oxidation or with gas re-
lease (water, ammonia) such as esterification. The oversized applicator structure per-
mits the design of dielectric pipe to manage such matter transfers. This equipment
can be also used for many reactions on solid supports. A typical unit is powered with
microwave generators units of 2 or 6 kW for a total microwave power close to 20 or
60 kW.
1.2.4.2 The Thermostar System

This industrial equipment has been designed by MES company [67]. The Thermostar
system is constituted by cylindrical vessel associated with parallelepiped applicator.
Circular pipes are very classical geometrical shape for industrial reactors. The Ther-
mostar device is constituted of parallelepiped microwave applicators crossing by a di-
electric pipe. Two variants of this device have been designed in relation to reactants
state (liquid or solid).
The first variant is designed for liquid phases. The Fig. 1.19 describes the micro-
wave applicator with the vertical or horizontal pipes according to nature of the pro-
duct to be treated.
Six successive units are visible on the Fig. 1.19 (left) and they are set to obtain the
heating of reactants in a vertical glass pipe. Each applicator is constituted by a paral-
lelepiped metallic box (200 × 200 × 300 mm3). The reactor is a dielectric pipe with
diameter between 70 and 100 mm. This pipe passes through the box following the
electric field direction within the excitation waveguide. This waveguide can be seen
Fig. 1.19 General view of the Thermostar sys- crossing by a vertical pipe (left) or horizontal pipe
tem. Six successive parallelepiped applicators with screw (right) (courtesy of MES Company).
on the Fig. 1.19 (left). This applicator±generator connection suggests a theoretical

TE033 propagation mode when the pipe is empty. This equipment is specified for li-
quid phases heating. The liquid moving from bottom to top with the higher tem-
perature in the high part of the pipe. The reactants can be only a liquid phases or a
gas and liquid phases with a gas release system in the bottom part of the pipe (for ex-
ample a bubble blowing system).
The second variant is designed for solid state reactants to the exclusion of liquid
or gas. This powder variant of Thermostar is described by the Fig. 1.19 (right). The
microwave applicator is the same as for the device for liquids heating but the reac-
tant transport is ensured by a metallic screw set within the dielectric pipe. This speci-
fic traveling metallic screw crosses all the microwave applicators. The coexistence of
this metallic screw with the electric field is ensured by the fact that the major electric
field direction is parallel to the major direction and perpendicular to the local cur-
ving of the screw. A typical industrial unit for solid or liquid reactants is powered
with microwave generators units of 2 or 6 kW for a total microwave power close to
20 or 60 kW.
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35
2
Microwave-assisted Organic Chemistry in Pressurized Reactors
Christopher R. Strauss
2.1
Introduction
The highest priorities for the chemical industry now are process and product safety
and the environment [1±5]. New technologies and methods for ªgreenº and sustain-
able chemistry are subjects of intense activity [6]. In that regard, the potential of
microwave heating for organic synthesis attracted interest soon after the first re-
ports [7, 8] appeared in 1986. Early reactions were performed with domestic micro-
wave ovens and relatively primitive containers. Rate enhancement of up to three or-
ders of magnitude was observed, but the time savings were offset by hazards such as
deformation of the vessels and explosions.
Thus, the major challenge confronting the early microwave chemists was to retain
or enhance the benefits of the technology while concurrently avoiding the risks. Sev-
eral groups concluded that microwave heating was incompatible with organic sol-
vents and investigated solvent-free conditions including ªdryº media, usually with
open vessels in domestic microwave ovens [9±12]. That area expanded rapidly, aided
by the ready availability of inexpensive microwave equipment and encouraged by a
diverse range of reactions awaiting exploration.
Synthetic chemists desire well defined reaction conditions. Process chemists de-
mand them. Nonuniform heating and difficulties with mixing and temperature
measurement are technical constraints that initially limited the scale of microwave
chemistry with ªdryº media and have not yet been overcome. Poor reproducibility
also has been reported, probably resulting from differences in performance and op-
eration of individual domestic microwave ovens [13±15]. Consequently, most, if not
all, of the disclosed applications of ªdryº media are laboratory-scale preparations.
However, as discussed in other chapters, this does not prevent their being interesting
and useful.
An alternative approach, developed by Bose [16±19] and termed ªmicrowave-in-
duced organic reaction enhancementº (MORE) chemistry, employed polar, high-boil-
ing solvents with open vessels in unmodified domestic microwave ovens. The sol-
vents had dielectric properties suitable for efficient coupling of microwave energy
and rapid heating to temperatures that although high, were typically some 20±30 8C

ISBN: 3-527-30514-9
36 2 Microwave-assisted Organic Chemistry in Pressurized Reactors
below boiling. Apparent disadvantages were the need for high boiling polar solvents
such as dimethylsulfoxide, ethylene glycol, diglyme, triglyme, N-methylmorpholine,
N,N-dimethylformamide and 1,2-dichlorobenzene that have relatively similar boiling
points and present difficulties for recycling and for isolation of liquid products.
The above strategies were pursued concurrently with our approach, its objective
being to interface microwave technology with conventional organic chemistry in-
cluding the use of low boiling organic solvents. Consequently, dedicated reactors
were required that could operate reliably, safely and routinely in the presence of
flammable compounds. When we began, such equipment was not available and ap-
parently not contemplated for manufacture by others.
Our f irst tasks were first to design and fabricate appropriate systems and then to
apply them to a diverse range of organic reactions. The following features were con-
sidered essential:
. measurement and control of reaction conditions in ªrealº time;

. immediate, automatic shutdown of microwave systems if reactions become un-
controllable;
. advantages that were unavailable with pre-existing laboratory equipment; and
. potential for scaling-up and scaling-down chemical processes.
2.2
Rationale for Pressurized Microwave Reactors
A practical approximation for chemists is that an increase of 10 8C in reaction tem-

perature can lead to a halving of the time required. If a reaction taking 18 h at 80 8C
could be performed at 200 8C, the time expected would be in the order of 212 faster i. e.
approximately 16 s. Thus, higher temperatures than normal offer opportunities for ef-
ficiencies in time and energy. An obvious extension is that lengthy batch processes
could be transformed into continuous operations merely by raising the temperature.
However, at 200 8C or above, at atmospheric pressure, the choice of solvents is lim-
ited. High-boiling solvents are inconvenient to remove and to repurify. These disad-
vantages can be avoided by heating low-boiling solvents in closed systems that can
withstand the increased internal pressure. After cooling and opening the vessel, con-
centration of products can be achieved readily by evaporation of the solvent, which
usually can be redistilled for reuse.
Increases in boiling points of many common solvents are significant with modest
rises in pressure. The temperature versus pressure curves have points of inflection
beyond which considerable increases in pressure afford relatively modest elevations
in the boiling point [20]. These properties indicate that reaction pressures of 2±
3 MPa would facilitate temperatures in the order of 200 8C for common solvents
such as EtOAc, MeOH, EtOH, MeCN and Me2CO, all of which boil below 85 8C at at-
mospheric pressure.
These benefits can be obtained with traditional, conductively heated autoclaves,
but heat losses increase with rises in temperature. Also, in the respective heating
and cooling steps, the rates of temperature increase and decrease are usually low
and thermal gradients are difficult to avoid.
It was surmised that with appropriate vessels, microwaves would be absorbed pre-
dominantly throughout the sample. In addition, the energy could be applied or with-
drawn instantaneously and the input could be adjusted readily to match that re-
quired. Thus, it appeared likely that direct, bulk heating, combined with efficient
stirring of the sample would diminish temperature gradients, particularly near the
walls of the vessel.
2.2.1
The Continuous Microwave Reactor (CMR)
Two years after the 1986 reports of Gedye [7] and Giguere [8], a prototype continu-
ous microwave reactor (CMR) was produced [21, 22]. It was the first microwave sys-
tem designed to cope with organic solvents. Patents were obtained. Commercial
systems developed under license, typically comprised a microwave cavity fitted with
a vessel of microwave-transparent, inert material (Fig. 2.1). Plumbing in the micro-
wave zone was connected to a metering pump and pressure gauge at the inlet end
and to a heat exchanger and a pressure-regulating valve at the effluent end. The
heat exchanger enabled rapid cooling of the effluent, under pressure, immediately
after it exited the irradiation zone. Temperature was monitored immediately before
and after cooling. Variables such as internal volume of the plumbing within the mi-
crowave zone, flow rate and control of the applied microwave power allowed flex-
ible operation. To withstand corrosive acids and bases within the plumbing, contact
was avoided between metal surfaces and reaction mixtures. Feedback microproces-
sor control allowed setting of pump rates and temperatures for heating and cooling
of reactions. Failsafe measures were instituted to shut down the system if the tem-
Fig. 2.1 Schematic diagram of the CMR [22]. 1, reactants for

processing; 2, metering pump; 3, pressure transducer; 4, micro-
wave cavity; 5, reaction coil; 6, temperature sensor; 7, heat ex-
changer; 8, pressure regulator; 9, microprocessor controller;
10, product vessel.
perature exceeded the maximum allowable by 10 8C, or in the event of blockage,

leakage or rupture.
Commercial units [23±25] had volumes up to 120 mL within the microwave zone,
80 mL within the cooling zone and could be operated at flow rates up to
100 mL min±1. Under such conditions residence times in the microwave zone were
typically 2±10 min.
2.2.2
The Microwave Batch Reactor (MBR)
A complementary laboratory-scale microwave batch reactor (MBR) was developed for

synthesis or kinetics studies (Fig. 2.2) [26]. It has a capacity of up to 200 mL and reac-
tions can be heated to 260 8C and 10 MPa (100 atmospheres). In practice, pressures
exceeding 5 MPa have been required only rarely. The main features include: rapid
heating capability (1.2 kW microwave output); infinitely variable control of micro-
wave power; measurement of absorbed and reflected microwave energy; a load
matching device to maximize heating efficiency; direct measurement of the reaction
temperature and pressure; a stirrer for mixing and to ensure uniform temperature
within the sample; valving and plumbing to facilitate sample introduction and with-
drawal during the heating period; chemically inert wettable surfaces and fittings;
rapid cooling postreaction and a facility for conducting reactions under an atmo-
sphere of inert gas.
Microwave power input is computer controlled. Heating can be performed at high
or low rates as required and designated temperatures can be retained for hours if de-
sired. A robotically operated microwave batch reactor designed along the lines of the
MBR, but with a capacity low enough (1±5 mL) to accommodate postreaction cooling
from outside the vessel, has been introduced for rapid synthesis of candidates for
drug discovery [27].
Fig. 2.2 Dr Ulf Kreher at work with the MBR.

2.2.3
Transfer of Microwave Energy
Microwave energy is not transferred primarily by conduction or convection as with

conventional heating, but by dielectric loss [28]. The dielectric loss factor (loss factor,
e@) and the dielectric constant (e') of a material are two determinants of the efficiency
of heat transfer to the sample. Their quotient (e@/e') is the dissipation factor (tan d),
high values of which indicate ready susceptibility to microwave energy. Important
parameters relevant to microwave dielectric heating have been discussed and re-
viewed [29].
The two main mechanisms by which materials dissipate microwave energy are di-
pole rotation and ionic conduction [30]. Dipole rotation refers to the alignment of
molecules that have permanent or induced dipoles, with the electric field component
of the radiation. At 2450 MHz, the field oscillates 4.9 × 109 times s±1. Sympathetic
agitation of the molecules generates heat. The efficacy of heat production through di-
pole rotation depends upon the characteristic dielectric relaxation time of the sam-
ple, which in turn, is dependent on temperature and viscosity. The second main dis-
sipation mechanism, ionic conduction, is the migration of dissolved ions with the os-
cillating electric field. Heat generation is due to frictional losses, which depend on
the size, charge and conductivity of the ions as well as on their interactions with the
solvent.
Compounds with high dielectric constants such as water, ethanol and acetonitrile,
tend to heat readily. Less polar substances like aromatic and aliphatic hydrocarbons
or compounds with no net dipole moment (e. g. carbon dioxide, dioxane, and carbon
tetrachloride) and highly ordered crystalline materials, are poorly absorbing.
Changes to the physical properties of a compound or material can have a dramatic
influence on the susceptibility to microwave radiation. For example, ice has dielectric
properties (e', 3.2; tan d, 0.0009; e@, 0.0029) that differ significantly from those of li-
quid water at 25 8C (e', 78; tan d, 0.16; e@, 12.48) [31], rendering it essentially micro-
wave-transparent. Although liquid water absorbs microwave energy efficiently, the
dielectric constant decreases with increasing temperature and supercritical water
(TC 374 8C) is also microwave-transparent.
Differences in sample size, shape and composition can also affect heating rates.
The last case particularly applies when ionic conduction becomes possible through
the addition or formation of salts. For compounds of low molecular weight, the di-
electric loss contributed by dipole rotation decreases with rising temperature, but
that due to ionic conduction increases. Therefore as an ionic sample is microwave-ir-
radiated, the heating results predominantly from dielectric loss by dipole rotation in-
itially, but the contribution from ionic conduction becomes more significant with
temperature rise.
2.4
Contrasts between Synthesis and Digestion
Before the advent of the MBR and CMR for synthesis, microwave heating with pres-
sure vessels had been used in analytical laboratories, to speed the rate of digestion
and dissolution of solid samples, such as ores, hair and foodstuffs [32]. Digestion is
a degradative process, typically involving treatment of a small sample with an excess
of a strong oxidizing acid such as nitric, perchloric or sulfuric. The objective is to ob-
tain a clear solution usually for quantitative analysis of mineral components, without
charring and physical loss of material. Although it is essential that digestions be
standardized for high precision, parameters such as temperature, reaction time,
sample stirring and cooling rate are not essential to the outcome and so are not ac-
tively controlled.
As technologies for microwave-assisted digestion gained favor over slower, tradi-
tional heating methods, microwave equipment manufacturers emerged during the
1970s and 1980s to satisfy these analytical applications. The field of microwave-as-
sisted organic chemistry developed after microwave digestion had become an ac-
cepted analytical tool. Not surprisingly, some manufacturers attempted to employ di-
gestion technologies for synthesis. However, they did not appear to fully appreciate
the differences between the applications. This probably slowed the introduction of
appropriate equipment for synthesis, rather than assisting it.
In contrast with digestion, synthesis is a constructive process. Reactants that are
not particularly stable to strong acids and bases may be required and in much larger
amounts than those used for digestion. They may be expensive and highly reactive,
even on the laboratory-scale. The ability to define and control conditions including
temperature, time, sample stirring, addition or withdrawal of materials and postreac-
tion cooling, is almost always vital for satisfactory outcomes and for reproducibility.
Digestion techniques are unsatisfactory for these tasks.
2.5
Advantages of the MBR and CMR
The MBR and CMR have the following advantages for synthesis:
. the reaction conditions can be measured and reproduced;

. response is rapid in comparison with conventional heating;
. microwave energy is adsorbed directly by the sample and not via the vessel;
. when the power is turned on or off, energy input starts or stops immediately; an
important safety consideration;
. thermally unstable products can be cooled rapidly, after the heating step;
. stirring of the sample limits thermal gradients: the temperature of the material
on the inner walls of the reaction vessel is not significantly different from that in
the body of the mixture, hence unwanted pyrolysis can be minimized;
. reactions that are known to require high temperatures and higher boiling solvents
can be performed under pressure at these temperatures, but in lower boiling sol-
vents, facilitating workup;
. the available temperature range for many solvents is increased dramatically;
. low boiling reactants can be heated to high temperatures and rapidly cooled under
pressure; losses of volatile compounds are minimized;
. reactions can be sampled for analysis while material is being processed; with the
CMR, reaction mixtures can be subjected to multiple passes if required, or the
conditions can be altered during a run;
. reactions performed on a laboratory scale are amenable to scale up, because the
conditions are defined;
. moderate to high temperature reactions can be performed in vessels fabricated
from inert materials such as PFA Teflon, PTFE, or quartz; this is beneficial where
strongly acidic or basic reactants or products are incompatible with metals or boro-
silicate glass; and
. in multiphase systems, selective heating is possible.
2.6
Applications of the MBR and CMR
The CMR and MBR are enabling technologies that can stand alone. They also can be
integrated with other technologies and methodologies for processes that utilize re-
newable resources, limit waste and afford useful, recyclable products [6, 33]. They lie
at the heart of an approach toward development of new tools for preparative organic
chemistry, the aim being to be able to select appropriate combinations to solve speci-
fic problems in environmentally acceptable ways [6, 34]. This strategy has some simi-
larity with combinatorial chemistry, which revolutionized approaches to drug discov-
ery in the mid-1990s. However, it was designed more to establish multiple chemical
processes than to accomplish many reactions by parallel applications of the same
process. Downstream processing is a key element, as environmental damage can de-
stroy the viability of chemical manufacturing practices.
To complement the reactors, a catalytic membrane of Pd on porous glass tubing
was produced [35]. As mentioned in Sect. 2.8, this has been used to perform various
thermal reactions including Heck arylative coupling and to develop new reactions in-
cluding a novel coupling±dehydrogenation and a new concerted process incorporat-
ing an oxidation±dehydrogenation±double-Heck coupling [36]. Both reactions pro-
ceeded well in the MBR.
Other methodologies feature solvent-free conditions with ªneatº starting material,
tandem or cascade, catalyzed or uncatalyzed reactions, the use of aqueous media at
high temperature and nonextractive techniques for product isolation. Examples ap-
pear among the following microwave-assisted applications.
2.6.1
Reactions with Sterically Constrained Molecules
Reactions that are unfavored through steric constraints are difficult to achieve con-
ventionally, but often proceed at higher than normal temperatures in the CMR or
MBR.
Heating of isopropanol under conventional reflux conditions, with 2,4,6-trimethyl-
benzoic acid and a catalytic amount of sulfuric acid, afforded the corresponding iso-
propyl ester in only 2 % conversion after 28 h. With the MBR, the product was iso-
lated in 56 % yield after 1 h at 148 8C [26] (Scheme 2.1 ± please note that in all
schemes herein, the use of a double headed arrow does not imply a balanced equa-
tion).
Scheme 2.1 Preparation of isopropyl 2,4,6-trimethylbenzoate.
In the CMR, a yield of 81% was obtained after four passes (total residence time,
6.4 min) at 155±164 8C [22]. As indicated by the pressure, these reactions were per-
formed at temperatures below those enabling esterification by elimination of the al-
cohol to propene, followed by addition of the acid to the olefin. Kinetics studies de-
monstrated that the significantly enhanced yields obtained under the microwave
conditions, resulted from the higher temperatures employed and not from any in-
trinsic microwave ªeffectsº [37, 38].
Similarly, hydrolysis of tertiary amides of carboxylic acids is usually slow under
conventional conditions. Hydrolysis of a morpholide occurred in only 48 % yield
with 2M HCl at reflux after 4 h, yet proceeded in 70 % yield after only 10 min at
200 8C in the MBR (Scheme 2.2) [26]. The convenience of operation and the rapid
throughput enabled preparation of multiple batches of the corresponding acid in a
few hours.
Scheme 2.2 Hydrolysis of a tertiary amide.

2.6.2
Preparation of Thermally Labile Products
Vessels for microwave-assisted chemistry are usually made from thermal insulators
such as PEEK, quartz, borosilicate glass or PTFE. Thus, the benefits of rapid heating
can be diminished if the opportunity for workup is delayed by slow cooling. Decom-
position of thermally unstable products also can occur.
In the CMR, rapid cooling takes place through an in-line heat exchanger adjacent
to the microwave zone. Mixtures can be cooled immediately, while still under pres-
sure, to prevent losses of volatile compounds and to minimize decomposition of
thermally labile products [22]. The MBR has a cold-finger that contacts the reaction
mixture directly. Cooling can be initiated at any time during operation and is effi-
cient because it is not via the container [26]. Temperature and pressure monitoring,
as well as stirring, can be maintained during the process, allowing access to the ves-
sel at the earliest opportunity.
2.6.2.1 Depolymerization of Cellulose

In the exploration of technologies based on renewable resources, a key challenge is
the depolymerization of cellulose to produce glucose or its oligomers from biomass.
These products may then be used as feedstock for fermentation to energy sources
and synthetic building blocks such as ethanol, acetic acid and lactic acid [39].
Although high temperatures and acidic conditions are required to cleave the glycosi-
dic bonds, the monosaccharide and oligosaccharides are more labile than the start-
ing material and readily decompose to 5-hydroxymethylfurfural and other undesired
compounds including polymeric tars. Thus, rapid heating and cooling are beneficial.
A method developed in the MBR involved heating the cellulose with 1% sulfuric
acid, from ambient to 215 8C within 2 min, maintaining this temperature for 30 s
and cooling. The entire operation was completed within 4 min and afforded glucose
in nearly 40 % yield, along with fermentable oligomers [26].
2.6.2.2 Hofmann Elimination

Aryl vinyl ketones are produced thermally from the corresponding quaternary am-
monium salts via Hofmann elimination. However, the conjugated ketones are heat-
sensitive and polymerization is difficult to avoid. Traditional preparations afforded
only moderate yields. Microwave conditions were established for Hofmann elimina-
tions, performed essentially quantitatively, by batch or continuous processes.
With the CMR, phenyl vinyl ketone was prepared by passage of a 5 % aqueous
slurry of N-(2-benzoylethyl)-N,N,N-trimethylammonium iodide through the micro-
wave zone. The product was immediately extracted from the cooled aqueous effluent
into chilled Et2O, avoiding polymerization of the monomer and giving near quantita-
tive yields [22].
With the MBR, individual components of multiphase systems can be heated at dif-
ferent rates according to differences in their dielectric properties. We have termed
this, differential heating. For example, the aqueous phase of a water/chloroform sys-
tem (1 : 1 by volume), heated more rapidly than did the organic layer and a tempera-
ture difference of 50 centigrade degrees or more, could be maintained for several

minutes. Differential heating was employed advantageously in Hofmann elimina-
tions. A mixture of N-[2-(4-ethoxybenzoyl)ethyl]-N,N,N-trimethylammonium iodide,
water and chloroform was heated, with stirring for 1 min at 110 8C (temperature of
the aqueous phase). During the reaction, 4-ethoxyphenyl vinyl ketone was formed,
extracted and diluted into the cooler organic phase. The isolated yield was 97 %
(Scheme 2.3) [26].
Scheme 2.3 Hofmann elimination by differential heating.
Differential heating is more easily achieved with microwave technology than by

conventional conductive methods and as Cundy suggested in his excellent review,
could well account for apparent rate enhancements obtained by others with organic
reactions on ªdryº media [40].
2.6.2.3 Alkyl 2-(hydroxymethyl)acrylates

Alkyl 2-(hydroxymethyl)acrylates are versatile functionalized monomers and syn-
thetic building blocks. Conventional preparations employ the Baylis±Hillman reac-
tion which involves the addition of formaldehyde to the parent acrylate ester, cata-
lyzed by 1,4-diazabicyclo[2.2.2]octane (DABCO). These reactions typically take sev-
eral days at room temperature, but can be achieved within minutes in the CMR and
MBR (Scheme 2.4). Rapid heating under pressure prevents loss of formaldehyde.
Subsequent cooling limits hydrolysis of the product, as well as dimerization and
polymerization [33].
Scheme 2.4 Baylis±Hillman reaction with formalin.
2.6.3
New Reactions that Require High Temperature
2.6.3.1 Etherification
Conditions employing elevated temperatures with less catalyst, a milder catalyst or
without addition of catalyst, can supplant those utilizing aggressive reagents at lower
temperatures. A recent example concerns a catalytic, thermal etherification that can
be performed near neutrality and that produces minimal waste [41]. This represents
a cleaner alternative to the traditional Williamson synthesis, in which the ether is
produced through substitution of an alkyl halide (RX) by a strongly basic alkoxide or

phenoxide. A stoichiometric amount of waste salt is generated and in some cases,
base catalyzed elimination of hydrogen halide can compete.
The new process is suited to production by MBR or CMR and is shown in
Scheme 2.5 for a symmetrical ether. An excess of alcohol (ROH) and a catalytic
amount of RX are heated. A solvolytic displacement reaction between RX and ROH
affords R2O along with HX or its elements (hereafter referred to as HX; Scheme 2.5,
Eq. 1). The liberated HX attacks another molecule of ROH to form water and to re-
generate RX (Scheme 2.5, Eq. 2). If the rates of both reactions are comparable, the
concentration of HX will be low throughout and that of RX will remain relatively
constant. Although HX and RX are stoichiometric reactants or products in Eqs. (1)
and (2), they do not appear in the sum, Eq. (3). The net procedure involves condensa-
tion of two molecules of ROH to give R2O plus water. The process has been demon-
strated with primary and secondary alcohols, including compounds labile to base
and acid. Advantages for clean production are high atom economy, that salts are not
formed, RX often is recoverable, the reaction does not require addition of strong
acids or bases and that water is the major byproduct.
Scheme 2.5 Pathway for the etherification catalyzed by RX.
The preparation of di-n-butyl ether is illustrative (Scheme 2.6). No reaction oc-

curred with n-butanol alone for 2 h at 200 8C. However, in the presence of 10 mol %
n-butyl bromide, 26 % conversion of the alcohol to the ether was obtained after 1 h,
without apparent depletion of the catalyst. It is known that addition of alkaline metal
salts can accelerate solvolytic processes, including the rate of ionization of RX [41].
This was confirmed when the introduction of LiBr (10 mol %) along with n-butyl
bromide, afforded a conversion of 54 % after 1 h at 200 8C. Ethers incorporating a sec-
ondary butyl moiety were not detected, precluding mechanisms involving elimina-
tion followed by Markovnikov addition.
Hydroxy and alkoxy groups are not readily displaced from carbon atoms. Protona-
tion with strong acids greatly facilitates their leaving. As demonstrated through the
inefficacy of tetrabutylammonium bromide, the presence of the halide ion alone was
insufficient to drive the reaction. HBr was required. Conversely, HBr and HI are
commonly employed as cleavage agents for ethers. This suggests that etherification
catalyzed by RX or HX is achieved through a shift in the position of equilibrium.
The microwave reactors facilitate the process through their ability to cope with and
retain HX at elevated temperature. Several reactions have been performed in the
MBR. The CMR has been employed to produce not only dibutyl ether, but also di-
benzyl ether from benzyl alcohol and a catalytic amount of benzyl bromide.
Scheme 2.6 Preparation of di-n-butyl ether.
2.6.3.2 Uncatalyzed Hydrogen-transfer Reduction

We recently reported a modified Meerwein±Ponndorf±Verley reduction in which
low-boiling alcohols such as EtOH and n-PrOH, but preferably i-PrOH, were used at
temperatures near 225 8C in the absence of aluminum alkoxides [42]. The carbonyl
moiety of an olefinic aldehyde such as cinnamaldehyde was reduced selectively to
the alcohol without the carbon±carbon double bond being affected (Scheme 2.7).
Since base was not present, aldol and Claisen±Schmidt condensations were avoided.
Scheme 2.7 Uncatalyzed thermal hydrogen transfer reduction of cinnamaldehyde.
This work elaborated upon that of Malwitz and Metzger [43] (who conducted the
majority of their investigations at 400 8C) and was performed by conventional heat-
ing. It further emphasizes opportunities for the discovery of new, clean reactions
that require high temperature.
2.6.4
Reactions Known to Require High Temperatures
2.6.4.1 Willgerodt Reactions

Phenylacetamides were prepared in the MBR from the corresponding styrene or
acetophenone derivatives by Willgerodt reactions (Scheme 2.8) [44]. Yields were com-
parable with those obtained by others with conventional heating. At similar tempera-
tures, the microwave-heated reactions were completed within minutes rather than
hours. Optimization was readily accomplished through the capabilities of the MBR
for rapid heating and cooling. The substantially shorter reaction times probably re-
Scheme 2.8 Willgerodt reaction under microwave conditions.
sulted from the convenience in the operation of the reactor in comparison with a
standard autoclave, indicating broader opportunities for microwave heating to im-
prove the conditions for established reactions that require high temperatures.
2.6.4.2 Jacobs±Gould Reactions under Solvent-free Conditions

The Jacobs±Gould intramolecular cyclization of diethyl N-(6-methyl-2-pyridyl)amino-
methylenemalonate to 3-ethoxycarbonyl-7-methyl-1,8-naphthyrid-4-one is another re-
action ideally suited to microwave heating, although conductively heated equipment
was employed for laboratory-scale experiments [45]. The product is a key intermediate
in the synthesis of nalidixic acid, the first of the quinolone antibacterials. The process
usually is conducted at temperatures of 200±250 8C and in high dilution, with heat
transfer oils such as the eutectic mixture of diphenyl ether and biphenyl. However, it
proceeded rapidly, predictably and controllably under solvent-free conditions.
The findings contrasted with common conceptions that intramolecular reactions
require dilution to restrict competing intermolecular processes. Indeed, under the
optimal conditions, the temperature (385 8C) was nearly 150 8C higher than that nor-
mally employed and the reaction time was less than 1 min instead of many minutes.
The yield was 86 % and the process was performed continuously under the newly es-
tablished conditions (Scheme 2.9) [45].
Scheme 2.9 Jacobs±Gould reaction in the absence of heat-transfer oil.
2.6.5
Viscous Reaction Mixtures
Typically, viscous materials transfer energy poorly. With conductively heated vessels,
pyrolytic degradation on the walls can co-occur with incomplete reaction towards the
center of the container. Large thermal gradients can result in suboptimum conver-
sions, loss of product and laborious cleanup procedures. Also, when high tempera-
tures are required, heat losses increase and conductive heating becomes inefficient.
Under microwave conditions these problems are diminished. This accounts for the
numerous applications for curing of polymers by microwave heating.
Reactions such as the acid catalyzed preparation of isopropylideneglycerol pro-
ceeded well in the CMR. A yield of 84 % was obtained after a residence time of
1.2 min, the exit temperature being 133 8C. A conventional literature method in
which the upper temperature was limited by the boiling point of acetone, required
one day for a comparable result [22].
2.6.6
Reaction Vessels
Being microwave-transparent, the reaction vessels will be no hotter than their con-
tents. As mentioned above, they usually are made from insulating polymeric materi-
als like polytetrafluoroethylene (PTFE), which have inherent advantages for cleaner
processing. In contrast with other materials, PTFE is resistant to attack by strong
bases or HF and is not corroded by halide ions.
This was significant in the preparation of 1,2-dimethyl-3-hydroxy-4-pyridone, em-
ployed clinically as an iron chelating agent. The aminoreductone is obtained by reac-
tion of methylamine with maltol. Traces of metal within the system readily form
highly colored complexes with reactant or product and these are difficult to remove.
With the CMR, the preparation was achieved in 65 % yield without the need for deco-
lorizing charcoal and the product was crystallized by collecting the effluent in acet-
one (Scheme 2.10) [22].
Scheme 2.10 Microwave preparation of 1,2-dimethyl-3-hydroxy-4-pyridone.
Another advantage of PTFE vessels is low adhesivity, which can help to reduce de-
tergent and organic solvent usage during cleaning operations that would otherwise
generate considerable effluent [6].
2.6.7
Reactions with a Distillation Step
With conductive heating, several factors militate against efficient distillation. Transf-
eral of heat to the liquid usually occurs from the inner surfaces of the vessel. Vapori-
zation from the surface and convection preclude a uniform temperature within the
liquid. To achieve distillation under those circumstances, the pot temperature must
be considerably higher than that of the distillate. With microwaves, energy is ab-
sorbed more uniformly, a larger volume of the sample in the pot is heated simulta-
neously, convection is reduced and distillation is more rapid.
The MBR can accommodate distillation through an outlet tube connected to a
port on the top flange. With that arrangement, a monodehydrobromination of 1,6-di-
bromohexane was performed in which the product 6-bromohex-1-ene was removed
from the mixture before a second molecule of HBr could be eliminated [26, 33].
2.6.8
Miscellaneous Reactions
The MBR and CMR have been instrumental for transformations including nucleophi-
lic substitution, oxidation, addition, elimination, isomerization, esterification, trans-
esterification, hydrolysis, oximation, acetalization, amidation, decarboxylation and
coupling. Most of the common organic solvents have been employed. ªNameº reac-
tions include Michael, Diels±Alder and aza Diels±Alder additions,Williamson etherifi-
cation, Claisen and Rupe rearrangements, Finkelstein, Knoevenagel, Claisen±
Schmidt, Mannich, Baylis±Hillman,Willgerodt, Meyer±Schuster, reactions, Heck ary-
lative coupling and Hofmann elimination. Improved conditions obtained in compari-
son with literature methods, typically involved one or more of the following: increased
convenience, savings in time, higher yields, greater selectivity, the need for less cata-
lyst, or employment of a more environmentally benign solvent or reaction medium.
2.6.9
Kinetic Products
If a reaction can give multiple products, that obtained first (the kinetic product) is
not necessarily the most stable (the thermodynamic product). The kinetic product
will be in equilibrium with the starting materials but not necessarily with the ther-
modynamic product.
Where multiple products are possible, the CMR and MBR have been employed to
optimize conditions for formation of specific components of a reaction sequence. Ex-
amples discussed below, were obtained by heating organic substrates such as allyl
phenyl ether [46] and carvone [47] in water. Rearrangements, addition or elimination
of water and isomerizations occurred, with each transformation favored under
tightly defined conditions.
Heating of carvone in water at 210 8C for 10 min afforded 8-hydroxy-p-menth-6-
en-2-one, the equilibrium position favoring the starting material by a factor of 4 : 1.
The hydroxymenthenone, although in equilibrium with the starting material, also
underwent elimination of water and isomerization to carvacrol, giving a 1 : 1:1 mix-
ture of these three substances at 230 8C after 10 min. At 250 8C, for 10 min, carvone
isomerized to carvacrol almost quantitatively (Scheme 2.11) [47].
Scheme 2.11 Kinetic and thermodynamic products from carvone in water.

Scheme 2.12 Kinetic and thermodynamic products from allyl phenyl ether in water.
Allyl phenyl ether was heated with water in the MBR for 1 h at different tempera-
tures [46]. It underwent Claisen rearrangement to 2-allylphenol (56 % yield) at
200 8C, 2-(2-hydroxyprop-1-yl)phenol (37 % yield) at 230 8C and 2-methyl-2,3-dihydro-
furan (72 % yield) at 250 8C (Scheme 2.12). Support for the reaction sequence was ob-
tained through experiments with authentic intermediates.
2.6.10
Gaseous Reactants and Media
Even though the CMR and MBR operate under conditions in which pressure is de-
veloped, gaseous reactants or media often can be handled in these systems without
problems arising through over-pressure. Mannich reactions with dimethylamine,
Baylis±Hillman reactions with formaldehyde, aminoreductone formation with am-
monia, all proceeded without difficulty, as did Willgerodt reactions in which gases
are formed during the process.
In an extension, we recently reported the formation of cyclic carbonates respec-
tively from epichlorohydrin (Scheme 2.13) and styrene oxide, with carbon dioxide
under catalysis by KI in the presence of a crown ether [48].
Scheme 2.13 Preparation of the carbonate from epichlorohydrin in the MBR.

2.7 High-temperature Water as a Medium or Solvent for Microwave-assisted Organic Synthesis 51
2.7
High-temperature Water as a Medium or Solvent for Microwave-assisted
Organic Synthesis
At ambient temperature water is a poor solvent for most organic compounds. How-
ever, its ionic product increases one thousandfold between 25 8C and 240 8C, making
it a stronger acid and base. The dielectric constant decreases from 78 at 25 8C to 20
at 300 8C, indicating that the polarity is lowered with temperature increase. These
properties suggest that in organic reactions, water could have a role that varied with
temperature. The MBR and CMR were ideally suited to investigations into organic
synthesis in high-temperature water [6, 33, 47].
A diversity of reactions and high selectivities was obtained with seemingly minor
variations in the conditions. Scaleup also was achieved, including to continuous op-
eration with the CMR, confirming the potential of aqueous high-temperature media
for the development of clean processes [49]. Obvious advantages of water include
low-waste workup, low cost, negligible toxicity and safe handling and disposal. Some
examples have already been discussed and additional ones appear below.
2.7.1
Biomimetic Reactions
Naturally occurring monoterpene alcohols were heated in water without prior deriva-
tization with typical biological water-solubilizing groups such as phosphates or glyco-
sidic units. Biomimetic reactions that normally would be acid-catalyzed, proceeded
on the underivatized compounds in the absence of added acidulant. Cooling of the
mixtures rendered the products insoluble, readily isolable and the aqueous phase
did not require neutralization before workup.
Geraniol, nerol and linalool are practically insoluble in water at ambient tempera-
ture. Although acid labile, they do not readily react in water at moderate temperature
and neutral pH. In unacidified water at 220 8C in the MBR, they reacted within min-
utes. Geraniol rearranged to a-terpineol (18 %) and linalool (16 %) predominantly.
Lesser amounts of the monoterpene hydrocarbons were also obtained, including
myrcene, a-terpinene (10 %), limonene (11%), g-terpinene, the ocimenes, a-terpino-
lene and alloocimenes (Scheme 2.14) [50].
Nerol and linalool underwent considerably more elimination than did geraniol, to
give the same hydrocarbons. The major products and their relative proportions were
Scheme 2.14 Reaction of geraniol in water at 220 8C in the MBR.

consistent with those for carbocationic rearrangement of derivatives of linalool, nerol

and geraniol under acidic conditions.
By a traditional method, a- and b-ionones can be converted to ionene, catalyzed by
HI along with small amounts of phosphorus. A cleaner cyclization occurred by heat-
ing b-ionone in water at 250 8C in the MBR [50]. In the workup the usual exhaustive
washing procedures were unnecessary. Similarly, as mentioned above, carvacrol was
prepared almost quantitatively, by isoaromatization of carvone in water at 250 8C for
10 min [47]. A conventional, literature method utilized acidic conditions, took a
longer time and proceeded in lower conversion. The above examples show that ele-
vated temperatures under neutral pH conditions can offer advantages over acidic (or
basic) reagents at lower temperatures.
2.7.2
Indoles
In the first example of water as the reaction medium for Fischer indole synthesis,
2,3-dimethylindole was obtained in 67 % yield from phenylhydrazine and butan-2-
one, at 220 8C for 30 min (Scheme 2.15). Neither a preformed hydrazone nor addi-
tion of acid was required [33].
Scheme 2.15 Fischer indole synthesis in water.
Interestingly, the Fischer indole synthesis does not easily proceed from acetalde-
hyde to afford indole. Usually, indole-2-carboxylic acid is prepared from phenylhy-
drazine with a pyruvate ester followed by hydrolysis. Traditional methods for decarb-
oxylation of indole-2-carboxylic acid to form indole are not environmentally benign.
They include pyrolysis or heating with copper±bronze powder, copper(I) chloride,
ªcopperº chromite, ªcopperº acetate or copper(II) oxide, in for example, heat-transfer
oils, glycerol, quinoline or 2-benzylpyridine. Decomposition of the product during
lengthy thermolysis or purification affects the yields.
In water at 255 8C, decarboxylation of indole-2-carboxylic acid was quantitative
within 20 min in the MBR (Scheme 2.16) [33].
A semisystematic study into the hydrolysis of ethyl indole-2-carboxylate in aqu-
eous media at high temperature, indicated that decarboxylation of the resultant acid
proceeded by an arenium ion mechanism and was inhibited by base. As base pro-
Scheme 2.16 Decarboxylation in water.

2.7 High-temperature Water as a Medium or Solvent for Microwave-assisted Organic Synthesis 53
moted hydrolysis of the ester, it was possible to obtain either the acid or indole from
the ester merely by manipulating the equivalents of base present [51].
2.7.3
Reactions in Aqueous Acid and Base
3-Methylcyclopent-2-enone typically is prepared by an intramolecular Claisen±

Schmidt condensation from 2,5-hexanedione. The product is usually required free
from traces of starting material but these substances co-distil. Accordingly, literature
methods have employed strong aqueous base in 2±3 % concentration at reflux and
have been continued until all of the starting material has been consumed. Under
those circumstances, the product also has undergone aldol and Claisen±Schmidt
condensations severely lowering the yield.
In a method with microwave heating at 200 8C, two orders of magnitude less con-
centrated base was employed [49]. Competing reactions were suppressed, salt forma-
tion was lowered and the enone was obtained in conversions of about 94 % and in
isolated yields of over 80 % depending on the scale (Scheme 2.17). The preparation
was readily scaled up by conversion to a continuous process with the CMR.
Scheme 2.17 Intramolecular Claisen±Schmidt condensation.
2.7.4
Avoiding Salt Formation
The manufacture of fine chemicals and pharmaceuticals generates in the order of

25±100 times more waste than product [52]. Inorganic salts account for the bulk of
the waste and are most often produced by neutralization of acidic or basic solu-
tions [53]. Salts can pollute soil and ground water, lower the pH of atmospheric
moisture and they may contribute to acid dew or acid rain [6]. For cleaner produc-
tion, their minimization is essential and hence our concentration on new processes,
such as the etherification (discussed in Sect. 2.6.3.1) and hydrogen transfer reduc-
tion (Sect. 2.6.3.2), that avoid salt formation and the use of salts.
The use of high-temperature water as a reaction medium can be beneficial in that
regard. For reactions necessitating addition of acid or base, less agent is usually re-
quired for high temperature processes than for those at and below 100 8C and the re-
actions often proceed more selectively. At the end of the process, the requirement for
less neutralizing agent lowers the formation of salt [6].
2.7.5
Resin-based Adsorption Processes
From the foregoing, microwave heating in pressurized systems facilitates organic re-
actions in aqueous media. Normally, the products would be recovered by extraction
with organic solvent. The aqueous phase would become saturated with the organic
solvent (and the solvent with water), complicating disposal and offsetting environ-
mental benefits gained through the use of water as the reaction medium in the first
place.
To avoid this, we have employed hydrophobic resins for concentration and isola-
tion of the products from aqueous media [49]. Organics are retained on the resin
and subsequently can be desorbed with solvents such as ethanol, which is useful for
ªgreenº chemistry as it is readily recyclable, renewable and biodegradable. Nonex-
tractive processes offer convenience, can be conducted with high throughput and af-
ford low waste owing to ready disposal of the spent water, recyclability of the resin
and the solvent used for desorption.
2.8
Metal-catalyzed Processes
The first reports of the use of microwave heating to accelerate Heck, Suzuki and
Stille reactions on the solid phase [54] and in solution did not appear until 1996 [55].
Since then, many metal-catalyzed reactions have been performed within minutes by
microwave heating in pressurized systems, sometimes with high regio- and enan-
tioselectivity [56, 57].
Palladium, its complexes and salts can catalyze transformations including oxida-
tion, hydrogenation and rearrangement. One of the most useful applications of the
metal though, is for activation of C±H bonds towards coupling reactions. The Heck
reaction, which involves C±C coupling of an aryl or vinyl halide with an alkene in the
presence of palladium derivatives has been the subject of intensive study [58]. Syn-
thetic transformations of terminal alkynes via homo- or heterocouplings of the Gla-
ser, Eglington, or Chodkiewicz±Cadiot type have also attracted interest.
Stille coupling involves the use of tin reactants. Tin is both toxic and difficult to re-
move. In an elegant extension of the pioneering work of Horvath [59], Curran and
his coworkers prepared fluorous tin reactants that facilitated Stille reactions and en-
abled the convenient isolation and separation of products afterwards [60]. Probably
owing to low solubility of fluorine-containing compounds in organic solvents, the re-
actions normally required about one day at 80 8C. With microwave heating, they
were completed within minutes [61].
Typically, the Pd species for Heck couplings are homogeneous catalysts, stabilized
by air-sensitive ligands. They present economic and environmental problems regard-
ing separation, regeneration and reuse. These difficulties can be diminished with
heterogeneous catalysts that are more easily recoverable from the reaction mixture.
As mentioned in Sect. 2.6, a catalyst consisting of palladium metal deposited on por-
2.9 Pressurized Microwave Systems Developed by Others for Organic and Organometallic Chemistry 55
ous glass tubing was developed for C±C coupling reactions [35]. It was used for reac-
tions conducted continuously or batchwise and could be reused for repeat or differ-
ent reactions. Reactions were performed in the presence of air, with either conven-
tional heating or under microwave irradiation in the MBR.
Coupling of aryl halides with terminal acetylenes affords internal alkynes. Typi-
cally, high amounts of catalyst (1±5 mol % Pd) and coaddition of copper salts (also
1±5 mol % in Cu) are needed, thus reducing the industrial viability of such proce-
dures. With palladium on porous glass, copper salts or activating ligands were not
necessary. In contrast with Heck reactions involving halogen-containing reactants
(usually aryl bromides or iodides), homocoupling of terminal acetylenes occurred
readily and with excellent atom economy [35].
A new oxidation±dehydrogenation±Heck coupling catalyzed by Pd on porous glass
or Pd(OAc)2 also proceeded under microwave heating in the MBR (Scheme 2.18)
[36]. With an excess of PhI, saturated alcohols including 1-propanol and 3-phenylpro-
panol afforded 3,3-diphenylpropenal as the major product, and trans-2,3-diphenylpro-
penal by a concerted process taking 10 min at 220 8C. The yields of this remarkable
transformation were low, however, and further work into several aspects is required
to make them more respectable.
Scheme 2.18 New cascade oxidation±dehydrogenation±double-Heck reaction.
Advantages of palladium on porous glass included ease of manufacture, mechani-

cal strength and obviation of air-sensitive and temperature-sensitive ligands. De-
pending on the specific application, the catalyst also showed thermal stability and re-
sistance to organic solvents. On occasions it was reused for repeat or different reac-
tions. Turnover numbers in the order of 15,000 were achieved for Heck reactions in
high-temperature water (with either Et3N or NaOAc as base). However, some of the
support dissolved and an alternative material may be advantageous for such condi-
tions [35].
2.9
Pressurized Microwave Systems Developed by Others for Organic and Organometallic
Chemistry
This account has been written from a personal perspective and thus has focused al-
most exclusively on the development and applications of the CMR and MBR. In that
context, the numerous significant contributions of others are beyond the present
scope and have been discussed comprehensively by the author elsewhere [6, 33, 34].
Nonetheless, they shall not be allowed to pass here without mention.
In their pioneering work, Gedye et al. used a domestic oven and commercially
available screw cap pressure vessels [7, 62]. The pressure was measured and tem-
perature was estimated through an infrared sensor, immediately after the power had
been turned off. The reactor of Baghurst and Mingos [63] employed a glass vessel
with a pressure-controlling device in a modified domestic oven. Pougnet and his
coworkers constructed a range of equipment mainly for analytical applications.
Among their developments was a pressure vessel [64] and a cylindrical microwave
cavity that housed containers for chemical reactions and distillation [65]. Abramo-
vitch et al. performed organic synthesis in a batch unit that incorporated a stirrer
and temperature control, but the details were not disclosed [66]. Majetich and Hicks
employed digestion bombs for 45 organic reactions in which a baristat was used to
indirectly maintain the temperature below 200 8C [67].
Chemat et al. have reported several microwave reactors, including systems that
can be used in tandem with other techniques such as sonication [68], and ultravio-
let radiation [69]. With the microwave±ultrasound reactor, the esterification of acetic
acid with n-propanol was studied along with the pyrolysis of urea. Improved results
were claimed compared with those from conventional and microwave heating [68].
The efficacy of the microwave±UV reactor was demonstrated through the rearran-
gement of 2-benzoyloxyacetophenone to 1-(2-hydroxyphenyl)-3-phenylpropan-1,3-
dione [69].
A specialized application of microwave-assisted organic synthesis involves the pre-
paration of radiopharmaceuticals labeled with short-lived radionuclides, particularly
for use in positron emission tomography [70±72]. This represented an excellent ap-
plication of microwave technology, where the products must be prepared quickly and
in high radiochemical yield, on a small scale.
Recent studies by Mingos and Whittacker into the optimum conditions have con-
firmed the benefits of pressurized systems for microwave chemistry [73].
2.10
Technical Considerations and Safety
As demonstrated above with examples, the CMR and MBR offer many advantages
for synthetic processes that benefit from rapid heating and cooling. These systems
are less useful and may be inappropriate when the reaction requires low tempera-
ture conditions throughout, when materials or reactions that are incompatible with
microwave energy (e. g. reactions involving predominantly nonpolar organics) are to
be employed or for reactions with ªdryº media.
With microwaves, high rates of heating are usually desired. A difficulty can arise,
however, when a material undergoing irradiation, possesses a dissipation factor that
increases with temperature. In contrast with conventional heating, microwave energy
is then absorbed more efficiently with temperature and the rate of temperature rise
accelerates. Although, this phenomenon can be beneficial for maintaining high tem-
peratures for catalysts, a thermal runaway can result unless the temperature is care-
fully monitored and the power controlled.
2.11 Conclusion 57
On the other hand, solvents usually show a decrease in dielectric constant with
temperature. Efficiency of microwave absorption diminishes with temperature rise
and can lead to poor matching of the microwave load, particularly as fluids approach
the supercritical state. Solvents and reaction temperatures should be selected with
these considerations in mind, as excess input microwave energy can lead to arcing.
If allowed to continue unchecked, arcing could result in vessel rupture or perhaps
an explosion, if flammable compounds are involved. Therefore it is important in mi-
crowave-assisted organic reactions, that the forward and reverse power can be moni-
tored and the energy input be reduced (or the load matching device adjusted) if the
reflected power becomes appreciable.
In the MBR, the applicator of plate steel was an important safety feature in the
possible event of vessel rupture or explosion. Temperature and pressure measure-
ments, stirring, infinitely variable control of microwave power input, the cold-finger,
as well as a pressure relief valve, have all contributed significantly to the safety and
reliability of the system.
Safety issues have been discussed comprehensively, in an earlier review [33]. At
time of writing, more than two thousand reactions have been conducted with a range
of solvents, times and temperatures in the CMR and MBR without accident or in-
jury.
2.11
Conclusion
From tentative beginnings, microwave-assisted organic chemistry has become a

field, experiencing exponential growth and commanding its own dedicated, interna-
tional conferences. The number of papers in peer-reviewed journals stood at two in
1986, 220 in mid-1995 [33] and was well over 1000 by 2002. Commercial microwave
reactors have been introduced, which have found applications for research and man-
ufacture of high-value low-volume chemicals. They meet the objectives set out in
Sect. 2.1, regarding measurement and control of reaction conditions, failsafe proce-
dures, advantages unavailable with conventional equipment and capabilities for scal-
ing up and scaling down chemical processes.
The CMR and MBR are capable of operation in the presence of organic solvents.
They have extended the useful operating temperature range for low-boiling organic
solvents and have facilitated the development of new chemical processes that require
moderate temperatures. Although debate continues to rage on the existence or other-
wise of so-called ªnonthermal microwave effectsº [74±76], the principles of micro-
wave chemistry now are well understood [33, 34].
Economic and safety considerations encourage minimal stockpiling of chemicals
and avoiding transportation of hazardous substances. These increasing demands of-
fer many opportunities for microwave chemistry in the development of environmen-
tally benign methods for the preparation of intermediates, specialty chemicals and
pharmaceuticals [6]. It appears likely that within the next few years, individual che-
mical reactors will be required for diverse tasks and will need to be easily relocated
as community pressure mounts to restrict movement of chemicals by road. Advan-

tages sought will include quick start up and shut down, high yield, low holding capa-
city, almost complete elimination of waste, with the potential for accidents during
transportation and storage being avoided by just-in-time, point-of-use production.
The MBR and CMR are portable, multipurpose and self-contained, features that
could become increasingly important in this regard. Their capabilities for rapid
throughput and the materials of construction enable easy cleaning for reuse and pro-
mote short turnaround times. Safety advantages include control and method of en-
ergy input, low volumes undergoing reaction at one time and opportunities for re-
mote, programmable operation.
Acknowledgments
The author is particularly indebted to the following dedicated coworkers, whose ef-
forts have helped to convert dreams into reality: A. F. Faux, T. Cablewski, R. W. Trai-
nor, K. D. Raner, J. S. Thorn, L. Bagnell, U. Kreher, L. Mokbel and F. Vyskoc.
References and Footnotes
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4 Tebo, P. V., Chemtech 1998, 28(3), 8. 16 Bose, A. K., Manhas, M. S., Banik,
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11 Langa, F., De la Cruz, P., De la 186.
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24 Bagnell, L., Bliese, M., Cablewski, T., 43 Malwitz, D., Metzger, J. O., Chem.
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Chem. 1997, 50, 921. 44 Strauss, C. R., Trainor, R. W., Org.
25 Braun, I., Schulz-Ekloff, G., Prep. Proc. Int. 1995, 27, 552.
Wohrle, D., Lautenschlager,W., 45 Cablewski, T., Gurr, P. A., Pajalic,
Micropor. Mesopor. Mater. 1998, 23, 79. P. J., Strauss, C. R., Green Chem. 2000,
26 Raner, K. D., Strauss, C. R., Trainor, 2, 25.
R. W., Thorn, J. S., J. Org. Chem. 1995, 46 Bagnell, L., Cablewski, T., Strauss,
60, 2456. C. R., Trainor, R. W., J. Org. Chem.
27 Manufactured by Personal Chemistry, 1996, 61, 7355.
Uppsala, Sweden. 47 An, J., Bagnell, L., Cablewski, T.,
28 Metaxis, A. C., Meredith, R. J., Indus- Strauss, C. R., Trainor, R. W., J. Org.
trial Microwave Heating, Peregrinus, Chem. 1997, 62, 2505.
London, 1988. 48 Kreher, U., Strauss, C. R.,
29 Gabriel, C., Gabriel, S., Grant, E. H., Walther, D., ECSOC-5, Electronic Conf.
Halstead, B. S. J., Mingos, D. M. P., Synth. Org. Chem., Sept. 1±30, 2001;
Chem. Soc. Rev. 1998, 27, 213. www.mdpi.net/ecsoc-5 [4e0041].
30 Neas, E. D., Collins, M. J. in: Introduc- 49 Bagnell, L., Bliese, M., Cablewski, T.,
tion to Microwave Sample Preparation, Strauss, C. R., Tsanaktsidis, J., Aust. J.
Kingston, H. M., Jassie, L. B. (eds.), Chem. 1997, 50, 921.
American Chemical Society, Washing- 50 Strauss, C. R., Trainor, R. W. in: Bio-
ton, DC, 1988, Chapter 2, pp. 7±32. technology for Improved Foods and Fla-
31 Schiffmann, R. F. in: Encyclopedia of vors; ACS Symposium Series, 637,
Chemical Processing and Design,Vol. 30, Takeoka, G. R., Teranishi, R., Wil-
McKetta, J. J., Cunningham, W. A. liams, P. J. (eds.), ACS,Washington,
(eds.), Marcel Dekker, New York, 1989, 1996, pp. 272±281.
p. 220. 51 Strauss, C. R., Trainor, R. W., Aust. J.
32 Kingston, H. M., Jassie, L. B. (eds.), Chem. 1998, 51, 703.
Introduction to Microwave Sample Pre- 52 Sheldon, R. A., Chem. Ind. (London)
paration, American Chemical Society, 1997, 12.
Washington, DC, 1988. 53 Sheldon, R. A., Chemtech, 1994, 24(3),
33 Strauss, C. R., Trainor, R. W., Aust. J. 38.
Chem. 1995, 48, 1665. 54 Larhed, M., Lindeberg, G., Hall-
34 Strauss, C. R. in: Handbook of Green berg, A., Tetrahedron Lett. 1996, 37,
Chemistry and Technology, Clark, J., Mac- 8219.
quarrie, D. (eds.), Blackwell, London, 55 Larhed, M., Hallberg, A., J. Org.
2002. Chem. 1996, 61, 9582.
35 Li, J., Mau, A. W.-H., Strauss, C. R., 56 Vallin, K. S. A., Larhed, M., Johans-
Chem. Commun. 1997, 1275. son, K., Hallberg, A., J. Org. Chem.
36 Bagnell, L., Kreher, U., Strauss, 2000, 65, 4537.
C. R., Chem. Commun. 2001, 29. 57 Bremberg, U., Larhed, M., Mo-
37 Raner, K. D., Strauss, C. R., J. Org. berg, C., Hallberg, A., J. Org. Chem.
Chem. 1992, 57, 6231. 1999, 64, 1082.
38 Raner, K. D., Strauss, C. R.,Vyskoc, F., 58 Beletskaya, I. P., Cheprakov, A. V.,
Mokbel, L., J. Org. Chem. 1993, 58, 950. Chem. Rev. 2000, 100, 3009.
39 Danner, H., Braun, R., Chem. Soc. Rev. 59 Horvath, I. T., Acc. Chem. Res. 1998,
1999, 28, 395. 31, 641.
40 Cundy, C. S., Collect. Czech. Chem. 60 Curran, D. P., Hoshino, M., J. Org.
Commun. 1998, 63, 1699. Chem. 1996, 61, 6480.
41 Bagnell, L., Cablewski, T., Strauss, 61 Larhed, M.; Hoshino, M.; Hadi-
C. R., Chem. Commun. 1999, 283. da, S.; Curran, D. P., Hallberg, A.,
42 Bagnell, L., Strauss, C. R., Chem. J. Org. Chem. 1997, 62, 5583.
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K. C., Can. J. Chem. 1988, 66, 17.
63 Baghurst, D. R., Mingos, D. M. P., crowave Power Electromag. Energy 1999,

J. Chem. Soc., Dalton Trans. 1992, 1151. 34, 55.
64 Pougnet, M. A. B., Schnautz, N. G., 70 Hwang, D.-R., Moerlein, S. M.,
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Energy 1993, 28, 113. 72 Stone-Elander, S. A., Elander, N.,
66 Abramovitch, R. A., Abramovitch, Thorell, J.-O., Solas, G., Svenneb-
D. A., Iyanar, K., Tamareselvy, K., Tetra- rink, J., J. Labelled Compd. Radiopharm.
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67 Majetich, G., Hicks, R., J. Microwave 73 Whittacker, A. G., Mingos, D. M. P.,
Power Electromag. Energy 1995, 30, 27. J. Chem. Soc., Dalton Trans. 2000, 1521.
68 Chemat, F., Poux, M., Di Martino, 74 Galema, S. A., Chem. Soc. Rev. 1997, 26,
J.-L., Berlan, J., J. Microwave Power 233.
Electromag. Energy, 1996, 31, 19. 75 Jacob, J., Chia, L. H. L., Boey, F. Y. C.,
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2001, 57, 9199.
61
3
Nonthermal Effects of Microwaves in Organic Synthesis
Laurence Perreux and Andr Loupy
Microwave (MW) activation as an unconventional energy source has become very

popular and useful technology in organic chemistry, as shown recently in an exhaus-
tive review [1]. The annual number of publications on microwave-assisted organic
chemistry is growing rapidly with more than thousand publications in print since
the pioneering work of Gedye [2] in 1986 (Fig. 3.1).
Most of these publications describe important accelerations of a wide range of or-
ganic reactions especially when performed under solvent-free conditions. The com-
bination of solvent-free reaction conditions and microwave irradiation leads to large
reductions in reaction times, enhancement of yield, and, sometimes [3, 4] in selectiv-
ity with several advantages of an eco-friendly approach, termed ªgreen chemistryº.
Many of these reports are, however, based on inaccurate or unfounded compari-
sons with classical conditions which do not enable unequivocal conclusions to be
drawn about the effects of microwaves. For this reason, apparent contradictions and
controversies have appeared in the literature [5±7]. To try to rationalize all of these re-
sults it is necessary to propose a plausible interpretation of effects based on accurate
1200
1000
annually
number of publications
800 cumulative
600
400
200
0
86
87
88
89
90
91
92
93
94
95
96
97
98
99
00
19
19
19
19
19
19
19
19
19
19
19
19
19
19
20
year
Fig. 3.1 The number of publications dealing with microwave irradiation

in organic synthesis during the period 1986±2000.

ISBN: 3-527-30514-9
62 3 Nonthermal Effects of Microwaves in Organic Synthesis
and reliable data resulting from strict comparisons of reactions performed under si-
milar conditions (reaction medium, temperature, time, pressure) except for micro-
wave irradiation or conventional heating [3, 8, 9]. A monomode microwave reactor
should preferably be used, because this enables wave focusing (reliable homogeneity
of the electric field) and accurate control of the temperature (by use of optical fiber
or infrared detection) throughout the reaction [3, 9]. This makes it possible to use
both types of activation with similar temperature-profile increases. On the basis of
such strict comparisons it becomes possible to make an educated judgment about
the suitability, or otherwise, of microwave irradiation depending on reaction type
and experimental conditions.
3.1
Origin of Microwave Effects
The acceleration of reactions by exposure to microwaves results from material±wave

interactions leading to thermal effects (which can easily be estimated by temperature
measurement) and specific (not purely thermal) effects. Clearly, a combination of
these two contributions can be responsible for the effects observed.
Thermal effects (dielectric heating) can result from dipolar polarization as a conse-
quence of dipole±dipole interactions of polar molecules with the electromagnetic
field. They originate in dissipation of energy as heat, as an outcome of agitation and
intermolecular friction of molecules when dipoles change their mutual orientation
at each alternation of the electric field at a very high frequency (n = 2450 MHz) [10,
11] (Scheme 3.1).
This energy dissipation in the core of materials results in a much more uniform
temperature than classical heating. Classical thermal phenomena (conduction, con-
vection, radiation, etc.) only play a secondary role in the a posteriori equilibration of
temperature.
In this range of frequency charge±space polarization [12] can also occur and can
be of prime importance with semiconductors, because it affects materials which con-
a) b) c)
Scheme 3.1 Effects of the surrounding to a continuous electric field; and (c) sub-
electric field on the mutual orientation of di- mitted to an alternating high frequency elec-
poles: (a) without constraint; (b) submitted tric field.
3.2 Specific Microwave Effects 63
tain free conduction electrons. This phenomenon is essential for heating of solid par-
ticles, more or less magnetic, such as a variety of mineral oxides or metallic species.
For liquid products (solvents), only polar molecules selectively absorb microwaves,
because nonpolar molecules are inert to microwave dielectric loss. In this context of
efficient microwave absorption it has also been shown that boiling points can be
higher when solvents are subjected to microwave irradiation rather than conven-
tional heating. This effect, called the ªsuperheating effectº [13, 14] has been attribu-
ted to retardation of nucleation during microwave heating (Tab. 3.1).
Tab. 3.1 Boiling points (8C) of some polar solvents under the action of MW irradiation in the ab-
sence or presence of a nucleation regulator.
Solvent Boiling point Microwave exposure

Multimode Monomode Monomode
[11, 12] (100 W) + boiling chips
Water 100 105 100 100

1-Heptanol 176 208 180 176
Ethyl acetate 77 102 92 77
Chloroform 61 89 85 62
Cyclohexanone 155 186 168 155
It is clearly connected with the effect of stirring and the presence of a nucleation
regulator [15]. It is also related to the microwave power. It has been shown that the
effect is eliminated when the experiments are performed on well-stirred mixtures
[16, 17] using low microwave power. It could be essentially a consequence of the ab-
sence of stirring, i. e. in closed vessels inside a domestic microwave oven.
3.2
Specific Microwave Effects
The origin of specific microwave effects is twofold ± those which are not purely ther-
mal and a special thermal effect connected with possible intervention of ªhot spotsº.
One of the few theoretical papers trying to explain acceleration under the action of
microwaves has recently been published by A. Miklavc [18]. He stated that large in-
creases in the rates of chemical reactions occur because of the effects of rotational ex-
citation on collision geometry. This could be cautiously considered when one has
knowledge of the quasi-nil energy involved by microwave interaction according to
Planck's law [E = hc/l = 0.3 cal/mol].
Non-purely thermal effects (other than simple dielectric heating) can be foreseen
to have multiple origins. These effects can be rationalized by consideration in terms
of the Arrhenius law [19, 20] and can result from modification of each of the terms
of this equation.
k A exp DG7=RT
The first possibility is an increase in the pre-exponential factor, A, which repre-

sents the probability of molecular impacts. The collision efficiency can be effectively
influenced by mutual orientation of polar molecules involved in the reaction. Be-
cause this factor depends on the frequency of vibration of the atoms at the reaction
interface, it could be postulated that the microwave field might affect this. Binner et
al. [21] explained the increased reaction rates observed during the microwave synth-
esis of titanium carbide in this way:
Calculations have shown that faster diffusion rates might be explained by an in-
crease in the factor A with no change in activation energy.
A decrease in the activation energy DG7 is certainly a major effect. Because of the
contribution of enthalpy and entropy to the value of DG7 (= DH7 ± TDS7), it might
be predicted that the magnitude of the ±TDS7 term would increase in a microwave-
induced reaction, because organization is greater than with classical heating, as a
consequence of dipolar polarization.
Lewis et al. [22] presented experimental evidence for such an assumption after
measurements of rate constants at different temperatures for the unimolecular imi-
dization of a polyamic acid (Eq. (1), Fig. 3.2, and Tab. 3.2).
Eq. (1)
2,20 2,25 2,30 2,35 2,40 2,45 2,50

-1,00
-2,00
-3,00
ln k
-4,00
-5,00 microwave
thermal
-6,00
-7,00
1000/T (K)
Fig. 3.2 First-order kinetic plots for microwave (MW) and ther-
mal (D) activation of the imidization reaction.
Tab. 3.2 Results from the Arrhenius plots in Fig. 3.2.
Activation mode DH (kJ mol±1) log A
MW 57 ± 5 13 ± 1
D 105 ± 14 24 ± 4
The apparent activation energy is evidently substantially reduced. The same expla-
nation, i. e. a decrease in DG7, was also proposed for the decomposition of sodium
hydrogen carbonate in aqueous solution [23].
Intervention of localized microscopic high temperatures is possible [8, 14, 24], as
advocated in sonochemistry to justify the sonochemical effect. There is an inevitable
lack of experimental evidence, because we can necessarily have access to macro-
scopic temperature only. It has been suggested [6, 19] that, in some examples, MW
activation could originate from hot spots generated by dielectric relaxation on a mo-
lecular scale.
3.3
Effects of the Medium
Microwave effects should also be treated according to the reaction medium. Solvent
effects are of particular importance [25, 26].
If polar solvents are used, either protic (e. g. alcohols) or aprotic (e. g. DMF,
CH3CN, DMSO etc), the main interaction might occur between MW and polar mole-
cules of the solvent. Energy transfer is from the solvent molecules (present in large
excess) to the reaction mixtures and the reactants, and it would be expected that any
specific MW effects on the reactants would be masked by solvent absorption of the
field. The reaction rates should, therefore, be nearly the same as those observed un-
der the action of conventional heating (D).
This is essentially true, as is evidenced by the rates of esterification in alcoholic
media of propan-1-ol with ethanoic acid [27] or of propan-2-ol with mesitoic acid [28].
The absence of a specific microwave effect became apparent from several experi-
ments carefully conducted in alcohols or in DMF under similar conditions but with
microwave or classical heating [7].
More recently [29] the microwave-mediated Biginelli dihydropyrimidine synthesis
(Eq. 2) was reinvestigated using a purpose-built commercial microwave reactor with
on-line temperature, pressure, and microwave power control. Transformations per-
formed with microwave heating at atmospheric pressure in ethanol solution resulted
in neither a rate increase nor an increase in yield when the temperature was identi-
cal to that used for conventional thermal heating. The only significant rate and yield
enhancements were found when the reaction was performed under solvent-free con-
ditions in an open system.
Eq. (2)
A rapid and efficient procedure for flash heating by microwave irradiation has
been described for attachment of aromatic and aliphatic carboxylic acids to chloro-
methylated polystyrene resins via their cesium salts (Eq. 3) [17].
Eq. (3)
Significant rate accelerations and higher loadings are observed when the micro-
wave-assisted and conventional thermal procedures are compared. Reactions times
are reduced from 12±48 h with conventional heating at 80 8C to 5±15 min with mi-
crowave flash heating in NMP at temperatures up to 200 8C. Finally, kinetic compari-
son studies have shown that the observed rate enhancements can be attributed to
the rapid direct heating of the solvent (NMP) rather than to a specific nonthermal
microwave effect [17].
The synthesis of b-lactams from diazoketones and imines can be realized not only
by using photochemical reaction conditions but also under the action of microwave
irradiation. When the reaction was performed in o-dichlorobenzene at 180 8C, how-
ever, the rates of thermal and microwave-assisted formations of b-lactams were
shown to be identical within the limits of experimental error (80±85 % conversion
after 5 min) [30].
As described above, however, some rather small differences could be observed,
taking into account the superheating effect of the solvent under the action of micro-
waves in the absence of any stirring. This probably occurs in the isomerization of sa-
frole and eugenol in ethanol under reflux [31] (MW 1 h, D 5 h to obtain equivalent
yields).
Superheating of the solvent was believed to be responsible of the observed rate en-
hancement under microwave irradiation in the synthesis of 3,5-disubstituted 4-amino-
1,2,4-triazoles when conducted in 1,2-ethylene glycol as (polar) solvent (Eq. 4) [32].
Eq. (4)
The yields obtained by use of MW and D were clearly different for very short reac-
tion times and became similar after 15 min at 130 8C (Fig. 3.3).
Fig. 3.3 Dependence of yield

on time for 3,5-diphenyl-4-ami-
notriazole at 130 8C. 100
80
yield (%)
60
40
classical heating
microwave irradiation
20
0
0 10 20 30
time (min)
More interesting is the use of nonpolar solvents (e. g. xylene, toluene, carbon tetra-
chloride, hydrocarbons), because these are transparent to MW and absorb them only
weakly. They therefore enable specific absorption by the reactants. If these reactants
are polar, energy transfer occurs from the reactants to the solvent and the results
might be different under the action of MW and D. This effect seems to be clearly de-
pendent on the reaction and is, therefore, the subject of controversy. In xylene under
reflux, for example, no MW-specific effects were observed for the Diels±Alder reac-
tion [5] whereas important specific effects were described for aryldiazepinone synth-
esis [33].
These examples will be discussed and explained later, during discussion of the de-
pendence of MW effects on reaction mechanisms.
Clearly, the effect of the solvent seems to be of great importance to the possibility
of MW-specific effects. These could decrease when the polarity of the solvent is in-
creased. This effect was shown in at least two studies by Berlan et al. [19] and, more
recently, by Bogdal [34]. In the first study acceleration of a nonsymmetric Diels±Al-
der reaction under the action of MW was much more apparent in xylene than in the
more polar dibutyl ether (Fig. 3.4).
In the second investigation [34], involving a coumarin synthesis by Knoevenagel
condensation, supported by rate constant measurements and activation energy cal-
culations, it was found that the effect of MW was more important when the reaction
was conducted in xylene ± it was noticeably reduced in ethanol (Eq. (5) and Tab. 3.3).
CHO CO2 Et k1 CO2Et CO2Et

+
piperidine CO2Et
OH CO2 Et solvent OH O O
Eq. (5)
Microwave effects are most likely to be observed under solvent-free reactions [3].
In addition to the preparative interest of these methods in terms of use, separation,
and economical, safe and clean procedures, absorption of microwave radiation
Fig. 3.4 Dependence of yields

on time for a nonsymmetric
Diels±Alder reaction at 95 8C.
Xylene
100
80
Yield (%)
60
40
classical heating
20 microwave
0
0 5 10 15 20 25 30
Time (h)
Dibutyl ether
100
80
Yield (%)
60
40 classical heating
microwave
20
0
0 5 10 15 20 25 30
Time (h)
Tab. 3.3 Rate constants (× 103) for the reaction depicted in Eq. (5).
T (8C) Xylene k1 (mol L s±1) Ethanol k1 (mol L s±1)

MW D MW D
60 5.7 2.2 6.9 4.9

80 12.2 3.7 12.9 8.6
a) b)
∆ MW
Scheme 3.2 Temperature gradients for materials subjected

either to traditional heating (a) or to microwave irradiation (b).
should now be limited only to the reactive species. The possible specific effects will
therefore be optimum, because they are not moderated or impeded by solvents.
They can be accomplished by three methods [3, 35]:
1. reactions between the neat reagents in quasi-equivalent amounts, requiring, prefer-

ably, at least one liquid phase in heterogeneous media and leading to interfacial reac-
tions [36, 37]. Kinetic considerations for the reaction between two solids have been
explained by considering the formation of a eutectic melt during the reaction [37];
2. solid±liquid phase-transfer catalysis (PTC) conditions for anionic reactions using
the liquid electrophile as both reactant and organic phase and a catalytic amount
of tetraalkylammonium salts as the transfer agent [38]; and
3. reactions using impregnated reagents on solid mineral supports (aluminas, sili-
cas, clays) in dry media [3, 4, 39].
These procedures coupled with microwave activation have proven beneficial and
have led to many success stories which are described in several reviews [3, 4, 39±42].
Some apparently specific effects can, however, arise from the supports. Mineral
supports are usually poor heat conductors, i. e. significant temperature gradients can
develop inside the vessels under the action of conventional heating, whereas they be-
have as efficient absorbers of microwave energy with consequently more tempera-
ture homogeneity (Scheme 3.2).
3.4
Effects of Reaction Mechanisms
Microwave effects result from material±wave interactions and, because of the dipolar
polarization phenomenon, the greater the polarity of a molecule (such as the solvent)
the more pronounced the microwave effect when the rise in temperature [43] is con-
sidered. In terms of reactivity and kinetics the specific effect has therefore to be con-
sidered according to the reaction mechanism and, particularly, with regard to how the
-
A + B A
δ+ δB
TS
∆G∆
∆GMW < ∆G ∆
∆GMW
GS
Fig. 3.5 Relative stabilization of a more polar TS when com-

pared with the GS (polar mechanism).
polarity of the system is altered during the progress of the reaction. These assump-
tions are evidently connected to the Hughes±Ingold model [44] universally adopted to
explain solvent effects [45] and especially the intervention of aprotic dipolar solvents.
Specific microwave effects can be expected for polar mechanisms, when the polar-
ity is increased during the reaction from the ground state towards the transition state
(as more or less implied by Abramovich in the conclusion of his review in 1991 [42]).
The outcome is essentially dependent on the medium and the reaction mechanism.
If stabilization of the transition state (TS) is more effective than that of the ground
state (GS), this results in enhancement of reactivity as a result of a decrease in the ac-
tivation energy (Fig. 3.5), because of electrostatic (dipole±dipole type) interactions of
polar molecules with the electric field.
3.4.1
Isopolar Transition-state Reactions
Isopolar activated complexes differ very little or not at all in charge separation or
charge distribution from the corresponding initial reactants. These complexes are
formed in pericyclic reactions such as Diels±Alder cycloadditions and the Cope rear-
rangement.
The polarity of ground and transition states are a priori identical, because no
charges are developed during the reaction path. Following this rule, specific micro-
wave effects would not be expected for these reactions, as has been verified when the
reactions were performed in a nonpolar solvent [5, 6]. Solvent effects in these reac-
tions are also small, or negligible, for the same reasons (Fig. 3.6) [46].
Such a conclusion is, nevertheless, connected with the synchronous character of
the mechanism. If a stepwise process is involved (nonsimultaneous formation of the
two new bonds), as for unsymmetric dienes and/or dienophiles or in hetero Diels±
Alder reactions, a specific microwave effect could intervene, because charges are de-
veloped in the transition state. This could certainly be so for several cycloadditions
[47, 48] and particularly for 1,3-dipolar cycloadditions [49]. Such an assumption has
O O O
TS
GS ∆GMW ∆G∆
=
Fig. 3.6 Similar stabilization of isopolar TS and GS

(concerted synchronous mechanism).
been verified experimentally and justified by considering theoretical calculations pre-

dicting an asynchronous mechanism in the cycloaddition of N-methylazomethine
ylide to C70 fullerene [25] (Eq. 6).
CH3NHCH2CO2H/HCHO
C 70 C70 N CH3 Eq. (6)
MW or ∆
During the course of a study of the cycloaddition of azidomethyldiethylphospho-

nate with acetylenes and enamines leading to alkyltriazoles under solvent-free condi-
tions we observed that specific effects can be involved, depending on the nature of
the substituents on the dipolarophiles [50] (Eq. (7) and Tab. 3.4).
Eq. (7)
The synthesis of biologically significant fluorinated heterocyclic compounds has

been accomplished by 1,3-dipolar cycloaddition of nitrones to fluorinated dipolaro-
philes [51]. This reaction was noticeably improved under solvent-free conditions and
using microwave irradiation (Eq. (8) and Tab. 3.5).
Eq. (8)
Tab. 3.4 Thermal or microwave activation for the cycloaddition depicted in Eq. (7).
R1 R2 Activation Conditions Yield (%) a

t (min) T (pC)
CH3 P(O)(OEt)2 D 20 90 5
MW 20 90 78
H CO2Et D 5 100 70
MW 5 100 92
C6H5 CO2Et D 10 160 >98
MW 10 160 >98
H C6H5 D 30 120 40
MW 30 120 >98
H CH2OH D 30 100 40
MW 30 100 >98
a
The ratio of the amounts of the two isomers formed was identical for both activation conditions.
Tab 3.5 Thermal or microwave activation for the cycloaddition depicted in Eq. (8).
Activation Conditions Yield (%)

Solvent Time Temp (pC)
D Toluene 24 h 110 65
MW None 3 min 119 98
D None 3 min 119 64
D None 30 min 119 98
It is apparent there is a definite advantage to operating under solvent-free condi-

tions. The specific microwave effect is here of low magnitude, but evident, because
after 3 min the yield increases from 64 to 98 %. Prolongation of the reaction time
with classical heating led to an equivalent result. The microwave effect is rather lim-
ited here, because of a near-synchronous mechanism.
3.4.2
Bimolecular Reactions between Neutral Reactants Leading to Charged Products
Typical reactions are amine or phosphine alkylation or addition to a carbonyl group

(Scheme 3.3). In these examples, because of the development of dipoles in the TS,
we are concerned with a polarity increase during the course of the reaction starting
from the GS towards the TS. Favorable microwave effects are, consequently, ex-
pected.
The magnitude of these effects might be related to the nature of substituents a to
N or P and to the structure of the leaving group, as exemplified by several observa-
tions that will be described and discussed below.
δ+ δ-
N + R X N R X N+ R, X-
δ+ δ-
P + R X P R X P+ R, X-
δ+ δ- + -
N + O N O N C O
u ncharg ed G S d ipo lar TS
R = alkyl group X = halide

Scheme 3.3
3.4.3
Anionic Bimolecular Reactions Involving Neutral Electrophiles
These reactions comprise nucleophilic SN2 substitutions, b-eliminations, and nu-

cleophilic additions to carbonyl compounds or activated double bonds, etc. They in-
volve the reactivity of anionic species Nu± associated with counterions M+ to form
ion-pairs with several possible structures [52] (Scheme 3.4).
The transition states are composed of loose ion pairs in so far as they involve a
charge-delocalized anion, thereby enhancing polarity compared with the ground
states (in which the ion pairs are tighter), because of an increase in anionic dissocia-
tion as the more bulky product anion is formed. As a consequence, specific micro-
wave effects, directly connected to polarity enhancement, should depend on the
structure of reactive ion pairs in the GS:
- + δ- δ-
Nu , M + R X Nu R X, M+
- -
δ δ
Nu -, M+ + O Nu O, M+
Scheme 3.4
. If tight ion pairs (between two hard ions) are involved in the reaction the micro-
wave-accelerating effect then becomes more important, because of enhancement
of ionic dissociation during the course of the reaction as tight ion pairs (GS) are
transformed into more polar loose ion pairs (TS).
. If, on the other hand, loose ion pairs (between soft ions) are involved, microwave
acceleration is limited, because ionic interactions are only slightly modified from
GS to TS.
This duality in behavior of some SN2 reactions can be foreseen and observed (vide
infra) by comparing reactions involving hard or soft nucleophilic anionic reagents ac-
cording to the cation and the leaving group.
3.4.4
Unimolecular Reactions
Entropic contributions to the acceleration of first-order reactions by microwaves

should be negligible (DS7= 0). When ionization (SN1 or E1) or intramolecular addi-
tion (cyclizations) processes are involved a microwave effect could be viewed as re-
sulting from a polarity increase from GS to TS, because of the development of dipo-
lar intermediates (Scheme 3.5).
3.5
Effect of the Position of the Transition State Along the Reaction Coordinates
The position of the transition state along the reaction coordinates in relation to the
well-known Hammond postulate [53] will now be considered. If the activation en-
ergy, DG7, of a reaction is only small the TS looks like the GS (it is depicted as a ªre-
actant-like transition stateº). Consequently, the polarity is only slightly modified be-
tween the GS and TS during the course of the reaction and only weak specific micro-
wave effects can be foreseen under these conditions.
δ+ δ-
R X R X
δ-
C X C X
+
N N δ
dipolar transition states

R = alkyl group X = halide Scheme 3.5
3.6 Effect on Selectivity 75
TS
TS
∆G
GS
∆G
(a) GS (b)
Scheme 3.6 (a) Small DG v early TS v little change in polarity
TS/GS v weak microwave effect. (b) Large DG v late TS v impor-
tant change in polarity TS/GS v large microwave effect.
By way of contrast, a more difficult reaction implies a higher activation energy.

The TS therefore occurs later along the reaction path and, consequently, the influ-
ence of polarity effects might be significantly larger. It might be assumed that a mi-
crowave effect should be more pronounced when the TS occurs later along the reac-
tion coordinates (depicted more as a ªproduct-like transition stateº) and is, therefore,
likely to become more polar (Scheme 3.6).
This conclusion is in agreement with Lewis who stated that ªslower reacting sys-
tems tend to show a greater effect under microwave radiation than faster reacting
ones [54]º.
Consequently, a microwave effect can be important when steric effects are in-
volved in a reaction, as exemplified by the increased magnitude of the effect for sapo-
nification of hindered mesitoic esters relative to benzoic esters [55] (vide supra).
3.6
Effect on Selectivity
The literature contains a few examples of increased selectivity [56±58] in which the
steric course and the chemo- or regioselectivity of reactions can be altered under the
action of microwave irradiation compared with conventional heating.
As a further consequence of these assumptions, it might be foreseen that micro-
wave effects could be important in determining the selectivity of some reactions.
When competitive reactions are involved, the GS is common for both processes. The
mechanism occurring via the more polar TS could, therefore, be favored under the
action of microwave radiation (Scheme 3.7).
Scheme 3.7 The more polar TS1 is more stabi-

lized by dipole±dipole interactions with the elec-
tric field and therefore more prone to microwave
effects.
Langa et al. [26, 59, 60], while conducting the cycloaddition of N-methylazo-
methine ylide with C70 fullerene, proposed a rather similar approach. Theoretical
calculations predict an asynchronous mechanism, suggesting that this phenomenon
can be explained by considering that, under kinetic control, ªmicrowave irradiation
will favor the more polar path corresponding to the hardest transition stateº.
3.7
Some Illustrative Examples
To illustrate these trends, we now present some typical illustrative examples. These
have been selected because strict comparisons of microwave and classical heating ac-
tivation were made under similar conditions (time, temperature, pressure, etc. ¼)
for the same reaction medium and using, preferably, a monomode system equipped
with stirring. They mostly involve reactions performed under solvent-free conditions
or, occasionally, in a nonpolar solvent, because these conditions are also favorable for
observation of microwave effects.
3.7.1
Bimolecular Reactions between Neutral Reactants
These reactions are among the most propitious for revealing specific microwave ef-
fects, because the polarity is evidently increased during the course of the reaction
from a neutral ground state to a dipolar transition state.
3.7.1.1 Nucleophilic Additions to Carbonyl Compounds

The most typical situation can be depicted for amine additions to a carbonyl group
(Eq. 9)
+ -
δ δ + -
N + O N O N O products
Eq. (9)
dipolar transition state
This example covers very classical processes such as syntheses of a wide variety of
compounds including imines, enamines, amides, oxazolines, hydrazones, etc ¼
Amines
Imine or enamine synthesis

It has been shown by Varma et al. [61] that reaction of primary and secondary
amines with aldehydes and ketones is substantially accelerated by microwaves under
solvent-free conditions in the presence of montmorillonite K10 clay, affording high
yields of imines and enamines (Eq. 10).
R
R R - N R1
δ R2 = H
O O R'
R'
R'
+
δ
R1
N
R N R2
N H R2
H R2 R1
R2 H
R1 R'
Eq. (10)
A more elaborate example is the Niementowski reaction to give access to quinazo-

linones and quinolines [62]. The determining step consists in the reaction of anthra-
nilic acid with some amides or ketones (Eq. 11).
Eq: 11
It has been shown that a mixture of an indoloquinazoline and anthranilic acid, ad-
sorbed on graphite, led to cyclization in good yields after 30 min at 140 8C, in less
time than for the purely thermal procedure under similar conditions, when a very
poor yield is obtained even after 24 h [63].
A large specific microwave effect was observed in the solvent-free synthesis of N-
sulfonylimines, a similar type of reaction [64] (Eq. 12).
Ar Ar δ-
O O
H Ar
H
+ N SO2Ar'
δ
N - H2 O H
N H SO 2Ar'
H SO2Ar' H
Eq: 12
H
Ar = C6 H5 Ar' = pCH 3-C6H4 6 min 190 °C MW 91 % ∆ 40 %
Hydrazone synthesis
In a typical example, a mixture of benzophenone and hydrazine hydrate in toluene
resulted in 95 % yield of the hydrazone within 20 min [65] (Eq. 13).
Ph Ph δ−
O O
Ph Ph
Ph
δ + N NHR
N - H2O Ph
N H NHR
H NHR H
Eq. (13)
H
The hydrazone was subsequently treated with KOH under the action of MW to un-
dergo Wolff±Kishner reduction (leading to PhCH2Ph) within 25±30 min in excellent
yields (95 %). As an extension, the reaction of neat 5- or 8-oxobenzopyran-2(1H)-ones
with a variety of aromatic and heteroaromatic hydrazines is substantially accelerated
by irradiation in the absence of any catalyst, solid support, or solvent [66] (Eq. 14).
NHR
O N
O O O O
RNHNH2
Eq. (14)
NHCOPh NHCOPh
Ex: R = 4-nitrophenyl MW 9min 130°C 98%

∆ 1h 130°C 80%
Amidation of carboxylic acids

Uncatalyzed amidations of acids have been realized under solvent-free conditions
and with a very important microwave effect [67 a]. The best results were obtained by
use of a slight excess of either amine or acid (1.5 equiv.). The reaction involves ther-
molysis of the previously formed ammonium salt (acid±base equilibrium) and is
promoted by nucleophilic attack of the amine on the carbonyl moiety of the acid and
removal of water at high temperature. The large difference in yields (MW 4 D)
might be a consequence of interaction of the polar TS with the electric field
(Eq. (15 a) and Tab. 3.6).
R R −
δ
O O
HO
HO
+
PhCH2NH3 , RCO2- δ+
N
N H CH2Ph
H CH 2Ph H
H
R
O
- H2O PhCH2 N
H
Eq. (15 a)
Tab. 3.6 Reaction of benzylamine with carboxylic acids at 150 8C for 30 min.
R Amine/acid Yield (%)

MW D
Ph 1:1 10 10
1.5 : 1 75 17
1 : 1.5 80 8
PhCH2 1:1 80 63
1.5 : 1 93 40
1 : 1.5 92 72
CH3(CH2)8 1:1 85 49
If it is considered that at 150 8C water can be removed equally under both types of
activation, the noticeable difference in yields is clearly indicative of an improvement
in the nucleophilic addition of the amine to the carbonyl group when performed un-
der the action of microwave irradiation, with important specific effects.
The preparation of aliphatic, aromatic, or functionalized tartramides directly from
tartaric acid and amines under solvent-free conditions and microwave activation was
very recently described [67 b].
Eq. (15 b)
Synthesis of 2-oxazolines
Oxazolines can be readily synthesized by means of a noncatalyzed solvent-free proce-
dure by two successive nucleophilic additions on a carbonyl group with the forma-
tion of an amide as an intermediate [68] (Eq. 16).
Ar
O Ar δ−
O O
HO HO Ar
+ HN OH
N Nδ OH - H2O
OH
H H OH
H HO
H OH
OH
HO HO
δ−
O Ar
Ar O δ+
C OH
HN
N - H2O
OH
OH
HO
OH
10 min 200 °C MW 80-9 5% ∆ < 5% Eq. (16)
Synthesis of aminotoluenesulfonamides
These compounds were prepared by reacting aromatic aldehydes with sulfonamides
under the action of microwaves in the presence of a few drops of DMF to enable bet-
ter energy transfer [69] (Eq. (17) and Tab. 3.7).
Ar
Ar δ− SO2NH 2
O O
H
H H 3C
δ+ - H2O
N SO2 NH2
N SO2NH 2 N
H Ar
H H
H CH3
CH3 Eq. (17)
Tab. 3.7 Reaction of 5-amino-2-toluenesulfonamide with aromatic aldehydes.
Ar Time (min) Yield (%)

MW (no DMF) MW (e DMF) D (e DMF)
p-NO2C6H4 1 40 98 5
o-ClC6H4 2 22 90 6
5-NO2-2-furyl 2 20 96 5
Leuckart reductive amination of carbonyl compounds

This reaction is well known but, unfortunately, using classical procedures is only
possible under very harsh conditions (temperature 240 8C, sealed containers, long re-
action times) and gives modest yields [70] (30 %). Its difficulty constitutes a good
challenge to check the effectiveness of microwave irradiation, because the mechan-
ism involves a dipolar transition state [71] (Eq. (18) and Tab. 3.8) and this should also
favor the involvement of a microwave effect.
R1 R1
O + HCONH2 + HCO2H C NHCHO
R2 R2
R1 R1 δ-
O O
R2
R2
products
δ+
N
N H CHO
H CHO H
Eq. (18)
H
Tab. 3.8 Microwave-mediated Leuckart reductive amination of carbonyl compounds in 30 min.
R1 R2 T (pC) Activation Yield (%)
Ph Ph 202 MW >98
202 D 2
p-CH3OPh p-CH3OPh 193 MW 95
193 D 3
Ph CH2Ph 210 MW 95
210 D 12
This study is a distinctive example of a pronounced microwave effect for a reaction

occurring with a very late dipolar transition state.
Synthesis of 1,4-dithiocarbonyl piperazines

A series of 1,4-dithiocarbonyl piperazines has been synthesized from aldehydes, pi-
perazine, and elemental sulfur under the action of microwave irradiation and sol-
vent-free conditions. An important nonthermal effect of the radiation was revealed
[72] (Eq. 19).
This is consistent with nucleophilic attack of neutral molecule (amine or sulfur)
on the carbonyl compound, leading to a dipolar TS.
S S
additive (3eq.)
RCHO + H N N H + S8 N N
R R
Eq. (19)
DMF 5min 100-102°C MW 85% ∆ 48%
EG 5min 105-107°C MW 80% ∆ 40%
Alcohols
Solvent-free esterification of fusel oil

Fusel oil basically comprises a mixture of alcohols such as isopentanol and isobuta-
nol. The synthesis of isopentyl stearate has been performed using both microwave ir-
radiation and conventional heating under solvent-free conditions (Eq. 20) [73].
CH3 CH3
HOTs (10%)
H 35C 17CO2H + HO-(CH2)2 CH C 17H35CO2-(CH2)2 CH
CH3 CH3
Eq. (20)
1min 20 90°C MW 98%
1min 20 120°C ∆ 13%
10min 120°C ∆ 57%
The very important specific microwave effect is consistent with the mechanism
which involves the formation of a dipolar TS from neutral molecules (Scheme 3.8).
H H
+
R O R Oδ
R' -
R' δ
O O
H O H O
Scheme 3.8
Synthesis of alkyl p-toluenesulfinates

The reactions of aliphatic alcohols with p-toluenesulfinic acid are accelerated by mi-
crowave irradiation under solvent-free conditions in the presence of silica gel, to af-
ford a high-yielding synthesis of p-toluenesulfinate esters [74] (Eq. 21).
H3C H3C H3C
δ−
S O S O - H2O S O
HO HO RO
+
O Oδ
R H R H Eq. (21)
R = (CH3)2CHCH2 70 °C MW 1.5 min 95% ∆ 30 min 1 0%
Synthesis of aminocoumarins by the Pechmann reaction

Efficient synthesis of 7-aminocoumarins has been performed via the Pechmann re-
action between m-aminophenols and b-ketonic esters. A comparative study of this
procedure showed that use of microwave irradiation reduced the reaction time from
several hours, if conventional heating was used, to a few minutes only (Eq. 22) [75].
CH3
+ 130°C
CH3COCH2CO2Et
N OH N O O
MW 12 min 62 %
∆ 390 min 62 %
Eq. (22)
Synthesis of cyclic acetals

Cyclic ketals (potential cosmetic ingredients) were obtained in excellent yields from
a cineole ketone under the action of microwaves in solvent-free conditions or in to-
luene. The results reported compared very favorably with those obtained by use of
conventional heating (Eq. (23) and Tab. 3.9) [76].
Eq. (23)
Tab. 3.9 Synthesis of ketal from cineole ketone and propylene glycol (R1 = CH3 R2= H).
Method Activation Time (min) Yield (%)
Alumina MW 30 78
D 300 27
Toluene MW 15 90
D 360 30
3.7.1.2 Michael Additions

Imidazole has been condensed via a 1,4 Michael addition with ethyl acrylate by use
of basic clays (Li+ and Cs+ montmorillonites) under solvent-free conditions with mi-
crowave irradiation [77] (Eq. 24).
N N
+ CO2Et
N N
H CH2 CH2CO2Et
Eq. (24)
montmorillonite Li+ 1 min 40 °C MW 40% ∆ 0%
5 min 75 °C MW 72% ∆ 2 7%
It was shown that microwave irradiation accelerated the 1,4 Michael addition of
primary and cyclic secondary amines to acrylic esters, leading to several b-amino
acid derivatives in good yields within short reaction times [78] (Eq. 25).
H
N δ+ OR
CO 2R + N H N
δ- O CO2R
R = Me, Bu Eq. (25)
1,2 asymmetric induction of up to 76 % diastereoisomeric excess was observed in

reactions of several amines with b-substituted acrylic acid esters from d-(+)-manni-
tol, in the absence of solvent, after exposure to microwaves for 12 min [79].
3.7.1.3 SN2 Reactions
Reaction of pyrazole with phenethyl bromide

In the absence of base the phenethylation of pyrazole under solvent-free conditions
is more rapid by far under the action of microwaves (8 min at 145 8C) when com-
pared with D, which requires 48 h [80] (Eq. 26).
δ+ δ-
N R Br N R Br N+
N N R
N Br -
H H H
R = C 6H5CH2 CH2
Eq. (26)
Ring opening of an epoxide by amines

Microwave-assisted ring opening of (R)-styrene oxide by pyrazole and imidazole
leads to the corresponding (R)-1-phenyl-2-azolylethanols. With pyrazole, use of mi-
crowave irradiation increases both chemo- and regioselectivity compared with the
conventional heating [81] (Eq. 27).
H
N
OH
N
N N δ+
Ph MW 3 min Ph N
Ph
O H via
N Oδ −
N OH
N dipolar TS
MW 6 min Ph
N
Eq. (27)
N-alkylation of 2-halopyridines
A microwave- (focused waves) assisted procedure for N-alkylation of 2-halopyridines
has been described; the noticeable microwave effect was indicative of a polar TS [82]
(Eq. 28).
δ+
N Cl N Cl
+N Cl
R Cl -
R CH2
CH2 CH2
R
δ−
Cl Cl Eq. (28)
R = CO2Et 165 - 170 °C MW 40 min 80%

∆ 23 h 46%
R = CN 165 - 17 0 °C MW 40 min 56%

∆ 50 h 10%
Nucleophilic aromatic substitutions

An expeditious microwave assisted SNAr reaction with cyclic amines has been re-
ported for activated aromatic substrates [83] (Eq. 29).
X
X
+
δ
X NH Cl
N + HCl
R Cl + δ
−
N
H
R
R
Eq. (29)
R = CHO, NO2 X = CH2 , O
The reactions were performed in a heterogeneous medium using K2CO3 in etha-

nol (MW or D) or basic alumina in dry media to trap the hydrochloric acid formed.
Because of the formation of a dipole in the TS, the microwave effect depicted in
Tab. 3.10 was observed.
Tab. 3.10 SNAr reaction between p-chlorotoluene and piperidine (X = CH2, R = CH3).
Activation mode Conditions Yields (%)
K2CO3±EtOH D 16 h Reflux 60
MW 6 min Reflux 70
Basic alumina MW 75 s ±a 92
a
Undetermined, but certainly a very high temperature because the vessel was placed inside an alumina
bath (prone to microwave absorption).
Synthesis of phosphonium salts

Using a domestic oven it was shown that reaction of triphenylphosphine with an or-
ganic halide is very rapid under the action of microwave irradiation. Reaction times
were reduced to a few minutes only, compared with 30 min to 14 days when conven-
tional heating is used [84].
Nucleophilic substitutions of benzyl chloride or benzyltrimethylammonium chlor-
ide as electrophiles with Ph3P or Bu3P as nucleophiles have been performed with ac-
curate control of the power and temperature by use of a monomode reactor. The re-
sults were carefully compared under similar conditions with microwave or D activa-
tion [85] (Eq. (30) and Tab. 3.11).
+
Ph −
δ δ + -
PPh3 + PhCH2 Cl Ph 3P C Cl Ph 3PCH2Ph, Cl
H H
dipolar TS Eq. (30)

Tab. 3.11 Solvent-free benzylation of triphenylphosphine in 10 min.
Temp (pC) Yield (%)

MW D
100 78 24
150 94 91
Although the microwave effect is not appreciable at 150 8C, it becomes clearly ap-
parent when the temperature is decreased to 100 8C. When delineating microwave
effects, careful attention needs to be paid to the temperature level. If this is too high,
the microwave effect will be masked and the temperature has to be minimized in or-
der to start from a low yield under the action of D and therefore have the possibility
of observing microwave enhancements.
This conclusion is in agreement with the kinetic results from Radoiu et al. [86] ob-
tained for the transformation of 2- and 4-tbutyl phenols in the liquid phase in the
presence of montmorillonite KSF as catalyst either under the action of MW or D
(Eq. (31) and Tab. 3.12).
OH OH OH OH
KSF
+ + +
MW or ∆
Eq. (31)
Tab. 3.12 Rate constants (r8) for the transformation of 2-tbutyl phenols under the action of MW or
D according to temperature.
Temp (pC) r pMW (103 s±1) r pD (103 s±1) r pMW/D
22 1.5 0.07 21.6

75 3.2 1.2 2.7
105 10.3 7.1 1.5
198 21.0 20.0 1.1
3.7.2
Bimolecular Reactions with One Charged Reactant
The TS for anionic SN2 reactions involves loose ion pairs as in a charge delocalized
(soft) anion. On the another hand, the GS could involve a neutral electrophile and
either tight or loose ion pairs depending on the anion structure (hard or soft) (Eq. 32).
δ- δ-
Nu-, M+ + R X Nu R X, M+ Nu R + M+, X-
Eq. (32)
3.7.2.1 Anionic SN2 Reactions Involving Charge-localized Anions

In this case, the anion being hard and with a high charge density, the reactions are
concerned with tight ion pairs. During the course of the reaction, ionic dissociation
is increased and hence polarity is enhanced from the GS towards the TS. Specific
microwave effects should be expected.
Selective dealkylation of aromatic alkoxylated compounds

Selective de-ethylation of 2-ethoxyanisole is observed using KOtBu as the reagent in
the presence of 18-crown-6 as the phase transfer agent (PTA). With the addition of
ethylene glycol (E.G.), the selectivity is reversed and demethylation occurs (Eq. (33)
and Tab. 3.13). If the involvement of microwaves is favorable in both examples, the
second reaction should be more strongly accelerated than the first [87].
Eq. (33)
Tab. 3.13 Reaction of KOtBu with 2-ethoxyanisole in the presence of 18-crown-6 and, optionally,
ethylene glycol.
Additive Time Activation Temp (pC) 1 (%) 2 (%) 3 (%)
± 20 min MW 120 7 0 90
± 20 min D 120 48 0 50
E.G. 1h MW 180 0 72 23
E.G. 1h D 180 98 0 0
Demethylation results from the SN2 reaction whereas de-ethylation occurred via
the E2 mechanism (Scheme 3.9).
Scheme 3.9 Mechanisms for demethylation and de-ethylation of ethoxyanisole.

The microwave-specific effect is more apparent in the case of demethylation

(SN2). The microwave acceleration clearly is more pronounced with the difficulty of
the reaction, thus constituting a clear example of an increased microwave effect with
a more difficult reaction, indicative of a later TS position along the reaction coordi-
nate. The microwave effect may also be connected to the more localized charge in
the SN2 transition state (three centers) when compared to that of b-E2 (charge devel-
oped over five centers).
Alkylation of dianhydrohexitols under phase-transfer catalysis (PTC) conditions

Dianhydrohexitols, important by-products of biomass (Scheme 3.10), were dialky-
lated under PTC conditions in the presence of a small amount of xylene.
Scheme 3.10 Structure of 1,4 : 3,6-dianhydrohexitols.

(A = isosorbide, B = isomannide, C = isoidide).
Dialkylations were attempted as model reactions before subsequent polymeriza-

tions and revealed very important specific microwave effects [88] (Eq. (34) and
Tab. 3.14).
Eq. (34)
Tab. 3.14 Yield (%) from dialkylation of dianhydrohexitols under PTC conditions.
RX t (min), T (pC) A B C
MW D MW D MW D
PhCH2Cl 5, 125 98 13 98 15 97 20
nC8H17Br 5, 140 96 10 74 10 95 10
These observations are consistent with the reactive species being constituted from
tight ion pairs between cations and the alkoxide anions resulting from abstraction of
hydrogen atoms in A, B and C (Scheme 3.11).
Scheme 3.11
The reaction of monobenzylated isosorbide D with ditosylates (Eq. 35) is more

subtle; the microwave-specific effect (Tab. 3.15) appeared when the temperature was
lowered to 80 8C (modulated by the presence of cyclohexane) whereas it was masked
by a higher temperature of 110 8C (maintained by the use of toluene) [89].
Eq. (35)
Tab. 3.15 Yield (% E) from reaction of monobenzylated isosorbide (D) with ditosylates for 15 min.
R T 110 pC (xylene) T 80 pC (cyclohexane)

MW D MW D
(CH2)8 95 91 96 39
(CH2)6 91 90 96 45
CH2CH2OCH2CH2 92 92 91 36
The Krapcho reaction

Dealkoxycarbonylation of activated esters occurs classically under drastic thermal
conditions [90]. It constitutes a typical example of a very slow-reacting system (with a
late TS along the reaction coordinates) and is therefore prone to a microwave effect.
The rate determining step involves a nucleophilic attack by halide anion and re-
quires anionic activation, which can be provided by solvent-free PTC conditions un-
der the action of microwave irradiation [91]. The above results illustrate the difficult
example of cyclic b-ketoesters with a quaternary carbon atom in the a position rela-
tive to each carbonyl group (Eq. 36).
Eq. (36)
Some typical results are summarized in Tab. 3.16.
Tab. 3.16 The Krapcho reaction under solvent-free PTC conditions.
R Reaction conditions Yields (%)

t (min) Temp (pC) MW D
H 8 138 96 <2
Et 15 160 94 <2
n-Bu 20 167 89 <2
n-Hex 20 186 87 <2
n-Hex 60 186 ± 22
n-Hex 180 186 ± 60
A definite microwave effect is involved when strict comparisons of MW and D acti-

vation are considered and is compatible with the mechanistic assumption that a very
polar TS is developed (Scheme 3.12).
O O H
-
δ δ-
+
O C Br, M
R
H CH3
Scheme 3.12 Transition state for the Krapcho
reaction.
Anionic b-elimination
Ketene acetal synthesis by b-elimination of haloacids from halogenated acetals under
well controlled conditions using thermal activation (D), ultrasound (US) or micro-
wave irradiation [92] (MW) has been described. From a mechanistic point of view, as
the TS is more charge delocalized than the GS and the polarity is enhanced during
the course of the reaction, a favorable microwave effect can therefore be observed
(Eqs. (37) and (38) and Scheme 3.13).
Ph Ph
O KO tBu (2 eq) O
Eq. (37)
O Br NBu4Br (5%) O
5 min 75 °C ∆: 36% US: 55% MW: 87%
nBu S t
KO Bu (2 eq) nBu S
Eq. (38)
nBu S NBu4Br (5%) nBu S
25 min 90 °C ∆: 15% US: 45% MW: 79%

-
δ
Br Br
-
δ
H H +
M
-
- + δ
tBuO M tBuO
tight ion pairs (GS) loose ion pairs (TS)
Scheme 3.13 Evolution of polarity in b-elimination.
3.7.2.2 Anionic SN2 Reactions Involving Charge-delocalized Anions

Weak or nonexistent microwave effects are expected for these reactions as the GS
and TS exhibit rather similar polarities since they both involve loose ion pairs.
Alkylation of potassium benzoate

Alkylation of several substituted benzoic acid salts with n-octyl bromide was per-
formed under solvent-free PTC with excellent yields (95 %) within a very short reac-
tion time [93] (2±7 min). Oil bath heating (D) led to yields equivalent to those pro-
duced under the action of microwave irradiation, which thus revealed only thermal
effects in the range of temperature used (145±202 8C) (Eq. 39).
K 2CO3
Z CO2H + nC 8H17Br Z CO2nC8H17
NBu4Br
Eq. (39)
Z=H 2.5 min 145 °C ∆ = MW 99 %
Z = OCH3 2 min 145 °C 98 %
Z = CN 2 min 202 °C 95 %
Conversely, when n-octyl bromide was used with the less reactive terephthalate
species, which constitutes a ªslow-reacting systemº, the yield was raised from 20 to
84 % under the action of microwaves compared with D, which can be attributed to a
later TS along the reaction coordinates (Eq. 40).
K2CO 3
HO2C CO 2H + RBr RO2C CO2R
NBu4Br
Eq. (40)
R = nC8H17 6 min 175 °C MW 84% ∆ 20%
Pyrazole alkylation in basic media [80]

A very important microwave-specific effect was evidenced in the absence of a base
for the reaction of pyrazole with phenethyl bromide (reaction times: MW = 8 min,
D = 48 h, Eq. 41). When the same reaction was performed in the presence of KOH,
the microwave effect disappeared (vide supra, Eq. 26).
PhCH2CH2Br N
N
N + KOH - N N
- H2O N
H CH2CH2Ph
K+
Eq. (41)
loose ion pair
8 min 145 °C MW 64 % ∆ 61 %
This effect could be predicted when considering the weak evolution of polarity be-
tween the GS and TS as the reactive species consist of loose ion pairs (involving a
soft anion).
Selective alkylation of b-naphthol in basic media

Alkylations in dry media of the ambident 2-naphthoxide anion were performed un-
der the action of focused microwave activation. Whereas the yields were identical to
those obtained under the action of D for benzylation, they were significantly im-
proved under microwave irradiation conditions for the more difficult n-octylation
(a less reactive electrophilic reagent). No change in selectivity was observed, however,
indicating the lack of influence of ionic polarization [94].
The absence or weakness of the microwave effect was assumed to be related to
loose ion pairs involving the soft naphthoxide anion in the GS and a small change in
polarity in an early TS. When the TS occurred later along the reaction coordinates
(e. g. for n-octylation requiring a higher temperature), more polarity is developed
and, consequently, the microwave effect could appear (Eq. (42) and Tab. 3.17 limited
here to the lithiated base).
Eq. (42)
Tab. 3.17 C-alkylation of b-naphthol in the presence of lithiated base under solvent-free conditions.
RX Li+ B± t (min) Temp (pC) Yield (%)

MW D
Mono C Di C Mono C Di C
PhCH2Br LiOH 4 190 98 2 97 2

LiOtBu 4 137 9 91 8 88
nC8H17Br LiOH 9 240 92 1 62 ±
LiOtBu 10 200 27 56 7 20
3.7.2.3 Nucleophilic Additions to Carbonyl Compounds
Saponification of hindered aromatic esters

This is a typical representative example of an enhanced microwave-specific effect re-
lated to the difficulty of the reaction, which presumably proceeds via a later and later
TS. Whereas essentially thermal effects are observed (around 200 8C) with methyl and
octyl benzoate, a microwave-specific effect is increasingly apparent with hindered es-
ters and becomes optimal with mesitoyl octanoate (Eq. (43) and Tab. 3.18) [95].
200 °C, 5 min

RCO2R' RCO2H
Eq. (43)
1) NaOH (2 eq), Aliquat 336 (10%)
2) HCl (2N)
Tab. 3.18 Solvent-free PTC saponification of aromatic esters.
R R Yield (%)
MW D
Ph Me 92 73
Ph n-Oct 98 86
Me 90 48
n-Oct 97 39
PTC transesterification in basic medium

The microwave-assisted PTC transesterification of several carbohydrates in basic
medium with methyl benzoate or laurate has been studied [96]. Small amounts of
DMF were necessary to provide good yields within 15 min at 160 8C. Rate enhance-
ments were compared to conventional heating (D) under the same conditions and
specific microwave activation was mostly seen when the less reactive fatty com-
pounds were involved (Eq. (44) and Tab. 3.19)
O O
O K2CO3 , NBu4 Br (5%) O

O O + CH3OH
OH ε DMF, RCO2CH3 OCOR
15 min, 160 °C
O O
O O
Eq. (44)
Tab. 3.19 Transesterification in 15 min at 160 8C in basic medium with methyl benzoate and
laurate (monomode reactor, relative amounts 1 : 2 : 2).
R Yield (%)
MW D
Ph 96 21
CH3(CH2)10 88 0
The reactive species under these conditions consist of tight ion pairs involving the
alkoxide anion from the carbohydrate (charge localized anion). The less reactive long
chain methyl laurate leads to a later TS along the reaction coordinates and the mag-
nitude of the microwave effect is therefore increased.
Ester aminolysis in basic medium

Ester aminolysis, in general, occurs under harsh conditions that require high tem-
peratures and extended reaction periods or the use of strong alkali metal catalysts.
An efficient solid state synthesis of amides from nonenolizable esters and amines
using KOtBu under the action of microwave irradiation [97] has been described. The
reaction of esters with octylamine was extensively studied to identify possible micro-
wave effects [98] (Eq. (45) and Tab. 3.20).
Eq. (45)
Tab. 3.20 Ester aminolysis with n-octylamine at 150 8C for 10 min.
R Base Yield (%)

MW D
Ph ± 0 0
KOtBu 80 22
KOtBu 87 70
336 87 70
PhCH2 ± 63 6
KOtBu + Aliquat 336 63 36
The microwave-specific effect is increased when the reaction is performed in the

absence of a phase transfer catalyst, showing that the nature of the reactive species is
of great importance in connection with ionic dissociation (Eq. 46).
Eq. (46)
As expected, the tighter ion pair (RNH±, K+) exhibits the larger microwave effect.
As an extension of this work, and in order to gain further insight, the effect of amine
substituents was studied [99] in the reaction with ethyl benzoate (Eq. (47) and
Tab. 3.21).
Eq. (47)
Tab. 3.21 Ethyl benzoate aminolysis with different amines at 150 8C for 10 min (relative amounts
PhCO2Et : RNH2 : KOtBu = 1.5 : 1 : 2).
R Yield (%)
Without NR4Cl With NR4Cl
MW D MW D
Ph 88 73 90 83
PhCH2 84 42 98 85
n-Oct 80 22 87 70
The microwave effects are clearly substituent dependent and, as in the former ex-
ample, disappear by adding a phase transfer agent. When the substituent R is able to
delocalize the negative charge on the amide anion (R = Ph), the ion pairs RNH±, M+
exist in a looser association. Consequently, a decrease in microwave effect is expected
as the evolution from the GS v TS occurs with only a slight modification of polarity
in the ion pairs. Conversely, the microwave effect is optimal with the tighter ion pair
(nOctN±, K+).
In a parallel study [100], it was shown that formamide, primary and secondary
amines react with esters in the presence of potassium tert-butoxide under the action
of microwave irradiation. Substituted amides are formed in yields (generally more
than 70 %) much higher than under the action of conventional heating (Eq. (48) and
Tab. 3.22).
Eq. (48)
Tab. 3.22 Ester aminolysis with different amines under the action of microwave irradiation during
3 min and with conventional heating.
Ester Amine T (pC) Yield (%)

MW D
CH3CO2Et BuNH2 95 70 25 (2 day)

Et2NH 129 74 30 (1 day)
C6H3CH2CO2Me BuNH2 105 97 36 (1 day)
Et2NH 204 70 25 (6 h)
3.7.2.4 Reactions Involving Positively Charged Reactants

Relatively few comparative MW/D studies are presently available in this area.
Friedel±Crafts acylation of aromatic ethers

Solvent-free benzoylation of aromatic ethers has been performed under the action of
microwave irradiation in the presence of a metallic catalyst, FeCl3 being one of the
most efficient [101]. With careful control of the temperature and other parameters,
nonthermal microwave effects have not been observed either in terms of yields or
isomeric ratios of the obtained products (Eq. 49).
FeCl 3 (5%)
MeO + PhCOCl COPh + HCl
MW or ∆ MeO
Eq. (49)
1 min 165 °C yield = 95% para/ortho = 94/6
The reactive species is the acylium ion resulting from abstraction of a chloride an-
ion from benzoyl chloride (Eq. 50). This reagent comprises an ion pair formed be-
tween two large (soft) ions which are therefore associated as loose ion pairs. Accord-
ing to these assumptions, the absence of a microwave effect should be expected as
the polarity evolution is very weak between the GS and TS (two loose ion pairs of si-
milar polarities).
Eq. (50)
This conclusion is also in agreement with the results obtained for the sulfonyla-
tion of mesitylene in the presence of metallic catalysts such as FeCl3 [102] (5 %)
(Eq. 51)
SO2Ph
FeCl 3 (5%)
+ PhSO2Cl + HCl
Eq. (51)
30 min 110 °C MW = 80% ∆ = 78%
A nonthermal microwave effect was not observed when identical temperature gra-
dients were produced by classical heating and microwave irradiation and if the reac-
tion temperature was strictly controlled.
Formylation using Vilsmeier reagent [103]

Substituted acetophenones were irradiated in a domestic microwave oven with
POCl3±DMF/SiO2 to give b-chlorovinylaldehydes in 2 min with yields of 75±88 %.
Under the same conditions, conventional heating lead to only 30±40 % (Eq. 52).
CHO
POCl3-DMF
Cl COCH3 Cl
SiO2
Et
Eq. (52)
2min 75-78°C MW = 79% ∆ = 35%
The specific microwave effect can be attributed to two different facts:
. improvement in the formation of chloroiminium species (so-called Vilsmeier re-

agent)
Cl
Cl
Cl P O δ-
Cl P O
Cl
Cl
O
O
+
N δ
N
. enhancement of subsequent electrophilic aromatic substitution.
SN2 reactions with tetralkylammonium salts

The SN2 reaction of triphenylphosphine with triethylbenzylammonium chloride (the
tertiary amine is thus the leaving group) was studied under solvent-free microwave con-
ditions. The reaction occurred only under the action of MW [83] irradiation (Eq. 53).
Ph
+ δ+ δ+
Ph3P + PhCH 2 NEt3, Cl- Ph3P C NEt3 , Cl-
H H Eq. (53)
tight ion pair very loose ion pairs

150 °C 10 min MW = 70% ∆ = 0%
This effect is readily attributable to the very loose structure of the ion pairs in the
TS (additionally involving delocalization in the phenyl groups of the phosphine) and
which are therefore far more polar than the initial ion pairs in the GS.
3.7.3
Unimolecular Reactions
3.7.3.1 Imidization Reaction of a Polyamic Acid [22]

The polyamic acid (Fig. 3.7) precursor was prepared by adding stoichiometric
amounts of 3,3,4,4-benzophenonetetracarboxylic acid dianhydride (BTDA) and diami-
nodiphenylsulfone (DDS). The solution in NMP was then submitted to either thermal
or MW activation with accurate monitoring of the temperature (Scheme 3.14).
Fig. 3.7 Polyamic acid structure.
Scheme 3.14
Analysis of the kinetic parameters showed that the apparent activation energy for
the reaction was reduced from 105 to 57 kJ mol±1 (Tab. 3.2). This observation is con-
sistent with the polar mechanism of this reaction implying the development of a di-
pole in the transition state (Fig. 3.8) even when the reaction was performed in a polar
solvent.
O
O
N δ+
H NH
HO C HO
O δ−
O
Fig. 3.8 Mechanism for the imidization reaction.
3.7.3.2 Cyclization of Monotrifluoroacetylated o-Arylenediamines

Cyclocondensation of N-(trifluoroacetamido)-o-arylenediamines leads to a series of
2-trifluoromethylarylimidazoles with good yields on montmorillonite K10 in dry
media under the action of microwave irradiation within 2 min. Using conventional
heating under the same conditions, no reaction was observed [104] (Eq. (54) and
Tab. 3.23).
H
R1 NHCOCF 3 K10 clay (R2)R1 N
CF 3 Eq. (54)
R2 NH 2 (R1)R2 N
Tab. 3.23 Cyclization of monotrifluoroacetylated o-arylenediamines.
R1 R2 Temp (pC) Yield (%)

MW (2 min) D (20 h)
H H 125 87 23
H CH3 127 84 19
NO2 H 134 95 28
This observation is consistent with the assumptions of the authors predicting mi-
crowave effects when the polarity is enhanced in a dipolar TS. The kinetic rate-deter-
mining step consists of an intramolecular attack of the nitrogen lone pair on the car-
bon atom of the carbonyl moiety (Scheme 3.15).
H H
-
δ
N O N O
CF 3 N δ
+ CF 3
N H H
H H
GS TS
Scheme 3.15 Mechanism of cyclocondensation.
3.7.3.3 Intramolecular Nucleophilic Aromatic Substitution

Pyrazolo-[3,4b]-quinolines and -pyrazoles have been synthesized by reacting b-
chlorovinylaldehydes and hydrazine or phenyl hydrazine using a catalytic amount of
p-toluenesulfonic acid (PTSA) under the action of microwave irradiation. The yields
are much better than under the action of D using the same conditions [105] (Eq. 55).
CHO
RNHNH2
N Eq. (55)
cat PTSA N
N Cl N
R
R= H 1.5 min 127-130 °C MW = 97% ∆ = 30%
The noticeable rate enhancement due to a microwave-specific effect is consistent

with a reaction mechanism in which the kinetic rate-determining step is nucleophi-
lic attack of an amino group on the chloroquinoline ring (Scheme 3.16).
CHO
RNHNH 2 NHR
N N
rapid slow N
N Cl N Cl N
(SN Ar)
R
N N +
δ
NHR δ
-
NHR
N Cl N Cl
GS dipolar TS
R = H, Ph
Scheme 3.16 Mechanism of internal SNAr.
3.7.3.4 Intramolecular Michael Additions

ortho-Aminochalcones were cyclized to tetrahydroquinolones in dry media using
K10 clay as the support under the action of microwave irradiation. The role of micro-
waves in accelerating the process was evidenced as a relatively extended reaction
time was required under the action of conventional heating to obtain similar yields
[106] (Eq. (56) and Scheme 3.17).
Eq. (56)
+
N Ar Nδ Ar
δ-
Scheme 3.17 Mechanism of
O intramolecular Michael addition
O
of an amino group.
A similar study has been reported with ortho-hydroxychalcones in dry media on si-
lica gel [107]. Conventional thermal cyclization, under the same conditions as for mi-
crowave irradiation, required a much longer reaction period (Eq. (57), Tab. 3.24, and
Scheme 3.18).
Eq. (57)
Tab. 3.24 Intramolecular Michael addition of o-hydroxychalcones during 20 min at 140 8C.
R1 R2 Mode Yield (%)
H H MW 82
D 44
CH3O H MW 61
D 22
H
δ+
R1 OH Ph R1 O Ph
-
δ
R2 R2
O O
GS dipolar TS
Scheme 3.18 Mechanism of intramolecular Michael addition

of an hydroxy group.
3.7.3.5 Deprotection of Allyl Esters

Carboxylic acids are regenerated from their corresponding substituted allyl esters on
montmorillonite K10 using microwave irradiation under solvent-free conditions to
afford enhanced yields and reduced reaction times when compared to thermal condi-
tions [108] (Eq. 58).
O R1 K10 O
Eq. (58)
Ph O R2 Ph OH
R1 = H R 2 = Ph 110 °C MW : 20 min 96% ∆:6 h 96%
R1 = R2 = H 110 °C MW : 20 min 98% ∆:5 h 94%
This effect can also get again be rationalized via a mechanism with the interven-
tion of a dipolar TS (Scheme 3.19).
O O
δ- δ+
Ph O Ph O
GS dipolar TS
Scheme 3.19 Mechanism of deprotection of allyl esters.
3.8
Illustrative Examples of the Effects of Selectivity
Very few results on selectivity effects are available due to a lack of strict comparisons
between microwave and D activation and in which kinetic details of reactions have
been described. Reports of the effect of microwaves on selectivity up to 1997 have
been reviewed by Langa et al. [57].
3.8.1
Benzylation of 2-Pyridone
Regiospecific N- or C-benzylations of 2-pyridone were observed under solvent-free

conditions in the absence of base. The regioselectivity was controlled by the activa-
tion method (MW or D) or, when using microwaves, by the emitted power level or
the leaving group of the benzyl halides [58] (Eq. 59).
R R R R
RX
+ + +
N O N O N O N O N O
H R H H H
N-alkyl
Eq. (59)
C-alkyl
PhCH2Br 5 min 196 °C MW : > 98% C-alkyl ∆ : > 98% N-alkyl
PhCH 2I 5 min 180 °C MW : > 98% C-alkyl ∆ : traces
To justify these results, it may be assumed that the TS leading to C-alkylation will
be more polar than that responsible for N-alkylation. This assumption, however, pre-
sumes the existence of kinetic control (which is not ensured in this case).
3.8.2
Addition of Vinylpyrazoles to Imine Systems
Upon microwave irradiation, vinylpyrazoles react with N-trichloroethylidene carba-

mate to undergo addition to the imine system through the conjugated vinyl group
[109] (Eq. 60).
Eq. (60)
The use of microwave irradiation as an energy source is crucial to conduct the re-
action and to avoid the decomposition or dimerization of the starting pyrazole,
which are observed in the absence of microwave irradiation.
A similar conclusion has been drawn during an examination of the Diels±Alder re-
action of 6-demethoxy-b-dihydrothebaine with methylvinylketone using microwave
irradiation [110]. When performed under conventional heating conditions, extensive
polymerization of the dienophile was observed whereas reaction is much more clea-
ner under microwave activation (Eq. 61).
Eq. (61)
3.8.3
Stereo Control of b-Lactam Formation [111, 112]
Formation of b-lactams by the reaction of an acid chloride, a Schiff base and a ter-
tiary amine (Eq. 62) appears to involve multiple pathways, some of which are very
fast at higher temperatures. When conducted in open vessels in unmodified micro-
wave ovens, high level irradiation leads to preferential formation of the trans b-lac-
tams (55 %) whereas, at low power, the cis isomer was obtained as the only product
(84 %). The failure of the cis isomer to isomerize to the trans compounds is an exam-
ple of induced selectivity.
Eq. (62)
This effect has recently been explained by considering that under the action of mi-
crowave irradiation the route involving direct reaction between the acyl chloride and
the imine competes efficiently with the ketone±imine reaction pathway, a situation
highlighted by theoretical calculations [113]. In the other words and according to our
assumptions, it can be stated that the transition state leading to the trans isomer
therefore seems to be more polar than that leading to the cis compound.
3.8.4
Cycloaddition to C70 Fullerene
The regioselectivity of the cycloaddition of N-methylazomethine ylide to C70 was

claimed to be slightly affected using microwave irradiation as the source. By choos-
ing an appropriate solvent (o-dichlorobenzene, ODCB) and the emitted microwave
power, the ratio 1 a:1 b is modified from 50 : 50 to 45 : 55 [26, 59] (Eq. (63) and
Tab. 3.25).
CH 3NHCH 2CO 2H/HCHO

C70 C 70 N CH3
MW or ∆
CH3 CH3
CH3 N N
N
1a (1-2 isomer) 1b (5-6) 1c (7-21)

Eq. (63)
Tab. 3.25 Yields of monoadducts and isomer distribution for cycloaddition (Eq. 63) in ODCB at
180 8C.
Mode Time (min) Yields (%) % 1a % 1b % 1c
MW 120 W 30 39 50 50 ±
180 W 30 37 45 55 ±
300 W 15 37 47 53 ±
D 120 32 46 46 8
Theoretical calculations predict an asynchronous mechanism and suggest that the

modification of the regiochemical outcome is related to the energies and hardness of
the TS involved. Perhaps, in other words, the more polar TS are favored under the
action of MW.
3.8.5
Selective Alkylation of 1,2,4-Triazole
Using MW irradiation under solvent-free conditions, it was possible to obtain regio-

specific benzylation in position 1 of 1,2,4-triazole whereas only the 1,4-dialkylated
product was obtained in poor yields under the action of conventional heating [114]
(Eq. 64).
PhH 2C Br-
N N N
+
N + PhCH2Br N + N Eq. (64)

N N N
H CH 2Ph CH2Ph
molar ratio 1:1 N1 N1, 4
5 min 165 °C MW: yield 70% 100% N1

∆: yield 14% 100% N1, 4
This observation may be explained by the increased efficiency of the first benzyla-
tion (SN2 reaction between two neutral reagents proceeding via a dipolar TS) under
microwave conditions.
As an extension towards azolic fungicides, phenacylation was next examined. Un-
der the action of microwave irradiation, exclusive reaction in position 1 (or equiva-
lent 2) occurred whereas mixtures of N1, N4 and N1, 4 products were obtained by D
under the same conditions [115] (Eq. (65) and Tab. 3.26).
Eq. (65)
Tab. 3.26 Phenacylations of 1,2,4-triazole.
Ar X Time (min) Temp. (pC) Mode Global yield (%) N1 N4 N1,4
Cl 25 140 MW 90 100 ± ±
D 98 33 29 38
Cl 20 140 MW 95 100 ± ±
D 98 38 27 37
Br 24 170 MW 90 100 ± ±
D 98 38 28 34
As kinetic control was ensured, this clear microwave effect could possibly be due to
a difference in polarity of the transition states, with apparently a more polar TS being
formed when p attack by the nitrogen atom in position 2 is concerned. Theoretical cal-
culations are in progress at the present time to try to confirm this assumption.
3.8.6
Rearrangement of Ammonium Ylides
Ammonium ylides can isomerize to (1,2) rearrangement products (Stevens rearran-

gement) or to (2,3) shift products (Sommelet±Hauser sigmatropic rearrangement)
when allyl or benzyl are located on the nitrogen atom. A strong microwave effect is
noticed (Eq. 66) [116].
CN
+ 2 min
Ph N CN Ph +
N N
CN
A (1,2) B (2,3)
Eq. (66)
MW yield 69% A : B = 70 : 30
∆ yield 56% A : B = 10 : 90
Under similar profiles of raising in temperature, it was shown that the selectivity
favoring 1,2 Stevens rearrangement is exemplified under the action of microwaves.
A tentative explanation can be to consider that, under the action of radiation, the
more polar mechanism (1,2 ionic shift) is favored when compared to less polar one
(2,3 radical shift). Maybe this result is indicative of a competition between ionic and
radical pathways.
3.9
Concerning the Absence of Microwave Effects
The absence of a microwave effect can result from at least three different origins:
(a) a similar polarity of the transition state when compared to the ground state. This
is the situation for synchronous mechanisms in some pericyclic reactions when
performed in nonpolar solvents [5, 6] or in neat liquids (Eqs. 67 and 68).
CO2Et
CO2Et
CO 2Et
toluene Eq. (67)
+
MW or ∆
CO 2Et
3.10 Conclusions 109
neat li quid Eq. (68)

O OH
H
(b) a very early transition state along the reaction coordinates (cf. Hammond postu-
late) which cannot allow the development of polarity between the GS and TS (re-
actant-like). This will occur when the reactions are rather easy and do not require
classically harsh conditions. This would be true for phthalimide syntheses by re-
acting phthalic anhydride and amino compounds [117], and chalcone syntheses
by reacting aromatic aldehydes and acetophenones [118], etc. ¼ Slight differ-
ences can appear when performing the reaction in the presence of a solvent due
to a superheating effect if no stirring is used.
(c) a too high temperature level, which may produce good yields in short reaction
times under the action of conventional heating. In order to find evidence of mi-
crowave effects, it is necessary to reduce the temperature under conventional
conditions in order to start from a rather poor yield (< 30±40 %) to appreciate pos-
sible microwave activation. These cases have been revealed in some studies
where a microwave effect appeared at relatively low temperatures but are masked
at higher temperatures where yields of conventionally heated reactions are ele-
vated [85, 86, 89].
3.10
Conclusions
We have proposed in this review a rationalization of microwave effects in organic

synthesis based on medium effects and mechanistic considerations. If the polarity of
a system is enhanced from the ground state to the transition state, it can result in an
acceleration due to an increase in material±wave interactions during the course of
the reaction. The most frequently encountered cases concern unimolecular or bimo-
lecular reactions between neutral molecules (as dipoles are developed in the TS) and
anionic reactions of tight ion pairs i. e. involving charge localized anions (leading to
ionic dissociation in TS). They could be more important in the cases of a product-
like TS in agreement with the Hammond postulate. By far the most useful situation
is related to solvent-free conditions (green chemistry procedures) as microwave ef-
fects are not masked or limited by solvent effects, although of course, nonpolar sol-
vents can always be used. Many types of carefully controlled experiments need to be
performed, however, to evaluate the reality and limitations of this approach in order
to make valid comparisons.
Finally, the magnitude of a specific microwave effect could be indicative of a polar
mechanism or to access the rate-determining step in a procedure involving several
steps. For instance, during the study of microwave effect in the solvent-free synthesis
of ketones from aldehydes and terminal alkenes by Wilkinson complex [Rh (I) com-
plex], a serious improvement was evidenced under the action of microwave when
compared to classical heating (Eq. (69) and Tab. 3.27).
Eq. (69)
Tab. 3.27 Solvent-free hydroacylation of 1-alkenes with aldehyde.
R R Time (min) Yield (%)

MW D
C6H5 n-C8H17 30 95 30
C6H5 CH2C6H5 10 84 30
n-C6H13 n-C8H17 10 61 30
This microwave effect is consistent with the fact that the rate-determining step
may be certainly the generation of aldimine A from aldehydes and 2-amino 3-pico-
line. It is in agreement with the transition state develops a dipole and, consequently
more polar than the ground state. To ascertain this hypothesis, it was effectively next
shown that the reaction involving reaction with preformed aldimine A, no revealed
any microwave effect [119].
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D. Barbry, 5th Int. Electronic Conf. Syn- 2001, 42, 4803±4805; A. Loupy,
thetic Organic Chemistry (ECSOC-5), S. Chatti, S. Delamare, D.Y. Lee,
2001, poster E001. J.H. Chung, C.H. Jun, J. Chem. Soc.
Perkin Trans. I, 2002, 1280±1285.
115
4
Organic Synthesis using Microwaves in Homogeneous Media
Richard N. Gedye
4.1
Introduction
Although the ability of microwaves (MW) to heat water and other polar materials has
been known for half a century or more, it was not until 1986 that two groups of re-
searchers independently reported the application of MW heating to organic synth-
esis. Gedye et al. [1] found that several organic reactions in polar solvents could be
performed rapidly and conveniently in closed Teflon vessels in a domestic MW oven.
These reactions included the hydrolysis of amides and esters to carboxylic acids, es-
terification of carboxylic acids with alcohols, oxidation of alkyl benzenes to aromatic
carboxylic acids and the conversion of alkyl halides to ethers.
Most of these reactions occurred much faster using MW irradiation (at increased
pressure and temperature) than under conventional heating (ambient pressure, re-
flux), with rate enhancements ranging from 5 to 1200 times.
Shortly after these results were published, Giguere and coworkers reported dra-
matic reductions in reaction times in other MW-assisted syntheses, including Diels±
Alder, Claisen rearrangements and ene reactions [2]. These reactions were also per-
formed at elevated pressures, but sealed glass vessels (inside a bath packed with ver-
miculite) were used rather than Teflon.
It is to be noted that the reactions mentioned so far were performed under homo-
geneous conditions and, in most cases, using polar solvents, which are efficient ab-
sorbers of MW energy. Rate enhancements were attributed to the superheating of
the solvent due to the elevated pressures generated in the closed vessels.
During the 15 years since these reports, a large number of synthetic applications
of MW in organic. synthesis have been reported and these have been summarized in
a number of reviews [3±10].
The use of dry media (solvent-free) conditions, in which the reactants are ab-
sorbed on inert solid supports, in MW-heated reactions, has received a consider-
able amount of attention recently and has been used in the synthesis of a wide
range of compounds [11±16]. These reactions generally occur rapidly and the
method avoids hazards, such as explosions, associated with reactions in solvents
in sealed vessels in which high pressures may be generated. Also the removal of

ISBN: 3-527-30514-9
116 4 Organic Synthesis using Microwaves in Homogeneous Media
solvents and their disposal are not required making the technique more environ-
mentally friendly.
MW heated reactions in homogeneous media, using either neat reagents or in the
presence of solvents, may also be performed at atmospheric pressure. This approach
has been used particularly by Bose et al. [17]. (MORE Chemistry), who reported, for
example, the rapid synthesis of heterocycles [18] in open vessels. Another approach,
which avoids hazards due to the flammability of solvents, is to perform the reactions
under reflux in a MW oven, which is modified to allow the reaction vessel to be at-
tached to a reflux condenser outside the MW oven [7, 19]. It should be pointed out,
however, that most of the available evidence shows that rate enhancements of MW
heated reactions in homogeneous media at atmospheric pressure are small or non-
existent [19]. This will be discussed in more detail later in this review (see also
Chapt. 5 of this book).
4.2
Reactions at Elevated Pressures
As mentioned previously, most of the earlier work on MW-assisted synthesis in-

volved homogeneous reactions in closed Teflon or glass vessels [1±3, 20]. The ob-
vious advantage of this technique is that reactions can be performed much more ra-
pidly than under conventional heating (reflux), due to elevation of the boiling point
of the solvent (or of the reactants in the absence of solvent) at increased pressures.
The technique is particularly suitable for reactions which are normally very slow, re-
quiring several hours, and in some cases days, of reflux under conventional condi-
tions. Although slow reactions can also be accelerated by heating in conventional
ovens or furnaces in sealed glass or stainless steel vessels, the rate of heating of the
reaction mixture is slower than under microwave heating and temperatures and
pressures are more difficult to control. Also, in conventional autoclaves heating is
conductive and this results in substantial thermal gradients near the walls of the re-
action vessel, which may result in decomposition or the formation of unwanted by-
products.
Teflon vessels are particularly suitable since they are transparent to MW and are
resistant to attack by chemicals or solvents (both organic and aqueous). The high
melting point of Teflon (320 8C) enables reactions to be performed relatively safely,
although vessels have been known to expand or explode at high pressures, particu-
larly when the temperature is also high [1, 7].
Until recently, the pressures used in MW reactions in sealed Teflon containers
have been restricted to 600±700 kPa (6±7 atm) for safety reasons. However CEM [21]
have developed computerized systems with pressure and temperature control using
vessels capable of withstanding pressures of 1500 kPa or more. Teflon bombs pro-
duced by Parr [22] can accommodate pressures up to 8 MPa (80 atm) and tempera-
tures up to 250 8C. However it has been reported that repeated use of the vessels
above 150 8C can lead to distortions which reduce the safe pressure level [7]. For
safety reasons, the vessels used in these higher pressure reactions are equipped
with pressure release valves, designed to vent when the pressure approaches an un-
safe level.
A continuous MW reactor (CMR), which operates by passing a reaction mixture
through a pressurized tubular microwave-transparent coil and a MW batch reactor
(MBR), have been developed by CSIRO in Australia and are used for organic synth-
esis on the laboratory scale [8]. The CMR can be operated at pressures up to
1400 kPa and temperatures up to 200 8C and the MBR at pressures and temperatures
up to 10 MPa and 260 8C.
Milestone [23] have produced a range of MW reactor systems for organic synth-
esis, including a quartz or ceramic MW reactor (MRS) for high pressure (up to
4 MPa) and temperature reactions, designed for large volume batch synthesis and a
multiple batch reactor MPR/HPR for up to 12 vessels, with volumes 2±270 mL for
operation at 3.5±10 MPa.
These instruments, designed by CSIRO and Milestone, include, in addition to
pressure and temperature measurement and control, a number of other features al-
lowing for greater safety and reproducibility of reaction conditions, such as stirring
to minimize temperature gradients, rapid cool-down at the end of the heating period
and energy shut-down if temperatures or pressures exceed safe levels.
The pressure generated in a reaction vessel, and hence the rate enhancement, de-
pends on a number of factors including the MW power level, the volatility of the sol-
vent, the dielectric loss of the reaction mixture, the size of the vessel and the volume
of the reaction mixture [7, 20]. Gedye et al. [20] found that, in the esterification of
benzoic acid with a series of aliphatic alcohols (Scheme 4.1) in closed Teflon vessels,
the most dramatic rate enhancements were observed with methanol (the most vola-
tile solvent).
The rate enhancement for the esterification of benzoic acid with methanol was
close to 100, when compared with the classical heating under reflux. On the other
hand, the rate enhancement for the esterification with n-pentanol, using the same
power level (560 W) was only 1.3. The approximate reaction temperature was almost
the same for the two alcohols (134 8C and 137 8C respectively). It should be noted,
however, that the rate enhancement for the esterification in pentanol increased to
6 times when a higher power level (630 W) was used, the reaction temperature being
higher (162 8C).
It is interesting to note that in the case of the reaction with pentanol (boiling point
138 8C), when the temperature of the MW reaction and the conventional reflux reac-
tion were about the same, there was very little difference in the reaction rates, sug-
gesting that the reaction rate depends on the reaction temperature rather than the
method of heating.
Scheme 4.1 Microwave-assisted esterification of benzoic acid.

Scheme 4.2 SN2 reaction of the 4-cyanophenoxide ion with

benzyl chloride.
The effect of the size of the reaction vessel on the rate of MW-heated SN2 reaction of
4-cyanophenoxide ion 1 and benzyl chloride 2 in methanol (Scheme 4.2) was investi-
gated by reacting identical amounts of reagents in Teflon vessels of different sizes.
It was found that there was an inverse relationship between the size of the vessel
and the reaction rate. In each case the time required for the reaction to go to 65 % com-
pletion was determined. It was shown that the rate of the reaction increases as the
pressure increases, since the pressure is inversely related to the volume of the vessel.
The heating rate, and hence the rate of pressure increase, also depends on the vo-
lume of the reaction mixture [20]. When the volume is small, the pressure increases
as the volume of the reaction mixture increases. However at a certain volume this
trend is reversed and a larger volume heats more slowly. For example when water
was heated in a 150-mL Teflon vessel, the greatest rate of pressure increase occurs
when 15 mL water are heated using a power of 560 W. The volume at which this
maximum heating rate, however, varies for different solvents. For example it occurs
at 20 mL for 1-propanol.
Using this information, it was possible to optimize the reaction conditions to
achieve a particularly high rate enhancement. The rate enhancement of the esterifi-
cation of benzoic acid with 1-propanol (Scheme 4.1) was increased from 18 to
60 times when the volume was increased from 10 mL to 20 mL at 560 W and in-
creased further to 180 times by increasing the power level to 630 W.
In this early work, pressure was measured by connecting the cap of a pressure-re-
lease Savillex [24] Teflon vessel to a pressure gauge outside the MW oven and the fi-
nal temperature estimated by pointing an infrared sensor at the mixture in the vessel
immediately after the heating was completed.
MW heating under pressure has been used to accelerate the rates of a wide variety
of reactions, which occur only slowly under conventional heating. This technique
has been particularly useful in accelerating Diels±Alder and related reactions. For
example the reaction of anthracene 3 with dimethyl fumarate 4 in p-xylene
(Scheme 4.3), gave an 87 % yield of the adduct in only 10 min by MW heating using
a sealed tube as the reaction vessel [2]. In contrast, the control reaction, performed
under reflux in p-xylene (bp 138 8C required 4 h to give a 67 % yield. It is to be noted
that the reaction temperature of the MW heated reaction was estimated to be in the
range 325±361 8C, approximately 200 8C higher than the control reaction.
Dimethyl formamide (DMF) has been found to be a particularly useful solvent in
these reactions because it absorbs MW irradiation strongly, has a relatively high boil-
Scheme 4.3 Diels±Alder reaction of anthracene with

diethyl fumarate.
ing point and is miscible with water, making it relatively easy to remove from the re-
action mixture. Majetich and Hicks [6] showed that the reaction of 1,4-diphenylbuta-
diene 5 with diethyl acetylenedicarboxylate 6 under reflux in DMF (Scheme 4.4) at
153 8C gave a 67 % yield of the Diels±Alder adduct 7 in 6 h. When the same reaction
was performed by use of MW heating in a CEM microwave system using Teflon ves-
sels with pressure and temperature monitoring (196 8C and 200 kPa), a comparable
yield of 7 was obtained in only 20 min.
The ortho-Claisen rearrangement of phenyl vinyl ether 8 to 2-vinylphenol 9
(Scheme 4.5) is a very slow reaction, requiring 80 h of reflux in DMF to give a yield
of only 34 %. Using the CEM microwave system an 80 % yield was obtained in 5 h at
196 8C and 200 kPa [6].
The Alder±Bong reaction of cyclohexene with diethyl acetylenedicarboxylate 6 in
DMF under reflux (Scheme 4.6) gives a 14 % yield of the tricyclic compound 10 in
Scheme 4.4 Reaction of 1,4-di-

phenylbutadiene with diethyl
acetylenedicarboxylate
Scheme 4.5 Rearrangement of phenyl vinyl

ether to 2-allylphenol.
Scheme 4.6 Reaction of cyclohexane with diethyl

acetylene dicarboxylate.
Scheme 4.7 Synthesis of [1-11C]tyrosine.
40 h, whereas a 50 % yield was obtained by MW heating in DMF at 182 8C and

650 kPa for only 20 min [6].
Mingos and coworkers have synthesized a number of organometallic compounds
by MW heating in Teflon autoclave vessels [7]. The synthesis of rhodium(I) and iri-
dium(I) dimers [M2Cl2(diolefin)2], from MCl3.xH2O and the diene requires several
hours under reflux in alcohol±water mixtures. Using MW heating in a Parr bomb
the same syntheses can be performed in good yield in less than 1 min.
A particularly useful application of MW-assisted synthesis at elevated pressure has
been in the preparation of radiopharmaceuticals containing isotopes with short half-
lives, such as C-11 (half-life 20 min) and F-18 (half-life 110 min) [25±27]. Clearly,
these compounds have to be synthesized very rapidly in order to give products with
high radiochemical yield. For example, [1-11C] tyrosine 12 was synthesized using the
two step Bucher±Strecker method by the reaction of p-hydroxyphenylacetaldehyde bi-
sulfite adduct 11 with K11CN and (NH4)2CO3 followed by hydrolysis with aqueous
NaOH (Scheme 4.7)
Using conventional heating each step involved heating at 170 8C for 10 min, giv-
ing an overall radiochemical yield of 40±60 %. In contrast, MW heating in a closed
Pyrex tube gave a radioactivity gain of 91% in a total reaction time of 1 min.
In some cases, MW heating at elevated pressures makes feasible reactions which
give negligible yields even after prolonged reflux in lower boiling solvents. The
choice of high boiling solvents (>150 8C) is limited and these solvents may be diffi-
cult to remove by distillation. Strauss and Trainor [8] showed that the reaction of the
sterically hindered mesitoic acid 13 with excess 2-propanol (bp 83 8C) in the presence
of sulfuric acid (Scheme 4.8) gives less than 3 % isopropyl mesitoate 14 after reflux
for 28 h. Using a MW batch reactor (MBR) at 148 8C, however, a 56 % yield of the
ester was obtained after only 1 h [8].
Another example is the preparation of methyl 2-phenylethyl ether 16 by the reac-
tion of 2-phenylethylbromide 15 with methanol (Scheme 4.9). This reaction is too
slow to give an appreciable yield of the ether at the boiling point of methanol. An al-
ternative approach is to use the reaction of sodium methoxide with the bromide, but
this causes elimination of HBr, giving styrene as the main product. In contrast, re-
4.3 Reactions at Atmospheric Pressure 121
Scheme 4.8 Synthesis of isopropyl mesitoate.
Br OMe
MeOH
Scheme 4.9 Preparation of methyl

2-phenylethyl ether. 15 16
acting the bromide with methanol using the MBR at 170 8C gave a 75 % yield of 16
in 20 min [8].
4.3
Reactions at Atmospheric Pressure
MW-assisted organic synthesis in homogeneous media at atmospheric pressure has

recently received a considerable amount of attention [7, 17, 19]. This might seem sur-
prising, since rate enhancements would be expected to be much smaller than in
MW heating at higher pressures. In fact, acceleration of reactions by MW compared
with conventional heating at the same temperature would not be expected unless the
participation of a specific or nonthermal MW effect was involved [19, 28]. The exis-
tence of such effects is still a matter of debate among researchers in the MW chemis-
try area and will be discussed in this review, as they pertain to MW heated reactions
in homogeneous media (see Chapt. 5 for a more general discussion).
The advantages of performing MW-heated reactions at atmospheric pressure are
that the danger of explosions due to pressure increases are eliminated and that the
equipment required is much less expensive. Reactions may be performed in open
vessels, such as Erlenmeyer flasks, with a funnel as a loose top, in domestic MW
ovens. This approach has been used particularly by Bose [17, 18] and has been
termed MORE (microwave-organic reaction enhancement) chemistry. Reactions are
usually performed in polar, relatively high boiling solvents. DMF is often the solvent
of choice and other solvents include chlorinated benzenes, ethylene glycol and di-
glyme. These solvents heat rapidly and the MW power is adjusted so that the tem-
peratures reach about 20±30 8C below their boiling points. Reactions are usually
complete within minutes when performed on a small scale (ranging from a few
milligrams to up to 5 grams of product). Some reactions have been scaled up to a
hundred grams or more, but this requires longer reaction times, since larger quanti-
ties of materials heat up more slowly.
Scheme 4.10 Synthesis of benzimidazole.
A number of syntheses of heterocycles were performed using the MORE tech-

nique [17, 18]. While most of these reactions had been reported in Organic Synthesis
to require reflux times of an hour or more, Bose et al. were able to obtain comparable
yields in a matter of minutes. For example, benzimidazole 18 was synthesized from
1,2-diaminobenzene 17 and formic acid, which served as both reagent and solvent,
in 70 % yield in 3 min (Scheme 4.10), compared with the recommended heating
time of 2 h [17].
In some of these syntheses the original reaction conditions were modified and
this might partly account for the much shorter reaction times. The synthesis of
phthalimidoacetic acid 20 from phthalic anhydride 18 and glycine in the presence of
triethylamine (Scheme 4.11) gives a yield of 83±90 % when the reagents are heated
under reflux in toluene for 1.5 h [29]. Bose found that good yields of the product
could be obtained in 1±3 min when the reaction was performed in DMF in a MW
oven [18].
This reaction was later re-examined by Westaway and Gedye [30], who showed that
the rate of the reaction was actually the same whether performed by MW heating or
conventional heating in DMF at the same temperature. Thus the rate increase ob-
served by Bose was due to an increase in polarity and temperature when DMF was
substituted for toluene.
The advantages of the MORE technique are that the apparatus required is simple
and inexpensive and that reactions can be performed rapidly and conveniently. It has
been used in teaching laboratories, making it feasible for the student to perform
syntheses which would normally require long reflux times, in a 2 or 3 h laboratory
period [31]. Disadvantages of the technique are that rate enhancements are smaller
than those of reactions performed under pressure and that high boiling solvents are
required to achieve fast reactions, leading to difficulties in separation of the products
from these solvents. Although lower boiling solvents can be used, reaction rates are
lower and fire hazards, due to the ready vaporization of the solvent, are significant.
Reactions at atmospheric pressure may also be performed using MW ovens modi-
fied so that a reflux condenser can be attached outside the oven [7, 19]. Since volatile
solvents are contained in MW reflux, the fire hazard is minimized. Mingos has re-
Scheme 4.11 Synthesis of phthalimidoacetic acid.

4.4 Effect of Microwaves on the Rates of Homogeneous Reactions in Open Vessels 123
ported the synthesis of a number of organometallic compounds using this techni-

que. For example, the rhodium dimer Rh(cod)Cl2 (cod is 1,5-cyclohexadiene) was
synthesized in 87 % yield by MW reflux in a reaction time of 25 min. compared with
a reported time of 18 h using conventional heating [7]. Although it is likely that the
conventional heating time to give a comparable yield could be reduced considerably,
an appreciable MW-induced rate enhancement of this reaction is probable. Mingos
has noted that many solvents can superheat by 10±30 8C when reacted under reflux
using MW heating [7]. It is well known that a temperature increase of 10 8C usually
doubles the reaction rate and so an increase in temperature of 30 8C would be ex-
pected to result in a rate enhancement of 8 times. It should be noted that this super-
heating effect largely disappears on stirring or on addition of boiling chips [44].
However, stirring is not feasible in an unmodified domestic MW oven and boiling
chips soon lose their effectiveness unless continuous MW power is supplied. For
these reasons it is likely that many reported rate enhancements of reactions per-
formed in solvents are due primarily to the superheating effect. There is also the pos-
sibility of nonthermal effects contributing to the rate enhancement, but this will be
discussed in the next section. In any case, much larger rate enhancements can be
achieved using high pressure conditions. The rhodium dimer referred to above was
synthesized in 91% yield in only 50 s under MW irradiation using a Parr bomb [22].
4.4
Effect of Microwaves on the Rates of Homogeneous Reactions in Open Vessels
There have been a number of reports which claim that MW heating causes signifi-
cant rate increases in some reactions in homogeneous media in open vessels, based
on comparisons between rates of reactions performed by MW heating and conven-
tional heating at the same temperature. This has led to the suggestion that specific
or nonthermal activating effects are responsible for these rate enhancements. How-
ever, some of these reactions have been re-examined and shown to occur at the same
rate, or only slightly faster, under MW irradiation.
4.4.1
Diels±Alder reactions
The first report suggesting specific activation of an organic reaction by MW was that
of Berlan et al. [28] who observed that some Diels±Alder reactions occurred more ra-
pidly on MW heating than under conventional heating at the same temperature
(95 8C). The reactions were performed in two different solvents, xylene and dibutyl
ether and the rate enhancements were slightly higher in xylene, the less polar sol-
vent. For example the rate enhancement of the reaction of 2,3-dimethyl-1,3-buta-
diene 21 with methyl vinyl ketone 22 was 8 times in xylene and 2.3 times in dibutyl
ether, based on the half lives of the reactions. Reaction of anthracene 3 with diethyl
maleate 23 in xylene (Scheme 4.12) resulted in an approximately fourfold rate in-
crease.
Scheme 4.12 Diels±Alder reactions reported to show a

specific microwave effect.
In a subsequent paper [32], however, Berlan himself cast doubt on the existence of
nonthermal effects, attributing the observed rate increases to localized hot-spots in
the reaction mixture or to superheating of the solvent above its boiling point. He
also mentioned the difficulty of measuring the temperature accurately in MW cav-
ities. Furthermore, kinetic studies by Raner et al. [33], showed that the Diels±Alder
reaction of 3 with 23 (Scheme 4.12) occurred at virtually the same rate under MW
and conventional heating at the same temperature.
4.4.2
Reactions of Biologically Important Molecules
Sun et al. [34] reported that the rate of hydrolysis of the biomolecule ATP under MW
irradiation was 25 times faster than under classical heating at similar temperatures.
However, the same research group [35] later observed that, with more accurate tem-
perature control, the hydrolysis rates were in fact almost identical.
There have also been reports [36, 37] that racemization of amino acids occurs
more rapidly using MW heating than conventional heating at the same temperature.
Chen et al. [36] observed that racemization of amino acids in acetic acid the presence
of benzaldehyde was accelerated by MW heating. Lubec et al. [37] reported that some
d-proline and cis-4-hydroxy-d-proline were found in samples of infant milk formula
when they were heated in a MW oven. On the other hand, conventionally heated
samples did not contain these unnatural d-amino acids. This report caused concern,
and received media attention because d-proline is neurotoxic and suggested that
MW heating of some foods could have deleterious effects on their nutritional value
and the health of the consumer.
However, Marchelli et al. [38]. were unable to detect any d-proline when milk for-
mula containing l-proline was heated in open vessels in a MW oven. Westaway and
Gedye [30] showed that very small amounts of d-proline (0.1±0.2 %) were produced
when an aqueous solution of l-proline was heated under reflux in a MW oven for
15 min. Although d-proline was not detected when the same solution was heated un-
der reflux conventionally for the same time, approximately 1% of d-proline was pro-
duced after 24 h of conventional reflux. MW did not have a significant effect on the
rate of racemization of l-proline in acetic acid in the presence of benzaldehyde [30].
The small increase in racemization rate observed when an aqueous solution of l-pro-
line was heated under reflux on a MW oven at atmospheric pressure could be attribu-
ted to localized superheating or a generalized superheating of the solvent. It is
known that water superheats by 4±10 8C when boiled in a MW oven [39, 40].
4.4.3
Other Reactions in Polar Solvents
We have investigated a number of reactions in polar solvents, most of which had

been previously reported to occur more rapidly under microwave heating than classi-
cal heating in open vessels, to see if there are any significant MW rate enhance-
ments, which could suggest to the involvement of a specific MW effect [19, 20].
It should be pointed out that many of these reports compared reaction times of
MW heated reactions with times previously reported in the literature for the same re-
actions under conventional heating. Unfortunately the conventionally heated reac-
tions are often complete in times which are much shorter than those quoted and it
is important to perform direct and careful comparisons between MW and thermal re-
actions, using the same quantities of reagents and solvents and the same reaction
temperature.
For example, large rate enhancements have been reported in the synthesis of chal-
cones by crossed-aldol condensations in open vessels, suggesting the participation of
specific MW effects [41]. The chalcone 24 was synthesized from cyclohexanone and
benzaldehyde in ethanol, in the presence of a catalytic amount of sodium hydroxide
(Scheme 4.13), in a MW oven in 90 % yield in only 1 min.
This was compared to a time, quoted previously, of 2 h of conventional heating to
obtain a 72 % yield, indicating a time saving of at least 120 times. We performed the
same reaction under MW and conventional heating (heating mantle) in open vessels
using the same proportions of reactants, catalyst and solvent. The conventionally
heated reaction was found to give a high yield of the product in a time much shorter
than 2 h at the boiling point of ethanol, and initial experiments showed only a two to
five fold rate increase under microwave heating. In fact, when the reactions were per-
formed under reflux to avoid evaporation of the solvent, an even smaller rate en-
hancement of 1.5 times was observed. When the reaction was performed in an open
Scheme 4.13 Microwave-assisted synthesis of chalcones.

Scheme 4.14 ortho-Ester

Claisen rearrangement of
geraniol.
vessel in the MW oven, substantial evaporation of the solvent occurred, resulting in a

more concentrated solution and a higher reaction temperature. The amount of eva-
poration in the conventionally heated reaction tended to be less, due to a slower heat-
ing rate, and so this reaction occurred more slowly.
Substantial rate enhancements of over 100 times have been reported in ortho-ester
Claisen rearrangements of allylic alcohols in DMF in open vessels [42]. For example,
geraniol 25 gave an 87 % yield of the ester 26 in 12 min in a domestic MW oven,
whereas the same reaction required 48 h of conventional heating to give a compar-
able yield (Scheme 4.14). In our laboratory, identical reaction mixtures of geraniol,
triethyl orthoacetate, propanoic acid and DMF were heated both conventionally and
with MW at the boiling point of DMF for 10 min, but in contrast to the previous re-
port, no significant rate enhancement was observed [19]. It should be pointed out
that it is not clear whether identical reaction mixtures or the same temperatures had
been used for the two heating methods in the previous report [42].
A major problem in performing meaningful comparisons between the rates of
MW and conventionally heated reactions is that the reaction temperature is diffi-
cult to control and to measure accurately in a domestic MW oven. In MW heated
reactions, the temperature typically rises faster than in conventionally heated reac-
tions and so even if the final temperatures are the same, the average temperature
of the MW reaction is likely to be higher, resulting in an apparently faster reac-
tion. Also, the MW fields are nonhomogeneous, making it difficult to obtain re-
producible results. These drawbacks can be overcome by using monomode reac-
tors with focused waves, producing a homogeneous electromagnetic field, with
temperature monitoring using fiber optic probes or infrared detectors [43]. These
systems are computerized giving accurate control of required conditions, including
temperature, allowing one to match closely temperature profiles of MW and con-
ventionally heated reactions [13, 44, 45]. The main limitation of these systems is
their relatively high cost
We have found it convenient to compare MW and conventional reactions using re-
flux conditions, since the temperatures are constant at the boiling point of the sol-
vent. To eliminate the problem of the time required to reach the reflux temperature,
reaction mixtures without one of the reactants or catalyst are heated to reflux and
then the other reactant or catalyst quickly added. The reflux times required to give si-
milar yields for a reaction, taken only partially to completion by MW and classical
heating, are then compared. Small rate enhancements might still be expected merely
because of superheating by up to 40 8C by the MW [39, 40, 46], and localized heating
Scheme 4.15 Knoevenagel reaction of salicylaldehyde

with diethyl malonate.
(hot spots) may also contribute. For this reason, these modest rate enhancements
should not necessarily be taken as evidence for nonthermal effects since rate in-
creases of less up to about 20 times can be explained by superheating, assuming re-
action rates double for every 10 8 rise in temperature. Mingos [47] has suggested that
rate enhancements should only be taken as evidence for nonthermal effects if they
are 100 times or more, but this includes the longer time required to reach the reac-
tion temperature by conventional heating.
Comparison between reaction rates using MW and conventional heating should
preferably be performed using kinetic studies [19, 33, 48], where rate constants can
be evaluated or plots of yield of product versus reaction time for the conventional
and MW reactions can be compared.
Bose et al. [18] reported that the Knoevenagel reaction between salicylaldehyde 27
and ethyl malonate 28 in the presence of piperidine gave a high yield of 3-carbethox-
ycoumarin 29 in 3 min in an open vessel in a MW oven (Scheme 4.15).
In their initial studies on this reaction, Westaway and Gedye [30] observed slightly
increased rates both in the presence of ethanol and in the absence of a solvent, when
MW heating was used in an open vessel. Since it was difficult to measure the tem-
perature accurately in the MW experiment, the reaction in ethanol was later per-
formed under reflux [19]. The yield of the product was found to be 73 % in 8 min
using MW reflux compared with a yield of 71% in 20 min under conventional reflux,
representing a rate enhancement of approximately 2.5 times.
The rate of the Knoevenagel reaction of acetophenone 30 with ethyl cyanoacetate
31 (Scheme 4.16) was observed to be considerably slower and it was therefore found
to be more suitable for rate studies [19].
A mixture of 30 and 31 and a small amount of acetic acid in ethanol was heated to
reflux in a domestic MW oven. A catalytic amount of piperidine was then added and
Scheme 4.16 Knoevenagel reaction of acetophenone

with ethyl cyanoacetate.
the mixture heated under reflux at low power (180 W). Heating was interrupted at
regular time intervals and aliquots taken for G.C. analysis. A plot of yield of the pro-
duct versus reaction time showed that the same yield of the mixture of isomers 32
and 33 (17 %) was obtained after heating under reflux for 120 min in the MW oven
and 320 min of conventional reflux, and hence the rate enhancement was 2.5±3.0
times.
The isomer ratio E : Z (33 : 32) was 1.2±1.6 over the course of the reaction and was
not affected by the heating method, so it was concluded that MW irradiation did not
affect the stereochemical outcome of this reaction, presumably due to the reaction
being under thermodynamic control.
It is interesting to note that when the same reaction was performed using a vari-
able frequency MW system [49] with temperature control at 80 8C in the absence of a
solvent, it occurred at the same rate as a similar reaction heated conventionally at
the same temperature. The use of variable frequency provides very uniform heating,
minimizing the possibility of hot spots. Thus it can be concluded that the modest
rate enhancement observed in ethanol under reflux was because of hot spots or to a
general superheating of the solvent. Again, it should be emphasized that these mod-
est MW rate enhancements should not be taken as hard evidence for nonthermal
MW effects.
Substantial MW rate enhancements have been reported in the Biginelli synthesis
of dihydropyrimidines [50, 51] under homogeneous conditions. The synthesis in-
volves a one-pot cyclocondensation of a b-ketoester with an aryl aldehyde and urea or
thiourea in the presence of a catalytic amount of HCl in ethanol solution. An exam-
ple of this synthesis is shown in Scheme 4.17.
The reactions were performed in an open beaker using a domestic MW oven, and
reaction times were reduced from 2±24 h of conventional reflux to 3±11 min under
MW irradiation.
Stadler and Kappe [52] re-examined this synthesis using a Milestone ETHOS 1600
series MW reactor [23] with on-line temperature and pressure control in order to in-
vestigate the existence of a nonthermal MW effect. They found, however, that when
the reactions were performed under the action of MW heating using a reflux con-
denser no significant rate increase occurred over conventional reflux at the same
temperature (80 8C). They confirmed that there was an increase in rate and yield
when the reaction was performed in an open beaker, but this could readily be ex-
plained by evaporation of the solvent, causing an increase in temperature and con-
centration solution. It is to be noted that the same explanation applies for the appar-
Scheme 4.17 Biginelli synthesis of a dihydropyrimidine.

ent rate enhancement in the MW-assisted synthesis of chalcones (vide supra,

Scheme 4.13). Thus there was no evidence for the participation of a nonthermal MW
effect.
4.4.4
Reactions in Nonpolar Solvents
There have been a few reports recently of substantial MW rate enhancements of re-
actions of polar reactants in nonpolar solvents [53, 54]. Soufiaoui et al. [53] have
synthesized a series of 1,5-aryldiazepin-2-ones 36 in high yield in only 10 min by the
condensation of o-aryldiamines 34 with b-ketoesters 35 in xylene under MW irradia-
tion in open vessels (Scheme 4.18). The temperature at the end of these reactions
was shown to be 136±139 8C. Surprisingly, they observed that no reaction occurred
when the same reactions were heated conventionally for 10 min at the same tem-
perature. These results could be taken as evidence for a specific MW effect.
Reddy et al. [54] performed a rather similar synthesis of trifluoromethyl aryl-
diazepines 38 and 39 by the reaction of o-aryldiamines 35 with the synthon 37
(Scheme 4.19).
Under MW irradiation (980 W) in xylene yields of 73±93 % were obtained in 10±
20 min, whereas under conventional conditions a complex mixture of products was
obtained, which was unsuitable for preparative work. Thus it would appear that these
reactions not only occur much faster under microwaves but also give cleaner pro-
ducts, indicating greater selectivity. Loupy [44, 45] has speculated that these reac-
tions, among others performed in nonpolar solvents or in the absence of solvent,
might be accelerated under MW irradiation due to the involvement of relatively polar
Scheme 4.18 Microwave-assisted synthesis of

1,5-aryldiazepines-2-ones.

trifluoromethyl aryldiazepines.
transition states, leading to lower activation energies. Specific effects would be more
likely when nonpolar solvents are used, since only the reactants would absorb MW
energy, whereas in polar solvents any such effects would be masked due to absorp-
tion of MW by the solvent.
Since there appeared to be strong evidence for a nonthermal effect in this type of re-
action, we repeated the reaction of o-phenylenediamine 34 (Scheme 4.13, R1 = R2 = H)
with ethyl acetoacetate 35 (R = CH3) [19], which was one of the reactions reported by
Soufiaoui [53] to give the diazepine only on MW heating. However, when the same re-
action mixtures were heated for10 min with the same temperature profile, almost
identical yields of the diazepines were obtained by MW and classical heating. Later,
this was also found to be the case in the reaction of 34 with ethyl benzoylacetate 35
(R = Ph).
However, the possibility of the participation of nonthermal effects in MW-assisted
reactions in nonpolar solvents is still an open question. Loupy et al. [55] observed an
increase in yield and purity of the diazepine 36, in the reaction of ethyl acetoacetate
with o-phenylenediamine using monomode MW reactor with focused MW heating,
when compared with conventional heating with the same temperature profile.
Recently Bogdal [48] observed, using kinetic studies, greater MW rate enhance-
ments when the Knoevenagel reaction of salicylaldehyde with ethyl malonate (vide
supra, Scheme 4.15) was performed in toluene than when ethanol was used as the
solvent. The calculated rate constants in toluene solution were more than three
times higher under MW irradiation than under conventional conditions, whereas
the rate constants of the reaction in ethanol were the same, within experimental er-
ror, under both heating methods.
In a joint paper, Loupy and Gedye [45] reported an investigation of the influence
of MW activation on the synthesis of phthalimides by the reaction of phthalic anhy-
dride with several amino compounds (Scheme 4.20) both in the absence of solvent
and in the presence of a nonpolar solvent.
This study was prompted by a report that phthalimidoacetic acid (R = CH2CO2H,
see also Scheme 4.11, vide supra) could be synthesized by the reaction of phthalic an-
hydride with glycine in the absence of solvent, which involves the reaction between
two solids [56]. However, in this study [45], it was established that the synthesis of
phthalimides under solvent-free reactions requires at least one liquid reactant in order
to occur. This was possible when reacting a liquid amine (e. g. R = CH2Ph) or a solid
with a sufficiently low melting point to melt rapidly under MW (e. g. R = (CH2)6OH,
m.p. 56±58). In these cases, the reaction temperature was typically over 135 8C after 2
or 3 min of MW heating resulting in dissolution of phthalic anhydride in the molten
Scheme 4.20 Microwave-assisted synthesis of phthalimides.

amine, thus producing a homogeneous mixture. Evidence was found in some cases
for a faster reaction under MW irradiation. For example the reaction of phthalic anhy-
dride with 6-amino-1-hexanol (R = (CH2)6OH) in mesitylene (a nonpolar solvent) gave
a 60 % yield of the phthalimide on heating for 10 min at 160 8C using an oil bath. The
yield increased to 97 % when the same reaction was performed using monomode MW
heating for 10 min at the same temperature. The same reaction also occurred faster in
the absence of a solvent when MW heating was used.
If no liquid phase is present, that is, for reactions between two solids, the reaction
will not take place and requires the use of a high-boiling solvent. Thus, contrary to
the previous report [56], the reaction of phthalic anhydride and glycine [R =
CH2CO2H, m.p. 240 8C] did not occur in the absence of a solvent, but when per-
formed in either DMF or xylenes gave a good yield (90 %) of the phthalimide after
only 10 min of MW heating. Finally, in all cases, excellent yields of phthalimides
(about 90 %) were obtained in short reaction times (5±10 min) giving products of
high purity.
Also, as mentioned earlier, Berlan et al. [28] had observed that the use of a nonpo-
lar solvent resulted in a more significant rate enhancement in a Diels±Alder reaction
(vide supra, Scheme 4.12), although later kinetic studies by Raner et al. [33] cast
some doubt on this result.
4.4.5
Reactions in Homogeneous Media Showing no MW Rate Enhancement
A number of other reactions in homogeneous media have been shown to occur at

the same rate under MW heating and classical heating at the same temperature.
In our early studies [20] we compared the rate of the esterification of benzoic acid
with propanol (vide supra, Scheme 4.1) using the two heating methods. Identical
mixtures of benzoic acid, propanol and sulfuric acid were heated in an open vessel
in a domestic MW oven and in an oil bath at 160 8C for 4 min. Although the tem-
perature of the MW reaction could only be estimated roughly using an infrared sen-
sor immediately after the reaction, the results showed that there was no significant
MW rate enhancement, the yields of propyl benzoate using MW and oil bath heating
being 25 % and 29 % respectively.
Later, in a more carefully controlled comparison, Pollington et al. [57] showed that
the esterification of acetic acid with 1-propanol also occurred at the same rate under
MW and conventional reflux.
Other reactions shown to occur at the same rate under the two heating methods
include the acid-catalyzed isomerization of carvone 40 to carvacrol 41 [33], and ene
reactions involving carbonyl enophiles (Scheme 4.21) [32]. The former reaction was
performed in a mixture of chlorobenzene (slightly polar) and dioxane (nonpolar) and
in the latter reaction a large excess of 1-decene was used and so the reaction was ef-
fectively performed in a solution of low polarity.
A recent study by Goncalo et al. [58] adds support to the hypothesis that observed
rate increases of MW heated reactions compared with classical heating are due only
to thermal effects. They studied the intramolecular cyclization of 2-hydroxyphenyla-
Scheme 4.21 Reactions occurring at the same rate under

the action of microwave and classical heating.
Scheme 4.22 Cyclization of 2-hydroxyphenylacetic acid

to coumaran-2-one
cetic acid 42 to.coumaran-2-one 43 in the presence of a trace of p-toluenesulfonic

acid under MW irradiation and conventional heating (Scheme 4.22).
The reactions were performed in the absence of a solvent or a solid support at tem-
peratures above the melting point of the acid 42. The use of a monomode MW oven
and an optical fluorescence thermometer allowed accurate measurement of tempera-
ture distribution in the reaction mixture and showed a large and unexpected tem-
perature heterogeneity. Initially it was observed that a yield of 85 % of 43 was ob-
tained after 6 min of MW heating at 200 8C, whereas when oil bath heating at the
same temperature was used the yield did not exceed 65 %. When the temperature
distribution in the reactor was taken into account (varying by 40 8C for a gap of
2±3 mm in the irradiated liquid), it was estimated that the average temperature was
at least 245 8C, and the reaction was therefore performed at 245 8C using oil bath
heating. Under these conditions, the same yield of 85 % of 43 was obtained either by
classical or MW heating. It was concluded that some previous studies, which have
shown faster reactions using MW heating than classical heating at the same tem-
perature, leading to postulations of nonthermal effects, may be flawed due to inac-
curacies in temperature measurement. It was emphasized, however, that the use of
monomode MW irradiation was an attractive and safe alternative to classical heating.
The short reaction time of 6 min included the time required for the rise in tempera-
ture, whereas it took at least 30 min to heat the oil bath to the required temperature,
when the bath became dangerously hot.
4.4.6
Reactions in Homogeneous Media Showing MW Rate Enhancement
As mentioned earlier, a number of reactions initially observed to show MW rate en-

hancements compared with conventionally heated reactions at the same tempera-
ture, have since, with more careful comparison, been shown to occur at the same
rate under the two heating modes. Other reactions, such as Knoevenagel reactions
in ethanol solution (vide supra, Schs. 15 and 16), have been shown to have modest
rate enhancements, occurring typically 2 or 3 times faster under MW heating than
under conventional heating at the same temperature. These rate increases are not
surprising considering that solvents superheat by 10 8C or more on MW reflux, parti-
cularly as the reaction mixtures were not stirred.
On the other hand, there have been a few reports of MW assisted reactions at at-
mospheric pressure which have been reported to show more substantial rate en-
hancements, and these will now be discussed.
Besson et al. have published a series of papers describing MW-assisted syntheses
of polyheterocyclic compounds of potential pharmacological value, such as quinazo-
lines [59±63]. These MW applications are of particular interest because of the sub-
stantial reductions in reaction time in multistep syntheses. The MW heated reac-
tions were performed in a monomode MW oven with focused irradiation, mostly
under reflux in homogeneous solution in polar solvents. For example, MW heating
in homogeneous solution was used in four of the steps in the synthesis of the thia-
zoquinazoline 45 from 2-amino-5-nitrobenzonitrile 44 (Scheme 4.23) leading to a
considerable overall time-saving in the seven-step synthesis. Based on the reaction
times for MW and conventional heating, rate enhancements for the individual
steps were in the range 6±8 times. The total time required for these four reactions
was reduced from 14 h (conventional heating) to 2 h (MW) and the overall yield
was increased. The reactions were also reported to be cleaner and the products
more easily purified.
The rates of certain reactions of polymers have been reported to be enhanced by
MW under homogeneous conditions at atmospheric pressure. Lewis et al. [64] per-
formed kinetic studies on the imidization of the polymer BDTA±DDS polyamic acid
46 in N-methylpyrrolidone (NMP) giving the polymer 47 (Scheme 4.24) and showed
that the apparent activation energy was reduced from 105 kJ mol±1 under conven-
tional heating to 55 kJ mol±1 under MW heating. Rate enhancements (kMW/kthermal)

a thiazoquinazoline.
Scheme 4.24 Imidization of polymer BDTA±DDS polyamic acid.
at various temperatures, were in the range 20±30 times It was suggested, however,
that these rate enhancements were due to nonuniform heating on a molecular scale
rather than to nonthermal effects.
Wei et al. [65, 66] compared the MW and thermal cure of epoxy resins for stoichio-
metric mixtures of diglycidyl ether of bisphenol A (DGEBA) and a curing agent of
high dipole moment, diaminodiphenylsulfone (DDS), and for DGEBA and a curing
agent of low dipole moment, m-phenylenediamine (mPDA) at the same tempera-
ture. They found significant increases in reaction rates in the MW cured DGEBA/
DDS samples but only slight rate increases for the MW cured DGEBA/mPDA sam-
ples. A possible explanation for the higher rate enhancements of the DGEBA/DDS
system is that when polymers are irradiated with MW, the energy is directly coupled
to the polar functional groups and it takes a finite time for the absorbed energy to
distribute itself evenly with the rest of the system. If this distribution time is signifi-
cantly longer than the reciprocal of the frequency of the MW irradiation, this will re-
sult in a localized higher molecular temperature in the case of the more polar DDS
than in the less polar mPDA [66]. However it was also suggested that nonthermal ef-
fects could be involved since the MW cured samples showed a higher glass transition
temperature, Tg than the thermally cured samples after gelation. It was argued that if
the effects were purely thermal, the Tg should be the same for the MW and thermally
cured samples at the same extent of cure [66].
Scola et al. [67] studied the kinetics of the MW cure of a phenylethyl-terminated
imide polymer model compound and an oligomer using a variable frequency MW
source and found that the activation energy of the MW cures were 68 % and 51% of
the thermal cure respectively. It should be noted that the reactions were performed
in the liquid phase in the absence of solvent.
4.4.7
Possible Explanations of MW Acceleration
In summary, observations of increased rates of MW-assisted homogeneous reactions,

compared with classically heated reactions at the same apparent temperature, may
be explained by one or more of the following problems or effects:
. localized or general superheating of the solvent;

. inaccurate temperature measurement;
. nonhomogeneous distribution of temperature in the reaction mixture;
. evaporation of the solvent in open vessels, leading to higher temperatures and
concentrations; and
. nonthermal effects.
Because observed rate enhancements are usually small, or zero, nonthermal ef-
fects do not seem to be important in MW heated reactions in homogeneous media,
except possibly in some reactions of polymers and reactions in nonpolar solvents.
Relatively few studies have been conducted on MW-assisted reactions of polar reac-
tants in nonpolar solvents. Also, since there is some disagreement as to whether or
not these reactions are accelerated significantly by MW, in comparison with conven-
tionally heated reactions at the same temperature, more research on the effect of
MW irradiation on the rates of these reactions is required. Nonthermal effects may,
however, explain the more substantial MW rate enhancements in solvent-free reac-
tions on solid supports [44] (see Chapt. 5) and solid state reactions [68, 69].
4.5
Selectivity in MW-assisted Reactions
Another interesting question is whether MW heating can result in changes in selec-

tivity, leading to different product compositions than those obtained using conven-
tional heating. The effect of MW irradiation on selectivity was discussed in a review
by Langa et al. in 1997 [9] and more recently by Loupy et al. [44, 70]
In this regard Gedye et al. studied reactions of alkyl halides with bases in which
the amounts of elimination and substitution were compared and a Diels±Alder reac-
tion in which the ratio of endo to exo adducts was investigated [71]. In the first set of
experiments, the ratios of elimination to substitution products for the reactions of 1-
and 2-bromooctane with methoxide ion in methanol and with tert-butoxide ion in
tert-butyl alcohol, obtained under MW heating in a sealed Teflon container, were
compared with those found using normal reflux conditions (Scheme 4.25).
It was observed that there were only slight differences in composition between
the products of the MW and conventionally heated reactions. The greatest change
in composition was observed in the reaction of 1-bromooctane with tert-butoxide
ion where the percent of the elimination product (the alkene) increased from 5 %,
under conventional reflux to 14 % under MW heating. On the other hand there
Scheme 4.25 Substitution and elimination reactions

of alkyl halides with base.
Scheme 4.26 Diels±Alder reaction of cyclopentadiene

with methyl acrylate.
was no significant change in composition in the reactions of 2-bromooctane with

base.
The Diels±Alder reaction of cyclopentadiene with methyl acrylate in methanol was
studied by Berson et al. [72] under conventional conditions, and shown to give a mix-
ture of the endo and exo isomers 48 and 49 (Scheme 4.26).
The endo isomer was the major product, but the proportion of the endo isomer de-
creased with temperature, from approximately 90 % at 0 8C to 85 % at 60 8C [69]. Ge-
dye et al. [71] performed the reaction in methanol solution under MW heating in a
closed Teflon container and found that the product contained 79 % of the endo iso-
mer at an estimated temperature of 110 8C. A plot of temperature versus percent
endo isomer is effectively linear between 0 8C and 60 8C and assuming it remains lin-
ear to 110 8C, the product should contain 80 % endo isomer at this temperature.
Thus it was concluded that the change in product composition was due to the
change in temperature rather than to some special effect of MW. At higher tempera-
tures there is an increase in the proportion of the exo isomer, which is thermodyna-
mically more stable than the endo isomer.
However, more significant modifications in selectivity, which have useful applica-
tions in synthesis, have been reported in a number of other reactions performed
under the action of MW irradiation [9, 44, 70]. Many of these reactions were per-
formed under heterogeneous and/or solvent-free conditions, and only those per-
formed under homogeneous conditions will be discussed here.
Linders et al. [73] studied the Diels±Alder reaction of 6-demethoxy-b-dihydrothe-
baine with an excess of methyl vinyl ketone (used both as reactant and solvent),
which gives a mixture of two isomeric adducts. When the reaction was performed
using classical heating extensive polymerization occurred, whereas much less poly-
meric material was formed when the reaction was performed in a modified MW
oven under reflux conditions, resulting in a 32 % yield of the isomeric mixture of the
mixture of adducts.
In some MW-assisted reactions, in which a mixture of products is formed, the ra-
tio of products may be influenced by the heating rate or by the polarity of the sol-
vent.
Stuerga et al. [74] showed that, in the sulfonation of naphthalene, the ratio of the
products, naphthalene-1- and 2-sulfonic acids, depends on the MW power applied.
Higher powers, which cause higher heating rates, increase the proportion of the
thermodynamically more stable product, naphthalene 2-sulfonic acid, in the product
mixture.
Alvarez-Builla et al. [75] have shown that the stereochemical outcome of the MW-
assisted addition of 2-aminothiophenol 50 to the glycidic ester 51 (Scheme 4.27) is
affected by the nature of the solvent and by the MW power output. When the nonpo-
lar solvent toluene was used, the cis isomer of the product 52 predominated, whereas
in the presence of acetic acid the trans isomer was the chief product. Increasing the
power level caused an increase in the proportion of the trans isomer when toluene
was used as the solvent. The reactions were performed in open vessels in a domestic
MW oven.
Also, Bose et al. [76] have shown that the steric course of b-lactam formation can
be influenced by the MW heating rate. For example, in the reaction of the benzoylox-
yacetyl chloride 53 with the Schiff base 54 (Scheme 4.28) the cis adduct 55 is the
main product at low irradiation power whereas high power favors the formation of
the trans adduct 56. Lactams of this type can serve as intermediates for the side chain
of taxol and its analogs.
Bose et al. [77] compared a similar reaction of the acid chloride of tetrachlor-
ophthaloyl glycine 57 with a Schiff base under MW irradiation and conventional
Scheme 4.27 Addition of 2-aminophenol to a glycidic ester.
Scheme 4.28 Microwave-assisted b-lactam synthesis.

Scheme 4.29 Reaction of the acid chloride of tetrachlorophthaloyl

glycine with a Schiff base.
Scheme 4.30 Mutarotation of glucose.
heating (Scheme 4.29). When MW heating was used, the trans isomer 58 was
formed almost exclusively, whereas a mixture of cis and trans isomers 59 and 58 was
obtained under conventional heating. It was noted that the temperature at which the
acid chloride was added to the imine solution was crucial for trans selectivity. The
imine solution was initially heated in the MW oven to about 100 8C and then the acid
chloride added and the mixture heated at a low power level for 3 min.
Pagnotta et al. [78] reported that the mutarotation of a-d-glucose 60 to b-d-glucose
61 in aqueous ethanol (Scheme 4.30) not only occurred more rapidly under MW
heating than conventional heating but also gave a different equilibrium composition,
with a larger concentration of a-d-glucose being obtained using MW irradiation.
Because this change in selectivity is difficult to explain by a classical heating effect,
Langa et al. [9] consider that it is one of the most convincing examples of a possible
specific microwave effect.
Langa et al. [79] recently observed that the regioselectivity of the cycloaddition of
N-methylazomethane to C70 fullerene could be modified by MW irradiation. The ex-
tent of the modification in selectivity, compared with conventional heating, was
shown to be greater in the presence of the polar solvent, o-dichlorobenzene, than in
the nonpolar solvent, toluene. It was suggested that the effect on selectivity in this re-
action could be because of (1) the presence of hot-spots, (2) the greater heating rate
induced by MW or (3) a selective interaction of the electromagnetic field with the
transition state, which gives rise to the different isomers if they have different polari-
ties.
Loupy et al. [70] have studied the effect of solvent on the selectivity of the alkyla-
tion of 1,2,4-triazole 62 by 2,2',4'-trichloroacetophenone 63 (Scheme 4.31) under
MW and conventional heating. The reactions were all performed at 140 8C.
Scheme 4.31 Alkylation of 1,2,4-triazole.
In contrast with the results of Langa et al. on the cycloaddition reaction to C70,
MW irradiation had no effect on the regioselectivity of the reactions in polar solvents,
but a substantial effect was observed both in the nonpolar solvent, xylene and under
solvent-free conditions. In polar solvents (pentanol and DMF) the ratio of products
64, 65, and 66 was 95 : 5 : 0 under both MW and conventional heating. In xylene and
in the absence of solvent the ratio of isomers changed from 32 : 28 : 40 (xylene) and
36 : 27 : 27 (no solvent) under conventional heating to 100 : 0 : 0, i. e. totally regioselec-
tive, under MW activation.
The effect of solvent on regioselectivity was attributed to nonthermal effects,
which are favored in nonpolar solvents and under solvent-free conditions, where pro-
ducts formed via more polar transition states would be expected to predominate.
Recently, Jankowski et al. [80] reported the application of MW to the Diels±Alder
synthesis of N-methyloctahydroisoquinoline adducts, which are important inter-
mediates in the synthesis of medicinally important compounds, such as HIV prote-
ase inhibitor isoquinoline carboxylate pharmaceuticals. The reaction of the arecoline
67 or its isomer 70 with Danishefsky's diene 68 in toluene (Scheme 4.32) was studied
under both conventional and MW heating in sealed tubes, i. e. at elevated pressure.
The MW-assisted reaction was performed in a focused MW extraction system (Pro-
labo Soxwave-10) and occurred not only much more rapidly than the conventionally
heated reaction, but also resulted in higher yields and purer products. Under con-
ventional heating (160 8C for 5 days) the yields of the adducts 69 and 71 from 68
with 67 and 70 respectively, were 30 % and 50 %. In contrast, the MW method re-
sulted in yields of 73 % of 69 and 63 % of 71 in only 5 min. The stereochemistry of
the products was not affected by the heating mode. Under conventional reaction con-
ditions a significant level of diene decomposition and polymerization as well as the
formation of dienophile dimers was observed. Under MW activation, however, the re-
action was cleaner and amount of dimerization was reduced. It is interesting to note
that in the case of the MW reaction of 70 with 68 a new ab-unsaturated pyridyl ke-
tone 72 was also produced. It was suggested that this product was formed via the iso-
merization of the double bond of the dienophile 70 from the conjugated position 3
to position 2 (presumably due to the higher temperature of the MW reaction) which
then reacts with the diene to afford compound 72.
Most of the changes in selectivity due to MW heating in homogeneous media dis-
cussed here may be explained by higher reaction temperatures or greater heating
rates in the MW-assisted reactions. However, the observations of Pagnotta et al. [78]
Scheme 4.32 Diels±Alder synthesis of isoquinoline carboxylates.
and Loupy et al. [70] suggest that nonthermal effects may be involved in some cases.
More detailed comparisons between the selectivity of MW and conventionally heated
reactions at the same temperatures and in solvents of different polarity need to be
conducted before definite conclusions can be reached (see also Chapt. 5).
4.6
Comparison of Homogeneous and Heterogeneous Conditions
As discussed earlier, careful comparisons of the rates of MW irradiated reactions in

homogeneous media, particularly in polar solvents, at atmospheric pressure show
that these rates are the same or only slightly higher than similar reactions under
4.6 Comparison of Homogeneous and Heterogeneous Conditions 141
conventional heating. Any small rate enhancements can be explained by hot-spots or

general superheating of the solvent.
In fact, most reports of substantial rate enhancements by MW in open vessels are
in reactions performed under dry-media conditions, in which the reactants are ab-
sorbed on inert solid supports [11±16]. Since one or more of the reactants is usually a
liquid at the reaction temperature [44], these reactions are performed under hetero-
geneous conditions. Although it is difficult to perform kinetic studies on these reac-
tions, there is little doubt that they generally occur considerably faster than similar
conventionally heated reactions.
There have also been a number of reports of accelerations of reactions in the li-
quid and gaseous phase in the presence of a solid catalyst which absorbs MW irradia-
tion [81].
Chemat et al. [82] compared the rates of esterification reactions under MW and
classical heating using homogeneous and heterogeneous catalysis. They showed
that rate enhancements of 1.5 to 2 times were observed with heterogeneous catalysts
whereas no rate enhancements were observed under homogeneous conditions. For
example, the rate constants for the esterification of acetic acid with propanol in the
presence of sulfuric acid (homogeneous conditions) under classical and MW heating
at 80 8C were almost identical, as previously observed by Pollington et al. [57]. On the
other hand, when iron III sulfate with montmorillonite was used as the catalyst (het-
erogeneous conditions) the rate constant of the MW-heated reaction was twice that
of the classically heated reaction.
These results suggest that selective heating of the catalyst to temperatures higher
than that of the liquid phase is responsible for the modest increases in rate in the
presence of a heterogeneous catalyst.
Adamek and Hajek [83] reported that the addition of CCl4 and CCl3CO2Et to
styrene in the presence of a homogeneous Cu(I)-amine catalyst in acetonitrile
(Scheme 4.33) occurred more rapidly under MW heating than conventional heating.
Gedye and Wei repeated this reaction, comparing the rates under MW and conven-
tional reflux [19]. When the catalyst solution, prepared by the reaction of CuCl with
n-butylamine in acetonitrile, was carefully filtered before mixing with the reactants
(homogeneous conditions), a MW rate enhancement of only 1.5 times was observed
for the addition of CCl3CO2Et and no rate increase was observed for the addition of
CCl4. Higher rate enhancements were observed, however, when the catalyst solution
was not filtered and some solid CuCl was present in the reaction mixture (heteroge-
neous conditions). The rate enhancements for the additions of CCl3CO2Et and CCl4
Scheme 4.33 Addition of CCl3X to styrene in the presence

of a Cu-amine catalyst.
to styrene were then 11 and 3 times respectively. Again, the higher MW rate en-
hancements under heterogeneous conditions can be accounted for by the increased
temperature of the solid catalyst. It has been reported that CuCl absorbs MW
strongly and heats at a rate of 20 8 s±1 in a 2.45 GHz MW cavity [84].
Recently, Hajek and Radoiu observed that MW not only increase the rate of hetero-
geneous catalytic reactions, but also affect the product selectivity [85]. The results
were explained in terms of MW-induced polarization, involving the absorption of
MW by highly polarized reagent molecules on the active site of the catalyst. On the
other hand there is little, if any, activation of homogeneous catalytic reactions in po-
lar solvents [86], presumably due to the high absorbent power of MW irradiation by
the solvent.
4.7
Advantages and Limitations of MW Heating in Organic Synthesis
The most obvious advantage of MW heating over conventional heating is that it al-
lows many reactions to be performed more rapidly. In addition there have been
many reports of increased yields and fewer side-reactions when MW heating is used.
Rate increases of two or three orders of magnitude are achievable by performing re-
actions in sealed containers and hence at increased pressures. Earlier applications of
this technique were limited to small-scale reactions at pressures of up to about
700 Kpa to avoid the possibility of vessel rupture or explosions [1±3, 20]. Computer-
ized MW systems with temperature and pressure control are now available allowing
reactions to be performed safely and rapidly [8, 21, 23]. Hence there can be consider-
able time savings in a synthesis, which may have one or more steps requiring long
reflux periods of conventional heating. Unfortunately, such systems are expensive at
present, and are not, for example, usually available for routine use in university re-
search laboratories. It can be expected, however, that this situation will change in the
next few years as organic chemists become more aware of their potential to drasti-
cally reduce the time required for slow reactions as well as for obtaining products of
greater purity.
MW-assisted reactions are often performed in comparatively inexpensive domestic
MW ovens at ambient pressure. The ovens are sometimes modified to allow the reac-
tions to be performed under reflux [7, 19], thus preventing rapid evaporation of the
solvent which could otherwise present a fire hazard. Alternatively, the MORE tech-
nique [17] can be used, where the reactants are dissolved in a high-boiling solvent
such as DMF or may be performed in the absence of a solvent. Although actual rate
enhancements are small and sometimes nonexistent, reaction mixtures can be
heated more rapidly than under classical heating leading to some time-saving. MW
heating avoids the use of dangerously hot oil baths, which also require a considerably
longer time to reach the required temperature [58].
The variability of domestic MW ovens, nonhomogeneity of the MW field, and diffi-
culties in temperature measurement often make it difficult to obtain reproducible
rates and yields [10], and this may partly explain why MW heating has not become
References 143
more widely used by synthetic organic chemists. These problems also apply to sol-
vent-free reactions on solid supports, when performed in domestic microwave ovens,
but they can be avoided by using focused microwaves in monomode systems [43].
Again, the expense of these systems has so far limited their use to specialized re-
search laboratories. However, with the impressive advances in technology for the de-
sign of MW systems for organic synthesis in the last few years, there is little doubt
that these systems will soon become much more widely used by organic chemists.
The MW technique offers considerable advantages over conventional heating for sol-
vent-free reactions on solid supports because of rapid heating, substantial rate en-
hancements and cleaner reactions.
For these reasons, and because avoidance of solvents makes the technique more
environmentally friendly, the majority of recent papers on MW-assisted organic
synthesis have reported the use of solvent-free reactions.
MW heating will, of course, only be effective if the reaction mixture absorbs MW
irradiation and so is limited to reactions of polar molecules, either in polar solvents
or in the absence of a solvent. In some cases, reactions of polar compounds in non-
polar or slightly polar solvents can be heated with MW [19, 53], but the solutions
must be must be sufficiently concentrated in order to heat effectively. Relatively high
MW powers are also required. For this reason, some reactions requiring several
hours of classical reflux in solvents of low polarity can be performed more rapidly in
a MW oven by using a more polar solvent [17].
Although most applications have been in small-scale syntheses, recent technology
has led to the design of continuous flow and batch systems [8, 23] making it feasible
to synthesize products on the kilogram scale. Many noteworthy applications of MW-
assisted synthesis have been reported including the synthesis of radiopharmaceuti-
cals containing atoms with short half-lives [27], the synthesis of organometallic com-
pounds [7] and the synthesis and cross-linking of polymers [64, 87, 88]. Recently, the
great potential of rapid MW-assisted organic synthesis for combinatorial chemistry
and drug discovery is receiving considerable interest and has been recognized in two
reviews [89, 90].
Finally, there are a number of reports of modifications in selectivity and this aspect
of MW synthesis [9, 44, 70] promises to receive much attention in the future.
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147
5
Microwave and Phase-transfer Catalysis
Andr Loupy, Alain Petit, and Dariusz Bogdal
5.1
Phase-transfer Catalysis
In the last three decades there have been many reports of organic reactions per-
formed under phase-transfer catalytic conditions (PTC) [1±4]. PTC has found numer-
ous applications in essentially all fields of organic syntheses, industrial chemistry,
biotechnology, and material sciences. It can be encountered in the manufacture of
advanced pharmaceuticals, fragrances, crop-protection chemicals, highly advanced
engineering plastics, materials for semiconductors, and electro-optical and data sto-
rage devices [5]. It is worth remarking that in the 1990s sales of products made by
use of phase-transfer catalysis exceeded 10 USD billion year±1.
The concept of PTC was developed mainly because of the work of independent re-
search groups led by Makosza [1] and, later, Starks [2], Brandstrom [3], and Dehm-
low [4]. They introduced techniques in which the reactants were situated in two se-
parate phases, e. g. liquid±liquid or solid±liquid. Because the phases were mutually
insoluble, ionic reagents (i. e. salts, bases, or acids) were dissolved in the aqueous
phase while the substrate remained in the organic phase (liquid±liquid PTC). In so-
lid±liquid PTC, on the other hand, ionic reagents can be used in their solid state as
a suspension in the organic medium. Transport of the anions from the aqueous or
solid phase to the organic phase, where the reaction occurred, was ensured by use
of catalytic amounts of lipophilic agents, usually quaternary onium salts or cation-
complexing agents (e. g. crown ethers). Because the reactions proceeded very slowly,
or not at all, in the absence of a catalyst, phase-transfer catalysts have been found to
be of utmost importance in the extraction of reaction species between phases so
that the reaction can proceed, thus increasing yields and rates of reactions substan-
tially.
In general, under PTC conditions, three types of catalytic procedure can be con-
sidered (Scheme 5.1).
1. Liquid±liquid PTC in which the inorganic anions or anionic species generated

from relatively strong organic acids are located in the aqueous phase and react
with organic compounds in a liquid±liquid two-phase system by transfer into the

ISBN: 3-527-30514-9
148 5 Microwave and Phase-transfer Catalysis
Scheme 5.1
organic phase as loose lipophilic ion pairs, because of the intervention of the
phase-transfer catalyst, which continuously transfers the anionic species from the
aqueous phase to the organic phase, in which the reaction occurs (Scheme 5.1;
path a);
2. Liquid±liquid PTC conditions in which weak organic acids (e. g. carboanions) re-
act in the presence of concentrated aqueous sodium or potassium hydroxide
which is in contact with the organic phase containing an anion precursor and or-
ganic reactants; the anions are created on the phase boundary and continuously
introduced, with the cations of the catalyst, into the organic phase, in which
further reactions occur (Scheme 5.1; path b).
3. Solid±liquid PTC conditions in which the nucleophilic salts (organic or mineral)
are transferred from the solid state (as they are insoluble) to the organic phase by
means of a phase-transfer agent. Most often the organic nucleophilic species can
be formed by reaction of their conjugated acids with solid bases (sodium or potas-
sium hydroxides, or potassium carbonate) (Scheme 5.1; path b). Another pro-
posed mechanism suggests that interfacial reactions occur as a result of absorp-
tion of the liquid phase on the surface of the solid.
The organic phase can be a nonpolar organic solvent (e. g., benzene, toluene, hex-
ane, dichloromethane, chloroform, etc.) or a neat liquid substrate, usually the elec-
trophilic reagent, which acts both as a reactive substrate and the liquid phase.
In chemical syntheses under the action of microwave irradiation the most success-
ful applications are necessarily found to be the use of solvent-free systems [6]. In
these systems, microwaves interact directly with the reagents and can, therefore,
drive chemical reactions more efficiently. The possible acceleration of such reactions
might be optimum, because they are not moderated or impeded by solvents. Reac-
tions on solid mineral supports and, in turn, the interaction of microwaves with the
reagents on the solid phase boundary, which can substantially increase the rate of
the reactions, are of particular interest [7].
PTC reactions are perfectly tailored for microwave activation, and combination of
solid±liquid PTC and microwave irradiation gives the best results in this area [8]:
1. after ion-pair exchange with the catalyst, the nucleophilic ion pair [Q+Nu±] is a
highly polar species especially prone to interaction with microwaves;
5.1 Phase-transfer Catalysis 149
2. the extraction processes, during the reaction, in which a PTC mechanism is

mainly involved, can be accelerated on the phase boundary, and an increase of re-
action rate might be expected; and
3. reactions under solid±liquid PTC-like reactions on mineral supports under sol-
ventless conditions often suffer from difficulties with heat transfer through the
reaction medium and homogenous heating under conventional conditions. Be-
cause microwave irradiation is a means of volumetric heating of materials, tem-
perature is more uniform under microwave conditions. Improvement of tempera-
ture homogeneity and heating rates implies faster reactions and less degradation
of the final products.
Similarly to classical PTC reaction conditions, under solid±liquid PTC conditions

with use of microwaves the role of catalyst is very important. On several occasions it
has been found that in the absence of a catalyst the reaction proceeds very slowly or
not at all. The need to use a phase-transfer catalyst implies also the application of at
least one liquid component (i. e. the electrophilic reagent or solvent). It has been
shown [9] that ion-pair exchange between the catalyst and nucleophilic anions pro-
ceeds efficiently only in the presence of a liquid phase. During investigation of the
formation of tetrabutylammonium benzoate from potassium benzoate and tetrabu-
tylammonium bromide, and the thermal effects related to it under the action of mi-
crowave irradiation, it was shown that potassium benzoate did not absorb micro-
waves significantly (Fig. 5.1, curves a and b). Even in the presence of tetrabutylam-
monium bromide (TBAB) the temperature increase for solid potassium benzoate
Fig. 5.1 Thermal behavior induced by microwave irradiation of

PhCO2K under different conditions (monomode reactor, 180 W).
was very modest (Fig. 5.1, curve c). In the presence of small amounts of xylene
(Fig. 5.1, curve d), a nonpolar solvent (i. e. inert to MW irradiation), a large tempera-
ture increase provides evidence of the formation of tetrabutylammonium benzoate
in the liquid phase, from which the positive thermal effect results (Fig. 5.1, curve d).
It must be stressed that a liquid component can be substituted with an efficient
absorber of microwave irradiation together with a low-melting component. The use
of most typical PTC solvents (nonpolar aromatic or aliphatic hydrocarbons, or highly
chlorinated hydrocarbons) is most interesting for microwave activation, because
such solvents are transparent or absorb microwaves only weakly. They can, therefore,
enable specific absorption of microwave irradiation by the reagents, and the results
or product distributions might be different under microwave and conventional con-
ditions [7].
Hence, by coupling microwave technology and solid±liquid phase-transfer conditions, we
create a clean, selective, and efficient methodology for performing organic reactions,
with substantial improvements in terms of conditions and simplicity in operating
procedures; this is essentially useful for poorly reactive systems involving, for in-
stance, hindered electrophiles or long-chain halides.
Numerous reactions in organic synthesis can be achieved under solid±liquid PTC
and with microwave irradiation in the absence of solvent, generally under normal
pressure in open vessels. Increased amounts of reactants can be used to ensure bet-
ter compatibility between the in-depth penetrability of materials and the radiation
wavelength.
Because microwave activation is rather a new technique, the number of examples
might seem limited at the present time; it is, however, increasing rapidly.
5.2
Synthetic Applications of Phase-transfer Processes
5.2.1
O-Alkylations
In conventional methods, PTC has provided interesting procedures for O-alkylation,

and coupling PTC conditions with microwave activation has proved to be quite fruit-
ful for such reactions.
5.2.1.1 Ester Synthesis
Alkyl acetates
Potassium acetate can be readily alkylated in a domestic microwave oven by use of
equivalent amounts of salt and alkylating agent in the presence of Aliquat 336
(10 mol%). Some important results, exemplified by Eq. (1), are given in Tab. 5.1
[10, 11].
+ -
CH 3COO K
- +
+ R X CH 3 COOR + KX Eq. (1)
Tab. 5.1 Alkylation of CH3COO±K+ under MW + PTC conditions (domestic oven, 600 W).
RX Time (min) Final temperature (pC) Yield (%)
n-C8H17Br 1 187 98
n-C8H17Cl 1 162 98
n-C8H17I 2 165 92
n-C16H33Br 1 169 98
Yields are always almost quantitative within 1±2 min, irrespective of chain length
and the nature of the halide leaving groups.
This procedure was scaled up from 50 mmol to the 2 mol scale (i. e. from 15.6 to
622.4 g total starting materials) in a larger batch reactor (Synthewave 1000) [12].
Yields were equivalent to those obtained under the original conditions (5 min,
160 8C) in the laboratory-scale experiment (Synthewave 402) (Tab. 5.2).
Tab. 5.2 Synthesis of n-octyl acetate under MW + PTC conditions (Synthewave, 5 min, 160 8C).
Reactor Amounts of materials [g (mol)] Total amount (g) Yield (%)

CH3COOK n-OctBr Aliquat
MW S402 4.9 (0.05) 9.7 (0.05) 1 (0.0025) 15.6 98

MW S1000 196 (2) 386 (2) 40.4 (0.1) 622.4 98
Xu et al. have obtained similar results with n-butyl bromide using TBAB
(10 mol%) and alumina (4 : 1 w/w) as the catalyst [13]. Benzyl acetate was also conve-
niently prepared from sodium acetate and benzyl halide by use of microwave irradia-
tion and PTC in synergy [14].
Long-chain esters
As a generalization of the above method, stearyl stearate was synthesized in 1 min in
quantitative yield (Eq. 2) [11].
- +
Aliquat 10%
C17 H35 COO K + n -C18 H37 Br C17 H35 COO n -C18 H37
MW (600 W) 1 min. Eq: 2
99%
It has been shown that reaction of carboxylic acids with benzyl halides, which
does not occur when heated conventionally, could be performed efficiently under the
action of MW irradiation in the presence of a quaternary ammonium salt as a cata-
lyst (Eq. 3) [15]. Typical results are given in Tab. 5.3.
+ -
Q X
Ar CH 2X + n C5H11 COOH Ar CH 2 O CO C 5H11 + HBr Eq: 3
Tab. 5.3 Reaction of benzyl halides with hexanoic acid under MW + PTC conditions (10 min,
560 W, 10 % PhCH2N+Me3Cl± ).
ArCH2X Yield (%)
Benzyl bromide 72
Benzyl iodide 90
a-Bromo-p-xylene 76
a-Iodo-p-xylene 92
a-Bromomesitylene 81
Aromatic esters
It is possible to alkylate benzoic acids directly, without the need to prepare reactive
potassium salts in a separate step, because they can be generated in situ by reacting
the acid with a base (potassium carbonate or hydroxide) in the presence of a phase-
transfer catalyst.
As an illustration of this principle, a volatile polar molecule is a byproduct, elimi-
nated as a result of the microwave heating (Eq. 4), and the equilibrium is shifted to
completion. The second effect of irradiation is activation of the alkylation step itself
(Eq. 5). All the reagents can be used in the theoretical stoichiometry. Some indicative
results are given in Tab. 5.4 [9].
Aliquat 10%
ArCOOH + KOH ArCOO-K+ + H2O Eq: 4
Aliquat 10%
ArCOO K
- +
+ R X ArCOOR + K X
+ -
Eq: 5
Tab. 5.4 Alkylation of potassium 4-Z-benzoate under MW + PTC conditions (domestic oven,
600 W, 10 % Aliquat).
Z Time (min) Yield (%)

Performed salt Salt in situ
H 2.5 99 99
NMe2 3 97 100
OMe 2 82 98
CN 3 80 95
NO2 2 81 95
A striking example in this series is the alkylation of terephthalic acid (Eq. 6). The
specific effect of the microwaves appears clearly in this example, because, other fac-
tors being equal, the yields are unambiguously much higher.
COOH COO n -Oct

2 K 2CO3
+ 2n -Oct-Br (Eq. (6)
Aliquat 10%
COOH COOn -Oct
MW (600 W) 7 min. 227°C 87%

Classical heating 7 min. 227°C 20%
5.2.1.2 Ether Synthesis
Aliphatic ethers
Yuan et al. studied two types of condition for this reaction ± use of either the alcohols
or the corresponding halides as starting materials [16, 17]. In the presence of qua-
ternary ammonium salts the reaction shown in Eq. (7) is complete within a few min-
utes. Typical results are given in Tab. 5.5.
+ -
PhCH 2N Me3 Cl
ROH + R'X R-O-R' + HX Eq: 7
Tab. 5.5 Synthesis of ethers under MW + PTC conditions (domestic oven, 560 W).
R RX Time (min) Yield (%)
Et PhCH2Cl 5 85
n-Bu PhCH2Cl 10 78
n-Oct PhCH2Cl 10 88
n-Oct n-BuBr 10 78
PhCH2 n-BuBr 10 92
More recently, this method has been extensively applied to a wide range of Wil-
liamson syntheses in dry media with K2CO3 and KOH as bases, TBAB as phase-
transfer agent, and a variety of aliphatic alcohols (e. g. n-octanol and n-decanol, yields
75±92 %) [18].
Furan diethers [19]

A new family of furan diethers has been obtained by alkylation of 2,5-furandimetha-
nol (Eq. 8) under the action of microwaves under PTC solvent-free conditions.
KOH
HOH 2C CH 2 OH + R X ROH2C CH 2OR Eq. (8)
O Aliquat O
Microwaves Monomode Reactor (30 W) 5 min. 180°C 93%
Conventional heating (Oil Bath) 5 min. 180°C 41%
The diethers were synthesized in high yield within short reaction times. When
compared with classical heating, under otherwise comparable conditions, reactions
times were improved by microwave activation.
Diethers from dianhydrohexitols
A series of new ethers has been obtained by alkylation of dianhydrohexitols (i. e. iso-
sorbide, isomannide, isoidide) under the action of microwave irradiation and PTC
conditions. Yields exceeded 90 %, a dramatically improvement compared with those
from conventional heating, despite similar temperature profiles. The best yields, for
example from isosorbide, were obtained in the presence of a small amount of xylene
and TBAB as catalyst at 140 8C (Eq. 9 and Tab. 5.6) [20].
Eq. (9)
Tab. 5.6 Reaction of isosorbide with several alkylating agents in the presence of KOH and TBAB
(relative amounts 1 : 3 : 3 : 0.1) under the action of microwave irradiation in a xylene solution.
R-X Time (min) Temperature (pC) Yield (%)

MW D
n-C8H17Br 5 140 96 10
C6H5CH2Cl 5 125 98 13
3-Cl-C6H4CH2Cl 5 125 95 15
4-Cl-C6H4CH2Cl 5 125 96 14
3-F-C6H4CH2Cl 5 125 95 15
CH3CH2OCH2CH2Br 30 100 78 45
Polyethers were next synthesized from isosorbide by means of a MW-assisted PTC

method (Eq. 10). In addition to increasing the rate of the reaction, the MW affected
the structure of the polymer (determined by MALDI/TOF mass spectrometry;
Tab. 5.7). Polymers of higher molecular weights, with ethylenic groups as chain ter-
minations, were obtained; conventional heating led to shorter hydroxylated com-
pounds [21].
Eq. (10)
Tab. 5.7 Polyethers from isosorbide and 1,8-dibromo- or dimesyloctane; yield and distribution
data for the microwave procedure (Mn and Mw are, respectively, the number average and weight
average molecular weights, the ratio Mw/Mn being the polydispersity index).
X Yield (%) Mn Mw Mw/Mn
Br 68 3300 4300 1.30

OMs 76 3650 5100 1.39
Phenolic ethers
Gram quantities of aryl-2-(N,N-diethylamino)ethyl ethers, compounds of biological
interest, have been prepared in a household microwave oven, with potassium hydro-
xide and glyme as the transfer agent, according to Eq. (11) [22].
OH O
KOH, glyme NEt2 Eq. (11)
ClCH 2CH 2 NEt2
R R
MW (600 W) 2 min. 92-99%
Under the action of microwave irradiation several phenol reacts remarkably fast in
dry media with primary alkyl halides to give aromatic ethers (Eqs. 12 and 13) [23, 24].
OH K2 CO3 / KOH, TBAB 10% OR

+ R X Eq. (12)
MW (300 W) 25-65 sec.
Y Y
Ex : Y = H R-X = PhCH 2Cl 50 sec. 78%
Me2SO4 25 sec. 87%
Y = p NH 2 PhCH 2Cl 40 sec. 89%
Eq. (13)
Catechol was reacted with b-methallyl chloride under the action of MW and PTC
conditions; yields of 2-methallyloxyphenols varied from 59 to 68 % under liquid±li-
quid conditions (Tab. 5.8), whereas no reaction was observed in a solid±liquid PTC
procedure (Eq. 14) [25].
CH3
OH CH 3 OH O CH 2 C
base, PTC CH2
+ CH 2 C + CH3
CH 3
OH CH2 Cl H2 O, MW 1-2 min O CH 2 C O CH 2 C
CH 2 CH 2
mono di
Eq. (14)
Tab. 5.8 Reaction of catechol with b-methallyl chloride (8 mmol) in the presence of base (2 mmol)
and phase-transfer catalyst (0.2 mmol) under microwave irradiation.
Base PTC Yield (%) Mono/di ratio
NaOH PEG-400 64 6.1

KOH TBAB 59 5.1
K2CO3 TBAB 68 6.4
A similar reaction is the methylenation of 3,4-dihydroxybenzaldehyde in the pre-

sence of a phase-transfer catalyst on a benign calcium carbonate surface [26]. Presum-
ably, bonding of the vicinal hydroxyl groups is low thereby enhancing the reaction with
the alkylating agent under the action of solvent-free microwave irradiation (Eq. 15).
HO O
ICH2I / TBAB / CaCO3 Eq. (15)
HO CHO Support / MW O CHO
3 min 157°C 95%
With the purpose of improvement and simplification of the synthesis of potential

cosmetic compounds, alkylation of mono- and dihydroxybenzaldehydes with long-
chain halides was efficiently realized under solvent-free MW + PTC conditions
(Eqs. 16 and 17 and Tab. 5.9) [27, 28].
O KOH O
C OH + C16H33Br C O C16H33 Eq. (16)
H Aliquat H
15 min 140°C
MW 96% ∆ 22%
O KOH + K 2CO3 O
C OH + RBr C OR Eq. (17)
H TBAB H
OH MW, 10 min 130°C OR
Tab. 5.9 Alkylation of 3,4-dihydroxybenzaldehyde with long chain alkyl bromides under the action
of MW + PTC conditions.
R C12H25 C14H29 C16H33 C18H37
Yield (%) 86 (D 18) 80 81 80

The synthesis of 8-quinolinyl ethers from 8-hydroxyquinolines and organic ha-

lides has also recently been reported under PTC conditions with microwave irradia-
tion (Eq. 18) [29].
Eq. (18)
Desyl ethers are key intermediates in the synthesis of biologically active furanopy-
rones. MW-assisted synthesis of these has been performed in an open vessel under
PTC solvent-free conditions (Eq. 19) by alkylation of 7-hydroxy-4-methyl coumarin
with desyl chloride [30].
H3C O O O Ph H3C O O O
K 2CO3/NBu 4HSO4
+ Cl CH COPh
MW 2 min
OH O CH COPh
98% Ph
Eq. (19)
Alkylations of phenols with epichlorohydrin under PTC conditions and microwave

irradiation were described twice in 1998. Subsequently, ring-opening reactions of the
epoxide group were also performed using microwaves (Eqs. 20 and 21) [31, 32]. In
the first catalytic synthesis of chiral glycerol sulfide ethers was described [31]; in the
second biologically active amino ethers were prepared [32].
O NaOH, TBAB Ar O O Ar'SH OH

Cl ArO S Ar'
ArOH +
MW NaOH, PEG-400
DMF
MW (750 W) 8 min. 67-92%
Eq. (20)
Cl O K 2 CO3 /KOH, TBAB Ar O O RNH 2 OH

ArOH + ArO NHR
MW K 2CO3 /NaOH, TBAB
67-96% Silica gel
MW 10-40 min. 67-89%
Eq. (21)
Condensation of salicylaldehyde and its derivatives with a variety of esters of chlo-

roacetic acids in the presence of TBAB led to the synthesis of benzo[b]furans by
means of a solid±liquid PTC reaction under the action of microwave irradiation [33].
This was a modification of one of the most popular routes to substituted benzo[b]fu-
rans, i. e. O-alkylation of o-hydroxylated aromatic carbonyl compounds with a-haloge-

nated carbonyl compounds, then intramolecular condensation. The mixture of alde-
hydes and chloroacetic acid esters were absorbed on potassium carbonate, then irra-
diated in an open vessel in a domestic microwave oven for 8±10 min (Eq. 22).
CHO CHO
K 2CO3, TBAB
+ Cl CO2R CO2R
OH 8-10 min O O
X X CO2R X
Y Y Y
(1) (2)
Eq. (22)
It was found that the first step was rate determining. When, moreover, the reac-
tion was run with the same reaction-temperature profiles under both conventional
(oil) and microwave (monomode cavity) conditions, different distributions of the in-
termediate (1) and final (2) products were obtained (Tab. 5.10). Indeed, the product
distribution was strongly affected by microwaves when the reaction was run at 85 8C
rather than 110 8C, and addition of a small amount of a polar or nonpolar solvent
also affected the product distribution. In this work two solvents capable of extensive
coupling (i. e. ethanol) and not coupling (i. e. cyclohexane) with microwaves were
used. Addition of ethanol strongly shifted the product distribution towards the final
product (2), whereas addition of cyclohexane resulted in much lower yield of 2 [34].
Tab. 5.10 Distribution of the intermediate (1) and final product (2) in the synthesis of benzo[b]fur-
ans under both conventional and microwave conditions.
Temperature (pC) Time (min) Solvent (mL) Yield (%)

1 2
110 10/MW ± 12 66
110 20/MW ± ± 100
110 20/D ± 4 96
85 20/MW ± 15 85
85 20/D ± 90 10
85 30/MW Cyclohexane/1.5 62 38
85 30/MW EtOH(100 %)/1.5 0 100
85 30/MW EtOH(96%)/1.5 0 100
85 30/D EtOH(100 %)/1.5 47 53
Phenolic polyethers
Polycondensations of 3,3-bis(chloromethyl)oxetane and a variety of bisphenols
were studied using the microwave-PTC technique (Eq. 23) [35]. The results ob-
tained showed the advantages of microwaves in terms of the molecular weights
for crystalline polymer, as reflected in higher values of the transition temperature
(Tg) and melting point (Tm) but also in reduction of reaction times for all types of
structure.
Eq. (23)
5.2.2
N-Alkylations
5.2.2.1 Saccharin [36]

Rapid N-alkylation of saccharin (Eq. 24) by a series of halides was performed on si-
lica gel via its sodium salt in a microwave oven. TEBA was shown to have a useful
co-catalytic effect (Tab. 5.11).
O O
Silica gel
N-Na+ + R Br N R Eq. (24)
S TEBA
S
O O O O
Tab. 5.11 N-Alkylation of saccharin with bromides under MW + PTC conditions (750 W).
R Catalyst Time (min) Yield (%)
PhCH2 None 4 8
SiO2 4 75
SiO2 + TEBA 4 92
n-C16H33 SiO2 6 82
SiO2 + TEBA 6 97
5.2.2.2 Benzoxazinones and Benzothiazinones

Rapid N-alkylation of title products was performed under PTC with MW irradiation
(Eq. 25) [37].
Y NaOH, TBAB Y
+ R X Eq. (25)
N O Silica gel N O
H R
Y = O, S MW 8-10 min. 72-90%
Y=O RX = MeI 8 min. 90%

PhCH 2Br 10 min. 84%
Y=S RX = MeI 9 min. 86%
PhCH 2Br 10 min. 80%
The Michael reaction of the same compounds with acrylonitrile and methyl acry-
late was promoted under the same conditions within 9±10 min [38].
5.2.2.3 Barbitone [39]

Under solid±liquid PTC conditions 5,5-diethylbarbituric acid was N,N-dialkylated in
a good yield in the presence of a lipophilic ammonium salts and potassium carbo-
nate when reaction mixtures were irradiated in a household microwave oven
(Eq. 26).
Et Et Et Et
+ -
O O K2CO3, Me 3N C16 H33 , Br O O
+ R X Eq. (26)
N N MW (400 W) 6-18 min. N N
H H R R
O O
Ex : PhCH2Br, 10 min., 99% 86-99%
5.2.2.4 Amides and Lactams

The N-alkylation of acetanilide under the action of microwave irradiation in the pre-
sence of a phase-transfer catalyst has also been reported (Eq. 27) [40].
O NaOH, TBAB O
H3 C + R X H3C Eq. (27)
NHPh MW N Ph
R
Ex : R-X = n -BuI 80 sec. 88%
N-Substituted amides and lactams can be rapidly N-alkylated under solid±liquid

PTC conditions by use of microwave irradiation. The reactions were performed sim-
ply by mixing an amide with 50 % excess of an alkyl halide and a catalytic amount of
TBAB. These mixtures were absorbed on a mixture of potassium carbonate and po-
tassium hydroxide [41] and then irradiated in an open vessel in a domestic micro-
wave oven for 55±150 s (Eq. 28).
R2 K CO , KOH, TBAB R2
1 2 3 1
R X + R N R N
O MW, 55-120 sec O
H R
R Eq. (28)
NH K2 CO3 , KOH, TBAB N
R X + (CH2 )n (CH2)n
MW, 80-150 sec
O O
Microwaves 55-120 sec 45-92%
The starting reagents in Gabriel amine synthesis, N-alkylphthalimides, were ob-

tained under the action of microwave irradiation in a solid±liquid PTC system. The
reactions were conducted with high yield (50±90 %) simply by mixing phthalimide
with 50 % excess alkyl halide and catalytic TBAB, which were later absorbed on po-
tassium carbonate. Irradiation of the reaction mixtures in a domestic oven led to the
desired phthalimide derivatives (Eq. 29) in a short time (4±10 min) [42].
O O
K2 CO3 , TBAB
N H + R X N R Eq. (29)
MW (450 W) 4-10 min.
O O
49-95%
Ex : R-X = PhCH 2 Cl 4 min. 93%
n -BuBr 4 min. 73%
n -C12 H 25 I 10 min. 95%
The same reaction (R±X = n-OctBr) was studied using TBAB and several basic
supports. Na2SO4 and CaCO3 (yields 93 and 95 %, respectively, within 3 min of MW
irradiation) were shown to be more efficient than K2CO3 (71%) [43].
5.2.2.5 Aromatic Amines

N-Ethylaniline was alkylated by reaction with benzyl chloride under liquid±liquid
PTC conditions in the presence of 30 % sodium hydroxide solution and CTAB as a
catalyst. Microwave irradiation (25 min) of the reaction mixture in a sealed vessel af-
forded N-benzyl-N-ethylaniline in 90 % yield, compared with 16 h of conventional
heating (oil bath) (Eq. 30) [24].
Et
NaOH / CTAB
PhNHEt + PhCH 2Cl Ph N CH 2Ph Eq. (30)
H2O
MW 25 min 90%
∆ 16h 90%
5.2.2.6 Phenylpyrrolidino[60]fullerene [44]

A facile synthesis of a series of N-alkylpyrrolidino[60]fullerenes by solvent-free PTC
under the action of microwaves has been described (Eq. 31).
Ph Ph
K 2 CO 3 , TBAB
N H + R X N R
MW (780 W) 10 min., 80°C
Eq. (31)
Ex : R-X = PhCH2 Br 70%
CH 2 =CH2 -CH2 Br 39%
n -C 8 H 17 Br 31%
The synergy between the dry media and microwave irradiation was convincingly
demonstrated in this work. For instance, with the allyl compound, the yield is only
16 % after 24 h in toluene under reflux, and no reaction occurs after 10 min at
100 8C (classical heating), thus revealing an important specific microwave effect.
5.2.2.7 Five-membered Nitrogen Heterocycles

Under microwave irradiation several azaheterocycles (i. e. pyrrole, imidazole, indole
and carbazole) can react remarkably fast with alkyl halides to give, exclusively, N-al-
kyl derivatives (Eqs. 32 and 33) [45, 46]. Such reactions have been performed simply
by mixing an azaheterocycle compound with 50 % excess alkyl halide and a catalytic
amount of TBAB. The reactants were absorbed either on a mixture of potassium car-
bonate and potassium hydroxide or on potassium carbonate alone and then irra-
diated in a domestic microwave oven for 30 s±10 min.
N K 2 CO 3 / KOH, TBAB N
+ R X Eq. (32)
N MW (300 W) 30 sec.-1 min. N
H R
Ex : PhCH 2 Cl, 40 sec., 89% 73-89%
K2CO3, TBAB
+ R X Eq. (33)
MW (450 W) 4-10 min. N
N
H R
79-95%
Ex : R-X = PhCH2Cl 4 min. 70%
n -BuBr 4 min. 73%
n-C10 H21 Cl 10 min. 95%
5.2.2.8 Pyrimidine and Purine Derivatives [47]

Selective N-alkylation of 6-amino-2-thiouracil with different halides has been per-
formed efficiently by use of MW-assisted methods in the presence of small amounts
of DMF to improve energy transfer (Eq. 34 and Tab. 5.12). No reaction was observed
under the same conditions in a thermoregulated oil bath.
O O
HN RX / DMF HN
Eq. (34)
Na 2 CO3 S N NH2
S N NH2
nBu4NI
H R
Tab. 5.12 Alkylation of 6-amino-2-thiouracil under PTC + MW conditions.
RX Time (min) Temperature (pC) Yield (%)
p-NO2C6H4CH2Cl 6 70± 75 91
p-BrC6H4COCH2Br 6 70± 75 95
Br-(CH2)5-Br 10 80± 85 87
n-C16H33Br 9 105±110 91
5.2.3
C-Alkylations of Active Methylenes [48±57]
Several monoalkylations of functionalized acetates (Eq. 35) have been described in a

series of papers; the reactions were performed on potassium carbonate, either pure
or mixed with potassium hydroxide. Some significant results are given in Tab. 5.13.
n-Bu4N+X- R COOEt
R COOEt + R' X + Base Eq. (35)
R'
Tab. 5.13 Monoalkylation of functionalized acetates in a microwave oven (650 W).
R R'X Time (min) Yield (%) Ref.
PhSO2 PhCH2Cl 3 76
n-BuBr 3 83 49
n-OctBr 3 79
PhCH=N PhCH2Cl 1 63 50
n-BuBr 2 55
PhS PhCH2Cl 4.5 83 51, 52
n-BuBr 4.5 59
CH3CO PhCH2Cl 3 81 53
n-BuBr 4.5 61
COOEt PhCH2Cl 2 72
n-BuBr 2 86 54
AllylBr 2 75
p-NO2-C6H4 Ph-(CH2)3-I 3.5 55 55
Ph-(CH2)8-I 7 79
p-NO2-C6H4 Ph-S-(CH2)6-Br 7 50 55
Ph-S-(CH2)8-Br 7 59
Rapid monoalkylations are achieved in good yield compared with classical methods.
Of particular interest is the synthesis of a-amino acids by alkylation of aldimines with
microwave activation. Subsequent acidic hydrolysis of the alkylated imine provides
leucine, serine, or phenylalanine in preparatively useful yields within 1±5 min [50].
Alkylation of phenylacetonitrile was performed by solid±liquid PTC in 1±3 min
under microwave irradiation (Eq. 36 and Tab. 5.14). The nitriles obtained can subse-
quently be quickly hydrolyzed in a microwave oven to yield the corresponding
amides or acids [56].
R
NaOH, TEBACl
PhCH 2 CN + R-X Ph CH CN + Ph C CN Eq. (36)
H2 O R R
Tab. 5.14 Alkylation of phenylacetonitrile under MW + PTC conditions (NaOH 6 equiv., TEBA
15 %).
R PhCH2CN/RX Time (min) Power (W) Yield (%)
PhCH2Br 1.5 1 350 62/32

1.5 3 160 58/35
n-HexBr 1.5 1 350 70/0
AllylBr 1.5 3 160 48/10
0.5 2 160 96/2
Functional groups were selectively introduced at the C-2 position of isophorone by

epoxide ring-opening by several nucleophiles with active methylene groups. Diffe-
rent behavior was observed depending on the reaction conditions and the nature of
the nucleophilic agents [57]. The best experimental systems involved PTC or KF-alu-
mina under solvent-free conditions and MW irradiation (Eq. 37 and Tab. 5.15).
O O X O X
X
K 2CO3 / Aliquat Y -H2 O Y
O + CH 2 OH
Y Eq. (37)
Tab. 5.15 Epoxyisophorone ring opening by reaction with several active methylene compounds un-
der MW + PTC conditions.
X Y Temperature (pC) Time Yield (%)

MW D
COOEt COOEt 95 2 min 83 40

CN Ph 70 40 s 91 51
CN CN 58 20 s 94 64
COMe COOEt 85 2 min 78 40
CN CONH2 90 1 min 91 54
5.2.4
Alkylations with Dihalogenoalkanes
5.2.4.1 O-Alkylations
Ethers from alkylation of furfuryl alcohol with dihalides were obtained under solvent
PTC + MW conditions with quasi-quantitative yields (Eq. 38) [19].
Eq. (38)
In an analogous manner, the selectively obtained exo mono-benzylated isosorbide

[58] was alkylated by reaction with alkyl dibromides to afford new ethers from dian-
hydrohexitols moieties separated by ether functions (Eq. 39 and Tab. 5.16) [59].
OH OH O R O
O PhCH2 Br, KOH O X-R-X O O
H2 O, reflux O KOH / TBAB O O

O
15 min, solvent O CH2 Ph
OH O CH2Ph PhCH2 O
Eq. (39)
Tab. 5.16 Reaction of monobenzyloxy isosorbide with X±R±X under microwave irradiation.
X R Solvent Temperature (pC) Yield (%)

MW D
Br (CH2)8 Toluene 110 63

OTs (CH2)8 Cyclohexane 80 96 39
OTs CH2CH2OCH2CH2 Cyclohexane 80 91 36
Tosylate seemed to be a better leaving group for minimizing competitive b-elimi-

nation [60].
5.2.4.2 S-Alkylations
6-Mercaptobenzimidazo[1,2-c]quinazoline reacts with dibromo derivatives under
PTC conditions (K2CO3/TBAB). Microwave irradiation enabled a striking reduction
in reaction times (12 h compared with 15 min) with similar yields (86 and 81%)
when compared with conventional heating (Eq. 40) [61].
N
N
N S
K2CO3, TBAB, DMF
+ Br-(CH2)n-Br (CH2)n Eq. (40)
N MW, 15 min, 60°C S
n = 1, 2
N N
HS N
N
n=1 86% n=2 81%
5.2.5
Nucleophilic Additions to Carbonyl Compounds
5.2.5.1 Aldol Condensation

Jasminaldehyde can be obtained classically from heptanal and benzaldehyde in 70 %
yield within 3 days at room temperature (Eq. 41). By use of a 600-W domestic micro-
wave oven, however, an enhanced yield of 82 % was achieved in only 1 min. The
amount of side-products (self condensation of n-heptanal) decreased from 30 to 18 %
when this technique was used [62].
KOH, Aliquat Ph CHO

PhCHO + CH3(CH 2 )5 CHO Eq. (41)
MW 1 min., 82% H C5 H11
A second example of aldolization (Eq. 42) is the ªdryº reaction of ferrocene carbal-
dehyde with carbonyl compounds in the presence of potassium hydroxide, and Ali-
quat as catalyst [63]. Reactions which are too slow at room temperature are efficiently
accelerated by use of microwaves, giving good yields within a few minutes.
O
CHO
R2
O R1
KOH, Aliquat
Fe + R 1 CH 2 R2 Fe Eq. (42)
-H2O
Microwave activation and solvent-free PTC have been shown to be of prime effi-
ciency for the synthesis of new benzylidene cineole derivatives (UV sunscreens) by
the Knoevenagel reaction. When performed classically by use of KOH in ethanol at
room temperature for 12 h (Eqs. 43 and 44) the yield was 30 %. This was improved
to 90±94 % within 2±6 min under PTC + MW conditions (Tabs 5.17 and 5.18) [27, 28].
O O
O
KOH (1,5 eq) CH R
+ H C R
Aliquat (5%)
no-solvent
O O Eq. (43)
Tab. 5.17 Benzylidene derivatives of 2-cineolylol from p-substituted benzaldehydes [27].
R Time (min) Temperature (pC) Yields (%)

MW D
CH3 2 180 90 20
N(CH3)2 2 180 94 40
OC16H33 6 200 94 12
O O
O
K 2 CO3 + KOH CH OR
+ H C OR
TBAB OR
OR
O O Eq. (44)
Tab. 5.18 Benzylidene derivatives of 2-cineolylol from 3,4-dialkoxybenzaldehydes [28].
R Time (min) Temperature (pC) Yields (%)

MW D
C12H25 60 140 80 13
C14H29 60 140 78
C16H33 60 140 81
C18H37 60 140 87
5.2.5.2 Ester Saponification

Esters are easily saponified in a few minutes by use of powdered potassium hydro-
xide (2 mol equiv.) and Aliquat (10 mol%) in the absence of solvent (Eq. 45 and
Tab. 5.19) [64].
1. KOH, Aliquat
R COOR' R COOH Eq. (45)
2. HCl
Tab. 5.19 Ester saponification under MW + PTC conditions.
R R' Multimode oven (250 W) Monomode reactor (90 W) Classical heating

Time (min) Yield (%) Time (min) T (pC) Yield (%) Time (min) T (pC) Yield (%)
Ph Me 0.5 87 1 205 96 1 205 90

Ph n-Oct 1 83 2 210 94 2 210 72
2,4,6-Me3C6H2 Me 2 75 2 140 84 2 140 38
2,4,6-Me3C6H2 n-Oct 2 57 4 223 82 4 223 0
From the few examples summarized in Tab. 5.19, three important conclusions can
be drawn:
. Rapid and easy reactions occur, even with the most hindered mesitoic esters,
which are otherwise practically nonsaponifiable under classical conditions [65].
. The advantage of using a monomode reactor rather than a domestic oven is clearly
apparent.
. More interesting fundamentally is the very strong specific nonthermal effect of
microwaves, as evidenced by comparison with classical heating. This effect grows
as ester reactivity falls.
In a more detailed study, it was shown that MW effects are strongly dependent on
the temperature and the nature of the cation associated with hydroxide anion [66]
(for example Eq. (46) and Tab. 5.20).
Aliquat
CO2CH3 + M OH
+ -
CO2H + CH3OH Eq. (46)
then HCl
Tab. 5.20 Saponification of methyl benzoate under MW + PTC conditions.
M+ Base (eq) Temperature (pC) Time (min) Yield (%)

Without Aliquat With Aliquat
MW D MW D
K+ 2 200 5 94 90 98 98
K+ 1 70 60 77 42 67 65
Na+ 2 200 5 92 77 90 73
5.2.5.3 Base-catalyzed Transesterifications

Transesterifications of methyl esters with high boiling alcohols, as shown in Eq. (47),
occur readily in microwave ovens because of displacement of the evaporation of the
polar volatile methanol (Tab. 5.21) [11].
Base
ArCOOMe + n -C8H17 OH ArCOOn -C8 H17 + MeOH Eq. (47)
Aliquat
Tab. 5.21 Base-catalyzed transesterifications under MW + PTC conditions (600 W).
Ar Base Time (min) Yield (%)
C6H5 KOH 3 40
KOt-Bu 3 42
K2CO3 2.5 90
2,4,6-Me3C6H2 KOH 10 64
KOt-Bu 10 68
K2CO3 10 89
This study was next extended to the synthesis of benzoyl and dodecanoyl deriva-
tives from protected carbohydrates [67]. Microwave-assisted PTC transesterifications
with methyl benzoate or dodecanoate were studied for several carbohydrates. Small
amounts of dimethylformamide (DMF) were shown to be necessary to provide good
yields (76±96 %) within 15 min. Rate enhancements when compared to conventional
heating (D) and specific microwave activation were especially noticeable when less
reactive fatty compounds were involved (Eq. 48).
O O
O OH K2 CO3, TBAB O OR
O O
+ RCO2 CH3 Eq. (48)
O 15 min., 160°C O
O O
R = Ph MW 44%
DMF MW 96% ∆ 21%
R = CH 3(CH 2)10 DMF MW 88% ∆ 0% (id. 12h)
5.2.6
Deprotonations
5.2.6.1 Base-catalyzed Isomerization of Allylic Aromatic Compounds [68]

Eugenol is a natural product available from a variety of essential oils (cinnamon-tree
or pimentos leaves). Its isomerization (Eq. 49) into isoeugenol, the starting material
for synthetic vanillin, is rather difficult and proceeds in modest yields under rela-
tively harsh conditions. It can, however, be very efficiently prepared by use of 2.2 mo-
lar equivalents of base and catalytic (5 %) amounts of Aliquat in the absence of sol-
vent.
OMe OMe
HO HO
t BuOK, Aliquat
Eq. (49)
MW (45 W) 18 min.
94%
5.2.6.2 Carbene Generation (a-Elimination) [69]

Dichlorocarbene has been generated under solid±liquid conditions by use of micro-
waves. Heating a mixture of CHCl3, powdered NaOH, and trace amounts of CTAB
under reflux in cyclohexene with microwave irradiation afforded 90 % dichloronor-
carane (Eq. 50) within 20 min, compared with 81% in 60 min without microwave ex-
posure, or only 12 % in 90 min without the catalyst.
NaOH ..
CHCl 3 CCl 2 Eq. (50)
CTAB
Cl Cl
5.2.6.3 b-Elimination
Bromoacetals in basic media can be converted to cyclic ketene acetals (Eq. 51). These
b-eliminations, previously performed under solid±liquid PTC without solvent and
with sonication [70], were further improved by microwave irradiation (Tab. 5.22) [71].
Br O Base O
Eq. (51)
O TBAB O
Tab 5.22 b-Elimination from bromoacetals in a monomode reactor (75 W); comparison with sonochemical condi-
tions and classical heating.
Base Ultrasound conditions Microwave conditions Classical heating

t (h) T (pC) Yield (%) t (min) T (pC) Yield (%) t (min) T (pC) Yield (%)
Ph O KOH, TBAB 1 75 81 10 130 81

t-BuOK, 1 35 70 5 75 87 5 75 36
O Br TBAB
O KOH, TBAB 1 75 81 10 28
t-BuOK, 1 45 70 5 60 95 5 64 41
O Br
TBAB
With potassium t-butoxide and TBAB, higher yields are obtained more rapidly
than under sonication conditions or with conventional heating.
5.2.7
5.2.7.1 Aromatic Nucleophilic Substitution (SNAr)

The irradiation of a mixture of ortho- or para-nitrochlorobenzene and ethanol in the
presence of sodium hydroxide and a phase-transfer agent yields the corresponding
ethoxy aromatic compounds within a few minutes (Eq. 52) [72]. The same procedure
was subsequently applied to 2-chlorophenol [73]. In both reactions PEG 400 was
shown to be the most efficient catalyst (Tab. 5.23).
Cl OEt
Catalyst 10%
Z + EtOH + NaOH Z Eq. (52)
-NaCl, -H 2 O
Tab. 5.23 Aromatic nucleophilic substitution under MW + PTC conditions (420±700 W).
Z Catalyst Time (min) Yield (%) Ref.
4-NO2 None 2 14
PhCH2N+Me3Cl± 2 51 72
PEG 400 2 99
2-NO2 PEG 400 2 99 72
2-OH None 2 63
PhCH2N+Me3Cl± 2 70 73
PEG 400 2 82
Solvent-free SNAr reactions under solid±liquid PTC conditions were realized by

using methoxide or phenoxide as nucleophiles. The main results, and comparison
with those from classical heating, are indicated in Tab. 5.24 for activated (e. g. 4-nitro-
halobenzenes) or nonactivated (e. g. a-naphthyl halides) substrates [74].
Tab. 5.24 Solvent-free PTC SNAr reactions under MW + PTC conditions (potassium salts).
Catalyst Time (min) Temperature (pC) Yield (%)

MW D
Cl NO2 + PhO- 18-crown-6 5 150 93 86
F NO 2 + PhO - ± 30 150 98 73
Cl NO 2 + CH 3 O- 18-crown-6 20 170 90 37
F NO2 + CH 3O- 18-crown-6 3.5 80 100 81
Cl
+ CH3 O- 18-crown-6 60 100 71 27
F
+ CH3 O- 18-crown-6 60 80 94 57
5.2.7.2 Dealkoxycarbonylations of Activated Esters (Krapcho Reaction)

This type of reaction is usually best performed in DMSO solution. A simpler proce-
dure has been proposed which uses anionic activation and microwave irradiation,
with a metallic salt as the reagent and a PTC in the absence of solvent [75]. This pro-
cedure was applied to the striking example of cyclic b-ketoesters with considerable
improvements (Eq. 53 and Tab. 5.25) which are readily apparent when the maximum
yields obtained under classical Krapcho conditions (< 20 % when R±H) are conside-
red [76].
O O
COOEt + - R
LiBr, Bu 4N Br
R Eq. (53)
H2O
Tab. 5.25 Dealkoxycarbonylation of cyclic b-ketoesters in a monomode reactor.
R Microwave conditions T (pC) Yield (%)

Time (min) Power (W)
H 8 30 138 96
Et 15 30 160 94
n-Bu 20 45 167 89
n-Hex 20 90 186 87
To verify the specific effects of microwave irradiation, the second experiment

(R = Et) was performed using conventional oil bath heating under the same condi-
tions of time and temperature (15 min, 160 8C). No reaction was observed. Further
heating for 3 h led to total conversion but the yield (60 %) was limited by product de-
gradation. Clearly, when compared with conventional heating, microwave heating re-
sults in a large reduction in time, simplified experimental conditions, and the pre-
vention of product degradation at high temperature.
5.2.7.3 1,3-Dipolar Cycloaddition of Diphenylnitrilimine [77]

Diphenylnitrilimine (DNPI) can be subjected to 1,3-dipolar cycloaddition with acti-
vated double bonds as dipolarophiles (Eq. 54). It can be generated in situ by reaction
of hydrazonoyl chloride with a base.
Eq. (54)
The cycloaddition can be performed almost quantitatively within 6 min under the
action of microwaves, with KF as base, and Aliquat. For the sake of illustration, re-
sults for substituted chalcones are listed in Tab. 5.26. When the same reactions are
performed all other factors being equal (time, temperature), no reaction occurs un-
der classical thermal conditions. This behavior once more confirms a specific radia-
tion effect.
Tab. 5.26 1,3-Dipolar cycloaddition of DNPI to chalcones in a monomode reactor (30 W).
Z Time (min) T (pC) Yield (%)
H 6 170 90
Br 5 170 93
Cl 6 174 95
Me 6 168 87
OMe 6 175 89
5.2.7.4 Synthesis of b-Lactams [78]

With KF in the presence of a phase-transfer agent (18-crown-6) silyl ketene acetals re-
act with aldimines to give b-lactams within a few minutes under the action of micro-
wave irradiation in closed Teflon vessels (Eq. 55).
H
Ph Ph
Me OSiMe 3 KF - 18-crown-6 Ph N
N + Eq. (55)
H Ph H OMe MW (300 W) 7 min. H
Me O
93% (anti/syn = 65/35)
5.2.7.5 Selective Dealkylations of Aromatic Ethers

Ethylisoeugenol and ethoxyanisole can be selectively demethylated or deethylated by
use of potassium t-butoxide in the presence of 18-crown-6 (Eq. 56) [79].
OEt OEt OH
OMe KOtBu + 18-crown-6 OH OMe
+ Eq. (56)
(Ethylene glycol)
R R R
R = CH=CH-CH3 , H 1 2
Under solvent-free conditions only deethylation is observed whereas in the pre-

sence of ethylene glycol (EG), the selectivity is totally reversed and demethylation be-
comes the major process. In both, considerable increases in reaction rate were ob-
served under the action of microwave irradiation when compared with classical hea-
ting (D) (Tab. 5.27).
Tab. 5.27 Selective dealkylations of 2-ethoxyanisole under MW + PTC conditions (R = H).
Time (min) Temperature (pC) Starting material (%) 1 (%) 2 (%)
± MW 20 120 7 ± 90
± D 20 120 48 ± 50
EG MW 75 180 ± 72 23
EG D 75 180 98 ± ±
This procedure was extended to the hundred-gram scale with success because, un-
der rather similar conditions, yields remained excellent (82 %) requiring only a slight
modification in temperature (140 instead of 120 8C) (Tab. 5.28) [12].
Tab. 5.28 Deethylation of 2-ethoxyanisole within 20 min under MW + PTC conditions (KOtBu 2
equiv.; TDA-1 10 %).
Reactor Temperature (pC) Amounts of materials [g (mmol)] Total amount (g) Yield (%)
Ethoxyanisole KOtBu TDA-1
MW S402 120 0.76 (5) 1.12 (10) 0.324 (1) 2.206 90

MW S1000 140 37.24 (245) 54.98 (490) 15.9 (49) 108.12 82
5.2.7.6 Synthesis of Dibenzyl Diselenides

A simple, rapid and efficient method has been reported for the synthesis of dibenzyl
diselenides under the action of MW irradiation. Benzyl halides are reacted with sele-
nium powder in the presence of a base and phase-transfer agent (Eq. 57 and
Tab. 5.29) [80]. The reactions were performed either in THF or in C6H6±H2O.
CH2 X NaOH - PEG 400 CH2 Se CH2 R

R + 2 Se R
C6 H6 - H2 O, MW
72 - 95%
Eq. (57)
Tab. 5.29 Dibenzyl diselenides under MW + PTC conditions (15 min, 750 W; 15 equiv. NaOH;
5 % PEG 400).
R X Yield (%)
H Cl 75
H Br 95
4-Br Br 85
4-CH3 Br 91
4-NO2 Br 72
The same authors have more recently described the synthesis of dibenzoyl disele-
nides by reaction of selenium with sodium hydroxide under PTC and MW irradia-
tion conditions to afford sodium diselenides which react further with benzoyl chlor-
ide at 0 8C [81].
5.2.7.7 Selective Hydrolysis of Nitriles to Amides [82]

As has already been mentioned (Sect. 5.3), nitriles can be hydrolyzed to amides or
acids [56]. Nitriles can be efficiently converted into the corresponding amides in the
presence of PEG-400 and aqueous sodium hydroxide system under the action of
MW irradiation (Eq. 58 and Tab. 5.30).
O
aq NaOH - PEG 400
R C N R C NH 2 Eq. (58)
MW
Tab. 5.30 MW-promoted hydrolysis of nitriles by use of the NaOH±PEG system.
R Time (s) Yield (%)
Ph2CH 90 94
Ph 45 83
PhCH2 90 71
C17H35 60 78
2-Pyridyl 40 52
5.2.7.8 Synthesis of Diaryl-a-tetralones [83]

One-pot syntheses of diaryl-a-tetralones by Michael condensation and subsequent
Robinson annulation reactions of isophorone with chalcones were performed effi-
ciently in a solvent-free PTC system under the action of MW irradiation. Compared
with conventional heating substantial rate enhancements were observed, within very
short reaction times, by use of microwaves (Eq. 59 and Tab. 5.31). They were far bet-
ter than those achieved by the classical method (NaOEt in EtOH under reflux for
24 h; 40±56 %).
Eq. (59)
Tab. 5.31 Synthesis of diaryl-a-tetralones from isophorone and chalcone under MW + PTC condi-
tions.
Ar Time (min) Temperature (pC) Yield (%)

MW D
C6H5 5 110 86 51
p-CH3O-C6H4 5 108 86 51
p-CH3-C6H4 6 120 89 52
o-Cl-C6H4 5 110 88 54
p-Cl-C6H4 6 110 86 56
5.2.7.9 Intramolecular Cyclization

Malonic acid allylic esters undergo intramolecular cyclization reaction under solid±li-
quid phase transfer catalytic conditions in the presence of Aliquat 336, potassium
carbonate, and iodine (Eq. 60) [84]. Application of microwave irradiation to this pro-
cedure enabled 2±3-fold reduction in the reaction time compared with conventional
conditions. It was found that use of microwaves affected the exo/endo diastereoi-
somers ratio ± a linear correlation between microwave power and exo isomer concen-
tration was observed [85].
COOEt
X X COOEt
K2CO3, I 2 H
O O Eq. (60)
Y Z
Y O Aliquat 336
toluene O
Z
Microwave (boiling toluene) 10-16 min 65-67%
Conventional heating (boiling toluene) 25-30 min 65-94%
Room temperature (toluene) 6-13 h 65-94%
5.2.7.10 Heck Cross-coupling Reaction

Reaction of organic halides with alkenes catalyzed by palladium compounds (Heck-
type reaction) is known to be a useful method for carbon±carbon bond formation at
unsubstituted vinyl positions. The first report on the application of microwave
methodology to this type of reaction was published by Hallberg et al. in 1996 [86].
Recently, the palladium catalyzed Heck coupling reaction induced by microwave irra-
diation was reported under solventless liquid±liquid phase-transfer catalytic condi-
tions in the presence of potassium carbonate and a small amount of [Pd(PPh3)2Cl2]-
TBAB as a catalyst [87]. The arylation of alkenes with aryl iodides proceeded
smoothly to afford exclusively trans product in high yields (86±93 %) (Eq. 61).
Pd(PPh 3)2Cl2 , K 2 CO3 Y

R I + R Eq. (61)
Y TBAB, H 2O
Microwaves 10 min 86-93%
Conventional heating 10 min 5-15%
3-7 h 54-90%
5.2.7.11 Oxidation Reactions

By a modification of Noyori's procedure of alcohol oxidation by hydrogen peroxide
[88], primary and secondary alcohols have been oxidized to the equivalent carboxylic
acids and ketones within 20±30 min under the action of microwave irradiation [89].
The reactions were performed under liquid±liquid phase-transfer catalytic conditions
using 30 % aqueous H2O2 in the presence of sodium tungstate and tetrabutylammo-
nium hydrogen sulfate (TBAHS) as a catalyst. The experimental procedure involves
simple mixing of an alcohol, Na2WO4.H2O, and TBAHS then addition of 30 % aque-
ous H2O2, in 25 : 1 : 1 : 125 molar ratios for primary alcohols and 25 : 1 : 1 : 40 molar ra-
tios for secondary alcohols, in an open vessel. The best results were obtained when
the temperatures of reaction mixtures were 90 8C and 100 8C for primary and sec-
ondary alcohols, respectively (Eq. 62)
O
Na2WO4, TBAHS
R OH + H2O2
MW, 20 min R OH
OH O
Na2 WO4 , TBAHS
+ H2O2
R1 R2 MW, 10 min R1 R2
Eq. (62)
OH O
Na2WO4, TBAHS
+ H2O2
MW, 10 min
OH OH
Microwaves 10-20 min 60-97%
Conventional heating at 90°C 4h 83-96%
5.3 Conclusion 177
Hydrogen peroxide has also been used with microwave irradiation for the epoxida-
tion of simple or cyclic alkenes. The reactions were accomplished under liquid±li-
quid PTC conditions in ethylene chloride solution in the presence of Na2WO4 and
Aliquat 336 as catalysts. The best results were obtained at 70 8C when the concentra-
tion of hydrogen peroxide was set to 8 % and the pH of aqueous phase was kept be-
low 2 (Eq. 63) [90].
Na 2WO4, Aliquat 336 O
n + H2 O2 n Eq. (63)
MW, 70°C
ethylene chloride
Microwaves 100 min 91-98%
Conventional heating 100 min 54-65%
5.2.7.12 S-Alkylation of n-Octyl Bromide [43]

The synthesis of octylthiocyanate by reaction of n-octyl bromide with KSCN, and its
subsequent isomerization to isothiocyanate, have been realized by use of TBAB un-
der the action of MW irradiation. The effect of inorganic solid supports was studied
(SiO2, K10, graphite, NaCl) (Eq. 64).
KSCN / TBAB
R-Br R-SCN R-NCS Eq. (64)
4 min - MW
support % R-SCN % R-NCS Σ Yield
SiO2 92 8 36
K10 95 5 30
Graphite 71 29 68
NaCl 52 48 94
5.2.7.13 Reductive Decyanation of Alkyldiphenylmethanes [91]

The reaction was performed in aqueous NaOH and PEG-400 as phase-transfer agent
(Eq. 65).
NC R R
NaOH / PEG 400
Eq. (65)
2 min - MW
R = H, (CH 2)nCH 3 , CH 2CH 2 CH 2NR 2 (R = H 94%)
5.3
Conclusion
The use of microwave irradiation to provide the activation energy for synthetic che-
mistry certainly leads to faster and cleaner reactions when compared to conventional
heating. The coupling of microwave technology with solvent-free solid±liquid PTC

conditions constitutes a new and particularly efficient, powerful and attractive
method.
Significant improvements in yields or reaction conditions can be achieved, to-
gether with considerable simplification of operating procedures. The powerful syner-
gistic combination of PTC and microwave techniques has certainly enabled an ever
increasing number of reactions to be conducted under clean and mild conditions.
The inherent simplicity of the method can, furthermore, be allied with all the advan-
tages of solvent-free procedures in terms of reactivity, selectivity, economy, safety,
and ease in manipulation.
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181
6
Organic Synthesis Using Microwaves and Supported Reagents
Rajender S. Varma
6.1
Introduction
In the electromagnetic radiation region, microwaves (0.3 GHz±300 GHz) lie be-
tween radiowave (Rf) and infrared (IR) frequencies with relatively large wavelengths
(1 mm±1 m). Microwaves, nonionizing radiation incapable of breaking bonds, are a
form of energy that manifest as heat through their interaction with the medium or
materials wherein they can be reflected (metals), transmitted (good insulators that
will not heat) or absorbed (decreasing the available microwave energy and rapidly
heating the sample). This unconventional microwave (MW) energy source has been
used for heating food materials for almost 50 years [1] and is now being utilized for a
variety of chemical applications including organic synthesis [2±11] wherein chemical
reactions are accelerated because of selective absorption of MW energy by polar mo-
lecules, nonpolar molecules being inert to the MW dielectric loss [12]. The initial ex-
periments with microwave heating exploited the use of high dielectric solvents such
as dimethyl sulfoxide (DMSO) and dimethylformamide (DMF) in a household
kitchen MW oven. The rate enhancements in such reactions are now believed to be
due to rapid superheating of the polar solvents and pressure effects [12]. However, in
these solution-phase reactions, the development of high pressures, and the use of
specialized sealed vessels are some of the limitations, although they have been cir-
cumvented by the introduction of commercial MW instruments with appropriate
temperature and pressure controls.
Heterogeneous reactions facilitated by supported reagents on inorganic oxide sur-
faces have received attention in recent years, both in the laboratory as well as in in-
dustry. Although the first description of the surface-mediated chemical transforma-
tion dates back to 1924 [13], it was not until almost half a century later that the tech-
nique received extensive attention with the appearance of several reviews, books and
account articles [14±22].
A related development that had profound impact on heterogeneous reactions is
the use of microwave (MW) irradiation techniques for the acceleration of organic re-
actions. Since the appearance of initial reports on the application of microwaves for
chemical synthesis in polar solvents [11], the approach has blossomed into a useful

ISBN: 3-527-30514-9
182 6 Organic Synthesis Using Microwaves and Supported Reagents
technique for a variety of applications in organic synthesis and functional group

transformations, as is testified by a large number of publications and review articles
on this theme [2±10, 22±25]. Although reactions in conventional organic solvents
[23], ionic liquids [26±28] and aqueous media [29] have grown in view of the availabil-
ity of newer commercial MW systems, the focus has shifted to less cumbersome sol-
vent-free methods wherein the neat reactants, often in the presence of mineral oxi-
des or supported catalysts [2±6, 8, 10, 22, 25], undergo facile reactions to provide
high yields of pure products, thus eliminating or minimizing the use of organic sol-
vents. The application of microwave irradiation with the use of catalysts or mineral
supported reagents, under solvent-free conditions, enables organic reactions to occur
expeditiously at ambient pressure [2±6, 8, 10, 22], thus providing unique chemical
processes with special attributes such as enhanced reaction rates, higher yields and
the associated ease of manipulation. These reactions are effected by the reagents im-
mobilized on the porous solid supports and have advantages over the conventional
solution phase reactions because of the good dispersion of active reagent sites, asso-
ciated selectivity and easier workup.
The ready availability of inexpensive household MW ovens that can be safely used
for solvent-free reactions and an opportunity to work with open vessels, thus avoid-
ing the risk of high pressure development, are the main reasons for the popularity of
this approach worldwide. The bulk temperature attained in these solvent-free reac-
tions is relatively low although higher localized temperatures may be reached during
microwave irradiation. Unfortunately, in many of the reactions reported such accu-
rate temperature measurements have not been made. Although there is relatively
poor understanding of the reasons for dramatic rate acceleration and some research-
ers are skeptical in terms of reproducibility, this MW strategy, however, has been the
most widely practiced approach in laboratories around the globe. The recyclability of
some of these solid supports makes these processes into truly eco-friendly green pro-
cedures.
6.2
Microwave-accelerated Solvent-free Organic Reactions
The initial laboratory-scale feasibility of microwave promoted solvent-free procedure

[24] has now been illustrated for a wide variety of useful chemical transformations
such as protection/deprotection (cleavage), condensation, rearrangement reactions,
oxidation, reduction, and in the synthesis of several heterocyclic compounds on
mineral supports [4, 8, 22]. A range of industrially significant chemical entities and
precursors such as, imines, enamines, enones, nitroalkenes, sulfur compounds and
heterocycles have been synthesized in a relatively environmentally benign manner
using MW approach [2±6, 8, 10, 22, 25]. A vast majority of these solventless reactions
have been performed in open glass containers such as test tubes, beakers and round-
bottomed flasks etc. using neat reactants in an unmodified household MW oven or a
commercial MW equipment usually operating at 2450 MHz. The general procedure
involves simple mixing of neat reactants with the catalyst, their adsorption on
mineral or ªdopedº supports, and exposing the reaction mixture to irradiation in a

microwave oven.
In many cases, the comparison of a reaction accelerated by microwave irradiation
has been made with the same reaction in an oil bath at the same bulk temperature.
Unfortunately, there have been quite a few reports in the chemical literature that
have not been conducted with such proper control of conditions and consequently a
fair comparison is not possible. Nevertheless, using this MW approach, the problems
associated with waste disposal of solvents that are used several fold in chemical reac-
tions, and excess usage of chemicals are avoided or minimized. The discussion per-
taining to the preparation of supported reagents or catalysts has not been included
in this chapter because numerous review articles are available on this theme [14±22].
6.2.1
Protection±Deprotection Reactions
The protection±deprotection reaction sequences constitute an integral part of or-

ganic syntheses such as the preparation of monomers, fine chemicals, and reaction
intermediates or precursors for pharmaceuticals. These reactions often involve the
use of acidic, basic or hazardous reagents and toxic metal salts [30]. The solvent-free
MW-accelerated protection/deprotection of functional groups, developed during the
last decade, provides an attractive alternative to the conventional cleavage reactions.
6.2.1.1 Formation of Acetals and Dioxolanes

Loupy and colleagues have prepared acetals of 1-galactono-1,4-lactone in excellent
yields [31] by adsorbing the lactone and the aldehyde on montmorillonite K 10 or
KSF clay followed by exposing the reaction mixture to microwave irradiation
(Scheme 6.1).
Aldehydes and ketones have been protected as acetals and dioxolanes using ortho-
formates, 1,2-ethanedithiol or 2,2-dimethyl-1,3-dioxolane by Hamelin and coworkers.
This acid-catalyzed reaction proceeds in the presence of p-toluenesulfonic acid
(p-TsOH) or KSF clay under solvent-free conditions (Scheme 6.2). The yields ob-
OH O
R
OH Clay, RCHO O
O O
O O
HO MW, 10 min, 60–66% HO
OH OH
Scheme 6.1 Formation of acetal derivatives of 1-galactono-1,4-lactone.
R1 OH R1 O
KSF or PTSA
C O +
R OH MW, 10–30 min R O
Scheme 6.2 Formation of dioxolanes.
Methanesulphonothioate,
R1 KF-Alumina R1 SMe
CH2 C
R MW R SMe
R1 = R = CN, Ph, CO 2R, PO(OEt)2

Scheme 6.3 Formation of thioacetals.
tained with the microwave method are better than those obtained using conventional
heating in an oil bath [32].
Thioacetals have been prepared using essentially a similar technique [33]. The ac-
tive methylene compounds are adsorbed on KF-alumina, admixed with methanesul-
fonothioate and are irradiated in microwave oven to produce thioacetals in good
yields (Scheme 6.3).
6.2.1.2 N-Alkylation Reactions

Several solvent-free N-alkylation reactions have been reported which involve the use
of phase transfer agent, tetrabutylammonium bromide (TBAB), under microwave ir-
radiation conditions, an approach that is described in Chapt. 5 [34].
6.2.1.3 Deacylation Reactions

The first report on the utility of recyclable alumina as a viable support surface for
deacylation reaction is credited to Varma and his colleagues [35]. This high school
science project demonstrated that the orthogonal deprotection of alcohols is possible
under solvent-free conditions on neutral alumina surface using MW irradiation
(Scheme 6.4). Interestingly, chemoselectivity between alcoholic and phenolic groups
in the same molecule has been achieved simply by varying the reaction time; the
phenolic acetates are deacetylated faster than alcoholic analogs [35].
In an utmost simplistic approach, an unmodified household microwave oven has
been used in this study with excellent results and the generation of higher tempera-
tures is simply avoided by intermittent heating [35].
(CH2)3 OCO CH3
HO
Alumina MW Alumina
MW
(CH2)3 OCO CH3 (CH2)3 OH

Alumina
CH3 CO O MW HO
Scheme 6.4 Deacylation of alcohols and phenols on alumina.
6.2.1.4 Cleavage of Aldehyde Diacetates

A brief exposure of diacetate derivatives of aromatic aldehydes to MW irradiation on
neutral alumina surface rapidly regenerates aldehydes (Scheme 6.5) [36]. The selectiv-
ity in these deprotection reactions is achievable by merely adjusting the time of irra-
diation. As an example, for molecules bearing acetoxy functionality (R = OAc), the al-
dehyde diacetate is selectively removed in 30 s, whereas an extended period of 2 min
is required to cleave both the diacetate and ester groups. The yields obtained are better
than those possible by conventional heating methods and the procedure is applicable
to compounds bearing olefinic moieties such as cinnamaldehyde diacetate [36].
CH(OAc)2 CHO
Neutral alumina
MW, 30-40 sec

R R
Where R = H, Me, CN, NO2, OCOCH3 (88-98%)

Scheme 6.5 Cleavage of aldehyde diacetates on alumina.
Interestingly, acylal formation has been accomplished with acetic anhydride [37]
on K 10 clay (75±98 %) as well as deacylation [38].
6.2.1.5 Debenzylation of Carboxylic Esters

An efficient procedure for the debenzylation of esters has been reported by Varma
et al. under solvent-free conditions (Scheme 6.6) [39]. By altering the surface charac-
CO2R CO2R CH CH CO2R
7 min/Acidic, 92% OMe

10 min/Acidic, 90%
(20 min) 7 min/Acidic, 89%
(20 min) (20 min)
CH2CH2CO2R NH2CHCO2R
CH2OH
3 min/Neutral, (92%)
(10 min)
OH
10 min/Acidic, (92%)
NH2CH2CO2R
4 min/Neutral, (95%)
(10 min)
Where R= CH2C6H5 and time in parentheses refer to deprotection in oil bath at the same
temperature
Scheme 6.6 Debenzylation of carboxylic esters on alumina.

teristics of the solid support, the cleavage of 9-fluorenylmethoxycarbonyl (Fmoc)

group and related protected amines can be achieved in a similar fashion. The opti-
mum conditions for cleavage of N-protected moieties require the use of basic alu-
mina and irradiation time of 12±13 min at ~130±140 8C.
The hydrolysis of allyl esters has been achieved with K 10 clay [40].
6.2.1.6 Selective Cleavage of the N-tert-butoxycarbonyl Group

This approach may find application in peptide bond formation that would eliminate
the use of irritating and corrosive chemicals such as trifluoroacetic acid and piperi-
dine as has been demonstrated recently for the deprotection of N-boc groups
(Scheme 6.7); a solvent-free deprotection of N-tert-butoxycarbonyl group occurs
upon exposure to microwave irradiation in the presence of neutral alumina ªdopedº
with aluminum chloride (Scheme 6.7) [41].
R1
Lewis acid R1
N O NH
R2 But MW R2
Scheme 6.7 Deprotection of N-tert-
O butoxycarbonyl group.
6.2.1.7 Desilylation Reactions

A variety of alcohols, protected as t-butyldimethylsilyl (TBDMS) ether derivatives,
can be rapidly regenerated to the corresponding hydroxy compounds on alumina
surface using MW irradiation (Scheme 6.8) [42]. This approach prevents the use of
corrosive fluoride ions that are normally employed for cleaving the silyl protecting
groups.
Deprotection of trimethyl silyl ether has also been accomplished (88±100 %) on K
10 clay [43] or oxidative cleavage (70±95 %) in presence of clay and iron(III) nitrate [44].
6.2.1.8 Dethioacetalization Reaction

Thio acetals and ketals are important protecting groups employed in organic manip-
ulations. The regeneration of carbonyl compounds by cleavage of acid and base
stable thioacetals and thioketals is a challenging task. Normally, the cleavage of
thioacetals requires the use of toxic heavy metals such as Ti4+, Cd2+, Hg2+, Ag2+, Tl3+,
or uncommon reagents such as benzeneseleninic anhydride [45]. A high yielding so-
lid-state dethioacetalization reaction has been reported by Varma et al. using clayfen
(Scheme 6.9) [45]. The reaction is quite general and is devoid of any byproducts for-
mation except for substrates bearing free phenolic groups where ring nitration may
compete with dethioacetalization.
A report on the deprotection of thioacetals with clayan (80±89%) soon followed [46].
6.2.1.9 Deoximation Reactions

Oximes have been used as protecting groups for carbonyl compounds owing to their
hydrolytic stability. Consequently, the development of newer deoximation reagents
CHO COCH3 CH2 (CH2)2 OR
OR OR OR
(10 min, 93%) (11 min, 78%)
(10 min, 91%)
O NH2
CH3 N
HN N
RO O N RO N N
O O
OH OH
(11 min, 75%) (18 min, 68%)
CH3
CH3
(11 min, 93%)

RO
Where R = tert-Butyldimethylsilyl (TBDMS)
Scheme 6.8 Desilylation reaction on alumina.
R1 S X R1
Clayfen
C C O
R2 S Y Room Temp. or MW R2
(87–98%)
Where R1 = Ph, p-CH3 C6H4, p-NO2C6H4; R2 = H ; X–Y = –(CH2)2–
R 1 = R 2 = C 2H5 ; X–Y = –(CH2)2– ; R1 = R2 = Ph ; X = Y = C2H5
R 1 = Ph ; R2 = CH3 ; X–Y = –(CH2)2–
R 1–R2 = isoflavanolyl , 2-Methylcyclohexyl; X–Y = –(CH 2 )2–
Scheme 6.9 Dethioacetalization reaction using clayfen.

R1
R1 Silica-Ammonium persulfate
C O
C NOH
MW, 1-2 min. R2
R2 (59-83%)
Where R 1 = C6H5, p-Cl C6H4, p-CH3 C6H4, p-CH3O C6H4; R2 = CH3

R1 = 2-thienyl, 1 naphthyl, C6H5, p-NO3 C 6H5, m, p-(CH3O)2 C 6H3; R 2 = H
and R 1 = R 2 = Cyclohexyl
Scheme 6.10 Deoximation of carbonyl compounds by silica-supported ammonium
persulfate.
has continued with the availability of a wide range of such agents namely, Raney
nickel, pyridinium chlorochromate, pyridinium chlorochromate±H2O2, triethylam-
monium chlorochromate, dinitrogen tetroxide, trimethylsilyl chlorochromate,
Dowex-50, dimethyl dioxirane, H2O2 over titanium silicalite-1, zirconium sulfophe-
nyl phosphonate, N-haloamides, and bismuth chloride [47, 48].
The quest for a solvent-free deprotection procedure has led to the use of relatively
benign reagent, ammonium persulfate on silica, for regeneration of carbonyl com-
pounds (Scheme 6.10) [48]. Neat oximes are simply mixed with solid supported re-
agent and the contents are irradiated in a MW oven to regenerate free aldehydes or ke-
tones in a process that is applicable to both, aldoximes and ketoximes. The critical
role of surface needs to be emphasized since the same reagent supported on clay sur-
face delivers predominantly the Beckmann rearrangement products, the amides [49].
R1
R1
Silica-Moist NaIO4
C O
C NOH
MW, 1-2.5 min. R2
R2 (68-93%)
Where R 1 = CH3 ; R2 = Ph, p-Cl C 6H4, p-Br C6H4, p-CH3 C 6H4, p-CH3O
C6H4; p-NH2 C 6H4,
R1 = R2 = Ph; R1 = R2 = Cyclohexyl, tetrahydronaphthyl,
and R 1 = C 2H5 , R2 = n-Butyl
Scheme 6.11 Deoximation of ketoximes with silica-supported periodate.
A facile deoximation procedure with sodium periodate impregnated on moist si-

lica (Scheme 6.11) has also been introduced that is applicable exclusively to ketox-
imes [50]. Aldehydes have been regenerated from the corresponding bisulfites (85±
98 %) on KSF clay surface [51].
6.2.1.10 Cleavage of Semicarbazones and Phenylhydrazones

Carbonyl compounds are also rapidly regenerated from the corresponding semicar-
bazone and phenylhydrazone derivatives using ammonium persulfate impregnated
R1 (NH4)2S2O8 - Clay R1
C N NH R C O
R2 MW or ))))) R2
(65-94%)
Where R 1 = C 4H9, Ph, p-Cl C6H4, p-CH3 C 6H4, p-OH C6H4;
R 2 = CH3; C 2H5
and R = CONH2 , Ph
Scheme 6.12 Regeneration of carbonyls from semicarbazone and
phenylhydrazone derivatives.
on montmorillonite K 10 clay (Scheme 6.12) [52]. Interestingly, the microwave or ul-

trasound irradiation techniques can be employed in these solventless procedures;
microwave exposure achieves deprotection in minutes whereas ultrasound-promoted
reactions require 1±3 h for the regeneration of carbonyl compounds [52].
Regeneration of carbonyl compounds from the hydrazones (75±98 %) [53] and from
semicarbazones (55±90 %) [54] has also been achieved with bismuth trichloride.
6.2.1.11 Dethiocarbonylation
Dethiocarbonylation, transformation of thiocarbonyls to carbonyls, has been accom-
plished with several reagents namely, trifluoroacetic anhydride, CuCl/MeOH/
NaOH, tetrabutylammonium hydrogen sulfate/NaOH, clay/ferric nitrate, NOBF4,
bromate and iodide solutions, alkaline hydrogen peroxide, sodium peroxide, thio-
phosgene, trimethyloxonium fluoroborate, tellurium based oxidants, dimethyl selen-
oxide, benzeneseleninic anhydride, benzoyl peroxide and halogen-catalyzed alkox-
ides under phase transfer conditions [55]. However, these methods have certain lim-
itations such as the use of the stoichiometric amounts of the oxidants that are often
inherently toxic or require longer reaction time or involve tedious procedures. In a
process that is accelerated by microwave irradiation,Varma et al. have demonstrated
efficient dethiocarbonylation process under solvent-free conditions using clayfen or
clayan (Schs. 6.13 and 6.14) [55].
S
O
R2
Clayfen or (Clayan) R2
1-1.5 Min
R1
R1 (90-95 %)
Where R 1 = H, R 2 = CH3; R1 = H, Br, CH3, R2 = Ph

Scheme 6.13 Solvent-free dethiocarbonylation using clayfen or clayan.
O R1 O R1
Clayfen or (Clayan)
1.5-2 Min
R R
S (85-91 %) O
Where R = H; R 1 = Ph, p-MeC6H4, p-MeOC6H4

R =OCH3; R 2 = p-MeC 6H4
Scheme 6.14 Transformation of thiocarbonyl derivatives of flavonoids with clayfen and clayan.
6.2.1.12 Cleavage of Methoxyphenyl Methyl (MPM) and Tetrahydropyranyl (THP)

Ethers
Using clay supported ammonium nitrate (clayan), selective deprotection of methoxy-
phenyl methyl (MPM) ether has been achieved recently using microwave irradiation
in solvent-free conditions (Scheme 6.15) [56]. The same reagent has been used for
the cleavage of tetrahydropyranyl (THP) ethers. A similar selective preparation and
cleavage of THP ethers has been achieved under microwave irradiation catalyzed by
iodine [57] or neat reaction in an ionic liquid [28].
Alcohols and amines have been regenerated by MW-promoted cleavage of sulfo-
nates (83±90 %) and sulfonamides (76±85 %) respectively, on basic KF-alumina sur-
face (Scheme 6.16) [58].
MW
R OMPM R OH
Clayan
R = alkyl, alkenyl, alkynyl, aryl, acetate, ester, benzyl or silyl ether groups
Scheme 6.15 Cleavage of methoxyphenyl methyl (MPM) ethers using clayan.
O
KF-Al2O3 R1
R1 KF-Al2O3 R1
NH X S Ph CH OH
R2 R2 R2
O (83–90%)
(76–85%)
Where X = N, CH-O-
Scheme 6.16 Cleavage of sulfonates and sulfonamides on a basic KF-alumina surface.
6.2.2
Condensation Reactions
A wide variety of MW-assisted aldol [59, 60] and Knoevenagel condensation reactions
have been accomplished using relatively benign reagents such as ammonium acetate
[61], including the Gabriel synthesis of phthalides with potassium acetate [62].
6.2.2.1 Wittig Olefination Reactions

Some difficult Wittig reactions of stable phosphorus ylides with ketones have been
accelerated by microwave irradiation (Scheme 6.17) [63]. When compared to conven-
tional method, an improved yield has been achieved within a shorter time using
MW irradiation in the absence of solvent.
Additional reports on olefination reactions have appeared [64] including the pre-
paration of several phosphonium salts using a domestic MW oven wherein the reac-
tion of neat triphenylphosphine and organic halide shows remarkable rate enhance-
ment in a pressure tube with a threaded Teflon cap [65].
6.2.2.2 Knoevenagel Condensation Reactions ± Synthesis of Coumarins

Knoevenagel condensation reaction of creatinine with aldehydes occurs rapidly un-
der solvent-free reaction conditions at 160±170 8C using focused microwave irradia-
tion (Scheme 6.18) [66].
5-Nitrofurfurylidines have been prepared by condensation of 5-nitrofurfuralde-
hyde with active methylene compounds under microwave irradiation using ZnCl2
and K 10 as catalysts [67].
The classical Pechmann approach for the synthesis of coumarins via the micro-
wave-promoted reaction [68] has been extended to solvent-free system wherein salicy-
(Ph)3 P=CHCOOEt
MW (200 W), 15 min

EtOOCHC
O
Scheme 6.17 MW-assisted Wittig olefination reaction.
Me R Me
N N
MW H
NH + RCHO NH
O N O N
H H
Scheme 6.18 Knoevenagel condensation reaction of creatinine with alde-
hydes.
CHO R3
R3 Base (Piperidine)
+
CO2Et MW
R1 OH R1 O O
R2 R2
Scheme 6.19 MW-assisted synthesis of coumarins.
laldehydes undergo Knoevenagel condensation with a variety of ethyl acetate deriva-

tives in the presence of piperidine to afford coumarins (Scheme 6.19) [69].
6.2.2.3 Synthesis of Imines, Enamines, Nitroalkenes and N-Sulfonylimines

The preparation of imines, enamines, nitroalkenes and N-sulfonylimines proceeds
via the azeotropic removal of water from the intermediate in reactions that are nor-
mally catalyzed by p-toluenesulfonic acid, titanium(IV) chloride, or montmorillonite
K 10 clay. A Dean±Stark apparatus is traditionally used which requires a large excess
of aromatic hydrocarbons such as benzene or toluene for azeotropic water elimina-
tion.
MW-expedited dehydration reactions using montmorillonite K 10 clay [70]
(Schs. 6.20 and 6.21) or Envirocat reagent, EPZG [71] (Schs. 6.20 and 6.21) have
been demonstrated in a facile preparation of imines and enamines via the reactions
of primary and secondary amines with aldehydes and ketones, respectively. The gen-
eration of polar transition state intermediates in such reactions and their enhanced
CH
CH O H2 N K 10 Clay or EPZG N
+
MW, 1–3 min.
R R
(90–97%)
Where R = H, o-OH, p-OH, p-Me, p-OMe, p-NMe2

Scheme 6.20 Clay-catalyzed formation of imines under solvent-free conditions.
Y Y
O ( )n ( ) n2
Y EPZG or K 10 Clay 2
N H2 O N
( )n
1
+ ( )n
2 MW, 2–6 min.
OH
N ( )n ( )n
H 1 1
n1 = 1 ; n2 = 2 ; Y = CH2 ; n1 = 1 ; n2= 2 ; Y = O (90–96%)

n1 = 2 ; n2 = 1 ; Y = CH2 ; n1= 2 ; n2 = 2 ; Y = CH2
n1 = 2 ; n2 = 2 ; Y = O
Scheme 6.21 Clay-catalyzed formation of enamines under solvent-free conditions.
coupling to microwaves is possibly responsible for these rapid imine- or enamine-

forming reactions. To prevent the loss of low boiling reactants, the use of microwave
oven at lower power levels or intermittent heating has been used [70, 71].
The condensation reaction of neat carbonyl compounds with nitroalkanes to af-
ford nitroalkenes, Henry reaction, also proceeds rapidly via this MW approach in the
presence of only catalytic amounts of ammonium acetate, thus avoiding the use of a
large excess of polluting nitrohydrocarbons normally employed (Scheme 6.22) [72].
The cycloaddition, reduction and oxidation reactions emanating from a,b-unsatu-
rated nitroalkenes provide easy access to a vast array of functionalities that include
nitroalkanes, N-substituted hydroxylamines, amines, ketones, oximes, and a-substi-
tuted oximes and ketones [73±75]. Consequently, there are numerous possibilities of
using these in situ generated nitroalkenes for the preparation of valuable building
blocks and synthetic precursors.
Expeditious preparation of N-sulfonylimines has been optimized for one-pot sol-
ventless operation that involves microwave thermolysis of aldehydes and sulfon-
amides in presence of relatively benign reagents, calcium carbonate and montmoril-
lonite K 10 clay (Scheme 6.23) [76].
Bis(indolyl)nitroethanes are obtained readily in 7±10 min in high yields (70±86 %)
on fine TLC-grade silica gel (5±40 mm) by Michael reaction of 3-(2'-nitrovinyl) indole
with indoles. The same reaction reported requires 8±14 h for completion at room
temperature [77]. Several functionalized resins have been prepared from Merrifield
resin via a MW-assisted procedure that utilized mixed solvent system to facilitate the
swelling of resins and coupling with microwaves [78]. These resins can function as
solid supports or polymeric scavengers in solid phase synthesis.
The formation of hydrazones from the corresponding carbonyl compounds has
been accomplished initially in toluene [79]. The treatment of hydrazone with alkali
(KOH) accomplishes Wolff±Kichner reduction that proceeds in good yield under
CHO NO2
NH4OAc
+ RCH2NO2
MW, 2.5–8 min. R
X X (80–92%)
Where R = H, X = H, p-OH, m,p-(OMe)2, m-OMe-p-OH, 1-naphthyl, 2-naphthyl
R = Me, X = H, p-OH, p-OMe, m,p-(OMe)2, m-OMe-p-OH
Scheme 6.22 MW-assisted preparation of a,b-unsaturated nitroalkenes.
R1 R1
CHO CaCO3/K 10 Clay CH=N SO2
R R
+
CH(OMe) 3, MW, 30-70 W
H2NSO2 (52 - 91%)
R2 R2
Where R = H, Me, COOMe, Cl; R1 = H, OMe, OCOMe, Br; R2 = H, OMe, OCOMe

Scheme 6.23 One-pot solventless preparation of N-sulfonylimines.
R R
O O O O
R1 NHNH2 R
R
MW
NHCOPh NHCOPh
O N
R1 NH
Where R = H or Me and R1 = Aryl and substituted aryl groups

Scheme 6.24 Formation of hydrazones under solvent-free and catalyst-free conditions.
MW irradiation conditions [80]. More recently, however, Varma and Kocevar's group
have shown that a solvent-free and catalyst-free reaction of hydrazines with carbonyl
compounds is possible upon MW irradiation (Scheme 6.24) [81]. Interestingly, the
general reaction proceeds smoothly even for solid reactants and is completed below
the melting points of the two reactants possibly via the formation of a eutectic. The
reactions have been conducted in household MW oven and the control experiments
are conducted concurrently in separate open beakers; the reactions can be essentially
followed by visual observation when a melt is obtained [82].
An interesting solid-state synthesis of amides has also been reported in a MW
oven that uses potassium tert-butoxide and easily accessible reagents, nonenolizable
esters and amines [83].
The kinetics of the acid-catalyzed esterification reaction of 2,4,6-trimethylbenzoic
acid in i-PrOH under microwave irradiation have been investigated [84]. A simple
and practical technique for MW-assisted synthesis of esters has been reported
wherein the reactions are conducted either on solid mineral supports or by using a
phase transfer catalyst (PTC) in the absence of organic solvents [85]. The esterifica-
tion of enols with acetic anhydride and iodine has also been recorded [86].
The detailed account of condensation reactions as applied to heterocyclic chemis-
try is found in subsequent section (Sect. 6.2.6), Chapt. 8 [87] and for cycloaddition re-
actions in Chapt. 9 [88].
6.2.3
Isomerization and Rearrangement Reactions
Numerous rearrangement and isomerization reactions have been reported using

MW irradiation. Some reactions are performed in solution phase while others on
graphite or mineral support surface often ªdopedº with Lewis acids and sometimes
even by heating the neat reactants. The notable examples are, Benzil±benzilic acid
rearrangement [89], solventless Beckmann rearrangement on K 10 clay [49], Fries re-
arrangement on K 10 clay that affords mixture of ortho and para products [90], and
thia-Fries rearrangement of arylsulfonates using aluminum and zinc chloride on si-
lica gel [91].
6.2.3.1 Eugenol±Isoeugenol Isomerization

Eugenol undergoes MW-assisted isomerization to isoeugenol under solvent-free con-
dition in the presence of potassium tert-butoxide, t-BuOK, and a catalytic amount of
phase transfer reagent [34].
6.2.3.2 Pinacol±Pinacolone Rearrangement

A solvent-free pinacol±pinacolone rearrangement has been reported using micro-
wave irradiation. The process involves the irradiation of the gem diols with Al3+-mon-
tmorillonite K 10 clay for 15 min to afford the rearrangement product in excellent
yields (Scheme 6.25) [24]. The comparative studies performed by conventional heat-
ing in an oil bath showed that the reaction times are too long (15 h).
An efficient ring-expansion transformation has also been described under solvent-
free conditions (Scheme 6.26) [92]. This microwave procedure is superior to the
same reactions conducted in traditional methanolic solution.
6.2.3.3 Beckmann Rearrangement

A simple montmorillonite K 10 clay surface is one among numerous acidic supports
that have been explored for the Beckmann rearrangement of oximes (Scheme 6.27)
[54]. However, the conditions are not adaptable for the aldoximes that are readily de-
hydrated to the corresponding nitriles under solventless conditions. Zinc chloride
has been used in the above rearrangement for benzaldehyde and 2-hydroxyacetophe-
none, the later being adapted for the synthesis of benzoxazoles.
Me Me
Me OH Al 3+ –Montmorillonite Me O
MW, 15 min Me
HO Me Me
Me
(98-99%)
Scheme 6.25 Pinacol±pinacolone rearrangement on Al3+-montmorillonite
K 10 clay.
SC6H5 SC6H5
Cl AgBF4–Al2O3
Cl
Cl MW, 10 min
(75%)
Scheme 6.26 MW-assisted ring expansion reaction on alumina.
R1 O
Montmorillonite K 10 clay
C N OH R1 C NH R2
R2 MW, 7-10 min.
Where R1= CH3 or Ph and R 2 = Ph or substituted phenyl
Scheme 6.27 Beckmann rearrangement of oximes on clay.
Among numerous other studies, Ferrier rearrangement is notable since it pro-

ceeds well (72±83 %) upon irradiation of neat reactants [93].
6.2.4
Oxidation Reactions ± Oxidation of Alcohols and Sulfides
Metal-based reagents have been extensively used in organic synthesis. Peracids, per-
oxides, potassium permanganate (KMnO4), manganese dioxide (MnO2), chromium
trioxide (CrO3), potassium dichromate (K2Cr2O7) and potassium chromate (K2CrO4)
are some of the common oxidizing reagents employed for organic functional groups
[94, 95].
The utility of such reagents in the oxidation processes is compromised due to their
inherent toxicity, cumbersome preparation, potential danger in handling of metal
complexes, difficulties encountered in product isolation and waste disposal pro-
blems. Immobilization of metallic reagents on solid supports has circumvented
some of these drawbacks and provided an attractive alternative in organic synthesis
because of the selectivity and associated ease of manipulation. Further, the localiza-
tion of metals on the mineral oxide surfaces reduces the possibility of their leaching
into the environment.
6.2.4.1 Activated Manganese Dioxide±Silica

Manganese dioxide (MnO2) supported on silica provides an expeditious and high-
yield route to carbonyl compounds. Benzyl alcohols are selectively oxidized to carbo-
nyl compounds by use of 35 % MnO2 ªdopedº silica under MW irradiation condi-
tions (Scheme 6.28) [96].
Manganese dioxide on bentonite clay has also been used for oxidation of phenols
to quinones (30±100 %) [97] and MnO2 on silica effects the dehydrogenation of pyr-
rolidines (58±96%) [98].
6.2.4.2 Chromium Trioxide±Wet Alumina

The deployment of chromium(VI) reagents in the oxidative transformation is com-
promised due to inherent toxicity, involved preparation of its various complex forms
(with pyridine or acetic acid) and cumbersome workup procedures. Chromium triox-
ide (CrO3) immobilized on premoistened alumina enables efficient oxidation of ben-
R1 MnO2-Silica R1
CH OH C O
R2 MW, 20-60 sec. R2
(67-96%)
Where R 1 = H; R 2 = Ph, p-MeC6H4, p-MeOC 6H4, PhCH=CH

R 1 = Et, Ph, PhCO; R 2 = Ph ; R 1 = R 2 = hydroquinone
R1 = p-MeOC6H4CO; R 2 = p-MeOC 6H4
Scheme 6.28 Oxidation of alcohols by silica-supported manganese dioxide.
R1 CrO3–Wet Al2O3 R1
CH OH C O
R2 MW, 40 sec. R2
(73-90%)
R1 = Ph, p-MeC6H4, p-MeOC 6H4, p-NO2C6H4 ; R2 = H
R1 = Ph ; R2 = Me, Ph, PhCO; R1 = R2 = ,
Scheme 6.29 Oxidation of alcohols by chromium trioxide supported on
premoistened alumina.
zyl alcohols to carbonyl compounds by simple mixing with various substrates

(Scheme 6.29). Interestingly, no overoxidation to carboxylic acids is observed and
products are devoid of tar contaminants, a typical occurrence in many CrO3 oxida-
tions [99].
6.2.4.3 Selective Solvent-free Oxidation with Clayfen

A facile method for the oxidation of alcohols to carbonyl compounds has been re-
ported by Varma et al. using montmorillonite K 10 clay-supported iron(III) nitrate
(clayfen) under solvent-free conditions [100]. This MW-expedited reaction presum-
ably proceeds via the intermediacy of nitrosonium ions. Interestingly, no carboxylic
acids are formed in the oxidation of primary alcohols. The simple solvent-free experi-
mental procedure involves mixing of neat substrates with clayfen and a brief expo-
sure of the reaction mixture to irradiation in a MW oven for 15±60 s. This rapid, ma-
nipulatively simple, inexpensive and selective procedure avoids the use of excess sol-
vents and toxic oxidants (Scheme 6.30) [100]. Solid state use of clayfen has afforded
higher yields and the amounts used are half of that used by Laszlo et al. [17, 19].
A ground mixture of iron(III) nitrate and HZSM-5 zeolite, termed ªzeofenº, has
also been used both, in dichloromethane solution and in solid state under MW irra-
diation conditions [101]. It has been suggested that the zeolite aids the reproducibil-
ity of the reaction but any other aluminosilicate support would probably be equally
effective. Recent studies point out attractive alternatives that do not employ any of
the solid supports in such oxidations with nitrate salts [102].
R1 Clayfen R1
CH OH C O
R2 MW, < 1 Min. R2
(87-96%)
Where R1 = H; R2 = Ph, p-MeC6 H4, p-MeOC6H4, 2-tetrahydrofuranyl

R1 = Et, PhCO; R2 = Ph ; R1 - R2 = cyclohexyl
R1 = p-MeOC6H4CO; R2 = p-MeOC6H4
Scheme 6.30 Solvent-free selective oxidation of alcohols with clayfen.
6.2.4.4 Oxidations with Claycop±Hydrogen Peroxide

Metal ions play an important role in several of these oxidative reactions as well as in
biological dioxygen metabolism. As an example, copper(II) acetate and hydrogen per-
oxide have been used to produce a stable oxidizing agent, hydroperoxy copper(II)
compound. The same oxidation system is also obtained from copper(II) nitrate and
hydrogen peroxide (Eq. 1) [103] but requires the neutralization of ensuing nitric acid
by potassium bicarbonate to maintain a pH & 5.
2 Cu (NO3)2 + H2O2 + 2 H2 O 2 Cu O2 H + 4 HNO3 Eq: 1
Copper(II) nitrate immobilized on K 10 clay (claycop)±hydrogen peroxide system

is an effective oxidant for a variety of substrates and provides excellent yields
(Scheme 6.31) [104] wherein the maintenance of pH of the reaction mixture is not
required.
R1 H2O2-Claycop R1
CH R3 C O
R2 MW R2
(71-85%)
Where R1 = Ph, p-NO2 C 6H 4; R2 = H, Ph; R 3 = H, Br, CN, NH2, COOH
Scheme 6.31 Oxidation reactions with claycop and hydrogen peroxide.
6.2.4.5 Other Metallic Oxidants ± Copper Sulfate or Oxone±Alumina

Symmetrical and unsymmetrical benzoins have been rapidly oxidized to benzils in
high yields using solid reagent systems, copper(II) sulfate±alumina [105] or Oxone±
wet alumina [105, 106] under the influence of microwaves (Scheme 6.32). Conven-
tionally, the oxidative transformation of a-hydroxyketones to 1,2-diketones is accom-
plished by reagents such as nitric acid, Fehling's solution, thallium(III) nitrate (TTN),
ytterbium(III) nitrate, ammonium chlorochromate±alumina and clayfen. In addition
to the extended reaction time, most of these processes suffer from drawbacks such as
the use of corrosive acids and toxic metals that generate undesirable waste products.
OH O
R2 Oxone –Al2O3 or CuSO4–Al2O3 R2
R1 MW, 2-3.5 min. R1
O O
(71-96%)
Where R1 = R2 = C 6H5, p-MeC6H4, p-MeOC6H4, p-ClC6H4,

O
R 1 = C6H5; R 2 = p-MeC6H4, p-MeOC6H4
and R 1 = Me; R2 = C6H5
Scheme 6.32 Oxidation of a-hydroxyketones with alumina-supported copper sulfate
or Oxone.
Under these solvent-free conditions, the oxidation of primary alcohols (e. g. benzyl
alcohol) and secondary alcohols (e. g. 1-phenyl-1-propanol) is rather sluggish and
poor and is of little practical utility. Consequently, the process is applicable only to
a-hydroxyketones as exemplified by various examples including a mixed benzylic/ali-
phatic a-hydroxyketone, 2-hydroxypropiophenone that delivers the corresponding
vicinal diketone [106, 107].
6.2.4.6 Nonmetallic Oxidants: Iodobenzene Diacetate (IBD)-Impregnated Alumina

Several organohypervalent iodine reagents have been used for the oxidation of alco-
hols and phenols such as iodoxybenzene, o-iodoxybenzoic acid (IBX), bis(trifluoroa-
cetoxy)iodobenzene (BTI), and Dess±Martin periodinane etc. But the use of inexpen-
sive iodobenzene diacetate (IBD) as an oxidant, however, has not been fully
exploited. Most of these reactions are conducted in high boiling DMSO or toxic acet-
onitrile media that results in increased burden on the environment.
Varma and coworkers have explored the use of hypervalent iodine compounds on
solid support for the first time and developed a facile oxidative procedure that rapidly
converts alcohols to the corresponding carbonyl compounds using alumina-sup-
ported IBD under solvent-free conditions and MW irradiation in almost quantitative
yields [108]. The use of alumina as a support improved the yields markedly as com-
pared to neat IBD (Scheme 6.33). 1,2-Benzenedimethanol, under these conditions,
undergoes cyclization to afford 1(3H)-isobenzofuranone.
R1 IBD / Neutral alumina R1

CH OH C O
R2 MW, 1-3 min
R2
(86-96%)
Where R1 = Ph, substituted Ph and R2 = H, C2H5, COC6H5

Scheme 6.33 Oxidation of alcohols using alumina-supported
iodobenzene diacetate.
6.2.4.7 Oxidation of Sulfides to Sulfoxides and Sulfones ± Sodium Periodate±Silica

The oxidation of sulfides to the corresponding sulfoxides and sulfones proceeds un-
der rather strenuous conditions requiring strong oxidants such as nitric acid, hydro-
gen peroxide, chromic acid, peracids, and periodate. Using MW irradiation, this oxi-
dation is achievable under solvent-free conditions and with desired selectivity to
either sulfoxides or sulfones using 10 % sodium periodate on silica (Scheme 6.34)
O
20% NaIO 4-Silica (3.0 eq.) 20% NaIO 4-Silica (1.7 eq.)
R1-SO2-R2 R 1-S-R2 R1-S-R2
MW, 1-3 min. MW, 0.5-2.5 min.
(72-93%) (76-85%)
Where R1 = R2 = Ph, PhCH2, n-Bu,

R1 = PhCH2 ; R2 = Ph ; R1 = Ph, n-C12H25 ; R 2 = Me
Scheme 6.34 Oxidation of sulfides to sulfoxides and sulfones by silica-supported sodium periodate.
[109]. A relatively reduced amount of the active oxidizing agent is employed which is
safer and easier to handle.
Several refractory thiophenes, that are often not reductively removable by conven-
tional refining processes, can be oxidized under these conditions, e. g. benzothio-
phenes are oxidized to the corresponding sulfoxides and sulfones using ultrasonic
and microwave irradiation, respectively, in the presence of NaIO4±silica [109]. A note-
worthy feature of the procedure is its applicability to long chain fatty sulfides that
are insoluble in most solvents and are consequently difficult to oxidize.
6.2.4.8 Oxidation of Sulfides to Sulfoxides ± Iodobenzene Diacetate±Alumina

As described earlier (Sect. 6.2.4.6), the solid reagent system, IBD±alumina, is a use-
ful oxidizing agent and its use is extendible to rapid, high yield and selective oxida-
tion of alkyl, aryl and cyclic sulfides to the corresponding sulfoxides upon microwave
activation (Scheme 6.35) [110].
O
IBD-Alumina
R1—S—R2 R—S—R2
MW, 40-60 sec.
(80-90%)
where R1 = R2 = i-Pr, n-Bu, Ph, PhCH2 ; R 1 = Ph ; R2 = Me, PhCH2
R1 = n-C 12H25 ; R1 = Me ; R1 = R2 = , O
Scheme 6.35 Oxidation of sulfides to sulfoxides by alumina-supported
iodobenzene diacetate.
6.2.4.9 Oxidation of Arenes and Enamines ± Potassium Permanganate (KMnO4)±

Alumina
KMnO4 impregnated alumina oxidizes arenes to ketones within 10±30 min under
solvent-free conditions using focused microwaves [111]. b,b-Disubstituted enamines
have been successfully oxidized into carbonyl compounds with KMnO4 ±Al2O3 in do-
mestic (255 W, 82 8C) and in focused microwave ovens (330 W, 140 8C) under sol-
vent-free conditions by Hamelin et al. [112]. The yields are better in the latter case.
When the same reactions are conducted in an oil bath at 140 8C, no carbonyl com-
pound formation is observed (Scheme 6.36).
O
O
N R1 KMnO4- Al2O3 R1
N + O
H R2 MW
R2
CHO
Scheme 6.36 Oxidation of enamines with alumina-supported potassium
permanganate.
6.2.4.10 Other Oxidation Reactions

A rapid self coupling reaction of b-naphthols occurs in presence of iron(III) chloride,
FeCl3.6H2O, using a focused MW oven under solvent-free conditions and is superior
to classical heating mode [113].
Additional examples of oxidative procedures with microwave irradiation include
the oxidation of benzylic bromides to corresponding aldehydes with pyridine N-oxi-
des (15±95 %) [114]. The catalyst system, V2O5/TiO2 and modified forms thereof by
addition of an effective MW coupling dielectric such as MoO3, WO3, Nb2O5 or Ta2O5
have been explored in the selective oxidation of toluene to benzoic acid under MW ir-
radiation. In the conventional heating process, the additives have no positive influ-
ence on catalyst's performance [115].
6.2.5
Reduction Reactions
In MW-assisted chemistry reduction reactions were the last to appear on the scene;
the use of ammonium formate and catalytic transfer hydrogenation were initial ex-
amples [23 b].
6.2.5.1 Reduction of Carbonyl Compounds with Aluminum Alkoxides

The pioneering work of Posner, on the reduction of carbonyl compounds with iso-
propyl alcohol and alumina [116], has now been adapted to an expeditious solvent-
free reduction procedure that utilizes aluminum alkoxides under microwave irradia-
tion conditions (Scheme 6.37) [117].
R1 Me R1 Me
Aluminum alkoxide
O + CHOH CHOH + O
R2 Me MW R2 Me
Scheme 6.37 Solvent-free reduction of carbonyls using aluminum alkoxides.
6.2.5.2 Reduction of Carbonyl Compounds to Alcohols ± Sodium Borohydride±

Alumina
Inexpensive and safe sodium borohydride (NaBH4) has been extensively used as a re-
ducing agent because of its compatibility with protic solvents. Solid-state reduction
of carbonyl compounds has been achieved by admixing substrates with NaBH4 and
storing the reaction mixture in a dry box for five days. The disadvantage in the het-
erogeneous reduction reaction with NaBH4 is that the solvent slows down the reac-
tion rate while in the solid-state reactions, the required time (5 days) is too long for it
to be of any practical utility [118].
Varma and coworkers reported, for the first time, a simple method for the expedi-
tious reduction of aldehydes and ketones that uses alumina-supported NaBH4 and
proceeds in the solid state using microwaves [119]. The process, in its entirety, in-
volves mixing of carbonyl compounds with (10 %) NaBH4±alumina and irradiation
of the reaction mixture in a household MW oven for 0.5±2 min (Scheme 6.38).
O OH
NaBH4-Al2O3
R1 C R2 R1 CH R2
MW, 0.5–2 min
(62–93%)
Where R 1 = Cl, Me, NO2 ; R2 = H ; R 1 = H ; R2 = Me, Ph

R1 = Ph ; R 2 = PhCH(OH) ; R1 = R2 = Me,
R1 = p-MeOC 6H4; R2 = p-MeOC6H4CH(OH)
Scheme 6.38 Reduction of carbonyl compounds using alumina-supported
sodium borohydride.
The useful chemoselective feature of the reaction is apparent from the reduction
of trans-cinnamaldehyde (cinnamaldehyde/NaBH4±alumina, 1 : 1 mol equivalent);
olefinic moiety remains intact and only the aldehyde functionality is reduced in a fa-
cile reaction.
No side products are formed and the reaction does not proceed in the absence of
alumina. Further, the reaction rate improves in the presence of moisture. The moist-
ure is absorbed by alumina during the recovery of the product. The alumina support
can be recycled and reused for subsequent reduction, repeatedly, by mixing with
fresh borohydride without any loss in activity. In terms of safety, the air used for cool-
ing the magnetron ventilates the microwave cavity, thus preventing any ensuing hy-
drogen from reaching explosive concentrations. The technique has been elegantly
utilized for MW-enhanced solid-state deuteration using sodium borodeuteride im-
pregnated alumina [120]. Further extension of this work in the specific labeling of
molecules has been explored [121] and is discussed elsewhere in this book [122].
6.2.5.3 Reductive Amination of Carbonyls

Sodium cyanoborohydride [123], sodium triacetoxyborohydride [124] or NaBH4
coupled with sulfuric acid [125] are common agents used for the reductive amination
of carbonyl compounds. These reagents either generate waste or involve the use of
corrosive acids. The environmentally friendlier procedures developed by Varma and
coworkers have been extended to a solvent-free reductive amination protocol for
carbonyl compounds using moist montmorillonite K 10 clay supported sodium boro-
hydride that is facilitated by microwave irradiation (Scheme 6.39) [126].
R1 Clay (Cat. Amount) R1 NaBH4–Clay R1 R2

C O + H2N R 2 C N R2 CH N
R MW, 2 min. R H2O, MW R H
(95–98%) (0.25–2 min.) (78–97%)
R = i-Pr, Ph, o-HOC6H4, p-MeOC6H4, p-NO 2C6H4 ; R 1 = H ; R 2 = Ph

R & R1 = –(CH2)5– ; R2 = Ph ; R & R1 = –(CH2)6– ; R 2 = n-Pr
R = p-ClC6H4 ; R1 = H ; R2 = o-HOC6H4 ; R = R1 = Et ; R2 = Ph
R = n-C 5H11 ; R1 = Me ; R2 = morpholine, piperidine ; R = i-Pr ; R1 = H ; R2 = n-C10H21
Scheme 6.39 Reductive amination of carbonyls using clay-supported sodium borohydride.
The practical applications of NaBH4 reductions on mineral surfaces for in situ

generated Schiff's bases have been successfully demonstrated. The solid-state reduc-
tive amination of carbonyl compounds on various inorganic solid supports such as
alumina, clay, silica etc. and especially on K 10 clay surface rapidly afford secondary
and tertiary amines [126]. Clay behaves as a Lewis acid and also provides water from
its interlayers thus enhancing the reducing ability of NaBH4 [22].
6.2.5.4 Solid-state Cannizzaro Reaction

The Cannizzaro reaction, the disproportionation of an aldehyde to an equimolar
mixture of primary alcohol and carboxylic salt [127, 128], is restricted to aldehydes
lacking the a-hydrogens that cannot undergo aldol condensation. This oxidation±re-
duction reaction is usually conducted under strongly basic conditions and suffers
from the disadvantage of the lower yields of the desired products [129, 130]. The
crossed Cannizzaro reaction [129], using a scavenger and inexpensive paraformalde-
hyde, however, has provided improved yields of alcohols prior to the introduction of
hydride reducing agents. The popularity of Cannizzaro reaction in synthetic organic
chemistry dwindled considerably after the discovery of lithium aluminum hydride,
LiAlH4, in 1946.
In numerous reactions involving arylaldehydes on a variety of mineral oxide sur-
faces, the formation of Cannizzaro-derived alcoholic contaminants has been consis-
tently observed [131]. Interestingly, no meaningful product formation occurs under
solventless MW-irradiation conditions on alumina surface with calcium hydroxide or
in the presence of a strong base such as sodium hydroxide; the reaction remains in-
complete with concomitant formation of several unidentified products reminiscent
of earlier described observations on basic alumina surface [131]. Finally,Varma et al.
discovered that the reaction proceeds rapidly on barium hydroxide, Ba(OH)2.8H2O
surface, which constitutes the first application of this reagent in a solvent-free
crossed Cannizzaro reaction [132]. In a typical experimental procedure, a mixture of
benzaldehyde (1 mmol) and paraformaldehyde (2 mmol) is mixed with barium hy-
droxide octahydrate (2 mmol) and irradiated in a MW oven (100±110 8C) or heated in
an oil bath (100±110 8C) (Scheme 6.40). Arylaldehydes bearing an electron withdraw-
ing substituent undergo reaction at a much faster rate than aldehydes with electron
releasing groups appended [132]. Soon thereafter, additional groups started explor-
ing the general utility of this reaction using microwaves [133, 134].
Ba(OH)2 . 8H2O
RCHO + (CH2O)n RCH2OH + RCOOH
MW or oil bath
(80-99%) (1-20%)
Scheme 6.40 Solvent-free crossed Cannizzaro reaction using paraformaldehyde.
6.2.6
Synthesis of Heterocyclic Compounds
Heterocyclic chemistry has benefited substantially from MW-expedited processes de-

veloped over the last decade. An exhaustive overview is provided in adjoining chap-
ters [87, 88] with limited solvent-free chemistry utilizing mineral supported reagents
being covered in this section.
6.2.6.1 Flavones
Naturally occurring flavonoids are widely distributed oxygen heterocyclic com-
pounds in plant kingdom, the most abundant being the flavones. Members of this
class display a wide variety of biological activities and have been useful in the treat-
ment of various diseases [135, 136]. Flavones have been prepared by a variety of
methods such as Allan±Robinson synthesis, and synthesis from chalcones via an in-
tramolecular Wittig strategy [137]. The commonly followed approach, however, in-
volves the Baker±Venkataraman rearrangement, wherein o-hydroxyacetophenone is
benzoylated to form the benzoyl ester followed by the treatment with base (KOH/pyr-
idine) to effect acyl migration, forming a 1,3-diketone [138, 139]. The ensuing dike-
tone is then cyclized under strongly acidic conditions with sulfuric acid and acetic
acid to afford flavone.
A solvent-free synthesis of flavones has been achieved that simply involves the
MW irradiation of o-hydroxydibenzoylmethanes adsorbed on montmorillonite K 10
clay for 1±1.5 min. A rapid and exclusive formation of cyclized flavones occurs in
good yields (Scheme 6.41) [140]. The intramolecular Michael addition of o-hydroxy-
chalcones on silica gel surface has also been reported [141].
R2
OH R2 O
K 10 Clay
MW, 1-1.5 min.

R1 R1
O O O
Where R1 = H ; R2 = H, Me, OMe, NO2
R1 = OMe ; R2 = H, Me, OMe
Scheme 6.41 Formation of flavones by cyclization of o-hydroxydibenzoylmethanes on K 10 clay.
6.2.6.2 2-Amino-substituted Isoflav-3-enes

The estrogenic properties of isoflav-3-enes are well known and consequently, several
derivatives of these chromene heterocycles have been the target of medicinal che-
mists. Varma and coworkers uncovered a useful enamine-mediated pathway to this
class of compounds [142±144]. Now the group has discovered a facile and general
method for the MW-expedited synthesis of isoflav-3-enes substituted with basic moi-
eties at the 2-position (Scheme 6.42) [145]. These promising results are especially ap-
pealing in view of the convergent one-pot approach to 2-substituted isoflav-3-enes
K 10 Clay
C C O + HN R C C N R
MW
H R R
(95–98%) Enamines
R4 R4
OH R R3 O R
R3 NH4OAc
+ H
R2 MW, 2–8 min R2 Ph
CHO Ph
R1 R1
(73–88%)
Where R = morpholinyl, piperidinyl or pyrrolidinyl
and R 1 = R3 = R4 = H ; R2 = H, Cl, NO2
Scheme 6.42 One-pot synthesis of 2-substituted isoflav-3-enes from in situ- generated
enamines.
wherein the in situ generated enamine derivatives have been subsequently reacted
with o-hydroxyaldehydes in the same pot (Scheme 6.42) [145].
6.2.6.3 Substituted Thiazoles

Thiazole and its derivatives are conventionally prepared from lachrymatory, a-halo-
ketones and thioureas (or thioamides) by Hantzsch procedure [146]. In a marked im-
provement,Varma et al. have synthesized the title compounds by the simple reaction
of in situ-generated a-tosyloxyketones, from arylmethyl ketones and [hydroxy(tosyl-
oxy)iodo]benzene (HTIB), with thioamides in the presence of K 10 clay using micro-
wave irradiation (Scheme 6.43); the process is solvent-free in both the steps [147].
R1
O R2
OTs N
K 10 clay
+
MW H S
R1
R2
H2N S (88-96%)
Where R1 = H, Me, OMe, Cl and R2 = Cl, OMe
Scheme 6.43 Synthesis of substituted thiazoles from in situ-generated a-tosyloxyketones.
The corresponding bridgehead heterocycles are difficult to obtain by conventional

heating methods since the reactions of a-tosyloxyketones with ethylenethioureas re-
main incomplete in an oil bath. The microwave-accelerated process, on the other
hand, gets completed in a short time (Scheme 6.44) [147, 148].
O OTS
H
K 10 clay N
+ HN NH
MW N
S
S
R1
R1 (85-92%)
Where R1 = H, Me, OMe, Cl
Scheme 6.44 Synthesis of bridgehead thiazoles from a-tosyloxyketones.
Several 1,4-dicarbonyl compounds have been successfully subjected to microwave-

mediated ring closure with Lawesson's reagent to afford useful S-heterocycle-con-
taining liquid crystalline targets. The new ring-closure methodology has proven use-
ful in improving the yield of an earlier synthesized liquid crystal entity and a num-
ber of newer reactions have been scaled up to several grams without compromising
the yield (Scheme 6.45) [149].
O O
X
Y
X Y R2 Lawesson's reagent
S
MW, 3-8 min R2
H H
R1 R1
(83-94%)
Where R1 = H, OMe, Br; R2 = Ph, O-alkyl
and X = Y = CH or N
Scheme 6.45 MW-assisted synthesis of S-heterocycle-containing liquid crystalline compounds.
6.2.6.4 Synthesis of 2-Aroylbenzofurans

In an analogous manner, pharmacologically important natural 2-aroylbenzofurans
are easily obtainable under basic solvent-free conditions from a-tosyloxyketones and
salicylaldehydes in the presence of potassium fluoride doped alumina using micro-
wave irradiation (Scheme 6.46) [147, 148].
6.2.6.5 Synthesis of Quinolones

The readily available 2'-aminochalcones provide easy access to 2-aryl-1,2,3,4-tetrahy-
dro-4-quinolones in yet another solvent-free cyclization reaction using montmorillo-
nite K 10 clay under microwave irradiation conditions [150]; the products are valu-
able precursors for the medicinally important quinolones (Scheme 6.47).
O
TsO
R1 CHO R1 R2
KF-Al2O3
+ MW
OH O
R2 (89-96%) O
Where R1 = H, Cl and R2 = H, Me, OMe, Cl

Scheme 6.46 Synthesis of 2-aroylbenzofurans on potassium fluoride doped alumina.
R1 R1
H
NH2 N
R2 K 10 clay R2
C ΜW, 1−2 min. C

(70–80%)
O O
Where R1 = Cl, Br, CH3, OCH3, NO2 ; R2 = H

R1 = R2 = H, OCH3
Scheme 6.47 Synthesis of 2-aryl-1,2,3,4-tetrahydro-4-quinolones via cyclization reaction
on clay.
6.2.6.6 Multi-component Reactions (Imidazo[1,2-a]annulated N-heterocycles ±

Ugi reaction)
Multiple component condensation (MCC) approach is attracting attention since the
diversity can be conveniently achieved in a single step simply by varying the reacting
components. The generation of small-molecule libraries requires the development
of efficient procedures with special emphasis on the ease of reaction manipulation.
Varma and Kumar have succeeded in developing such a facile procedure which is
amenable to the generation of a library of imidazo[1,2-a]pyridines, imidazo[1,2-a]pyr-
azines and imidazo[1,2-a]pyrimidines under solvent-free conditions using MW irra-
diation (Scheme 6.48) [151]. This is a marked improvement over the conventional
two-component synthesis that requires lachrymatory a-haloketones and restricts the
generation of a diverse library of these molecules.
Aldehydes and the corresponding 2-aminopyridine, pyrazine, or pyrimidine are
admixed in presence of a catalytic amount of clay (50 mg) to generate iminium inter-
mediate. Isocyanides are subsequently added to the same container and the reactants
are further exposed to MW to afford the corresponding imidazo[1,2-a]pyridines, imi-
dazo[1,2-a]pyrazines and imidazo[1,2-a]pyrimidines (Scheme 6.48). The process is
general for all the three components, e. g. aldehydes (aliphatic, aromatic and vinylic),
isocyanides (aliphatic, aromatic and cyclic) and amines (2-aminopyridine, 2-amino-
pyrazine and 2-aminopyrimidine). A library of imidazo[1,2-a]pyridines, imidazo[1,2-
a]pyrazines and imidazo[1,2-a]pyrimidines can be readily obtained by varying the
three components [151].
R
NH2 N
R CHO R1
N X Microwave N N X
+ Y Clay
H
Y
R1 NC
X= Y= C X= Y= C
X= C, Y= N X= C, Y= N
X= N, Y=C X= N, Y=C
Scheme 6.48 Synthesis of imidazo[1,2-a]annulated N-heterocycles via the Ugi reaction.
A similar strategy has been used for the Biginelli condensation reaction to synthe-
size a set of pyrimidinones (65±95 %) in a household MW oven [152]. This MW ap-
proach has been successfully applied to combinatorial synthesis [153]. Yet another
example is the convenient synthesis of pyrroles (60±72 %) on silica gel using readily
available enones, amines and nitro compounds [154].
6.2.7
6.2.7.1 Transformation of Arylaldehydes to Nitriles

Arylaldehyde to nitrile conversion is an important chemical transformation [155].
Usually the reaction proceeds via an aldoxime intermediate that is subsequently de-
hydrated using a wide variety of reagents such as chloramine/base [156], O,N-bis-(tri-
fluoroacetyl)hydroxylamine or trifluoroacetohydroximic acid [157], p-chlorophenyl
chlorothionoformate/pyridine [158], triethylamine/dialkyl hydrogen phosphinates
[159], TiCl4/pyridine [160], triethylamine/phosphonitrilic chloride [161] and 1,1-dicar-
bonylbiimidazole [162]. The dehydration of aldoxime is a time consuming process
even for one-pot reactions [163]. The application of hydroxylamine hydrochloride im-
pregnated clay developed by Varma et al. reduces the entire operation to one-pot
synthesis using microwaves wherein arylaldehydes are rapidly converted into nitriles
in good yields (89±95 %) in the absence of solvent [107, 164]. In this general reaction,
CHO CN
NH2OH.HCl / K 10 clay
MW, 1-1.5 min
R2 R2
R1 R1
Where R1 = H, R2 = H, OCH3, NO2, OH, Br, CH3 (89-95 %)
R1 = R2 = OCH3
Scheme 6.49 Transformation of arylaldehydes to nitriles by hydroxylamine hydrochloride±clay.
a variety of aldehydes undergo this facile conversion to the corresponding nitriles in

a short time (1±1.5 min) upon MW irradiation (Scheme 6.49). However, in the case
of aliphatic aldehydes, only poor yields of nitriles (10±15 %) are obtained with conco-
mitant formation of undesirable products.
Several variations of the aforementioned transformation soon followed using silica
as surface [165±167]. The nitriles have been obtained from carboxylic acids (20±93 %)
on alumina support [168] and from the corresponding amides (80±95 %) in toluene
[169].
6.2.7.2 Nitration of Styrenes ± Preparation of b-Nitrostyrenes

Solid-state synthesis of b-nitrostyrenes has been reported by Varma et al. in a process
that uses readily available styrene and its substituted derivatives and inexpensive
clay-supported nitrate salts, clayfen and clayan (Scheme 6.50) [170]. In a simple ex-
periment, admixed styrene with clayfen or clayan is irradiated in a MW oven (~100±
110 8C, 3 min) or heated in an oil bath (~100±110 8C, 15 min). For clayan intermit-
tent heating is recommended with 30-s intervals to maintain the temperature below
60±70 8C. Remarkably, the reaction proceeds only in solid state and leads to the for-
mation of polymeric products in organic solvent.
NO 2
CHO
Clayfen (Clayan)
+
MW or oil bath
(minor)
R R R
Where R = H, Cl, CH3, OCH 3
Scheme 6.50 Preparation b-nitrostyrenes using clay-supported nitrate salts.
6.2.7.3 Organometallic Reactions (Carbon±Carbon Bond-forming Reactions)

Palladium catalyzed reaction of aryl halides and olefins provide a useful synthetic
method for C±C bond formation reaction [171, 172]. The commonly used catalyst is
palladium acetate, although other palladium complexes have also been used. A sol-
vent-free Heck reaction has been conducted in excellent yields using a household
MW oven and palladium acetate as catalyst and triethylamine as base (Scheme 6.51)
[173]. A comparative study revealed that the longer reaction times and deployment of
high pressures, typical of classical heating method, are avoided using this MW pro-
cedure.
H R
PdL2X2 + -
C C + RX + Base C C + BaseH X
Scheme 6.51 Palladium-catalyzed carbon±carbon bond forming reactions using microwaves.
R2
I
Pd-CuI-PPh3
KF-Al 2O3
+ R2 H
MW
R1 R1
Scheme 6.52 MW-expedited Sonogashira coupling reaction on palladium-doped alumina.
A rapid MW-assisted palladium-catalyzed coupling of heteroaryl and aryl boronic

acids with iodo- and bromo-substituted benzoic acids, anchored on TentaGel has
been achieved [174]. An environmentally friendly Suzuki cross-coupling reaction
has been developed that uses polyethylene glycol (PEG) as the reaction medium
and palladium chloride as a catalyst [175]. A solventless Suzuki coupling has also
been reported on palladium-doped alumina in the presence of potassium fluoride
as a base [176]. This approach has been extended to Sonogashira coupling reaction
wherein terminal alkynes couple readily with aryl or alkenyl iodides on palladium-
doped alumina in the presence of triphenylphosphine and cuprous iodide
(Scheme 6.52) [177].
A fast and efficient molybdenum-catalyzed asymmetric allylic alkylation under
noninert conditions has been reported using MW-accelerated reaction [178]. Inter-
molecular hydroacylation of 1-alkenes with aldehydes has been presented as a
greener alternative to classical approach using a homogeneous catalyst in toluene.
6.2.7.4 Synthesis of Radiolabeled Compounds ± Exchange Reactions

The earlier described MW-expedited borohydride reduction reaction [119] has been
adapted for the efficient deuteration and tritiation procedures using MW irradiation
and solid hydrogen/deuterium/tritium donors with minimal radioactive waste gen-
eration, a contrast from the classical tritiation efforts [179]. Jones and coworkers
have circumvented the traditional disadvantages associated with tritium labeling
techniques as demonstrated in the deuterated and tritiated borohydride reductions
[120, 121], based on similar MW-expedited reduction executed on alumina surface
[119]. The hydrogen exchange reactions that require prolonged reaction time (24 h)
[180, 181] and elevated temperatures are the primary beneficiary of this microwave
approach (Scheme 6.53) [120, 122]. The high purity of labeled materials, efficient in-
sertion and excellent regioselectivity are some of the advantages of this emerging
technology.
D
_ _
NH3+ Cl ND3+Cl ND3+ Cl
_
D2 O D2O
MW
CH3 CH3
D CH3
Scheme 6.53 Deuteration and tritiation reactions using MW irradiation.
Me Me Me Me
- + + -
2TCOOH + N(CH2)2N 2TCOO H N(CH2)2N H O2CT
Me Me
Me Me
Scheme 6.54 Hydrogenation reactions using formates.
In a faster, selective and cleaner applications of the microwave-accelerated reac-

tions, Stone-Elander et al. have synthesized a variety of radiolabeled (with 3H, 11C,
and 19F) organic compounds via the nucleophilic aromatic and aliphatic substitution
reactions, esterifications, condensations, hydrolysis and complexation reactions
using monomodal MW cavities on microscale [121]. A substantially reduced level of
radioactive waste is generated in these procedures that are discussed, at length, in
Chapt. 13 [122].
Hydrogenation reactions in which H2/D2/T2 gases are replaced by various for-
mates proceed very rapidly under MW irradiation conditions (Scheme 6.54) [182].
The pattern of labeling can be easily modified and the advantages are especially note-
worthy in the case of tritium where high specific activity tritiated water is hazardous
to use.
6.2.7.5 Enzyme-catalyzed Reactions

In conventional synthetic transformations, enzymes are normally used in aqueous
or organic solvent at moderate temperatures to preserve the activity of enzymes.
Consequently, some of these reactions require longer reaction times. In view of the
newer developments wherein enzymes can be immobilized on solid supports [183],
they are amenable to relatively higher temperature reaction with adequate pH con-
trol. The application of MW irradiation has been explored with two enzyme systems
namely Pseudomonas lipase dispersed in Hyflo Super Cell and commercially avail-
able SP 435 Novozym (Candida antarctica lipase grafted on an acrylic resin).
The resolution of racemic 1-phenylethanol has been achieved under solvent-free
microwave irradiation conditions by transesterification using above set of enzymes
(Scheme 6.55) [184]. A comparison of the MW-assisted reaction with conventional
heating revealed an enhanced enantioselectivity for the former presumably due to
the efficient removal of low molecular weight alcohols or water upon exposure to mi-
crowaves or alternatively an entropic effect due to dipolar polarization that induces a
previous organization of the system. Thermostable enzymes such as crude homoge-
nate of Sulfolobus solfataricus and recombinant b-glucosidase from Pyrococcus furiosus
have been successfully applied to transglycosylation reactions where recycling of the
biocatalyst is feasible.
OH OH
H H OCOR'
Me Lipase
Me Me
+ R'CO2R +
Scheme 6.55 MW-assisted resolution of racemic 1-phenylethanol via transesterification.

6.2.7.6 Solvent-free Synthesis of Ionic Liquids

Room temperature ionic liquids (RTIL) consisting of N-alkylimidazolium cations
and a variety of anions [185], have received tremendous attention due to their poten-
tial in a variety of commercial applications especially as substitutes for traditional
volatile organic solvents [186, 187]. They are polar in nature but consist of poorly co-
ordinating ions and provide a polar alternative for biphasic systems. Other important
attributes of these ionic liquids include negligible vapor pressure, potential for re-
cycling, compatibility with various organic compounds and organometallic catalysts,
and ease of separation of products from reactions [188]. Unfortunately, most of the
conventional preparative procedures for the synthesis of ionic liquids involve several
hours of heating in solvents under reflux and use a large excess of alkyl halides/or-
ganic solvents that diminish their true potential as ªgreenerº solvents.
Ionic liquids, being polar and ionic in character, couple to the MW irradiation very
efficiently and therefore are ideal microwave absorbing candidates for expediting
chemical reactions. An efficient preparation of the 1,3-dialkylimidazolium halides
via microwave heating has been described by Varma et al. that reduces the reaction
time from several hours to minutes and avoids the use of a large excess of alkyl ha-
lides/organic solvents as the reaction medium (Scheme 6.56) [26±28].
N N
MW R X
+
PF6 - NH4 PF6
X - NH4 BF4 -
BF4
+ +
N N N N N N
R R MW
R
Where R = alkyl groups

Scheme 6.56 MW-assisted preparation of ionic liquids.
The approach precludes the usage of volatile organic solvents, is relatively much
faster, efficient, and eco-friendly. Significant rate enhancements are reported in the
1,3-dipolar cycloaddition reactions including the use of covalently grafted dipolaro-
philes on the ionic liquids [189].
6.3
Conclusions
Microwave heating, being specific and instantaneous, is unique and has found a
place in the expeditious chemical synthesis domain. Specifically, the solvent-free re-
References 213
actions are convenient to perform and have demonstrated clear advantage over the
conventional heating procedures as summarized in this chapter. Numerous selective
organic functional group transformations have been accomplished more efficiently
and expeditiously using a variety of supported reagents on mineral oxides as cata-
lysts. Although a large body of work has been performed around the world using an
unmodified household microwave oven (multimode applicator), more recent work
does point out the advantages of using commercial systems wherein not only the im-
proved temperature/power control is possible but also the relatively large-scale reac-
tions can be conducted [190, 191] with additional options for a continuous operation.
The engineering and scale-up aspects for the chemical process development have
also been discussed [192].
There are distinct advantages of these solvent-free procedures in instances where
catalytic amounts of reagents or supported agents are used since they provide reduc-
tion or elimination of solvents, thus preventing pollution ªat sourceº. Although not
delineated completely, the reaction rate enhancements achieved in these methods
may be ascribable to nonthermal effects. The rationalization of microwave effects
and mechanistic considerations are discussed in detail elsewhere in this book [25,
193]. A dramatic increase in the number of publications [23 c], patents [194±203],
a growing interest from pharmaceutical industry, with special emphasis on combina-
torial chemistry, and development of newer microwave systems bodes well for micro-
wave-enhanced chemical syntheses.
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219
7
Microwave-assisted Reactions on Graphite
Andr Laporterie, Julien Marqui, and Jacques Dubac
7.1
Introduction
During the last 15 years numerous papers dealing with the use of microwave (MW)
irradiation, rather than conventional heating, in organic and inorganic chemistry
have reported dramatic reductions of reaction time and significant enhancement of
yields and purity of the products. Despite the possibility of operating with pressur-
ized reactors [1], however, MW irradiation of chemical reactions involving low boil-
ing reagents and/or products can involve serious safety problems. Consequently,
MW-assisted solvent-free reactions (ªdry mediaº) have been widely investigated in or-
ganic synthesis [2]. Among the materials most often used as supports are alumina,
silica, clays, and zeolites, which are sometimes also used as catalysts. When properly
dried, however, these materials are weak MW absorbers and poor thermal conduc-
tors. For reactions which require high temperatures the idea of using a reaction sup-
port which takes advantage both of strong MW coupling and strong adsorption of or-
ganic molecules has stimulated great interest. Because most organic compounds do
not interact appreciably with MW radiation, such a support could be an ideal ªsensi-
tizerº, able to absorb, convert, and transfer energy provided by a MW source to the
chemical reagents.
Most forms of carbon, except diamond, which are renowned as supports for pre-
cious metal catalysts in certain applications [3], interact strongly with MW [4]. Amor-
phous carbon and graphite, in their powdered form, irradiated at 2.45 GHz, rapidly
(within 1 min) reach very high temperatures (>1300 K). This property has been used
to explain MW-assisted syntheses of inorganic solids [5]. In these syntheses carbon is
either a ªsecondary susceptorº which assists the initial heating but does not react
with other reactants, or is one of the reactants, e. g. in the synthesis of metal car-
bides. MW±carbon coupling has also been widely developed:
. by Wan et al. for gas-phase reactions; for example, in the synthesis of hydrogen cy-
anide from ammonia and carbon or methane [6], in the MW-induced catalytic re-
action of water and carbon [7], and in the removal and/or destruction of acid gas-
eous pollutants such as SO2 and NOx [7, 8]; and

ISBN: 3-527-30514-9
220 7 Microwave-assisted Reactions on Graphite
. for the processing of polymers and composites in which carbon black or graphite
particles or fibers are included in the material [9].
The MW-promoted cracking of organic molecules in the presence of silica-sup-

ported graphite [10 a] or activated charcoal [10 b] has also been reported.
Graphite, the most stable of the three allotropic forms of carbon, has two structures,
a (hexagonal form) and b (rhombohedral form), which interconvert easily [11]. In a
graphite layer, each carbon atom is strongly bonded to three other carbon atoms in a
planar configuration (sp2 hybridization), and the remaining p electrons (one per car-
bon) are delocalized. The resulting carbon±carbon bonds are very strong (477 kJ mol±
1
). The interlayer bonds, in contrast, are weak (17 kJ mol±1), giving rise to the mechan-
ical (lubricant) and chemical (intercalation) properties of graphite. Electronically, gra-
phite is a semimetal of high electrical and thermal conductivity [11]. As for other semi-
metallic materials, the electronic current (s) is the main factor in the graphite±MW in-
teraction [5]. The rate of heating of a MW-irradiated material has been estimated to be
DT/t = s|E|2/rC, where E is the electric field, r is the density, and C is the specific heat
capacity of the material [5]. Compared with other dielectric solids graphite has an unu-
sually high thermal conductivity (a weak C, 0.63 kJ kg±1 K±1 at room temp.) [11]. This
thermal conductivity, which decreases exponentially with increasing temperature, is a
determining factor in the high rate of heating of graphite on MW irradiation, although
other types of MW interaction, e. g. the excitation of weak interlayer bonds, and, espe-
cially in graphite powder, eddy currents or localized plasma effects, can also lead to
very rapid dissipation of energy in graphite [5].
Because of its strong coupling with MW, its good adsorbent properties towards or-
ganic molecules [12], and its layer structure which enables it to form intercalated
compounds [13], graphite has great potential in MW-assisted synthetic applications
in organic chemistry, despite its weak fractal dimension (D & 2) [14].
Before the works of Laurent et al. [15, 16], which described several examples of MW-
assisted organic syntheses in the presence of graphite (Sects. 7.2.1, 7.2.2, 7.2.4, 7.2.7,
7.3.2, and 7.3.3), Bond et al. [17] (Sect. 7.2.3), and Villemin et al. [18] (Sect. 7.2.4), no
other studies were reported in this field. Literature results are, therefore, very recent.
They are presented here in two parts. The first concerns reactions in which graphite
behaves as an energy converter (or ªsensitizerº) capable of conveying the energy car-
ried by MW radiation to the chemical reagents. The second includes results which re-
veal surprising catalytic activity of some metal inclusions of graphite.
7.2
Graphite as a Sensitizer
This section covers reactions in which graphite is a sensitizer, without participation

of its metal inclusions as possible catalysts, although a catalyst can be added to the
graphite. The amount of graphite can be varied. It is generally at least equal to and
most often greater than that of the reagents, resulting in a graphite-supported/mi-
crowave (GS/MW) process.
7.2.1
Diels±Alder Reactions
Many Diels±Alder (DA) cycloadditions have been studied under MW irradiation [19].
The use of a ªdry processº, as in GS/MW coupling, is of great interest for difficult re-
actions which need high temperatures, particularly for those involving poor MW-ab-
sorbing reagents. Some reactions which normally require use of an autoclave can,
moreover, occur in an open reactor, owing to retention of a possibly volatile reagent
by the graphite.
Among the dienes known as weakly reactive are anthracene (1), metacrolein di-
methylhydrazone (2) and 3,6-diphenyl-1,2,4,5-tetrazine (3). DA cycloadditions with
these dienes require long reaction times under classical heating conditions (Tab. 7.1).
Three reactions of 1 successively with diethyl fumarate, maleic anhydride, and di-
methyl acetylenedicarboxylate (DMAD) are highly representative of the variety of ex-
perimental conditions used in the GS/MW process [26, 27]. Continuous MW irradia-
tion (CMWI) with an incident power of 120 W for 1 min led to a high increase in
temperature (Tmax > 300 8C). Adduct 4 was obtained almost quantitatively (Tab. 7.1,
entry 1), whereas only traces of adducts 5 and 6 were detected. When the incident
power was reduced (30 W) and sequential MW irradiation (SMWI) was used, adducts
5 and 6 were obtained in good yield (Tab. 7.1, entries 3 and 4). This controlled irra-
diation enabled the temperature to be limited (Tmax < 200 8C) and avoided the retro-
DA reaction. In the reaction between 1 and diethyl fumarate similar SMWI condi-
tions also gave the adduct 4 in high yield (Tab. 7.1, entry 2).
Other DA reactions of 1 (and some of its derivatives) in SMWI processes have
been reported [28]. Under powerful irradiation (Tmax > 300 8C), all products decom-
posed by the retro-DA reaction.
222
Tab. 7.1 Diels±Alder reactions of dienes 1±3 using the GS/MW process [15, 16].
Entry Adduct SG/MW irradiation Conventional heating

Conditions a (Tmax) Yield (%) b Conditions Yield (%)
c
1 4 120 W; 1 min , (370 8C) 92 Dioxane, reflux, 60 h [20] 90
2 4 30 W; 1 min × 3d, (147 8C) 92
3 5 30 W; 1 min × 3d, (155 8C) 75 p-Xylene, reflux, 10 min [21] 90
4 6 30 W; 1 min × 3d, (130 8C) 97 ± e [20] Quant.
5 7 30 W; 1 min × 10d, (171 8C) 50 No reaction [21, 22]
6 8 30 W; 1 min × 10d, (157 8C) 62 CHCl3, reflux, 120 h f 70
7 9 30 W; 1 min × 5d, (168 8C) 72 CCl4, 60 8C, 3 h [23] ±e
8 10 b 30 W; 1 min × 5d, (154 8C) 93 75 8C, 30 min [24] ±e
9 11 30 W; 1 min × 20d, (160 8C) 60 Toluene, reflux, 50 h [25] 94
a
See typical procedure; reagents used in equimolar amounts (entries 1±5) or in excess dienophile, 5/1
(entries 6, 7, 9), 2/1 (entry 8)
b
Yield of isolated product relative to the minor reagent
c
Continuous MW irradiation (CMWI); applied incident power; irradiation time; maximum tempera-
ture indicated by IR pyrometer
d
Sequential MW irradiation (SMWI); applied incident power; time and number of irradiations; interval
between two irradiations: 2 min (entries 2±5), 1 min (entries 6±9)
e
Not given
f
This work
The hetero-DA reaction with azadienes, a well known synthetic method for obtain-
ing nitrogen heterocycles, suffers from some difficulties, because of the low reactiv-
ity of the diene. For example, azadiene 2 did not react with DMAD under the action
of conventional heating [22]. Sequential exposure to MW irradiation (30 W) for
10 min on a graphite support (Tmax = 171 8C) led to the adduct 7 with 60 % conver-
sion (50 % in isolated product) [26, 27]. An equivalent yield was obtained by ultra-
sonic irradiation of the neat reaction mixture at 50 8C for 50 h [29].
The DA reaction of tetrazines such as 3 was also studied by use of the GS/
MW process [26, 27]. The expected adduct, however, decomposed by nitrogen
elimination followed by dehydrogenation, giving a pyridazine or a dihydropyrida-
zine [23±25]. With 2,3-dimethylbutadiene and cyclopentadiene as dienophiles,
SMWI gave dihydropyridazines 8 and 9, as with classical heating [23] (Tab. 7.1,
entries 6 and 7).
Under classical conditions, the reaction between 3 and styrene required 50 h of
heating at 110 8C, and gave the dihydropyridazine adduct 10a [24]. After SMWI
with 30 W incident power for 5 min (Tmax = 154 8C), the adduct 10a was not de-
tected whereas the totally dehydrogenated product, pyridazine 10b, was isolated in
almost quantitative yield (Tab. 7.1, entry 8). Ethyl vinyl ether and 3 gave the same
product, pyridazine 11, under both classical heating [25] and MW irradiation con-
ditions (Tab. 7.1, entry 9). In this instance the DA adduct lost nitrogen and etha-
nol.
The synthesis of these adducts was realized in very short times compared with the
same reactions under the action of classical heating. The efficiency of the MW pro-
cess is all the more noteworthy because the three dienophiles dimethylbutadiene, cy-
clopentadiene and ethyl vinyl ether are volatile. Although an excess of these reagents
with respect to 3 was used, the adsorption power of graphite was responsible of their
retention, because the temperature of the reaction mixture exceeded their boiling
points of approximately 120±130 8C.
This retention of reagents by the graphite support has been shown in a series of
experiments involving volatile dienes such as 2,3-dimethylbutadiene (12) and iso-
prene (13) (Tab. 7.2) [30, 31]. The reaction of 12 with diethyl mesoxalate gave 14 in
75 % yield after SMW irradiation at low power (30 W) for 20 × 1 min only (Tab. 7.2,
entry 1). When conventional heating was used a satisfactory yield was obtained after
4 h at 135 8C in a sealed tube [32]. Ethyl glyoxylate is a weaker carbonyl dienophile
Tab. 7.2 Diels±Alder reactions with 2,3-dimethylbutadiene (12) and isoprene (13) by use of the
GS/MW process [27, 30, 31].
Entry Adduct GS/MW irradiation Conventional heating

Conditions a (Tmax) Yield (%) b Conditions Yield (%)
1 14 30 W; 1 min × 20 c, (165 8C) 75 MeCN, 135 8C d, 4 h [32] 86

2 15 30 W; 1 min × 10 c,e, (165 8C) 87 140 8C, 6 h [33] 65
3 16 30 W; 1 min × 10 c, (249 8C) 54
4 17 30 W; 1 min × 10 c, (126 8C) 89 Xylene, 95 8C, 80 h [35] ±f
5 18 30 W; 1 min × 10c, (133 8C) 77 Benzene, 150 8C d [36] 65
6 19 30 W; 1 min × 2 c,e, (89 8C) 54 CH2Cl2(AlCl3), 20 8C, 24 h [37] 26
7 20 30 W; 1 min × 10 c,e, (146 8C) 73 CH2Cl2 (SnCl4), 20 8C, 18 h [34] 10
a
Reagents used in equimolar amounts (entries 4±6) or in excess of diene, 5/1 (entries 2, 3), 3/1 (entry
7), 2/1 (entry 1)
b
Yield of isolated product relative to the minor reagent.
c
Sequential MW irradiation (SMWI); applied incident power; time and number of irradiations; interval
between two irradiations: 1 min (entries 1±3), 3 min (entries 4±7)
d
Reaction in sealed tube
e
Reaction performed in the presence of a catalyst: ZnCl2 (entries 2, 7), AlCl3 (entry 6)
f
Not given.
than diethyl mesoxalate, and a catalyst (ZnCl2) was added to afford the expected DA
adducts with dienes 12 and 13 in good yields (Tab. 7.2, entries 2 and 7). For reaction
with 13 the catalyst SnCl4 [34] was substituted by ZnCl2 to prevent the formation of
the ene reaction product (Tab. 7.2, entry 7). Although adduct 16 was previously pre-
pared from 15 [32], its direct DA synthesis from 12 and glyoxylic acid could be per-
formed under the action of MW and without a catalyst (Tab. 7.2, entry 3).
Reactions performed with methyl vinyl ketone and metacrolein as ethylenic dieno-
philes also showed the clear advantage of SMWI conditions over conventional heat-
ing (Tab. 7.2, entries 4±6) [31]. In the reaction of isoprene with methyl vinyl ketone
(Tab. 7.2, entry 6) selectivity for the para adduct (54 %) was much better than when
conventional heating was used (26 %), probably owing to the shortening of reaction
time.
Another example of the retention of volatile DA reagents is that of cyclopentadiene
in a tandem retro-DA/DA ªprimeº reaction [15, 16, 38]. This reaction type is the ther-
mal decomposition of a DA adduct (A) and the generation of a diene (generally the
initial diene) which is trapped in situ by a dienophile leading to a new adduct (B)
[39]. Cyclopentadiene (22) (b.p. 42 8C) is generated by thermolysis of its dimer at ap-
proximately 160 8C [40]. An equimolar mixture of commercial crude dicyclopenta-
diene (21) and dimethyl maleate was irradiated in accordance with the GS/MW pro-
cess, in an open reactor, under 60 W incident power, for 4 min (8 × 30 s). The ex-
pected adduct 23 was isolated in 40 % yield (Scheme 7.1). The isomeric composition
of 23 (endo±endo/exo±exo = 65/35) was identical with that obtained under classical
conditions from 22 and methyl maleate [41]. The overall yield of this tandem reac-
tion can be increased from pure dimer 21 (61%) and the same tandem reaction has
also been reported using ethyl maleate as dienophile [31].
Scheme 7.1
The main advantages of the GS/MW process are the rapid increase of tempera-
ture, the retention of organic molecules, and the possibility of performing some re-
actions under one-pot conditions.
7.2.2
Ene Reactions
The ene reaction (or Alder reaction) is a cycloaddition which requires an activation
energy higher than that of the Diels±Alder reaction [41]. Without a catalyst it usually
occurs under pressure and/or at high temperature. The reaction with an alkene
(ene) is much easier if the latter is more substituted (high HOMO) and the enophile
is more electron-poor (low LUMO).
The alkene 1-decene (24) was poorly reactive in the carbonyl±ene reaction with
ethyl mesoxalate and required a temperature up to 170 8C for a very long time (5 h)
[42]. When performed in a homogeneous liquid medium at the same temperature
but under the action of MW irradiation the reaction gave a similar result. Reaction
time was appreciably shortened by use of GS/MW coupling [30]. Thus, irradiation at
60 W for only 10 min led to the ene adduct 25 in 50 % yield (Scheme 7.2). Under
these conditions a maximum temperature of 230 8C was measured. To obtain the
same yield with conventional heating at 170 8C reaction for 1 h is required. The
stereoselectivity of the reaction was not related to the mode of heating. A higher con-
Scheme 7.2
version of 24 was obtained by increasing the irradiation (incident power >60 W), but
the occurrence of side products made the isolation of 25 more difficult.
(±)-b-Pinene (26), a more reactive ene than 24, reacted with ethyl mesoxalate un-
der CCl4 reflux in 90 % yield after 5 h conventional or MW heating [42]. The reaction
supported on graphite occurred in only 2 × 1 min of MW irradiation with an incident
power of 60 W. The adduct 27 was obtained in 67 % isolated yield (Scheme 7.3) [30].
This yield was obtained after 2 h of reaction under CCl4 reflux.
The intramolecular cyclization of (+)-citronellal (28) leads to a mixture of isomeric
pulegols (29) and, particularly, to the (±)-isopulegol (29a) which is an intermediate in
the synthesis of (±)-menthol [43]. The reaction can be performed by heating in the
absence [44] or presence [43, 45] of a catalyst, including zeolite [46] and montmorillo-
nite [42] under the action of MW. The cyclization of 28, when performed by the GS/
MW process ± 4 min (8 × 30 s) of irradiation at 30 W incident power ± resulted in
88 % conversion (80 % isolated yield) to the pulegols (29) (Scheme 7.4).
Scheme 7.3
Scheme 7.4
The same reaction with conventional or MW heating at a constant temperature of

180 8C yielded only 50 % conversion after 4 h [42]. Considering that the maximum
temperature measured during GS/MW irradiation was only 210 8C, and that the re-
action was not catalyzed, the acceleration was clearly very strong. It has been ob-
served that, in contrast with clays such as montmorillonite, graphite in catalytic
amounts does not accelerate the cyclization of 28 from room temperature to 180 8C
[42]. We believe that under the heterogeneous conditions of the GS/MW process the
temperature shown by the IR pyrometer is too low and gives no indication of prob-
able ªhot spotsº produced at the surface of graphite grains (Sect. 7.4.2). The stereose-
lectivity was, moreover, somewhat different from that obtained by classical heating ±
although the amount of (+)-neoisopulegol (29b) was increased (±)-isopulegol (29a)
remained the main diastereoisomer (68 %).
7.2.3
Oxidation of Propan-2-ol
Reaction of an alcohol over basic catalysts favors dehydrogenation to give the corre-
sponding carbonylated derivative. This reaction has been studied for propan-2-ol
over a series of alkaline carbon catalysts, under the action of conventional heating
and MW irradiation (Scheme 7.5) [17].
Scheme 7.5
The main effect of MW irradiation on the graphite- and charcoal-supported cata-

lysts is to reduce the average temperature required for the reaction to occur. The
authors believe this is the result of ªhot spotsº formed within the catalyst bed
(Sect. 7.4.2). Graphite-supported catalysts, moreover, seem to be more selective than
the equivalent charcoal-supported catalysts, especially under the action of MW irra-
diation ± 83.6±97.7 % compared with 68.4±86.3 %. This might be because of the hy-
drophobic nature of the graphite which directs the reaction away from the produc-
tion of water by dehydration of the alcohol.
7.2.4
Thermolysis of Esters
The thermolysis of esters is a much used reaction in organic [47] and organometallic
[48] syntheses, generally for the creation of a carbon±carbon double bond. The me-
Scheme 7.6
chanism is often like that of the retro-ene reaction, requiring high temperatures.
Among the esters, those of carbamic acid are more easily decomposed than those of
carboxylic acids.
The high temperatures reached in the GS/MW process have been used to achieve
the thermal decomposition of O-alkylcarbamates (Scheme 7.6) [15, 16]. The latter are
prepared from corresponding alcohols and phenyl isocyanate in the presence of stan-
nous octanoate [49].
With 1,1-dimethylbenzyl phenylcarbamate (30), a tertiary carbamate:
. heating in p-xylene under reflux for 10 h led to no decomposition;

. MW irradiation (150 W) of pure crystalline 30 led to 45 % 2-methylstyrene (32)
after 60 min (6 × 10 min); and
. MW irradiation of graphite powder impregnated with 30 gave 90 % 32 after 3 min
(3 × 1 min) under 60 W incident power (Tmax = 320 8C).
This example shows that the GS/MW process can be used to accomplish thermal
decomposition which cannot be performed efficiently by use of MW irradiation
alone, because of weak MW absorption by the starting compound (30) of probable
low dielectric loss.
The decomposition of a secondary carbamate, 1-methylbenzyl phenylcarbamate
(31), was more difficult, and only 60 % of styrene (33) was obtained under the same
conditions (Tmax = 340 8C). Attempts to decompose a primary carbamate, 1-octyl phe-
nylcarbamate, failed because its sublimation preceded its decomposition [15, 16]. All
these reactions have been performed in an open reactor by the above procedure
(Sect. 7.2.1).
Some esters not having an aliphatic hydrocarbon chain are liable to thermal rear-
rangement. This is observed for O-arylthiocarbamates, for which rearrangement into
S-arylthiocarbamates has been studied by Villemin et al. on different supports and
under the action of MW irradiation (Scheme 7.7) [18].
No rearrangement was observed for the pure compound 34a, adsorbed or not on
KF-Al2O3, probably owing to its low dielectric loss. By using supports known to con-
vert MW energy into thermal energy, the authors observed a conversion rate of 15 to
90 % for 34. The best yields (30 (35e) to 90 % (35c)) were obtained on graphite pow-
der.
Scheme 7.7
7.2.5
Thermal Reactions in Heterocyclic Syntheses
Many reactions in heterocyclic multistep syntheses involve thermal condensations.

Thermal heating of benzimidazoquinazoline 36 and anthranilic acid gave the cy-
clized tetraazaanthracenone 37 (Scheme 7.8).
As Besson et al. have shown, the yield of this reaction depends on the mode of
heating [50]. Thus, thermal heating of the two starting compounds, neat at 120 8C or
in butanol under reflux for 48 h, did not give more than 50 % of product 37. MW
heating enabled reduction of the reaction time but not improvement in the yield.
A longer heating period resulted in degradation products.
MW irradiation of a mixture of 36 and anthranilic acid adsorbed on graphite pow-
der led to the product 37 in high yield (95 %) and in a short time (1.5 h) [50]. When
this GS/MW process was extended to the reaction between 36 and 5-methylanthrani-
lic acid it gave the corresponding cyclized product in 75 % yield.
Among polyheterocyclic systems, coumarins are synthesized by many routes, in-
cluding the Pechmann reaction, which involves condensation of phenols with b-ke-
toesters [51]. This reaction, which has been the most widely applied method, has re-
Scheme 7.8
cently been studied under the action of MW irradiation by several authors [52], in-
cluding the GS/MW process for 4-substituted 7-aminocoumarins [53]. Synthesis of
aminocoumarin 38 by the Pechmann reaction involves heating a mixture of m-ami-
nophenol and dimethyloxalacetate at 130 8C (Scheme 7.9). Under such conditions,
however, the yield of the reaction is variable, and usually low (36 %). Use of graphite
as a support led to 38 in slightly better yield (44 %).
Scheme 7.9
Addition of a solid acid catalyst such as Montmorillonite K10 increased the yield
significantly under the action of either thermal heating (64 %) or MW irradiation
(66 %) [52 c]. Under the latter conditions the reaction time was reduced. Comparable
results were obtained for the synthesis of aminocoumarins 39±42 (Tab. 7.3) [53].
Tab. 7.3 Preparation of 7-aminocoumarin derivatives 38±42 using GS,K10/D and GS,K10/MW
processes [53].
Entry Product MW irradiation a Conventional heating b

Reaction time (min) Yield (%) Reaction time (min) Yield (%)
1 38 30 66 66 64
2 39 8 61 45 54
3 40 5 65 30 66
4 41 8 75 56 68
5 42 12 62 390 62
a
The irradiation was programmed to furnish a constant temperature of 130 8C
b
Reactions were performed at 130 8C (oil bath)
We believe that shortening of the reaction times for all GS,K10/MW experiments,
compared with those using GS,K10/D, are the result of ªhot spotsº in the graphite
powder (Sect. 7.4.2).
7.2.6
Decomplexation of Metal Complexes
Decomplexation of some metal complexes calls for drastic conditions. This is true
for (Z-arene)(Z-cyclopentadienyl)iron(II) hexafluorophosphates, [FeAr(Cp)][PF6] [54,
55]. Although their chemical decomplexation is known [55 a], the most widely used
method is pyrolytic sublimation at high temperatures (>200 8C) [55 b]. To evaluate
MW irradiation as the method of decomplexation of such iron complexes, Roberts et
al. performed the reaction in the presence of graphite [54]. They discovered that the
yield of the free ligand from the [Fe(Z-N-phenylcarbazole)(Z-Cp)][PF6] complex (43)
depended on the kind (flakes or powder) and amount of graphite, and on the irradia-
tion time. In an optimized experiment 96 % N-phenylcarbazole was obtained from

43 (1 g) by use of 1 g graphite flakes and 2 min MW irradiation. Experiments were
performed using a conventional MW domestic oven; the temperature of the reaction
mixture at the end of the irradiation was not given.
Pentamethylbenzene, N-phenylpyrrole, and 1,2-diphenylindole have been decom-
plexed from corresponding iron(II) complexes by use of the same GS/MW process;
yields were 94 %, 62 %, and 71%, respectively. The results showed this to be a rapid
and efficient method of decomplexation.
7.2.7
Redistribution Reactions between Tetraalkyl- or Tetraarylgermanes and Germanium
Tetrahalides
Synthesis of alkyl (or aryl) halogermanes (46) from a germanium tetrahalide (44) oc-
curs in two steps (Scheme 7.10) [56]. The most difficult to realize, and the least selec-
tive, is the second, i. e. the redistribution between alkyl (or aryl) and halide substitu-
ents of R4Ge and GeX4 compounds. Depending on the ratio of these two compounds
the reaction gives alkyl (or aryl) halogermanes, 46a, 46b, or 46c. It requires a catalyst,
the most frequently used being the corresponding aluminum halide, and its amount
must be relatively high (approx. 20 mol %) [56]. The experimental conditions are,
moreover, rather drastic ± heating in a sealed tube between 120 8C (arylated series)
and 200 8C (alkylated series) for several hours.
These redistribution reactions are possible at atmospheric pressure under the ac-
tion of MW; irradiation is performed for a few minutes in the presence of the same
catalysts [57]. These reactions with the less volatile germanium tetrabromide (44b)
(b.p. 184 8C) have also been performed by use of the GS/MW process, without added
catalyst (Tab. 7.4, entries 1 and 3) [15, 16]. In this instance, despite the use of weaker
incident power, the temperature reached 420 8C, very much higher than that ob-
tained under the action of MW irradiation of a reaction mixture containing AlBr3
(200 8C to 250 8C) (Tab. 7.4, entries 2 and 4). The presence of this catalyst consider-
ably favors redistribution towards the dibrominated products (46b) (84 % for
R = nBu, 85 % for R = Ph) relative to the monobrominated compounds (46a), which
are the major products of the GS/MW process (78 % and 43 % respectively). The tri-
brominated products (46c), the most difficult to prepare, have been obtained with a
rather high selectivity (73 to 80 %) by use of the catalytic process under the action of
MW [57]. In this reaction, therefore, the GS/MW process seems less effective than
the MW-assisted and AlX3-catalyzed process.
Scheme 7.10
Tab. 7.4 Redistribution reactions between germanium tetrabromide (44b) and tetrabutyl- or tetra-
phenylgermanes (45) under the action of MW irradiation [15, 16].
Entry R Initial mixture (mmol) Exp. conditions Products (%) c

GeBr4 R4Ge AlBr3 R4Ge 46 (a/b/c) Yield d
1a n
Bu 5.20 5.75 90 W, 3 min e 17 83 (78/3/19) 80
2b n
Bu 5.20 6.10 1.0 300 W, 8 min f 100 (8/84/8) 87
3a Ph 5.75 5.20 90 W, 3 min e 9 91 (43/32/25) 85
4b Ph 5.70 5.20 1.0 210 W, 8 min f 3 97 (9/85/6) 96
a
Reaction performed by the GS/MW process with 6 g graphite as support
b
Ref. [57]
c
Products were analyzed by GC and 1H NMR after alkylation [57]
d
Recovered Ge products
e
Continuous irradiation
f
Sequential irradiation, 2 min × 4
7.2.8
Pyrolysis of Urea
The reaction usually used to produce cyanuric acid (48) is the thermolysis of
urea (47) between 180 8C and 300 8C (Scheme 7.11) [58]. The reaction occurs
with formation of ammonia, which itself can react with 48 to give secondary pro-
ducts. It is, therefore, necessary to eliminate NH3 and to operate with an open
reactor.
This reaction has been studied with classical and MW heating under homoge-
neous and heterogeneous conditions [59]. Tab. 7.5 summarizes the results. When
the reaction was conducted in the homogeneous phase at 200 8C (Tab. 7.5, entries
1±4), identical reaction rates and similar yields and selectivities were obtained for
both heating modes. Kinetic data for the first-order equation were similar:
Ea (MW) = 159 ± 3 kJ mol±1, Ea (D) = 160 ± 3 kJ mol±1 ; ln A (MW) = 35 ± 1, ln A
(D) = 34 ± 1. In contrast, in the presence of graphite (47/graphite = 4/1, w/w), im-
proved yield and selectivity were obtained under the action of MW irradiation com-
pared with conventional heating (Tab. 7.5, entries 5±8) at the same bulk tempera-
ture. The authors ascribed this phenomenon to localized superheating (ªhot spotsº)
on the graphite surface (Sect. 7.4.2).
Scheme 7.11
Tab. 7.5 MW-assisted thermolysis of urea (47) under solvent-free conditions (Scheme 7.11) [59].
Entry Conditions a,b Tmax (pC) Time (min) Yield (%) Selectivity (%) Reaction rate (103 s±1)
Homogeneous phase c
1 MW 200 1 5.2 20.2 8.8
2 D 200 1 4.5 30.3 8.7
3 MW 200 30 68.4 73.6 8.8
4 D 200 30 67.9 72.2 8.7
Heterogeneous phase d
5 MW 200 1 9.9 56.3 21.9
6 D 200 1 4.6 33.6 8.7
7 MW 300 3 61.2 93.5 12 028
8 D 300 3 15.2 45.6 7156
a
Microwave (MW) or conventional (D) heating
b
The incident MW power was adjusted to furnish the maximum temperature (Tmax)
c
From 20 g urea (mp 133±135 8C)
d
From 20 g urea + 5 g graphite.
7.2.9
Esterification of Stearic Acid by n-Butanol
Esterification of stearic acid (49) by butanols has been studied under homogeneous
and heterogeneous conditions [60]. The yield of butyl stearates [Me(CH2)14COOR
(50), R = nBu (a), sBu (b), tBu (c)] depended on the catalysts, on the isomeric form of
the butanol, and on the mode of heating (conventional heating and MW irradiation).
The esterification yield was similar under homogeneous conditions, irrespective of
the mode of heating. In contrast, under heterogeneous conditions (e. g. with iron(III)
sulfate or potassium fluoride as catalyst), after 2 h at the same bulk temperature
(140 8C), the MW-irradiated reaction resulted in a higher (1.2 to 1.4-fold) yield of 50a
than did conventionally heating. This difference was more evident when graphite
was added to the reaction mixture ± similar yields (75±95 % 50a) were obtained after
only 5 min MW irradiation. Despite the small amount of added graphite (about 1/
10, w/w, relative to the reagents), the reaction mixture rapidly reached a much higher
temperature (250 to 300 8C) than in the absence of graphite.
7.3
Graphite as Sensitizer and Catalyst
As a support for chemical reactions graphite has often been ªmodifiedº by addition of a
variety of substances which can be intercalated between the carbon layers (GIC ± gra-
phite intercalation compounds) or dispersed on the graphite surface, depending on the
preparation conditions [13]. The resulting compounds, especially the GIC, have been
used as reagents and as catalysts in numerous reactions, particularly in organic transfor-
mations [13, 61]. Depending on the intercalating guest the carbon lattice can behave as
an electron acceptor (e. g. with metals ± C8K) or as an electron donor (e. g. with halogens
± C8Br). The electron power does not, however, seem to give Lewis-type catalytic activity
to the graphite itself. As long ago as 1994 [15, 16] we reported that reactions known to re-
quire a Lewis acid catalyst can be conducted in the presence of unmodified graphite;
this has been confirmed more recently by other authors [62±65]. We showed that the cat-
alytic ability of graphite is a result of metal impurities, not the carbon lattice [66]. Most
reported graphite-catalyzed reactions have been performed under the action of conven-
tional heating, in the presence of a solvent and a small amount of graphite [62±64].
Use of graphite-supported methodology has been reported for three types of reac-
tion ± the Friedel±Crafts acylation [15, 16, 27, 66], the acylative cleavage of ethers [15,
16], and the ketodecarboxylation of carboxylic diacids [67, 68], either with conven-
tional heating (GS/D) or MW irradiation (GS/MW coupling); these are discussed be-
low. First, however, we describe the analysis of two commercial graphites of different
purity which are used for these experiments.
7.3.1
Analysis of Two Synthetic Commercial Graphites
The two synthetic, unmodified graphites used in the experiments were:
. graphite A, Aldrich 28,286±3; purity 99.1%; particle size 1±2 mm; and
. graphite B, Fluka 50870; purity 99.9 %; similar granulometry.
Elemental analysis of graphites A and B by X-ray fluorescence and optical emis-

sion (ICP±MS) spectrometry showed the presence of approximately a dozen ele-
ments. Graphite A contained more iron and aluminum than graphite B ± A: Fe
0.41%, Al 0.02 %; B: Fe 0.007 %, Al 0.002 % (by weight). Other elements (Ca, K, Si,
Ti,V, Mn) were also present at lower concentrations. A careful study by transmission
electron microscopy (TEM) of graphite A revealed small crystallites; the EDX spec-
trum of these showed that iron and oxygen were the main elements (Fig. 7.1). From
these crystallites it was possible to obtain X-ray diffraction patterns in which, in addi-
tion to ring-shaped spots from graphite, heavy spots corresponding to magnetite
(Fe3O4) were observed [66]. In a sample of graphite B, these particles were not notice-
able owing to their small density.
We were therefore using two graphites of sharply different purity. The high iron
content (0.41%) of graphite A leads one to expect catalytic action, either directly by
the oxide (Fe3O4) or after a possible transformation on contact with MW radiation or
a chemical reagent.
7.3.2
Acylation of Aromatic Compounds
Acylation of aromatic compounds (Friedel±Crafts (FC) acylation), of great industrial

interest, suffers from an important catalysis problem [69]. Most of the Lewis acids
used as catalysts (traditionally metal chlorides such as AlCl3) complex preferentially
Fig. 7.1 Three results from transmission electron microscopy (TEM)

with a Philips CM20 instrument operating at 200 kV. The first image
shows a bright field of carbon deposited on a thin amorphous carbon
layer supported by a copper grid. A small crystallite (dark contrast) is
clearly apparent; this is also evident in other regions of the sample. The
X-ray diffraction pattern (second figure) was obtained by examining the
circled area of the bright-field image. The indexation is in good agreement
with the magnetite (Fe3O4) cubic structure with a cell dimension of
8.39 â, known as magnetite in the PDF database. The final figure corre-
sponds to the EDXS analysis obtained with the electron beam focused on
the small crystallite. The X-ray signal was captured by an Si(Li) detector.
This clearly shows the presence of iron and oxygen inside the crystallite.
with the ketone produced instead of with the acylating agent [70] (Scheme 7.12).
Rarely does a metal chloride complex preferentially with the acylating agent, except
bismuth(III) chloride with acid chlorides [71, 72].
A stoichiometric amount of promoter, at least, is required for the reaction to pro-
ceed, leading to an environmentally hostile process with gaseous effluents and
mineral wastes. With some metal salts, however, an increase in reaction temperature
sets them free from their complex with the ketone, and a true catalytic reaction be-
comes possible [73]; this is observed for iron(III) chloride [74] and some metal tri-
flates [72, 75], including their use under the action of MW heating [76].
In 1994 our preliminary results revealed, surprisingly, that FC acylation could be
realized in the presence of graphite A, under solvent-free conditions, under the ac-
Scheme 7.12
tion of either classical heating or MW irradiation [15, 16]. More recently the same re-
action has been reported in the presence of a small amount of the same graphite
and using a solvent [62]. We have explained this ªcatalytic effectº of graphite [66].
The procedure entailed MW irradiation, at atmospheric pressure, of graphite pow-
der A impregnated with reagents. The first experiments were performed with an ac-
tivated aromatic, anisole (51), using a variety of acylating reagents (Tab. 7.6). With vo-
latile acid chlorides such as acetyl or isobutyryl the reaction occurred in convenient
yields (entries 1 and 2), and boiling was delayed as a result of graphite adsorption.
With nonvolatile benzoyl chloride, the conversion became quantitative (entry 4).
Good yields were also obtained for a long-chain derivative, which is more difficult to
desorb from graphite, and for a furan derivative, known to resinify in the presence
of a Lewis acid (entries 3 and 5).
Tab. 7.6. Graphite-supported acylation of anisole (51) by use of a variety of acylating reagents
(RCOX) under the action of MW irradiationa [27, 66].
Entry RCOX b Conditions c, (Tmax) Product d Conversion and yield (%) e
1 MeCOCl 45 W; 1 min × 8, (230 8C) 58 g 62 (54)

i
2 PrCOCl 60 W; 1 min × 8, (260 8C) 59 g 80 (74)
3 UndCOCl f 90 W; 2 min × 4, (410 8C) 60 g 82 (74)
4 PhCOCl 150 W; 20 s × 15, (330 8C) 61 g 100 (91)
5 FuCOCl f 90 W; 2 min × 5, (430 8C) 62 h 60 (50)
6 (MeCO)2O + FeCl3 i, 60 W; 2 min × 6, (310 8C) 58 g 65 (56)
7 (iPrCO)2O + FeCl3 i, 90±30 W; 10 min j, (260 8C) 59 g 69 (63)
a
Graphite A, 5 g; 51, 10 to 20 mmol
b
51/RCOX (mol) = 2/1 (entries 1, 2), 4/1 (entries 3±7)
c
Applied incident power; sequential irradiation time; period between two irradiations 2 min, except
entry 4, 1 min 40 s
d
Products: MeO(C6H4)COR, R = Me(58), iPr(59), Und(60), Ph(61), Fu(62)
e
Conversion determined by GC; yield of isolated product (in brackets) relative to the minor reagent
f
Und = undecyl; Fu = 2-furyl
g
p/o 6 95/5
h
p/o = 82/18
i
FeCl3/(RCO)2O = 1/10 (mol)
j
Continuous MW irradiation with degressive power
The method was also applied to the benzoylation of other aromatic compounds
(Tab. 7.7). The benzoylation of benzene itself, volatile and less reactive, seemed more
difficult to perform (Tab. 7.7, entry 4). Silyl-substituted aromatics reacted by ipso Si-
substitution [77], and were less volatile. With trimethylsilylbenzene, benzoylation oc-
curred with an overall yield higher than for benzene, but the competitive H-substitu-
tion was also observed (entry 5).
Tab. 7.7 Graphite-supported benzoylation of aromatics under MW irradiationa [27, 66].
Entry ArH b Conditions, c (Tmax) Product d Conversion and yield (%) e
1 52 90 W; 2 min × 5, (390 8C) 63 73 (64)

2 53 60 W; 2 min × 7, (350 8C) 64 f 54 (45)
3 54 90 W; 2 min × 6, (450 8C) 65 g 85 (76)
4 55 60 W; 2 min × 7, (370 8C) 66 23 (15)
5 56 150 W; 20 s × 15, (328 8C) 66 42 (25)
67 (8)
6 57 90 W; 2 min × 4, (380 8C) 61h 60 (50)
a
Graphite A, 5 g; 51, 10 to 20 mmol
b
ArH: veratrole (52), toluene (53), naphthalene (54), benzene (55), Me3SiPh (56), p-Me3Si(C6H4)OMe
(57); ArH/PhCOCl (mol) = 4/1 (entries 1±5), 1/1.2 (entry 6)
c
Applied incident power; sequential irradiation time; interval between two irradiations: 2 min, except
entry 5, 1 min 40 s
d
Products: 2,4-MeO(C6H3)COPh (63), Me(C6H4)COPh (64), C10H8COPh (65), PhCOPh (66), p-Me3-
Si(C6H4)COPh (67)
e
f
p/o = 85/15
g
a/b = 55/45
h
p/o = 95/5
If graphite A has catalytic activity in these reactions, the amount of graphite could
be reduced, and 0.5 g (instead of 5 g) of graphite A was, indeed, sufficient to promote
these reactions (Tab. 7.8) [66]. In the process in which a small amount of graphite
was used:
. the temperature gradient was lower than for the GS/MW process; and
. vaporization of the reactants was not delayed.
Consequently:
. sequential MW irradiation was preferable to continuous (compare Tab. 7.8, entries
3 and 5); and
. the MW power must be reduced and the reaction time increased (compare
Tab. 7.6, entry 4, and Tab. 7.8, entry 5).
Comparative attempts at graphite-supported acylation of anisole, toluene, and

naphthalene using classical heating afforded interesting results [66]. With nonvola-
tile reactants the yields were almost identical with those obtained under the action of
MW. In contrast, if at least one reactant was volatile (MeCOCl, iPrCOCl) or sublim-
Tab. 7.8 Acylation of aromatic compounds in the presence of a small amount of graphite and under the action of
MW irradiation [27, 66].
Entry ArH a RCOX b Graphite c Conditions d, (Tmax) Product a Conversion and yield (%) e
1 51 MeCOCl A 45 W; 1 min × 8, (120 8C) 58 f 27 (20)

i
2 51 PrCOCl A 60 W; 1 min × 8, (120 8C) 59 f 90 (80)
3 51 PhCOCl A 300 W; 1 min, (165 8C) 61 f 85 (76)
4 51 PhCOCl C 300 W; 1 min, (159 8C) 61 f 95 (85)
5 51 PhCOCl A 60 W; 2 min × 7, (178 8C) 61 f 100 (98)
6 53 PhCOCl A 150 W; 20 s × 60, (120 8C) 64 g 36 (29)
7 54 PhCOCl A 300 W; 1 min, (160 8C) 65 h 40 (35)
a
ArH: anisole (51), toluene (53), naphthalene (54)
b
ArH/RCOX (mol) = 4/1 (entries 3±6), 2/1 (entries 1, 2, 7)
c
Graphite C: iron-graphimet (Alfa 89 654)
d
Continuous (entries 3, 4, 7) or sequential (entries 1, 2, 5, 6) MW irradiation; interval between two irradiations: 1 min
(entry 5), 2 min (entries 1, 2), 40 s (entry 6)
e
f
p/o 6 93/7
g
p/m/o = 82/2/16
h
a/b = 70/30
able (naphthalene), the yield obtained under the action of MW was higher. SMWI
enables control and limitation of these phenomena.
With regard to a mechanistic hypothesis, the catalytic effect of graphite itself be-
having as a Lewis acid was excluded ± the use of graphite B instead of graphite A re-
sulted in no reaction, or sometimes only a trace of the acylation product [27, 66]. The
presence of relatively large amounts of Fe3O4 in graphite A (Sect. 7.3.1) led us to be-
lieve this impurity was responsible for the catalytic activity observed. Several further
experiments supported this.
Graphites combined with a variety of metals (ªGraphimetsº) are known for their
catalytic properties [13]. The iron±graphite compound in which the presence of
Fe3O4 crystallites has been shown [78] proved very efficient for the acylation of ani-
sole (Tab. 7.8, entry 4). Because the iron content (5 %) was much higher than that of
graphite A, this graphimet could be a convenient material for GS/MW experiments,
but its cost, especially relative to that of graphite A, limits its use.
For the benzoylation of anisole (Tab. 7.6, entry 4), graphite A was replaced by gra-
phite B doped with Fe3O4 (28 mg for 5 g graphite, the same iron content as in gra-
phite A). Although unachievable with graphite B alone, benzoylation of anisole was
now possible, but with lower yield than for use of graphite A (50 % instead of 100 %).
This showed the activity of Fe3O4 became much stronger when subjected to the high
graphitization temperature.
The catalytic effect of graphite A thus depends on iron impurities, e. g. Fe3O4, and
probably also on iron sulfides or sulfates, because sulfur is also present in this gra-
phite, and all these iron compounds are known catalysts of FC acylation [69, 73, 74]. In
this respect, it seems that FeCl3 could be the true catalyst generated in situ by the reac-
tion of the different iron compounds with acid chloride and hydrogen chloride. In the
absence of a chlorinating agent, for example using an acid anhydride as the reagent
and an iron oxide (Fe2O3 or Fe3O4) as the catalyst, acylation does not occur. We have ef-
fectively shown that the GS/MW process using acid anhydrides as reagents is efficient
only after addition of a catalytic amount of FeCl3 (Tab. 7.6, entries 6 and 7).
Finally, a sample of graphite A was analyzed after acylation using an acid chloride
as reagent. No Fe3O4 crystallites were observed and an EDX spectrum revealed small
deposits containing iron, chlorine, and oxygen. Thus formation of FeCl3 from Fe3O4
crystallites is highly probable. Loupy et al. have shown that a-Fe2O3 can be generated
from Fe3O4 under the action of MW at high temperature [79]; the formation of FeCl3
would be a result of chlorination of Fe3O4 and/or Fe2O3. Because Fe3O4 interacts
strongly with MW [4], the presence of hot spots in the region of Fe3O4 crystallites
could also lead to increased catalytic activity.
Comparison with previous FC acylations, the above processes are clean, without
aqueous workup, and therefore without effluents (ªgreen chemistryº). The graphite
is, moreover, inexpensive and can be safety stored or discarded. Its activity is, how-
ever, limited to activated aromatic compounds.
The process which seems to have the most possibilities for a scale-up development
is that using a low amount of graphite, for which the desorption treatment can be to-
tally suppressed in a continuous flow system. We recently proposed the use of such
a process to perform FC acylations under the action of MW with FeCl3 as catalyst
[76 d]. The replacement of FeCl3 by a graphite bed is quite conceivable in the same
continuous flow apparatus.
7.3.3
Acylative Cleavage of Ethers
The preparation of esters using an acid chloride as reagent is usually performed

from alcohols and rarely from ethers [80]. However, the protection of the hydroxyl
group as ether derivatives constitutes a widely used method in organic synthesis
[81]. The acylative cleavage of ethers is one of possible deprotection processes. It oc-
curs with an acid halide or anhydride in the presence of a catalyst, usually a Lewis
acid. In 1998, Kodomari et al. reported a cleavage of some ethers (benzylic, allylic,
tert-butylic, and cyclic) with acid halides in the presence of graphite A [63]. The reac-
tion was performed under reflux in dichloroethane. Under these conditions, how-
ever, cleavage of primary or secondary alkyl ethers did not occur.
According to the solvent-free GS/MW process, which enables reaction at high tem-
peratures, the cleavage of these alkyl ethers became possible (Scheme 7.13) [15, 16].
An equimolar (10 mmol) mixture of benzoyl chloride and n-butyl oxide adsorbed
on 5 g graphite A was sequentially irradiated with 90 W incident power. The conver-
sion reached 80 % (Yield of isolated n-butyl benzoate (69): 62 %). With ethyl oxide,
the yield of ethyl benzoate (68) was lower, but noteworthy considering the volatility
of this oxide, and the significant retentive power of graphite towards organic com-
pounds. These preliminary results have not yet been expanded, but it is certain that
more reactive ethers, like those substituted with sec- or tert-alkyl, benzylic or allylic
groups, are cleavable in the same way.
Scheme 7.13
Concerning the mechanism of such a reaction and the nature of the catalyst, we
do not think that the graphite itself is the catalyst. In fact, diethyl- and di-n-butyl
ethers are inert towards benzoyl chloride in the presence of graphite B. Moreover, it
is known that metal chlorides, especially FeCl3 [82], are catalysts for this reaction.
After the careful mechanistic study realized in the case of FC acylations (Sects. 7.3.1
and 7.3.2), we propose that the catalyst of the graphite-assisted acylative cleavage of
ethers is FeCl3 generated in situ from Fe3O4 (and/or Fe2O3) and the acid chloride.
Then, the C±O bond cleavage would involve the O-acylation of ether ([R2O±COR']+)
followed by the nucleophilic displacement (SN1 or SN2) of one of the two hydrocar-
bon groups (R) of ether by the anionic part of the reagent (Cl±), as with the FeCl3±
Ac2O system [82]. It is interesting to note here that phenolic ethers, such as anisole
or veratrole, preferentially give the acylation of aromatic nuclei towards the cleavage
of the ether group (Sect. 7.3.2).
7.3.4
Ketodecarboxylation of Carboxylic Diacids
Thermal decomposition of carboxylates gave ketones by a decarboxylation mechan-

ism [83]. The same ketones were obtained directly from the corresponding carboxylic
acids by a decarboxylation±dehydration process in the presence of several catalysts,
such as thorium [84] or manganous [85] oxides. This catalytic way allows a lowering
of the reaction temperature, which still remains high (250±350 8C). Even though the
method is of little use in the synthesis of aliphatic ketones, it is an important route
for preparing cyclic ketones from carboxylic diacids [83, 86]. Among these ketones,
the cyclopentanone is an important industrial compound [87]. For its synthesis from
adipic acid, typical procedures using various catalysts (barium hydroxide [88 a], metal
oxides [83], carbonates [88 b], potassium fluoride [88 c]) have been described. How-
ever, the search for an efficient and eco-friendly industrial process is still the subject
of current interest [89, 90]. In this respect, with a view to reducing energy and raw
material consumption, a new approach has been undertaken using graphite-sup-
ported chemistry [67, 68].
The catalytic cyclization of a diacid requires two contradictory thermal conditions:
a temperature high enough to have a convenient reaction rate, but low enough to
avoid vaporization of the diacid. For adipic acid, the limiting temperature is about
290±295 8C [83, 86, 88]. Thanks to its properties of rapid conversion of MW energy
and retention of organic molecules, graphite could allow a high reaction temperature
to be reached rapidly, although it delays the vaporization of the diacid. Moreover,
since magnetite (Fe3O4) is a catalyst for the decarboxylation of acids [91], no added
catalyst would be necessary.
To determine approximately the optimum temperature of a graphite-supported cy-
clization of adipic acid, a series of experiments was performed with classical heating.
Using the two graphites A and B (Sect. 7.3.1), no significant vaporization of adipic
acid (70) was observed up to 450 8C at atmospheric pressure. Graphite A proved to be
the more efficient, giving 90 % yield of cyclopentanone (74) after 30 min of heating
(Tab. 7.9, entry 1). Graphite B gave a lower yield under the same conditions (entry 2).
Tab. 7.9 Graphite-supported thermal ketodecarboxylation of diacids 70±73a,b [67, 68].
Entry Diacid Graphite Ketone yield (%) c
1 70 A 74, 90 (85)
2 70 B 74, 22
3 71 A 75, 60
4 71 A 75, 80 (74)
5 72 A 76, 80 (72)
6 73 A 77, 17
a
Temperature of the electrical oven: 450 8C; reaction time: 30 min (entries 1±4), 60 min (entries 5, 6);
pressure: atm. p. (entries 1±3), 300 mm Hg (entries 4±6)
b
Optimized diacid/graphite ratio: 15 mmol/5 g
c
Conversion determined by GC and isolated yield (in brackets) from four experiments
The retentive power of graphite towards adipic acid and the catalytic effect of the
magnetite, especially present in A, are obvious. TEM examinations of a graphite A
sample before and after reaction showed that crystallites of Fe3O4 appeared to be
smaller after the reaction. However, the same graphite sample was reused for three
successive reactions without significant loss in yield. When applied to the synthesis
of other cyclic ketones (Scheme 7.14), less volatile than 74, it was observed that pres-
sure had an effect on the recovery of product (Tab. 7.9, entries 3 and 4). A slightly re-
duced pressure (300 mm Hg) was necessary to obtain 3-methylcyclopentanone (75)
or cyclohexanone (76) in convenient yield (Tab. 7.9, entries 4 and 5). For the cycliza-
tion of suberic acid (73), a less favorable structure, the yield in cycloheptanone (77)
remained low (Tab. 7.9, entry 6).
Some MW-promoted decarboxylations have been reported in the literature [92],
even the decarboxylation of magnesium, calcium and barium salts of alkanoic acids
[92 a]. We have shown for FC acylations and acylative cleavage of ethers (Sects. 7.3.2
and 7.3.3) that the graphite-supported process takes advantage of MW, since graphite
and magnetite are among the solids having the most efficient MW absorbing power
[4], and then providing elevated temperature in core. Consequently, the cyclization of
70 was realized under GS/MW conditions. A SMWI mode was optimized and
Scheme 7.14
coupled with a limitation of the reaction temperature to 450 8C, using the two gra-
phites A and B (Tab. 7.10, entries 1±4). Graphite A showed again its superiority, giv-
ing under these optimized conditions (entry 2) a 90 % yield in cyclopentanone (74)
after only 6 × 2 min of irradiation. Under the same conditions, graphite B gave only
a 33 % yield (entry 4).
Tab. 7.10 Graphite-supported ketodecarboxylation of adipic acid (70) under MW irradiationa [67, 68]
Entry Graphite and added catalyst MW conditions b,c Yield (%) d
1 A; none 90 W; 2 min × 2 60
2 A; none 90 W; 2 min × 2 + 75 W; 2 min × 4 90
3 B; none 90 W; 2 min × 2 19
4 B; none 90 W; 2 min × 2 + 75 W; 2 min × 4 33
5 B; Fe3O4 (28 mg) 90 W; 2 min × 2 51
6 B; Fe2O3 (29 mg) 90 W; 2 min × 2 51
7 B; FeO (26 mg) 90 W; 2 min × 2 35
8 B; Al2O3 (28 mg) 90 W; 2 min × 2 15
9 B; Bi2O3 (28 mg) 90 W; 2 min × 2 16
10 B; KF (21 mg) 90 W; 2 min × 2 14
11 B; Na2CO3 (80 mg) 90 W; 2 min × 2 29
12 B; Cs2CO3 (244 mg) 90 W; 2 min × 2 26
13 Fe3O4 (3.47 g) without graphite 90 W; 2 min × 2 10
a
Mass of 70: 2.19 g (15 mmol); mass of graphite: 5 g
b
Sequential MW irradiation controlled to a maximum temperature of 450 8C
c
Applied incident power and irradiation time; interval between two irradiations: 2 min
d
Yield of cyclopentanone (74) from GC analysis
To compare their activities further, various catalysts were added to graphite B, and
the results were analyzed with respect to the reference experiment (Tab. 7.10, en-
try 3) which gave a low yield (19 %). When doped with Fe3O4, graphite B gave a 51%
conversion of 70 (entry 5), almost as much as graphite A alone (entry 1). The two
other iron oxides, Fe2O3 and FeO, seemed to be active but other catalysts, Al2O3,
Bi2O3 and KF were inactive.
Because Fe3O4 itself is strongly absorbent of MW [4] and is a good catalyst for dec-
arboxylations [91], is the graphite necessary? When Fe3O4 was used in the absence of
graphite, the yield in ketone 74 decreased dramatically (10 %) (Tab. 7.10, entry 13).
Adipic acid was recovered almost completely on the walls of the reactor and on the
cold finger. Consequently, the presence of graphite as a support, able to adsorb and
retain the adipic acid, and then allow the cyclization before its vaporization, is essen-
tial.
Comparison of reaction times revealed a shortening under MW irradiation
(Tab. 7.10, entry 2: overall reaction time = 22 min) with respect to conventional heat-
ing (Tab. 7.9, entry 1, 30 min), for the same maximum temperature. This can be ex-
plained by a higher temperature gradient and the presence of ªhot spotsº at the gra-
phite surface under MW.
A reaction mechanism with Fe3O4 as catalyst has been proposed [68], in agree-
ment with previous work concerning decarboxylation of acids in the presence of a
metal oxide [83]. After the transient formation of iron(II) and iron(III) carboxylates
from the diacid and Fe3O4 (with elimination of water), the thermal decarboxylation
of these salts should give the cyclic ketone and regeneration of the catalyst.
This ªdryº, solvent-free GS/MW process, which allows high temperatures rapidly,
is very useful for the ketodecarboxylation of diacids. This has several advantages
such as:
. medium grade commercial graphite, of low cost, can be used;

. the diacid is confined to the graphite which prevents its vaporization; and
. the volatile ketone produced is recovered by distillation as the only organic com-
pound.
A large-scale process could be devised by using a continuous supply of diacid (as a

solid or in the molten state) in a graphite bed.
7.4
Notes
7.4.1
MW Apparatus, Typical Procedures, and Safety Measures
Graphite reflects MW like a metal and its heating depends strongly on particle size.
With large particles (flakes), electric discharges were observed under MW irradia-
tion, whereas with fine ones (powder) a rapid increase of temperature was obtained.
The temperature of the reaction mixture must be controlled to avoid melting point
of the reactor, if it is Pyrex glass. The use of a quartz reactor is highly preferable.
A MW applicator, such as the Synthewave 402 from Prolabo or nowadays Discover
from CEM, equipped with:
7.4 Notes 245
. a monomode cavity;
. open vessels allowing reactions at normal or reduced pressure;
. a rotating reactor;
. a MW power modulator;
. an IR pyrometer allowing a continuous record of reaction mixture temperature;
. a computer to monitor the different irradiation modes and the main experimental
parameters (incident MW power, temperature and time),
is a convenient apparatus to perform graphite-supported reactions [2a±c, 93]. The re-

actor equipment was completed by a dry-ice condenser allowing an easy rotation of
the whole set.
Typical procedures for the GS/MW process have been described in the literature
cited above. The deposition of nonvolatile reactants on graphite was performed using
a volatile solvent (generally Et2O), removed under reduced pressure before MW irra-
diation. When one of reactants was volatile, it was added neat to the graphite powder
previously prepared with the nonvolatile reactant as above. The ether used for im-
pregnation of graphite must be totally evaporated before MW irradiation; if not, in
some cases, owing to high reaction temperatures reached, Et2O can react with one of
reactants. For example, the formation of the ester RCOOEt resulting from an acyla-
tive cleavage of Et2O by RCOCl (Sect. 7.3.3) has been observed in FC acylations [15,
27]. In such cases, the impregnation can be performed by use of another volatile and
inert solvent, such as dichloromethane. The desorption of the reaction product(s)
was performed by washing of graphite with a proper solvent. The use of an ultraso-
nic bath can be advantageous.
7.4.2
Temperature Measurement
A knowledge of the temperature of the reaction media is fundamental. Under MW

irradiation, this measurement poses some conditions [94]. In stirred homogeneous
media, the measurement with an IR pyrometer is significant enough. However, an
optical fiber thermometer is preferable, but limited in high temperature levels. Con-
sequently, for the temperature measurement of graphite-supported reactions under
MW irradiation, the IR pyrometer was used which allows to measure the tempera-
ture of the lower reactor walls, and not inside of the reaction mixture. Stuerga and
Gaillard showed that the temperature of a MW-irradiated heterogeneous (especially
solid) medium was not uniform, but there were ªhot spotsº [95]. We had ourselves
observed, using a thermocouple at the end of a reaction, that the temperature inside
the graphite powder was 20 8C to 50 8C higher than that indicated by the IR pyrom-
eter. At the time of the MW irradiation of C-supported catalysts in the absence of ni-
trogen carrier, Bond et al. [17] observed very small bright spots within the catalyst
bed. They proposed that these bright emissions, of continually fluctuating positions,
would be due to the generation of plasmas.
Moreover, some MW absorbing impurities on the graphite surface, such as the
Fe3O4 crystallites, could induce other local superheating.
7.4.3
The Retention Mechanism of Reactants on Graphite
The adsorption phenomenon of organic molecules by graphite is well known, mole-

cular arrangements on surfaces have been recorded and thermodynamic data have
been determined [12]. The specific surface of graphite A is 13 m2 g±1 [15]. Therefore,
adsorption of 2 mL of an organic compound by 5 g of graphite would give a layer of
thickness 300 â. Van der Waals interactions, responsible for the adsorption, is not ef-
fective on such a large thickness. Other dynamic phenomena must be considered,
such as intercalation and diffusion between carbon layers. Molecules of appreciable
size, such as aromatic hydrocarbons and C60 fullerene, have been intercalated [96].
In view of the high temperatures in the GS/MW process, operation of these different
phenomena (adsorption, diffusion, intercalation) seems likely. The interlayer spaces
could behave as microreactors (or micro-ªpressure cookersº) in which reactants, or
at least a part of them, should be confined. However, after a reaction, we have not ob-
served (by XRD) any change in the interlayer distance of graphite. Consequently, at
the end of the reaction, and at room temperature, the interlayer distance should re-
vert to its basic value (3.354 â) [11], after ejecting the reaction product to the surface.
It must be noted here that the intercalation of organic compounds (pyridine deriva-
tives) into a layered mineral oxide (a-VO(PO4).2H2O) occurs more rapidly using MW
than with conventional thermal methods [97]. Moreover, as the graphite used is of
low granular size (1±2 mm), intergrain confinement due to capillary action is also
possible.
7.4.4
Graphite or Amorphous Carbon for C/MW Coupling?
Because amorphous carbon as graphite heats up strongly under MW irradiation [4],

its use as a sensitizer has been widely reported [5±10] (Sect. 7.1). Recently, MW-as-
sisted esterification of carboxylic acids with alcohols was performed on activated car-
bon in good yields (71±96 %) [98]. For our part, when charcoal powder was used as a
support, we had difficulty in desorbing the reaction products [15]. Even with a contin-
uous extractor, the desorption was never quantitative. The desorption of reaction pro-
ducts from graphite powder is much easier than from amorphous carbon powder.
Charcoals and various carbon blacks show great variability of their structure and
properties as a function of the carbonaceous starting material and the preparation
conditions [3, 11]. The graphitization of carbon, which is required to achieve a high
corrosion resistance, lead to materials of more homogeneous structures and proper-
ties, allowing a good reproducibility of reactions.
Therefore, graphite is preferable in a supported reaction, although the use of inter-
calated reagents remains possible.
Acknowledgments 247
7.5
Conclusion
Owing to a particularly strong interaction with MW radiation and a high thermal

conductivity, graphite is an efficient sensitizer. It is capable of converting radiation
energy to thermal, which is then transmitted instantaneously to supported chemical
compounds. High temperatures, which must be controlled, are rapidly reached, and
reaction times are most often shortened with respect to the same reactions effected
by classical heating. Two reaction types take advantage of this graphite/MW cou-
pling:
1. reactions which require a high temperature

2. reactions involving chemical compounds which, as in the case of organic ones,
have low dielectric loss and do not heat up sufficiently under MW irradiation.
Its inert behavior towards numerous chemical compounds and its adsorbent prop-
erties (responsible for the retention of volatile or sublimable organic compounds),
make graphite the choice support for thermal reactions. Among its impurities, mag-
netite was revealed to be an active catalyst, and some reactions can be performed
without any added catalyst. Two processes are then possible, the graphite-supported
reaction (ªdryº process), and the reaction in the presence of a small amount of gra-
phite (solid±liquid medium).
In a broad perspective, large scale development seems possible for some reactions,
either by a continuous-flow process through a MW-irradiated graphite plate (solid±li-
quid (or gas) reactions), or by a continuous supply of solid starting compound on a
graphite bed (ªdryº reactions). In this respect, continuous processes have recently
given excellent results in large scale development of MW-assisted reactions in homo-
geneous and heterogeneous media [76 d, 99].
Acknowledgments
We thank Professor M. Onyszchuk (McGill University, Montreal), for his assistance

in the preparation of the manuscript, and Drs M. Audhuy-Peaudecerf, M. Poux (In-
stitut National Polytechnique, Toulouse), P. Baul s (Center d'Elaboration de Matri-
aux et d'Etudes Structurales, C.N.R.S., Toulouse), J.-R. Desmurs, N. Roques (Rhodia
Organique Fine, France), our co-workers B. Garrigues, R. Laurent, and C. Laporte
for their effective and friendly collaboration.
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253
8
Microwaves in Heterocyclic Chemistry
Jack Hamelin, Jean-Pierre Bazureau and Franoise Texier-Boullet
8.1
Introduction
This chapter will deal with applications of microwave irradiation in the synthesis of
heterocycles by a variety of means, excluding cycloadditions, which will be described
in the next chapter. We have chosen to report first reactions in solution in organic
solvents, then heterogeneous reactions without solvent under a variety of conditions,
and finally to deal with emerging techniques which employ ionic liquids.
8.2
Microwave-assisted Reactions in Organic Solvents
In this section we will examine examples of organic transformations performed by

using microwave energy to heat organic mixtures. In all the examples included in
this section, the chemical reagents are dissolved in a solvent that couples effectively
with microwaves and generates the heat energy required to promote the transforma-
tions.
8.2.1
Heck, Suzuki, and Stille reactions
The palladium-catalyzed Heck [1], Suzuki [2] and Stille [3] reactions are robust and
general methods for C±C bond-formation and have therefore emerged as important
reactions in the synthesis of natural heterocyclic compounds.
Hallberg and coworkers [4 a] have used a single-mode microwave oven [4 b] at
50 W to improve radical-mediated reduction and cyclization of the heterohalide 1
with HSn(CH2CH2C10F21)3 2 in benzotrifluoride (BTF). The authors claim the pre-
paration of 3 in high yield (93 %) after 5 min, as illustrated in Scheme 8.1.
The efficiency of fluorous Stille coupling reactions [5 a] is enhanced by use of mi-
crowave irradiation (Scheme 8.2). The reaction proceeds in 79 % yield after 2 min
with DMF as the microwave-active solvent.

ISBN: 3-527-30514-9
254 8 Microwaves in Heterocyclic Chemistry
I
AIBN, BTF
HSn(CH2CH2C10F21)3
N 5 min./50W N
Cbz Cbz
1 2 3 (93%)
Scheme 8.1
PdCl2 (PPh 3)2, CuO

N DMF N
(C 6F13CH2CH2) 3Sn Br CN CN
2 min. / 60W
79%
Scheme 8.2
The same authors performed a microwave assisted Stille reaction on the Rink
amide (RAM) Tentagel polymer-tethered 4-iodobenzoic acid [5 b]. Successful palla-
dium-catalyzed coupling of heteroaryl boronic acid with anchored 4-iodobenzoic acid
enabled both >99 % conversion of the starting material within 3.8 min (45 W) and a
minimal decomposition of the solid support. The coupling reactions were realized
in a mixture of polar solvents (H2O±EtOH±DME, 2.5 : 1.5:6).
A recent report [6] has discussed the effect of monomode microwave irradiation in
the palladium-catalyzed phenylation of 5-iodouracil 4 with the nontoxic sodium tet-
raphenylborate 5 as phenyl reagent (Scheme 8.3). The authors showed that the use
of monomethylformamide (MMF) as solvent increases the yield of 6 (70 %), because
MMF has a high boiling point (180 8C) and is more polar (e = 182.5) than other
amides used in microwave-activated reactions.
A regiocontrolled Heck vinylation [7] of commercially available 2-hydroxyethyl vi-
nyl ether 7 in dry DMSO has been reported (Scheme 8.4). Flash heating by micro-
O O
I Pd(OAc)2
HN HN
Ph4BNa
O N MMF O N
H H
8 min./10W
4 5 6 (70%)
Scheme 8.3
OTf O O
Pd(OAc)2
O
OH
MeO DPPP, Et3N
MeO
DMSO
7 8 9 89 % (5 min./5W)
69 % (20 h./40°C)
Scheme 8.4
wave irradiation (5 min, 5 W), as a complement to the standard thermal heating

(20 h, 40 8C), was used to reduce reaction times drastically, with better yields of iso-
lated product 9.
8.2.2
Aziridine Synthesis
Aziridines, the smallest heterocycles, are an important class of compounds in or-

ganic chemistry. Interesting access [8] to aziridines by using Bromamine-T as a
source of nitrogen in the copper (II)-catalyzed aziridination of olefins in MeCN was
recently reported. Application of microwaves has resulted in enhanced yields for azir-
idines [9] with short reaction times (Scheme 8.5).
O Br CuBr 2
Me S N N Ts
O Na MeCN
81 % (MW, 12 min.)
Scheme 8.5
8.2.3
b-Lactam Chemistry
Bose and coworkers [10] have described hydrogenation using ammonium formate as
hydrogen donor and Pd/C as catalyst for selective transformations (Tab. 8.1) of b-lac-
tams 10, as shown in Scheme 8.6.
Y Ph HCO2NH 4 , 10 % Pd/C, MW Z Ph
H
N N
O R HO O R
OH
Scheme 8.6 10 11 (80-90 %)
Tab. 8.1 Transformations of b-lactams 10 by hydrogenation under the action of microwaves.
Product 10 Y R Product 11 Z Yield of 11 (%)
10a CH2=CH An 11a CH3±CH2 83

10b MeC(=CH2) An 11b MeCH(Me) 80
10c CH2=CH Ph 11c CH3±CH2 90
10d CH2=CH±CHO An 11d CH3CH2CH2O 87
10e OBn An 11e OH 80
10f OPh An 11f OPh 84
10g CH2=CH Bn 11g CH3±CH2 85
10h OBn Bn 11h OH 83
Ph = C6H5, An = C6H4OMe-4, Bn = CH2C6H5

Ph Ph Ph
O Et3N
N N N
Cl 118°C, MW O Me O Me
Me
12 13 10 min. , 90% 14 cis (20) 14 trans (80)
Scheme 8.7
OTBDMS
H H
OTBDMS S NH-Boc
H H N
S conditions, O
NH-Boc see Table 8.2 CO2PNB
O MeP(OEt)3 18
N
O CO
PNB OTBDMS
16 O O H H S
17 NH-Boc
N O
O
CO2PNB 19
Scheme 8.8
The authors report reaction times similar to those achieved with a preheated oil
bath at 130 8C on a small scale; on a larger scale, however, microwave-assisted reac-
tions seem to proceed more rapidly.
The same authors also studied recently the preparation of substituted vinyl b-lac-
tams 14, with efficient stereocontrol [11], by use of limited amounts of solvent (chlor-
obenzene) (Scheme 8.7). Microwave oven-induced reaction enhancement (MORE)
chemistry techniques have been used to reduce pollution at the source and to in-
crease atom economy.
A comparative study [12] of the reactivity of the oxalimide 16 in a variety of sol-
vents (xylene, chlorobenzene, toluene) and of methylphosphinite 17 was performed
with the focused microwave Synthewave 402 reactor (Merck Eurolab, div. Prolabo,
France), using different conditions of power and exposure time (Scheme 8.8). In all
experiments yields were better than those of previous procedures with classical heat-
ing (Tab. 8.2), and the authors wrote ªit is clear that microwave technique is applic-
able to highly functionalized compounds containing stereogenic centers without ap-
preciable modification of these centersº.
Tab. 8.2 Cyclization of 16 under the action of microwave irradiation.
Solvent Time (min) Power (W) Final temp. (pC) Yield of 18 (%)
Xylene 10 300 140 50

Chlorobenzene 2 300 150 35
Neat 10 300 80 0
8.2.4
1,2,4-Triazole, Pyrazole Synthesis
Barbry and coworkers conducted extensive investigations leading to the development

of a range of microwave-assisted synthesis of 3,5-disubstituted 4-amino-1,2,4-tria-
zoles [13 a] as potentially good corrosion inhibitors. The group found, for example,
that the 4-amino-1,2,4-triazole 22 is quickly prepared (5 min) by reaction of the 2-cya-
nopyridine 20 on hydrazine dihydrochloride in the presence of excess hydrazine hy-
drate in ethylene glycol under the action of microwave irradiation (95 % yield). The
analogous reaction performed with conventional heating proceeds in 85 % yield and
requires a longer reaction time (ca. 45 min) (Scheme 8.9 a).
Interestingly, the same authors [13 b] have isolated the 1,2-dihydro-1,2,4,5-tetra-
zine intermediate 21 by condensation of 2-cyanopyridine 20 with hydrazine hydrate
in presence of flower of sulfur (Scheme 8.9 b). The reaction time is reduced under
the action of microwave irradiation (125 W); protic solvents also promote the trans-
formation.
Kidwai et al. have demonstrated that formic acid can be used to catalyze and accel-
erate cyclocondensation of hydrazones to give new fungicidal pyrazoles [14], as
shown in Scheme 8.10.
The significance of their work using microwave heating is that the classical ap-
proach to cyclocondensation of hydrazones requires 30±35 h with constant heating
HO NH 2
OH N N N N
N
N CN H2N-NH 2, HCl N N N N
H2N-NH 2, H2O N N
H H
20 21 22
MW oil bath
95% in 5 min. 85% in 45 min.
Scheme 8.9 a
H2N-NH 2, H2O N N
68%, 10 min. in DMF
77%, 10 min. in EtOH
N CN S, N2 N N N N
solvent H H
125W
20 21
Scheme 8.9 b
R O
H MW R = phenoxy, octyl
N Ar = 2-hydroxyphenyl, 2-hydroxynaphthyl
R N Ar N H
HCO 2H Ar 3-nitrophenyl, phenyl, 4-chlorophenyl
O N
4-7 min. 4-methoxyphenyl
H
75-86%
Scheme 8.10
at 100±120 8C whereas the same reaction is complete in 4±7 min with improved yield
when performed under the action of microwave irradiation.
8.2.5
Multistep Synthesis of Polyheterocyclic Systems
The purpose of this section is to highlight the applications of microwave irradiation

to multistep synthesis of polyheterocyclic systems with potent pharmaceutical value.
When conventional thermal procedures (metal or oil bath) fail, and irrespective of
the conditions needed in the homogeneous phase, microwave irradiation can be
used as an alternative to classical methods enabling development of easy and rapid
access to new heterocycles.
Besson and coworkers reported an original approach for the synthesis of the rare
thiazolo-[5,4-f ]-quinazoline 29 in six steps [15] from commercially available 2-amino-
5-nitrobenzonitrile 22 (Scheme 8.11). The authors studied the transposition of four
steps (ii, iii, vi, and vii) of the synthesis of thiazoloquinazoline 29 to microwave irra-
diation of solutions, with the same concentration of starting material and volume of
solvent, and found that yields of the desired compounds were better than those ob-
tained by conventional heating (Tab. 8.3). The overall time for the synthesis of 29
was considerably reduced and the overall yield was enhanced.
A new means of access to 5a,10,14b,15-tetraazabenzo[a]indeno-[1,2-c]-anthra-
cen-5-one 33 and to benzimidazo-[1,2-c]-quinazoline 31 was reported recently [16]
(Scheme 8.12). The preparation of 6-mercaptobenzimidazo-[1,2-c]-quinazoline 31
OEt
NC NO 2
i S S NC NO 2 ii NO 2 iii
N N
H2N 78% N MW MW
Cl NC N
22 23 24
OEt OEt Br OEt Br Cl

NH2 NH 2 N
N iv N v N
N
S S
NC N 74% NC N 66% NC N
25 26 27
CN
OEt S O S
vi N vii H N
N N
MW MW
NC N N
28 29
Scheme 8.11 Reagents and conditions (for reflux; (iii) SnCl2.2H20, EtOH, 70 8C; (iv) Br2,
time and yields of steps ii, iii, vi, and vii see AcOH, rt, 24 h; (v) 4,5-dichloro-1,2,3-dithiazo-
Tab. 8.3). (i) 4,5-dichloro-1,2,3-dithiazolium lium chloride, rt, 4 h; (vi) CuCN, pyridine, reflux;
chloride, pyridine, rt, 10 h; (ii) NaH, EtOH, (vii) HCl, reflux.
Tab. 8.3 Comparison of conventional heating and microwave irradiation for steps (ii), (iii), (vi),
and (vii) of Scheme 8.11.
Step Starting material Product Conventional heating Microwave irradiation

Reaction time Yield (%) Reaction time Yield (%)
(min) (min)
ii 23 24 640 37 80 61
iii 24 25 60 72 10 94
vi 27 28 90 50 20 53
vii 28 29 60 49 10 50
was easily accomplished at 60 8C (in 55 min), under the action of focused microwave
irradiation, by reaction of the starting 2-(2-aminophenyl)benzimidazole 30 with CS2
in the presence of KOH and a protic solvent (MeOH). Under the same conditions
conventional heating led to the same yield but with a reaction time of 24 h.
Alkylation of 31 with dibromomethane and 1,2-dibromoethane was performed un-
der solvent-PTC conditions with good yields and short irradiation times (15 min)
[16]. The synthesis of original benzimidazo-[1,2-c]-quinazoline dimers 32(a,b) was
successfully achieved by use of potassium carbonate in the microwave active DMF
solvent (Scheme 8.13).
N N ii N
i
N MWI N 95% N
H H2N 95% N N
HS MeS
31 32
30
N
N
iii, MWI 33a : R = H, (95%), 1.5 h. under MWI
N
N 33b : R = Me (75%), 2 h. under MWI
R NH2 O
CO2H
33
R
Scheme 8.12 Reagents and conditions: (i) CS2, MeOH, reflux,
MW, 55 min; (ii) MeI, NaH, DMF, 25 8C, 5 min; (iii) graphite, MW.
N
N
N Br-(CH2)n-Br S
32a : n = 1 (86%)
n 32b : n = 2 (81%)
N K2CO3 S
N TBAB, DMF N
HS 60°C, MW, 15 min. N
31
N
Scheme 8.13
H NH2 N2
N O H i ii
N N N
O R X X
X
O R OR
O
33 34 35 36
Me
N3 N
iii iv X = H, Cl, Br
N R = Me, allyl
X X N
OR O
R
37 38
Scheme 8.14 Reagents and conditions: (i) DMF, reflux, 1 h, MW.

(ii) HCl N, NaNO2, AcOH, 30 min (iii) NaN3, Et2O, 40 min (iv)
DMF, MW.
The benzodiazepine nucleus is a well studied traditional pharmacophoric scaffold

that has emerged as a core structural unit of a variety of sedative±hypnotic, muscle
relaxant, anxiolytic, antihistaminic, and anticonvulsant agents. The literature on this
subject, although very copious, is mainly patents. Among many of these reports, an
original investigation [17] was described by the group of Santagada for the prepara-
tion of 1,5-benzodiazepin-5-ones 38 (Scheme 8.14).
Noticeable improvements were achieved for steps (i) and (iv) when the experimen-
tal conditions were realized under the action of microwave irradiation with the same
concentration of starting material and volume of dimethylformamide. Product 35a
(R = Me, X = H) was obtained in 91% yield after 5 min under the action of micro-
wave irradiation at 150 W; conventional heating in oil bath resulted in only 65 %
yield of 35a after 180 min (DMF, reflux). For step (iv), transposition of the conven-
tional heating conditions for reaction of 38a (40 % yield, 60 min, reflux) to micro-
wave irradiation of solutions gave the desired compound 38a in better yield (60 %)
and reduced reaction time (5 min, 80 8C, 150 W).
Thiaisatoic acid is a starting material of great interest in the field of heterocyclic
chemistry, as a potential new pharmacological scaffold. Rault and coworkers [18], in
the synthesis of 2-thiaisatoic anhydride 41 and 3-thiaisatoic anhydride 44 performed
the alkaline hydrolysis of ortho aminoesters 39 and 42 as a key step in the prepara-
tion of these anhydrides (Scheme 8.15).
The authors showed that it was possible to perform this reaction in a multimode
microwave oven [19] in a few minutes on a large scale in water containing a slight ex-
cess of potassium hydroxide but without cosolvent. Under the action of classical
heating the major problem with these syntheses is the instability of the thiophene
o-amino acids, which readily decarboxylate at room temperature to give aminothio-
phenes which are themselves unstable [20 a] and have to be used as soon as they are
prepared. With large quantities of reactants, moreover, the hydrolysis step is not easy
to perform because of the low reactivity of thiophene carboxylates 39 and 42 [20 b].
H
NH 2 NH 2
KOH, H 2O COCl 2 N O
CO2Me CO2K O
S MW, 30 min. S S
O
39 40 41
O
CO2Me CO2K
KOH, H2O COCl2 O
NH 2 MW, 15 min. S NH 2
S S N O
H
42 43 44
Scheme 8.15
Me
H N
O 1
R N Cl R1 N N
R1 N i ii
2
R R2
R2 N HN N Me
N N
O H H
45 46 47
Scheme 8.16 Reagents and reaction conditions: (i) POCl3, pyridine,
reflux, MW (700 W), 1 h 45 min; (ii) DMF, 240 8C, 6 bar; MW, 1 h.
After microwave heating, the potassium carboxylates 40 and 43 could be treated

directly by bubbling phosgene in the aqueous solution to yield the anhydrides 41
and 44 in 85 and 67 % yields, respectively, with purity >90 %.
Under conventional heating the rearrangement [21] of pyrrolo-[2,1-c]-benzodiaze-
pine, 45, in boiling phosphorus oxychloride, into benzo-[h][1,6]-naphthyridine 46 re-
quired a long reaction time (5 h) (Scheme 8.16).
Under microwave heating conditions compound 46 is obtained with reduced reac-
tion time (1.5 h) and better purity. A dramatic improvement was achieved when 46
was treated with N-methyl piperazine in DMF in a sealed glass vessel. After 1 h
under microwave irradiation, the N-methyl piperazino derivative 47 was obtained in
68 % yield.
8.2.6
Claisen Rearrangement
For preparation of allyl coumarins and dihydrofuranocoumarins by tandem Claisen

rearrangement±cyclization the usual procedures required vigorous reaction condi-
tions, workup procedures were tedious, and long reaction times led to low yields.
The rearrangement of allyloxycoumarins 48 to dihydrofuranocoumarins 49 has been
optimized in good yields in a sealed Teflon containers with BF3±ether in N-methyl-
R3
R3
NMF, H2O
HO O O
R1 O O O MW, 10 min.
R2 R1
R2
48 R3
BF3/Et2O, NMF
R1, R2 = H, Me O O
MW, 10 min. O
R3 = H, Me, Ph
R2 R1 49
Scheme 8.17
formamide (NMF) [22]; the short reaction time (10 min) associated with the micro-
wave-assisted procedure is the best means of preparation of these compounds, as
shown in Scheme 8.17.
8.2.7
Hantzsch Cyclocondensations
Alvarez-Builla and coworkers have used microwave irradiation to improve Hantzsch-

1,4-dihydropyridine synthesis [23] (Scheme 8.18). Reduced reaction times and im-
proved yields are generally associated with this procedure as exemplified by the pre-
paration of 52 from 2-chlorobenzaldehyde 50.
Khadilkar and Madyar [24] have developed a large scale and continuous Hantzsch-
1,4-dihydropyridine-3,5-dicarboxylate synthesis in aqueous hydrotope solution [25],
using a modified domestic microwave oven. The authors used novel reusable aqu-
eous hydrotope solution [26] as a safe alternative to inflammable organic solutions,
in a microwave cavity, for synthesis of commercially important calcium blockers
such as nifedipine, nitrendipine, and a variety of other 1,4-dihydropyridines (DHP)
(Scheme 8.19).
Nitrendipine (R = 3-NO2, R1, R2 = Me) has been obtained in 94 % yield (50 g) after
24 min by microwave irradiation of the reaction mixture (final temperature: 86 8C)
at a flow rate of 100 mL 7 min±1. The reaction mixture was circulated through the
Cl
O O O NH3, H2O
RO2C CO2R 55%, 4 min., MWI
EtOH, reflux, MWI 44%, 24 h, oil bath
Cl OR
Me N Me
H
50 51 52
Scheme 8.18
R
Aq. hydrotope,
O CO2R1 MW
R R1O2C CO2R1
CO2R1 MeO2C Me
Me N Me
NH 2 H
50 53 52
Scheme 8.19
microwave cavity in four cycles of 6 min each; a 2-min gap between each cycle was
imposed to avoid excessive heating.
It should be noted that the Hantzsch-1,4-DHP synthesis can be conducted with a
soluble polymer. Successful derivatization of poly(styrene±co-allyl alcohol) under the
action of microwave irradiation with a variety of ethyl oxopropanoates and ethyl
3-aminobut-2-enoates were reported by Vanden Eynde's group [27].
Khmelnitsky and coworkers have also examined microwave-assisted parallel
Hantzsch pyridine synthesis [28]. They have demonstrated the benefits of microwave
irradiation in a 96-well plate reactor for high throughput, automated production of a
pyridine combinatorial library (Scheme 8.20).
In each reaction ethyl acetoacetate 51 a was used as one of the components of the
Hantzsch synthesis, whereas the second 1,3-dicarbonyl compound 51 (or 53) and the
aldehydes 50 were used in all possible combinations (one unique combination per
O O O O MW
R2 O
O RO R1 NH 4NO 3 / bentonite
DMF
51a 51 50
O R2 O O R2 O O R2 O
O O RO OR RO OR
N R1 N R1 R1 N
α
52α β
52β 52γγ
O
O O MW
R3 R2 O
O NH 4NO 3 / bentonite
O
DMF
51a 53 50
O O R2 O
R2 O O R2 O
O O O R3 R3
R3
N N
N
α
52α α
54α β
54β
Scheme 8.20
well). Each well plate containing ammonium nitrate (on bentonite) was impregnated
with N,N-dimethylformamide as energy-transfer medium. The 96-well reactor
placed in a microwave oven (1300 W) was irradiated for 5 min at 70 % power level.
8.2.8
1,3,4-Oxadiazole Synthesis
In the preparation of novel 1,3,4-oxadiazoles 56 from 1,2-diacylhydrazines 55, Brain

and coworkers [29] used a highly efficient cyclodehydration assisted by use of micro-
waves, in THF as solvent, using polymer-supported Burgess reagent (Scheme 8.21).
O O THF
R1 O R2
R1 R2 O N NEt 3
PEG S
N N 2-4 min.,100W N N
H H O O O
55 56 (75-98%)
R1 = furyl, 3-pyridyl, 4-pyridyl, PhSO 2 CH 2
R2 = Ph, Me, NHPh
Scheme 8.21
Microwave irradiation coupled with poly(ethylene glycol)-supported Burgess re-

agent reduced the reaction time to 2±4 min and led to improved yields. Use of harsh
reagents, e. g. SOCl2, POCl3, and polyphosphoric acid, for the cyclodehydration were
avoided.
8.2.9
Biginelli Cyclocondensation
In recent decades, the Biginelli-type dihydropyrimidinones (DHPM) have received

considerable attention, because of the interesting pharmacological properties of this
heterocyclic scaffold [30]. It was soon established that DHPM has a similar pharma-
cological profile to the well-known dihydropyridine (DHP) calcium-channel modula-
tions of the Hantzsch type [31].
The introduction of a fluorine atom or CF3 group into an organic molecule fre-
quently provides compounds of pharmacological interest, compared with their non-
fluorinated analogs. Microwaves have been found to greatly accelerate the Biginelli
synthesis of fluorine-containing ethyl 4-aryl-6-methyl-1,2,3,4-tetrahydropyrimidin-2-
one/thione-5-carboxylates [32] 58 in unsealed vessels with ethanol as energy-transfer
medium and a small amount of concentrated HCl as catalyst (Scheme 8.22). Short
reaction times, enhanced yields, and easy workup are the main advantages observed
by Dandia and coworkers. This Biginelli reaction has also been studied recently [33].
Varma and Kappe have developed a method that enables the rapid and parallel
synthesis of DHPM 58 (Scheme 8.22) but does not rely on polymer-supported build-
ing blocks and therefore does not require the development of solid-phase linking±
cleaving chemistry. They showed that polyphosphate ester (PPE) serves as an excel-
MW R2
O H (30% of 360W) O H
N NH 2 N
R2 O R
O O X EtOH, HCl cat. Me N X
8-11 min.
R
51a 50 57 58 (65-80%)
,
R2 R F
F3C F
Scheme 8.22
lent reaction mediator in the microwave-assisted three-component Biginelli reaction

[34]. The DHPM 58 obtained by use of the microwave/PPE-mediated Biginelli proce-
dure was usually at least 95 % pure. In most experiments a very significant increase
(20±50 %) in yield can be achieved by use of the MW-induced procedure (a 800-W
microwave oven was used at 50 % power level).
Simultaneously the reaction time is reduced from typically 4±8 h under reflux (tra-
ditional heating) to a few minutes (MW irradiation).
8.2.10
Condensation Reactions with Creatinine and Thiohydantoin
Microwave-mediated condensation can be used to prepare heterobicycles [35] as illu-

strated in Scheme 8.23.
Imino derivatives 61 were obtained directly from 3-formylchromone [36] 59 and
creatinine [37] 60, with DMSO as solvent and boric acid as catalyst, and with micro-
wave irradiation and classical heating (Tab. 8.4). The authors have also investigated
the preparation of the 2-thioxo-5-imidazolidin-4-ones 63 from thiohydantoin 62 in
Me
N NH
NH O Me
O N N
H 60 N H
R
H3BO3, DMSO O O
O MW (270W) 61
O SH
R AcOK, (AcO) 2O O
N
O MW (270W)
N H
59 R
H O
O
R = H, Me, Cl, Br, AcO, NO 2 N 63
S
O N
H 62
Scheme 8.23
the presence of potassium acetate and acetic anhydride as solvent, using both meth-
ods. Here, the effect of microwave irradiation was shortening of the reaction times
and a small increase in the yields.
Tab. 8.4 Condensation of 3-formyl chromone 59 with creatinine 60 and thiohydantoin 62.
Product R Conventional heating Microwave irradiation

Reaction time (min) Yield (%) Reaction time (min) Yield (%)
61a H 60 71 3 75
61b Cl 60 72 2 76
63a H 60 72 8 79
63b Br 60 88 9 96
8.2.11
Deprotection of N-Cbz and N-Bn derivatives; Deuterium-labeled Aromatic
Dehalogenation
Microwave irradiation has been shown to be of particular utility [38] in functional

group protection and deprotection strategies. The benzyl carbamate (Cbz) and the
benzyl (Bn) groups are very popular for protection of amines. Following Bose's re-
port [10] on the effect of microwaves on the catalytic hydrogenation of double bonds
[39], Daga and coworkers [40] found that amino groups protected by Cbz and Bz can
be deprotected in few minutes by microwave-assisted transfer hydrogenation with
Pd/C 10 % in i-PrOH as the solvent and HCO2NH4 as the hydrogen donor. For di-
peptide 64, deprotection was complete (95 % yield of the free amine) after three cy-
cles of irradiation (1 min at 600 W then at least 1 min of rest were applied until no
trace of the starting material was detected by TLC analysis). No racemization was ob-
served (Scheme 8.24).
Ph Ph
O O
i
CbzHN OMe H2N OMe
MW (600W) O
O 3 cycles OH
OH
64 65 (95%)
OH OH
Ph Ph
i
O NBz 2 O NH2
MW* (30W)
OCH2Ph 75°C, 20 min. OCH2Ph
66 67 (70%)
Scheme 8.24 Reagents and conditions: (i) HCO2NH4

(4 equiv.), Pd/C 10 %, i-PrOH. *Synthewave 402 oven, Prolabo, Fr.
H O H O
N MW 20% of 750W N
N N
20 sec.
DCO2K, H2O
R Pd(AcO) 2 cat. D
68 (R = Br, I) DMSO 69 (95%)
Scheme 8.25
This procedure was also compatible with the benzyl ester, as demonstrated in
Scheme 8.24 by selective deprotection of compound 66 (67 was isolated in 70 % yield
by chromatography after 20 min irradiation at 75 8C (30 W) in the Synthewave 402
reactor).
It is interesting to remark that classical hydrogenation is a method used to prepare
deuterium-labeled compounds by aromatic dehalogenation, but the usual reaction
conditions suffer from several limitations. A microwave-enhanced catalytic dehalo-
genation procedure for rapid and specific deuterium labeling of N-4-picolyl-4-
halogenobenzamide 68, by use of deuterated formate, [41] was recently reported
(Scheme 8.25).
8.3
Solvent-free Synthesis
Although the initial reason for the development of solvent-free conditions for micro-
wave irradiation was safety, it soon became apparent that use of these conditions had
many other benefits ± simplicity, efficiency, easy work-up, very often higher yields,
and enhanced reaction rates. The absence of solvent is, furthermore, time- and
moneysaving and often enables elimination of waste treatment.
Solvent-free synthesis can be realized under a variety of conditions; for each we
give selected results and, when available, results from comparison with the same sol-
vent-free conditions but with classical heating.
8.3.1
Solvent-free Synthesis under Acidic Conditions
This section covers synthesis catalyzed either by organic acids or by inorganic acidic
supports.
8.3.1.1 Tetraphenyl Porphyrin Synthesis [42]

A simple and rapid synthesis of tetrapyrrolic macrocycle has been achieved under dry
media conditions with microwave activation. Pyrrole and benzaldehyde adsorbed on si-
lica gel afford tetraphenylporphyrin within 10 min (Scheme 8.26), whereas with con-
ventional methods (e. g. acetic acid in the presence of pyridine) 24 h were necessary.
In the monomode Prolabo Synthewave 402 reactor (at 135 W) a yield of 9.5 % was
obtained compared with 4 % in a multimode domestic oven. The advantages of the
Scheme 8.26
H O
Silica gel N N
+ H
"dry media" H
N N
N-H
method are its rapidity and more straightforward workup; yields suffer from the
same limitations as under classical conditions. It has been shown later that the yield
increases to 31% when the irradiation was performed in the presence of toluene [43].
8.3.1.2 Acetalization of L-galactono-1,4-lactone [44]

Acetals of l-galactono-1,4-lactone (an abundant byproduct of the sugar beet industry)
have thermotropic liquid crystalline properties. Acetalization in DMF containing
H2SO4 in the presence of anhydrous CuSO4 gave (after 12 to 24 h at 40 8C) yields of
20±35 % (Scheme 8.27).
Use of montmorillonites KSF or K10 as acidic supports and irradiation at 60 W
(monomode oven, final temperature 155 8C) led to yields threefold higher in 10 min.
8.3.1.3 Aziridine Synthesis

A dry-media technique with microwave irradiation for synthesis of aziridines has re-
cently appeared in the literature [45] (Scheme 8.28).
H2C OH H2C O
CH R
HC OH HC O
O R-CHO O
HO O HO O
HO HO
Example : R = CH3-(CH2)11
DMF, H2SO4, CuSO4 24 h 40°C 25%
KSF "dry media" 10 min. 60W 66%
K10 "dry media" 10 min. 60W 89% Scheme 8.27
R R X H
+ RCH=C(X)Br
Bentonite
R(Br)HC CH(Br)X 1
H N H + H N X
R NH2
R1 R1 + R-CH=N-R1
X = electron withdrawing group Scheme 8.28
The reaction was studied under the action of focused microwaves and conven-
tional heating and it is noteworthy that elimination is more efficient than Michael
addition (leading to aziridines) under irradiation, the conditions being the same.
8.3.1.4 Lactam Synthesis [46]

In 1979, Olah [47] reported a one step conversion of alicyclic ketones into lactams by
means of hydroxylamine O-sulfonic acid and formic acid under reflux for a few
hours. More recently this reaction has been realized under solvent-free conditions
with SiO2 as inorganic support and focused irradiation, as exemplified in
Scheme 8.29 for caprolactam synthesis.
OSO3H OH
O NH2OSO3H N H2 O N
+ H2SO4
H2O
H2SO4
H
H2SO4/H2O N
HSO4-, +NH 3(CH2)5CO2H O
Scheme 8.29 NaOH
Ketone Lactam Time a (min) Yield (%)
Cyclopentanone Valerolactam 15 60
Cyclohexanone Caprolactam 10 86
Cycloheptanone 2-Azacyclooctanone 20 72
Cyclooctanone 2-Azacyclononanone 15 65
Cycloundecanone 2-Azacyclododecanone 15 72
Cyclododecanone 2-Azacyclotridecanone 20 82
a
Irradiation at 30 W, the temperatures reached by the reaction mixture are in the range 100±120 8C, de-
pending on the nature of the ketone.
In a multimode oven the power is too high and cannot be modulated, so only de-
composition products are obtained.
8.3.1.5 Arylimidazole Synthesis

In 1996, the condensation of orthoesters with ortho-phenylenediamines leading to
benzimidazoles [48] was achieved either in toluene under reflux or without solvent
by use of focused microwaves (Scheme 8.30).
A more striking example was reported more recently by Soufiaoui et al. [49 a] who
studied the cyclocondensation of N-(carbotrifluoromethyl)-ortho-arylenediamines on
clay K10 in dry media under the action of irradiation for 2 min in a domestic oven
(Scheme 8.31). It is worth noting that with classical heating under the same condi-
NH 2 Scheme 8.30
OEt KSF N
+ H C OEt
NH 2 OEt N
H
Monomode MW, dry media 60W 5 min. 74%
∆, toluene 110°C 12 h 79%
R1 NH 2 R1 NHCOCF3 R1 N
N-trifluoroacetylation Acid
CF3
R2 NH2 R2 NH2 R2 N
H
Deprotection N-trifluoroacetylation Acid
R1 NHCOCF3
Scheme 8.31 R2 NHCOCF 3
tions only traces of heterocycles are observed. The difference is discussed in terms of
the polarity of the transition state compared with that of the initial state (cf. Chapt. 3
and Ref. [49 b]).
8.3.1.6 Pyridine, Pyrazine, and Pyridine Derivatives

A rapid one-pot synthesis of imidazo-[1,2-a]-pyridines, pyrazines and pyrimidines
was described in 1999 by Varma et al. [50], who used recyclable montmorillonite clay
K10 under solvent-free conditions and microwave irradiation (Scheme 8.32).
The whole process, formation of the iminium ion by condensation of the aldehyde
with an amine (1 min at 900 W in a domestic oven) then nucleophilic attack of the
isocyanide (1 min at 450 W and 1 min cooling) takes 3 min to give yields ranging
from 56 to 88 % of the pure product.
Also of interest is a new easy means of preparing (S)-3-substituted 2,3,6,7,12,12a-
hexahydropyrazino-[1,2 : 1,6]-pyrido-[3,4-b]-indole-1,4-diones [51] (Scheme 8.33).
This process is much more efficient than the classical procedure with TFA in
CH2Cl2 for 2 h at 30 8C which leads to 60 % yield instead of 95 % after 5 min under
irradiation.
A one-pot synthesis of N-substituted 4-aryl-1,4-dihydropyridines (Scheme 8.34)
was recently [52] mentioned at the Fifth International Electronic Conference on Syn-
R
R-CHO NH 2
Clay 1 N
R
+ N X N
MW N X
R1-NC Y H Y
X=Y=C
X=C;Y=N
X= N ; Y = C Scheme 8.32
Scheme 8.33 O
H H
CO2CH3
S NHBoc a, b S NH
S
N N
N R N R
H
H O H O
a) adsorption on flash column silica gel (250-400 mesh)
b) irradiation 5 minutes at 500 W
H Ar
R1O2C CO2R1
O 1+ 2
+ 2 H C C CO2R R NH 2
Ar H N
Scheme 8.34 R2
thetic Organic Chemistry (ECSOC-5), a special session of which was devoted to mi-
crowave-assisted synthesis.
Among various solid supports (K10, acidic alumina, zeolite HY, silica gel) silica
gel proved to be the best; after irradiation for 4 min the reactions led to yields
ranging from 62 to 94 %.
8.3.1.7 Quinolines and Quinoxalines

It is of primary interest to avoid corrosive mineral acids in synthetic processes. This
can easily be achieved by use of acidic solid supports coupled with microwave irra-
diation. This has been applied to the preparation of quinolines [53] (Scheme 8.35).
This procedure is a safe, green alternative to the use of H2SO4 at more than 150 8C.
In the same way, quinoxaline-2,3-diones were prepared [54] by use of single-mode
irradiation. Previous attempts in solution led to explosions, but the authors success-
fully used solvent-free conditions with acidic supports or catalysts (the best being
p-toluenesulfonic acid) and irradiation times of 3 min (Scheme 8.36).
p-Toluenesulfonic acid proved to be the best catalyst for the formation of pyrazolo-
[3,4-b]-quinolines from 2-chloro-3-formylquinolines and hydrazine hydrate±phenyl
hydrazine under irradiation [55].
R3
R2 R2
InCl3 / SiO 2
R + R1 R3 R
MW
NH 2
O 5 to 10 minutes N R1
55 to 87% yield
Scheme 8.35
H
O NH 2 N O
H+
OEt +
EtO MW
O NH 2 N O
Scheme 8.36 H
8.3.1.8 Pyrroles, Indoles and Related Compounds; Imidazoles

Efficient synthesis of highly substituted alkylpyrroles and fused pyrroles has been
achieved by three-component coupling of:
. an a,b-unsaturated aldehyde or ketone, an amine, and a nitroalkene on the surface

of silica gel;
. an a,b-unsaturated nitroalkene, an aldehyde or ketone, and an amine on the sur-
face of alumina without solvent under microwave irradiation.
The various routes are as shown in Scheme 8.37 [56].
O R1 R2
4 SiO 2
R1 R3 + R NH 2 +R5 NO 2
MW R5 N R3
R2
R4
R5 R1
R5 NO 2
H Al 2O3
R1 + R2NH 2 +
O R4 MW R4 N H
R2
O R2
R2 NO 2
Al 2O3
+ R1NH 2 + ( )n
( )n
R3 MW R3 N
R1 Scheme 8.37
A wide range of starting compounds was used and yields of isolated products ran-
ged from 60 to 86 % for irradiation times of 5 to 15 min. This green procedure avoid-
ing solvents is a better and more practical alternative to existing methods. Different
heterocycles [57 a], e. g. furan, pyrrole, N-benzylpyrrole, indole, and pyrazole react
with methyl a-acetamidoacrylate to give a-amino acid precursors under irradiation
with silica-supported Lewis acids as catalysts. In homogeneous catalysis, long reac-
tion times were required. The reaction of vinylpyrazoles with imines has also been
realized [57 b].
A variety of bisindolylnitroethanes [58] has been obtained in high yields (70±86 %)
by reacting 3-(2-nitrovinyl)indole with indole and 1- or 2-alkylindoles on silica gel
(TLC-grade) under irradiation (Scheme 8.38).
Silica gel or zeolite HY have also been used successfully for the synthesis of imida-
zoles, isoxazoles, and pyrazoles [59], under irradiation, without solvent (Scheme 8.39).
8.3.1.9 Preparations of Coumarins

Coumarins are important compounds with applications as pharmaceuticals and
agrochemicals.
An easy means of access has recently [59] been reported by NH4OAc on silica gel
as catalyst for the condensation of salicylaldehyde (and 2-hydroxy-1-naphthylalde-
NO 2 NO 2
X
Silica gel (TLC) (3-Indolyl) X
+ R'
N N MW ; 7-10 min. R'
or rt ; 8-14 h N
H R 2 eq.
1 eq. R
a: R = R' =X = H d: R = Et ; R' = X = H
MW: 70-86%
b: R = CH3 ; R' = X =H e: R = i-Pr ; R' = X = H
rt: 69-84%
c: R = CH3 ; R' = H, X = Br f: R = X = H ; R' = CH3
Scheme 8.38
Ph O Ph
Ar O Zeolite HY N
+ + RNH 2 + NH4OAc
H or silica gel
Ph O Ph N Ar
MW
R
Scheme 8.39 without RNH 2 : R = H
CHO CO2R SiO 2 CO2R

+
CO2R NH4OAc
OH MW O O
Scheme 8.40
CO2Me
O O
+ MeO
OMe
H2N OH H2N O O
O
Conventional heating 45 min. (54%)
Scheme 8.41 MW 8 min. (61%)
hyde) with ethyl and methyl malonate under solvent-free conditions and with MW ir-
radiation (Scheme 8.40).
Irradiation for 2±15 min, rather than many hours under reflux in a variety of sol-
vents in the presence of base (pyridine or piperidine), gives high yields.
Some 7-aminocoumarins-4-carboxylates [60 a] were synthesized by the Pechmann
reaction, by microwave irradiation of the reactants on solid supports (graphite±K10)
(Scheme 8.41). Synthesis of unsubstituted coumarins (C-4 position) has been also re-
ported [60 b].
8.3.1.10 Dioxolane Synthesis

A mixture of an aldehyde or a ketone with ethylene glycol (EG) and p-toluenesulfo-
nic acid (pTSA) leads to the corresponding dioxolane, after irradiation [61]
(Scheme 8.42).
R1 R2 Scheme 8.42
R1 R2 HO pTSA
+ O O + H2O
O MW
HO
Example: R1 = Ph; R2 = H
Focused microwave oven, EG 1.5 equiv. 15 min 80 8C 80 % [61]
Domestic oven, EG: 10 to 15 equiv. 2 min 650 W 81% [62]
Example: R1 = Ph; R2 = CH3
Focused microwave oven, EG 3 equiv. 30 min 120 8C 90 % [61]
Domestic oven, EG: 10 to 15 equiv. 2 min 650 W 71% [62]
Unfortunately, the comparison is not reliable because the temperature was not
measured in the domestic oven. Dioxolane formation by acid-catalyzed exchange be-
tween 2,2-dimethyl-1,3-dioxolane (DMD) and a ketone in a inert solvent, or simply
in excess DMD, requires 4 to 7 h under classical conditions [63]. This reaction
is readily achieved under microwave irradiation in high yields in 4 to 30 min
(Scheme 8.43).
R1 R2 Me Me R1 R2
MW
+ O O O O + Me2CO
O catalyst
DMD 60 to 100% Scheme 8.43
R1 R2 DMD Catalyst Power (W) Time (min) T max (pC) Yield (%)
Ph H 1.5 KSF 300 4 80 90

Ph Me 3 pTSA 150 30 110 95
Ph Ph 3 pTSA 150 30 120 60
±(CH2)5 ± ±(CH2)5 ± 3 pTSA 150 30 120 100
Me CH2COMe 3 pTSA 150 30 110 100
Me CH2COMe 3 pTSA 150 30 120 95
It has been shown [61] that yields are higher under the action of irradiation. This
dioxolane exchange was subsequently scaled up to 250 g in the Synthewave 1000
with the same yields [64] and this type of carbonyl protection was extended to dithio-
lanes and oxathiolanes [65].
8.3.1.11 Carbohydrate Glycosylations

Peracetylated D-glucopyranose were glycosylated with decanal (1.5 eq.) without sol-
vent under irradiation in the presence of ZnCl2 [66] (1 eq.) (Scheme 8.44).
The reaction was performed in a Synthewave 402 apparatus under controlled tem-
perature conditions to avoid decomposition of alkyl glycosides. Comparison with
classical heating under strictly the same conditions revealed that yields dropped dra-
matically.
Scheme 8.44 OAc OAc

AcO O CH3(CH2)9OH AcO O
AcO OAc ZnCl 2 AcO O(CH 2)9CH3
AcO AcO
Monomode MW 60W-20W 3 min. 113°C 74%

∆ (oil bath) 3 min. 113°C 0%
∆ (oil bath) 5h 113°C 25%
8.3.2
Reactions under Basic Conditions
Some examples of the in situ generation of 1,3-dipoles in basic media followed by

1,3-dipolar cycloaddition are reported in Chapt. 9.
8.3.2.1 Lactam Synthesis

The reaction of silyl ketone acetals with imines under irradiation has been explored.
The versatility of the microwave approach is illustrated in Scheme 8.45.
When the reactions are performed by adsorption of the reagents on to K10 mon-
tmorillonite clay the aminoester is formed but when the reaction is performed by
mixing the neat reagents with KF and 18-crown-6 and irradiation in a closed vessel
b-lactams were isolated in moderate to good yields [67].
The same group reported the formation of heterobicyclic lactams as illustrated be-
low [68] (Scheme 8.46).
The reaction was performed by supporting the reagents on alumina and irradia-
tion in an open vessel.
Me OSiMe 3 Ph
K10, MW NHPh
PhCH N Ph +
H OMe 5 min., 65% CO2Me
Me
KF,
18-C-6
MW, 7 min., 93%
Ph Ph
N
Scheme 8.45 Me O
H
O Al 2O3 N
+ HN NH 2
2 MW, 15 min. N
CO2Et
86%
Scheme 8.46 O
8.3.2.2 Lactone Preparation

An interesting ring opening of a fatty oxirane has been reported by Loupy [69].
Diethyl acetamidomalonate opens the oxirane ring according to Scheme 8.47.
Addition of lithium chloride is necessary for the reaction to proceed. Whereas no
reaction was observed under salt-free conditions, the lactone is obtained in 90 %
yield within 5 min in the presence of LiCl impregnated with KF on alumina (KF±
LiCl±Al2O3 = 1 : 1 : 4 by weight) under the action of focused microwave irradiation at
150 W. With conventional heating no reaction occurred.
CO 2Et R
R KF/LiCl/Al 2O3
+ CO 2Et CO 2Et
H MW, 150 W O
O NHCOMe NHCOMe
O Scheme 8.47
8.3.2.3 N-substituted Imidazoles and Imidazolines

Imidazole has been condensed with ethyl acrylate by using two basic clays (Li+ and
Cs+ montmorillonites) as catalysts in a microwave oven [70]. The role of alkali pro-
moters (Li+ and Cs+) was studied and it was found that the greater the basicity and
the irradiation time and power, the higher were the conversions. The yield of N-sub-
stituted imidazole is maximum for 0.1 g Cs+ montmorillonite at 850 W after irradia-
tion for 5 min (Scheme 8.48).
N Basic clay N
+ CO2Et
N N
H
CO2Et Scheme 8.48
The reaction proceeds with high yields and selectivity under the action of irradia-
tion and is more efficient than with conventional heating.
Quite recently [71] an expeditious solvent-free synthesis of imidazoline derivatives,
using basic or neutral alumina under microwave irradiation, was reported. The reac-
tion time was reduced from hours to minutes with improved yield compared with
conventional heating.
8.3.2.4 Base-catalyzed Reactions of Glyoxal Monohydrazones

with Active Methylene Compounds
Several 3-(2H)pyridazinones have been prepared from monophenyl hydrazones of
1,2-dicarbonyl compounds and a variety of active methylene compounds within 1±
20 min without solvent under focused irradiation in the presence of carefully ad-
justed amounts of piperidine or solid potassium tert-butoxide (isolated yields 50±
89 %), in accordance with Scheme 8.49 [72, 73].
In the synthesis of the pyridazinone (X = CN, R1 = Me, R1 = R2 = H) microwave ir-
radiation has no specific effect, because the result (72 %) was identical with that ob-
Scheme 8.49 R1
1 2
R R X R2
+ X-CH2-CO2R'
O N-NH-Ph N
O N
Ph
- H2 O - R'OH
R2
1
R N-NH-Ph
—
OR'
X
O
tained by use of classical heating under the same conditions. With the dry media
procedure it was possible to isolate the intermediate alkene, which was not obtained
in the previously reported procedure. When the active methylene compound is a
keto ester the reaction follows a different pathway [73].
8.3.2.5 Annelated Pyridines and Dihydropyridines

The condensation of b-formyl enamides with cyanomethylenes under irradiation is
catalyzed by basic alumina to afford fused pyridines in excellent yields in very short
times [74] (Scheme 8.50). This procedure avoids harsh conditions.
The Hantzsch dihydropyridine synthesis has been performed [75] in a single-
mode microwave cavity. In comparison with both conventional methods and micro-
wave-assisted reactions performed in a domestic oven, reaction times were shorter
and yields were higher (Scheme 8.51).
The improved yields under microwave conditions enable the synthesis of a small
library.
R2 CHO MW R2 R3 - CH2=C=O R2 R3
3
+ R CH2CN
Al 2O3
R1 NHAc R1 N NH R1 N NH 2
3 H
R = CN or CO2Et O C
Scheme 8.50 H2
R
O
EtO2C CO2Et
NH3, H2O
RCHO + O
N
O
H
R = XPh, iPr, n-heptyl, cyclohexyl
Scheme 8.51 yields from 51 to 92% in 10 minutes
8.3.2.6 Stereoselective Route to 3,5-Dihydroimidazol-4-one Derivatives

An efficient solventless synthesis of imidazolones via the Knoevenagel reaction using
microwave irradiation has appeared recently in Green Chemistry [76] (Scheme 8.52).
R S N Scheme 8.52
S N O S N ( )n
R O ( )n
N N N
Method A or B MW, 70°C
O O catalyst O
catalyst MW, ∆ R1
O 2
catalyst R
R1 N R1
S N 2
S
R
NH 5% N N R2
OH - H2O
O O
In method A the reaction is performed under reflux in CH2Cl2. Method B is with-

out solvent under irradiation. It has been shown that yields are higher and reaction
times much lower for method B. This methodology was applied to the synthesis of
the precursor of leucettamine B (mediator of inflammation).
8.3.2.7 Oxidation using KMnO4 ±Al2O3

Oxidation of b,b-disubstituted enamines have been performed over KMnO4 ±Al2O3
and the results compared with those obtained by use of a domestic oven, a focused
oven, and classical heating (Scheme 8.53) [77].
O O
KMnO 4/Al 2O3
Ph
N Ph N +
O
15 min. O Me
H Me H
Domestic oven 255 W 73%
Monomode reactor 300 W 140°C 83%
Classical heating 140°C <2% Scheme 8.53
8.3.2.8 Synthesis of 1,8-Cineole Derivatives [78]

1,8-Cineole derivatives, of interest as potential cosmetic products, were obtained un-
der a ªgreen chemistry procedureº, i. e. one without solvent, with microwave activa-
tion according to Scheme 8.54.
The yields are significantly better than for a previously reported procedure (90±
98 % instead of 50±70 %) and the reaction times are considerably reduced. These im-
provements are connected ªto the intervention of highly polar reactants and then
consequently prove to develop strong interactions with microwavesº.
O KF/Al 2O3 O
+ CH3CH2COCl
MW O
OH O CCH2CH3 Scheme 8.54
R1 R3 R4
O O N N +
R2 O O
R3
N R1 = Ph, R2 = H
O N R1 = R2 = Me
R4 O Me
Ph
MW N Me
O R1 20°C
Piperidine Piperidine O N
N N
O R
4
4-20°C R1 = Ph R3 4 R2 O
4 O R O R
R R2 = H 3 OH R 4
OH R1 = R2 = Me R
3 R = H or Me
R 3
O N R
N H
Ph
Scheme 8.55
8.3.2.9 1-Aminopyroles and Related Compounds

Starting from glyoxal monohydrazones and active methylene compounds, N-anilino-
pyrroles were prepared under solvent-free conditions by use of piperidine as catalyst
[79] (Scheme 8.55).
Further microwave irradiation isomerizes the anilinopyrroles.
8.3.3
Enzymatic Catalysis in ªDry Mediaº
Enzymes are usually used in aqueous or organic media and the temperature is lim-
ited to 40 8C to preserve enzyme activity; as a consequence the reactions need very
long times. With enzymes immobilized on solid supports [80] it is possible to ope-
rate at higher temperatures.
Systems such as Pseudomonas lipase dispersed inside Hyflo Supercell (a diatoma-
ceous silica of pH 8.5±9) and SP 435 Novozym (Candida antarctica lipase grafted
on an acrylic resin) are thermally stable and have optimum activity in the range 80±
100 8C. They can therefore be used with conventional or microwave heating if the
temperature is strictly controlled.
8.3.3.1 Regioselective Esterification of Glycopyranosides

The regioselective esterification at position 6 of a-d-glucose and a-d-glucopyrano-
sides with fatty acids [81] is readily achieved by use of Novozym 435, in accordance
with Scheme 8.56.
OH OCOR
Novozym 435
HO O + R CO2H HO O + H 2O
HO HO
Scheme 8.56 OH OCH3 OH OCH3
Reaction conditions and yield of the esterified product (R = CH3(CH2)11) are:

(i) classical method, solvent-free, reduced pressure, 24 h, 70 8C, 53 %; (ii) microwave,
single-mode reactor, 12±40 W, 5 h, 95 8C, 95 %; (iii) 120±60 W, 2 h, 110 8C, 97 %;
(iv) conventional heating (oil bath), 5 h, 95 8C, 55 %.
8.3.3.2 Transglycosylations
The transesterification of phenyl-b-d-glucoside catalyzed by Sulfolobus solfataricus
[81 b] was quantitative within 2 h at 110 8C under the action of irradiation whereas
the yield was only 60 % after 40 h under classical conditions (Scheme 8.57).
OH
OH Enzyme
O +
HO OPh HO
HO Me (support)
OH
OH OH
Me + HO O
HO O O
O OH HO OH
HO
OH OH
Me Scheme 8.57
8.3.4
Solvent-free Solid±Liquid Phase-transfer Catalysis (PTC)
This method is described in Chapt. 5; it is specific for anionic reactions because it in-
volves ªanionic activationº.
8.3.4.1 b-Eliminations of Halogenated Acetals

Ketene acetals and dithioacetals have been prepared in a solvent-free procedure by
base catalyzed b-elimination under PTC conditions. The yields obtained by use of ir-
radiation are much higher than those obtained by use of ultrasound or conventional
heating under the same conditions [82] (Scheme 8.58).
These results are obviously indicative of a specific effect of irradiation.
Ph O KOtBu (2eq.) Ph O
NBu 4Br (10%)
O Br O
MW monomode reactor 75W 5 min. 75°C 87%
Ultrasound (cleaning bath) 5 min. 75°C 55%
Conventional heating (oil bath) 5 min. 75°C 36%
nBu-S KOtBu (2eq.) nBu-S

NBu 4Br (10%)
nBu-S Cl nBu-S
MW monomode reactor 155W 25 min. 89°C 79%
Ultrasound (cleaning bath) 25 min. 89°C 45%
Conventional heating (oil bath) 25 min. 89°C 15% Scheme 8.58
8.3.4.2 Synthesis of Furanic Diethers

Among the various derivatives of biomass, furanic compounds obtained from fur-
fural are important (200,000 t year±1). A new family of furanic diethers has been ob-
tained by alkylation of 2,5-furandimethanol or furfuryl alcohol under microwave irra-
diation with PTC solvent-free conditions [83] (Scheme 8.59).
KOH
+ R-X Aliquat
HOH 2C CH2OH ROH 2C CH2OR
O (10%) O
Reaction conditions and yields for example: RX = C 12H25 Br

1. Microwave monomode reactor 30 W: 5 min/180°C, 93%.
2. Conventional heating (oil bath): 5 min/180°C, 41%.
Scheme 8.59 3. Conventional heating (oil bath): 30 min/180°C, 89%.
Reaction times were improved by microwave irradiation, and the same conditions
were extrapolated to the synthesis of a series of new furanic diethers by alkylation of
furfuryl alcohol by dihalides [83].
8.3.4.3 Synthesis of Diethers and New Diols Derived from Dianhydrohexitols

Loupy et al. [84] have synthesized new diethers by alkylation of dianhydrohexitol un-
der the action of irradiation with PTC conditions. The yields were very good (>90 %)
within a few minutes. Even when similar temperature profiles were used the yields
were much lower under the action of conventional heating (Scheme 8.60).
In the same way, new diols have been obtained from dianhydrohexitol ethers [85].
HO RO
O Base, PTC O
+ R-X
O MW O
OH OR
Scheme 8.60 Yields > 90%
8.3.4.4 Preparation of Benzo[b]furans

Benzo[b]furans have been formed by condensation of salicylaldehydes with a variety
of esters of chloroacetic acids, in the presence of tetrabutyl ammonium bromide
(TBAB), under the action of irradiation without solvent [86] (Scheme 8.61).
Potassium carbonate (20 mmol), TBAB (0.5 mmol) and salicylaldehyde derivative
(5.0 mmol) were mixed and a chloracetic ester (10 mmol) was then added dropwise.
CHO
K2CO3/TBAB
+ ClCH2CO2R3 CO2R3
R1 MW, 8-10 min. R1 O
OH
R2 R2
R1 = H, Et3N R3 = Et, allyl, cyclohexyl Yields : 65 to 96%
Scheme 8.61 R2 = H, OMe
The mixture was stirred and then irradiated for 8 to 10 min. After extraction with
CH2Cl2 and evaporation, the products were purified by column chromatography. In
an oil bath, the full conversion of an aldehyde needs usually 3 h.
8.3.4.5 Cineole Derivatives

The PTC process was also used for the synthesis of cineole derivatives already cov-
ered in Sect. 8.3.2.8, and more recently in Green Chemistry [87].
8.3.5
Solvent-free Reactions without Support or Catalyst
In heterocycle synthesis these conditions have been particularly used in 1,3-dipolar

cycloadditions and Diels±Alder reactions (Chapt. 9). These conditions are, in fact,
ideal for ªgreen chemistryº.
8.3.5.1 Condensation of Creatinine with Aldehydes

Knoevenagel condensation under the action of microwave irradiation has been
widely studied; it has also been used for synthesis of heterocycles in accordance with
Scheme 8.62 [88].
CH3 R CH3
N MW H N
R-CHO + NH NH
O N O N
H H Scheme 8.62
At 160±170 8C under the action of focused irradiation (40±60 W), condensation oc-
curs within 45 s to 4 min, without solvent, without base, and without catalyst. Unfor-
tunately, no comparisons were made with conventional heating and classical me-
thods.
8.3.5.2 Addition of Isocyanates to 2-substituted 1H-Perimidine

New heterocyclic ketene aminals have been obtained in yields ranging from 60 to
94 % [89] starting from ethyl 1H-perimidine-2-acetate or acetonitrile and isocyanates
(Scheme 8.63).
The reaction was studied at room temperature, under the action of irradiation and
with conventional heating. No specific effect of microwaves was evidenced.
H X
N R1 R2N=C=X N NHR 2
N EWG N EWG
H H
R1 = H ; EWG = CO2Et, CN R1 = H ; EWG = CN ; X = O, S Scheme 8.63
8.3.5.3 Pyridine Derivatives
Synthesis of 2,3-dihydroimidazo-[1,2-c]-pyrimidines
Focused irradiation of N-acylimidates mixed with imidazolidine ketene aminals
provides a new means of access to 2,3-dihydroimidazo-[1,2-c]-pyrimidines [90]
(Scheme 8.64).
H X
R2 H R1 N
N - EtOH
N +
1
EtO R N X
- H2 O N N
O
H R 2
X = CN
Scheme 8.64 X = CO2Et
Microwave-mediated Biginelli reactions

Quite recently this reaction was revisited by Kappe [91] et al. who reinvestigated the
Biginelli synthesis under the action of microwave irradiation under a variety of dif-
ferent conditions. At atmospheric pressure in ethanol solution there is no difference
from conventional heating. Under pressure the yield is reduced and byproducts are
formed. In an ªopen systemº rate and yield enhancements are significant and this is
rationalized by the rapid evaporation of the solvent which means that this is in fact a
solvent-free reaction. This was confirmed by running the reaction without solvent
under the action of microwaves and with thermal heating. (Scheme 8.65)
Ar
Ar NH 2 EtO2C + EtO 2C H
H N
+ +
H O H2N Z MW or ∆
Me O Me N Z
Scheme 8.65 Z = O, S H
This was later extended to the synthesis of novel pyrimido-[1,3-a]-pyrimidines under

solvent-free conditions; ethyl-2-amino-4-aryl-1,4-dihydro-6-phenylpyrimidine-5-car-
boxylates react regioselectively with 3-formyl chromone or diethyl (ethoxymethylene)
malonate, without solvent, to afford pyrimido-[1,3-a]-pyrimidines [92] (Scheme 8.66).
8.3.5.4 Phthalimide Synthesis

Solvent-free microwave reactions between phthalic anhydride and amino com-
pounds were carefully re-examined by Gedye et al. [93], who showed that the reaction
needs at least one liquid phase. The reaction occurs after melting of the phthalic an-
hydride and subsequent solubilization in the amine. It was concluded that reactions
between two solids might not occur and that a high-boiling joint solvent might be
necessary. Excellent yields (>90 %) were always obtained within short reaction times
(5±10 min) (Scheme 8.67).
Ar H
EtO 2C
N O MW (400 W) Ar H OH
+
Ph N NH 2 20 min. EtO 2C
O N O
H
O H Ph N N H
H
60 to 80%
Ar H Ar H O
EtO 2C EtO CO2Et EtO 2C CO2Et
N MW (400 W) N
+
10 min.
Ph N NH 2 H CO2Et Ph N N H
H H
Yields > 95%
Scheme 8.66
O O
O + NH2R N R + H2O
O O
R = PhCH2, -(CH2)6OH, -(CH 2)7CH3, -CH2CO2H Scheme 8.67
O O
X
N N
H2N NH 2
O O
O MW O
N O
OHOH O H
X = O 63%, 10 min.
X = S 85%, 15 min. Scheme 8.68
More recently this procedure has been used for a new synthesis of thalidomide,
now a ªrehabilitated drug [94]º (Scheme 8.68).
8.3.5.5 Pyrazoles and Triazoles
Pyrazoles
Condensation of aromatic acyl compounds with N,N-dimethylformamide diethyl
acetal in a pressure tube under the action of microwave irradiation affords easy ac-
cess to 1-aryl-3-dimethylaminoprop-2-enones in almost quantitative yield after
6 min. These intermediates can then be reacted with hydrazine hydrate under con-
ventional reflux in ethanol to form the corresponding 3-substituted pyrazoles [95]
(Scheme 8.69).
b-Hydrazinoacrylates derived from benzimidazole, benzoxazole and benzothiazole
are readily prepared in good yields by transamination of the corresponding 3-di-
methylamino acrylates with a variety of hydrazines [96] (Scheme 8.70).
Scheme 8.69 H
OCH 3 N N
O MW N2 H4, H 2O
+ H N(CH3)2 N
R 360 W O Reflux, EtOH
OCH 3
R R
R = C 6H5, C5H 4N, C6H4OH, naphthyl
R1
N R2
N NMe 2 R1 N N
+ H2N N H
X CO2Et R2 -Me 2NH
71-95% X CO2Et
X = NH, O, S
N NMe 2 R1 = H N H
N
X -EtOH X N
CO2Et
74-96% R2
X = NH, O O
R1 Me Me C6H5 CO2Me
H2N N H2N N H2N N H2N N H2N N
Scheme 8.70 R2 H Me H H
These hydrazino acrylates can then be cyclized to the corresponding 1,2-dihydro-

pyrazol-3-ones either under the action of irradiation or by heating conventionally.
These last compounds have also been prepared directly from the starting acrylates.
Phenacylation of 1,2,4-Triazole [97]

Selective alkylation of 1,2,4-triazole in position 1 is of primary interest for the synth-
esis of biologically active molecules such as fungicides (fluconazole, flutriafole ¼).
Direct alkylation with classical heating gave a mixture of 1- and 4-alkylated triazole
together with quaternary salts resulting from alkylations at both the 1 and 4 posi-
tions. Interestingly, it has been shown [97 a] that benzylation and phenacylation oc-
curred selectively at position 1 without any base under the action of irradiation and
solvent-free conditions (Scheme 8.71). The reaction with (2,4-dichloro)phenacyl
chloride was studied in particular depth. Benzylation of 1,2,4-triazole and benzotria-
zole has been achieved by de la Hoz and coworkers [97 b].
This reaction has been scaled-up to more than one hundred grams by use of a
Synthewave 1000 oven.
8.3.5.6 Pyridines and Pyridones

A survey of microwave activation in the chemistry of Hantzsch 1,4-dihydropyridines
(1,4-DHP) has recently been reported [98]. The experimental method proposed more
than a century ago remains the most widely used to synthesize these heterocycles.
Since 1992 this process has been adapted to microwave irradiation under a variety of
conditions to reduce the reaction time and enhance the yield. Among these experi-
ments, Zhang [99] reported a solvent-free process starting from 3-aminocrotonate
R R Scheme 8.71
N4 MW N N N
1
2
N + R-X
No solvent
N + N + N X
N N N N
H R R
N1 N4 N1, N4
N
N
ClH2C N
R-X = C Cl H2C
O C Cl
Cl O
MW 20 minutes 140°C N1 92% Cl
∆ oil bath 140°C 36% N1 / 27% N4 / 37% N1, N4
NHR 2
OH
MW, 600 W
+ R2NH 2
14-20 min.
H3C N O
H3C N O
R1
Yields 60 to 91% Scheme 8.72
(20 mmol) methylacetoacetate (20 mmol) and arylaldehydes (20 mmol) in a domestic
oven. Yields from 59 to 77 % are reported for 10 min reaction.
A variety of conditions (solution, dry media, solvent-free) has been used for micro-
wave-assisted synthesis of Hantzsch 1,4-DHP; only procedures involving solvent-free
conditions under the action of irradiation led to the aromatized pyridine derivatives.
2-Pyridones were studied for N- and C-alkylation reactions by de la Hoz et al.
[100]; as already mentioned for 1,2,4 triazoles, the selectivity of the alkylation is
highly dependent on the activation technique (microwave or conventional heating).
The microwave-assisted nucleophilic substitution of 4-hydroxy-6-methyl-2(1H)-
pyridones [101] has also been studied (Scheme 8.72).
It is noteworthy that the reaction works with araliphatic amino compounds. This
is, nevertheless, an improvement on classical methods.
8.3.5.7 Synthesis of 3-Aryl-4-hydroxyquinolin-2(1H)ones

The title compounds, which are of pharmaceutical interest, are easily obtained in a
one-pot procedure as a result of the formal amidation of malonic ester derivatives
with an aniline followed by the cyclization of the intermediate malondianilides [102]
(Scheme 8.73).
OH
CO2Et R2
+ R 2 MW, 500 W
NHR 1 CO2Et 15 min N O

R R
R1 Scheme 8.73
8.4 Room-temperature Ionic Liquids (RTIL) 287
The synthesis of Merck's glycine NMDA receptor or antagonist L-701,324 is illus-

trative, it can be prepared in one step by use of this procedure; the reported synthetic
procedure comprises several reaction steps.
8.4
Room-temperature Ionic Liquids (RTIL) ± Synthesis and Applications in Organic
Synthesis under the Action of Microwaves
RTIL are a new class of solvents composed entirely of ions, most often alkylpyridi-
nium or dialkylimidazolium salts and a Lewis acid [103]. These solvents have a num-
ber of interesting properties, especially their lack of vapor pressure, a wide accessible
temperature range, lack of flammability, and ease of reuse [104]. RTIL have emerged
as a set of new green solvents [105], mainly as a replacement for conventional volatile
organic solvents. The use of a large excess of conventional volatile solvents to per-
form a chemical reaction is of ecological and economic concern. Much attention has
been focused on organic reactions catalyzed by RTIL, and several organic reactions
of high importance catalyzed by ionic liquids have been reported.
8.4.1
Synthesis of 1,3-Dialkylimidazoliums as RTIL
The preparation of 1,3-dialkylimidazolium halides by conventional heating in sol-

vent under reflux requires several hours to afford reasonable yields and also uses a
large excess of alkyl halides and/or organic solvents as the reaction medium. To cir-
cumvent these problems Varma and coworkers [106] investigated the preparation of
a series of ionic liquids 72 (Scheme 8.74), using microwave irradiation as the energy
source, by simple exposure of neat reactants, in open containers, to microwaves by
use of an unmodified household MW oven (240 W).
It is interesting to point out that under the action of microwave irradiation the for-
mation of ionic liquid 72 could be monitored visibly in the reaction ± when it turns
from a clear solution to opaque and finally clear. After the first irradiation for 30 s at
240 W (bulk temperature ~70±100 8C) the homogeneity of the reaction mixture
changes because of the formation of a small amount of ionic liquid 72. Additional ir-
radiation was then repeated for 15 s until the formation of a clear, single-phase ionic
liquid product. A series of ionic liquids 72 was prepared by microwave heating and
the procedure was then compared with conventional heating (oil bath at 80 8C) using
the same preparation (Tab. 8.5).
The purity of ionic salts obtained by use of microwave heating was found to be
superior to that of those prepared by use of conventional heating methods. This eco-
240W R
N N R X N N
70-100°C ,X
Scheme 8.74 70 71 (X = Cl, Br, I) 72
Tab. 8.5 Comparison of conventional and microwave heating for preparation of ionic liquids.
Alkyl halide 71 MW time (s) RTIL 72 Yield (%)a Yield (%)b
1-Chlorobutane 30 + 15 + 15 + 15 + 15 72a 76 50
1-Bromobutane 30 + 15 + 15 + 15 72b 86 76
1-Bromohexane 30 + 15 + 15 + 15 72c 89 78
a
Use of MW, power 240 W
b
Oil bath at 80 8C
friendly method uses only stoichiometric amounts of reactants and yields were en-
hanced.
This method has some major drawbacks, however:
. the hygroscopic nature of salts might not enable large-scale preparation by the pre-
vious method, because the reaction is performed in an open vessel;
. heating irritant volatile alkyl halides in an open container in a microwave oven
can be hazardous;
. the waste contains corrosive and hygroscopic methyl imidazole.
Khadilkar and Rebeiro have investigated a new method [107] that overcomes all
these problems and is far safer. The authors used closed pressure reactor [108], with
no apparent loss of yield. The microwave reactor used for these reactions has a possi-
bility for recording temperature and pressure during irradiation. For example, 1-bu-
tyl-3-methylimidazolium chloride was isolated in 91% yield in 24 min [109] at 150 8C
and 57 psig was the maximum pressure reached.
8.4.2
N-alkylation in RTIL
Indole 73 can be selectively alkylated [110] (Scheme 8.75) by benzyl bromide to give
74 in high yield (>90 %) when the reactants were mixed with 1-butyl-3-methylimi-
dazolium hexafluorophosphate ([bmim][PF6]) as polar solvent and the reaction was
performed with brief (1 min) microwave irradiation at 180 8C. Product 74 was fully
extracted with diethyl ether and [bmim][PF6] was reused in another cycle of syn-
thesis.
Ba(OH) 2
Br
N
N [bmim][PF 6]
H MW180°C, 60 s
73 74 (>90%) Scheme 8.75
8.5 Conclusions 289
8.4.3
Knoevenagel Reactions on a Grafted Ionic Liquid Phase
Previous work [111] by our group has demonstrated that RTIL-catalyzed 1,3-dipolar
cycloaddition under the action of microwave irradiation leads to dramatically shorter
reaction times with better yields of isolated products. We have recently investigated
the reactivity of the formyl group covalently grafted on the ionic liquid phase 75
in the Knoevenagel reaction with malonic derivatives 76 [112], as shown in
Scheme 8.76.
CN 76
O CO2Me (CN) O
N N O N N O
O O CN
, BF4 O piperidine (2%) 113 , BF4
75 MW, 80°C 77 (98%) CO2Me (CN)
15 min.
OH
MeONa, MeOH N N
MeO2C O
25°C, 18 h. CN , BF4
78 (97%) CO2Me (CN) [hydemim][BF4 ]
Scheme 8.76
The bound products 77 prepared in high yields (98 %) with reduced reaction times
(15 min) were subjected to a very efficient cleavage from the IL-phase. The expected
products 78 were extracted with dichloromethane in 97 % yield and the insoluble [hy-
demim][BF4] was reused in another cycle of synthesis.
8.5
Conclusion
These examples of the use of microwave irradiation in the synthesis of heterocyclic

compounds show the great versatility of this technique, which can be used under a
variety of experimental conditions. Even when there is no improvement of yields, or
rates, or specificity, the technique is worthwhile owing to its simplicity. It can be fore-
seen that microwave ovens are going to be among the basic equipment of research
laboratories in the near future. Combinatorial and parallel synthesis under the ac-
tion of microwave irradiation is becoming a powerful tool for discovery of new mole-
cules and should develop very rapidly.
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nol. 1997, 68, 351. 113 Abdallah-El Ayoubi, S.; Texier-Boul-
104 Welton, T. Chem. Rev. 1999, 99, 2071. let, F.; Hamelin, J. Synthesis 1994, 258.
295
9
Microwaves in Cycloadditions
Antonio de la Hoz, Angel DÌaz-Ortiz, and Fernando Langa
9.1
Introduction
Cycloaddition reactions, which increase molecular complexity by formation of a cyc-

lic compound and, simultaneously, two C±C or C±X bonds [1], are among the most
widely used reactions in organic synthesis. The reactions are also regio- and stereose-
lective. For these reasons, such processes are usually the key step in the multistep
synthesis of natural products.
The successful application of microwave irradiation in chemistry dates from 1975
[2]. Several examples have been described in analytical [3], environmental [3 a, 4],
and materials and inorganic chemistry [5], radiochemistry [6], and organometallic [7]
and organic chemistry [8].
Cycloaddition reactions often require the use of harsh conditions such as high
temperatures and long reaction times. These conditions are not compatible with sen-
sitive reagents or products such as natural products. The applicability of Diels±Alder
cycloadditions is, moreover, limited by the reversibility of the reaction when a long
reaction time is required. The short reaction times associated with microwave activa-
tion avoid the decomposition of reagents and products and this prevents polymeriza-
tion of the diene or dienophile. All these problems have been conveniently solved by
the rapid heating induced by microwave irradiation, a situation not accessible in
most classical methods. With the aid of microwave irradiation, cycloaddition reac-
tions have been performed with great success [9, 10].
In this paper we review the techniques and applications of microwave irradiation
in cycloaddition reactions. This mode of heating requires not only appropriate micro-
wave equipment and glassware, but also a new experimental outlook. A special sec-
tion will focus on modifications of chemo-, regio- and stereoselectivity which result
from use of microwaves, and possible explanations of this behavior will be given.

ISBN: 3-527-30514-9
296 9 Microwaves in Cycloadditions
9.2
Reactions in Solution
9.2.1
Reactions under Pressure
The first examples of microwave-induced reactions were cycloadditions and pericyc-

lic reactions performed under pressure, because of the use of domestic ovens, to
avoid the risk of igniting flammable solvents (Scheme 9.1) [11, 12].
Reactions were performed in sealed thick-walled glass tubes or in Teflon acid-di-
gestion vessels, in domestic microwave ovens [13]. Teflon vessels can be used at pres-
sures up to 14 atm, at temperatures below 250 8C, and are resistant to most com-
monly used chemicals, although they deform at temperatures >250 8C.
The lack of temperature and pressure control in these systems could lead to safety
problems, because of overpressure resulting from the heating rate caused by micro-
waves. These problems can be reduced by using solvent-free methodology, which
also enables the use of larger quantities of reagents. Yields have been greatly im-
proved, and reaction times reduced, in comparison with conventional procedures in
solvents under reflux.
These reactions were next revisited by Strauss and it was shown that, under identi-
cal conditions in xylene, the reaction rates were strictly identical within experimental
error [14].
9.2.2
Reactions under Reflux
Reactions involving a solvent under reflux require the use of modified commercial
microwave ovens. In these modified systems the oven is perforated on the top to ac-
commodate a reflux condenser and a 10 cm pipe is used to avoid microwave leakage;
the turnable dish is replaced by a magnetic stirrer or by monomode reactors espe-
cially designed for chemical synthesis [15].
The advantage of reactions involving solvent is that the reaction temperature is
controlled by the reflux temperature of the solvent [16]. It should, however, be re-
MeO2 C
MeO2 C CO 2Me
2 CO 2Me
1 3
MICROWAVE CONTROL
10 min 4h
p-xylene, 87% p-xylene, 67%
Scheme 9.1 325º<361 ºC 138 ºC
membered that overheating by between 13 and 26 8C above the normal boiling point
of polar solvents can occur as a result of the ªinverted heat transferº effect, because
boiling nuclei are formed at the surface of the liquid [17]. This superheating effect
was shown to disappear when the experiments were performed with efficient stir-
ring and use of low microwave power [18].
For instance, cycloadditions of [60]fullerene (4) under the action of microwave ir-
radiation usually require the use of this technique, because reactions are performed
on a very small scale and C60, in common with many dienophiles, does not absorb
microwaves efficiently [19].
9.2.3
Microwave Organic Reaction Enhancement (MORE)
Microwave organic reaction enhancement (MORE) chemistry was described by Bose

as a safe and convenient alternative to pressure reactions and modified microwave
ovens [20].
In MORE chemistry the solvent of choice absorbs microwaves in an energy-effi-
cient manner and is, therefore, heated rapidly under microwave irradiation. The sol-
vent should also have a boiling point at least 20±30 degrees higher than the desired
reaction temperature [17].
High-boiling polar solvents such as dimethylformamide (b.p. 160 8C), chloroben-
zene (b.p. 132 8C), 1,2-dichlorobenzene (b.p. 180 8C), and 1,2,4-trichlorobenzene
(b.p. 214 8C) have been used. It is not necessary to employ a large volume of the reac-
tion medium and, often, a slurry at room temperature was found to give a clear solu-
tion during the rapid rise in temperature resulting from microwave heating. This
type of methodology is particularly valuable for medium-scale operations. Tall,
loosely covered beakers with a capacity much greater than that of the reaction mix-
ture were employed and the use of closed vessels and overpressure were avoided,
thus reducing the possibility of explosions [21]. Subsequent removal of the high-boil-
ing solvent is, however, always the main drawback of this methodology.
Several reactions have been performed by use of this methodology, including [4+2]
and [2+2] cycloadditions; reaction time was significantly reduced and yields im-
proved.
9.3
Solvent-free Conditions
Solvent-free conditions are especially suitable for microwave activation. Several ad-
vantages of this approach are evident [22]:
. in the absence of solvent the radiation is absorbed directly by the reagents, so the
effect of microwaves is more marked.
. solid supports can be used efficiently; many mineral oxides are poor conductors of
heat yet absorb microwave radiation very efficiently [23].
. this methodology can be used in conjunction with other synthetic methods, e. g.

phase-transfer catalysis in the absence of solvent [24].
Particular advantages of solvent-free methods are enhancement of reactivity, be-

cause of the increased concentration, and specific selectivity, because of the restricted
mobility.
The use of solvent-free methods is particularly interesting because environmen-
tally benign syntheses can be easily designed:
. the use of large volumes of solvent can be avoided, thus reducing solvent emis-
sions and precluding the need for redistillation;
. work-up procedures are considerably simplified, because the pure product can of-
ten be obtained directly from the crude reaction mixture by simple extraction, dis-
tillation, or sublimation;
. recyclable solid supports can be used efficiently in place of mineral acids and oxi-
dants;
. scale-up is facilitated by the absence of solvent; and
. under these conditions, reaction times are very short, which leads to savings in
time, money, and energy.
These solvent-free conditions are included in the twelve principles of Green

Chemistry [25], and facilitate the design of sustainable processes for the chemical in-
dustry.
9.3.1
Reactions using Mineral Supports
Alumina, silica, clays, and zeolites are increasingly used as acidic or basic supports
[26]. Cycloaddition reactions often require Lewis-acid catalysts if good yields are to be
obtained. Clay and doped silica gel catalysts have emerged as useful alternatives to
the use of Lewis acids. Cycloaddition of furan (5) under solvent-free conditions, cata-
lyzed by K10 montmorillonite, results in a decrease in the reaction time; the endo±exo
relationship is no different that obtained by use of classical heating (Scheme 9.2) [27].
The use of silica-supported Lewis acids as catalysts for the Diels±Alder reactions of
2,5-dimethylfuran leads to fairly good yields of adducts [28]. Solid supports such as
O O O
O
K 1O
+ NPh O + NPh
O
NPh O
O O
5 6 7 8
Conventional heating 1.3 1

Microwave irradiation 1.5 1
Scheme 9.2
silica gel [29] and alumina [30] have also been used to generate 1,3-dipoles and, in
this way, heterocyclic compounds can be obtained in a one-pot procedure. In these
reactions changes in the regioselectivity of the reaction have not been observed un-
der the action of microwave irradiation.
9.3.2
Reactions without Support
An alternative to the use of supported reagents is the use of uncatalyzed ªneat reac-
tionsº. Under these conditions the radiation is absorbed directly by the reagents and
this results in spectacular acceleration, higher yields and purity of the reaction pro-
ducts, a simple workup procedure, and sometimes changes in the selectivity of the
cycloaddition.
Diels±Alder reactions [31] and 1,3-dipolar cycloadditions [32, 33] have been per-
formed by use of this methodology. For example, DÌaz-Ortiz described the hetero-
Diels±Alder and 1,3-dipolar cycloaddition reactions of ketene acetals. The reactions
were improved and products were isolated directly from the crude reaction mixture
without polymerization of the ketene acetals [34].
When the enantiomerically pure ketene acetal 16 was used, cycloaddition with
N,a-diphenylnitrone (11) or chalcone (12) was achieved within 3 min in 98 and 96 %
yield, respectively. Under the same reaction conditions the use of classical heating in
the absence of solvent at 120±124 8C for 3 min caused the yields to decrease to 3±
4 %. These results suggest that the excellent yields achieved by use of microwave irra-
diation are perhaps not entirely a result of the rapid heating of the reaction mass
(Scheme 9.3).
9.3.3
Reactions with a Heat Captor
Garrigues described the use of graphite as a heat captor under the action of micro-
wave irradiation. Graphite is a chemically inert support that couples strongly with
microwaves by a conduction process and is able to transmit intense thermal energy
to the supported reagents [35].
Methods have been described that involve microwave-assisted graphite-supported
dry media for the cycloaddition of anthracene, 1-azadienes and 1,2,4,5-tetrazines
with several C±C dienophiles and carbonyl compounds in hetero-Diels±Alder reac-
tions [35]. This technique leads to a shortening of reaction times, a situation that en-
ables work to be undertaken at ambient pressure in an open reactor to avoid the for-
mation of unwanted compounds by thermal decomposition of reagents or products.
Similarly, the use of a higher input power in retro-Diels±Alder reactions of anthra-
cene derivatives has been reported to afford complete reaction in 3±5 min [36]. This
method is an alternative to the use of flash thermolysis. The use of graphite is a pre-
requisite for obtaining high temperatures in a short time.
This methodology has been extended by the same author to include carbonyl-ene
reactions [37]. The cyclization of (+)-citronellal (19) to pulegols 20 and 21 is faster
O O
O Ar N
Ar C N O O 11 Ph O
O 10 Ar
O O
MW O MW H N
Ar N
9
13 Ph
R1 14
MW
12
O R2
R1 H
O
R2 O
O
15
H Ph Ph H
O Ph O Ph
N N
Ph O Ph O
Ph O O
MW 17a (38%) 17b (36%)
O O + Ph N
3 min H Ph
O Ph H
Ph 16 11 O
N O
Ph O N
O Ph O
Ph O
17c (18%) 17d (8%) Ph
H Ph Ph H
O O
Ph O Ph Ph
Ph Ph O
O O
MW 18a (43%) 18b (37%)
O O +
3 min H Ph Ph H
Ph Ph O
16 12
O O
Ph O Ph O
O O
18c (14%) Ph 18d (6%) Ph
Scheme 9.3
9.4 Specific Effects in Cycloaddition Reactions 301
MW
+
CHO Graphite
OH OH
80%
Scheme 9.4 19 20 21
when performed under the action of microwave irradiation with a graphite support
and the stereoselectivity was different from that obtained by use of classical heating,
with the amount of (+)-neoisopulegol (21) being greater in the former (Scheme 9.4).
9.4
Specific Effects in Cycloaddition Reactions
The existence of results that cannot be explained solely by the effect of rapid heating
has led authors to postulate the existence of a so-called ªmicrowave effectº. Hence,
acceleration or changes in reactivity and selectivity could be explained by a specific
radiation effect and not merely by a thermal effect. Several reviews have collected
synthetic results that have been attributed to the microwave effect [5 b, 38, 39].
Several authors have proposed that changes in thermodynamic behavior under
the action of microwave irradiation are the cause of the ªmicrowave effectº. When a
compound absorbs microwaves, however, dielectric heating causes an increase in
the temperature of the system. When the internal energy of the system is raised it is
distributed among translational, rotational, or vibrational energies, irrespective of
the mode of heating. Consequently, it was concluded there should be no kinetic dif-
ferences between reactions heated by microwaves or by classical heating if the tem-
perature is known and the solution is thermally homogenous [8 c, 40].
The existence of the so-called ªmicrowave effectº has not been proved. It does,
however, seem to have been demonstrated that overheating of polar liquids [17] oc-
curs and that ªhot spotsº are present in heterogeneous systems, especially at the in-
terface [38]. Similarly, microwave irradiation results in an increase in the molecular
mobility in solids [5 b].
The utility of microwaves in improving numerous processes or in modifying
chemo, regio-, or stereoselectivity is evident. These changes often seem to arise from
the rate of heating which results from use of microwaves, a situation that is not pos-
sible with classical heating. Suard considered two important differences between
conventional heating and microwave radiation [41 a]. First, under the action of micro-
wave irradiation the initial slope of the sample temperature is different from zero
and, second, in contrast with the situation observed with conventional heating, con-
duction flow is the major flow of the system. As a consequence, a rapid heating rate
must be responsible for the observed effects [41 b].
In cycloaddition reactions few examples have been described in which changes in
selectivity have been observed on use of microwave irradiation. In concerted pro-
cesses the regio- and stereoselectivity of the reaction is governed by frontier orbital
interactions, and changes in selectivity are not expected unless a change in the reac-
tion mechanism occurs.
These effects have been justified in competitive reactions by two compatible hy-
potheses:
1. by considering that under the action of microwave irradiation the more polar
route will be favored [42]; and
2. by considering that the relative ratio of isomers is related to the hardness and, un-
der the action of microwave irradiation, formation of the intermediate of greatest
hardness should be favored [43].
Some examples of this behavior will be described in the following sections.
9.5
[4+2] Cycloadditions
9.5.1
Diels±Alder Reactions
The usefulness of the Diels±Alder reaction in organic synthesis comes from its ver-
satility and its high regio- and stereoselectivity. A wide variety of dienes and dieno-
philes can be used with a varied range of substitution patterns. Numerous types of
ring structure can be designed by use of this approach. Not all the atoms of the diene
or dienophile need be carbon atoms, meaning that both carbocyclic and heterocyclic
rings can be constructed.
The Diels±Alder reaction is important because it is frequently used at an early stage
of a synthesis to establish a structural core which can then be elaborated to give the
more complex target structure. Classical Diels±Alder reactions have been greatly im-
proved by the use of microwaves ± yields have been increased and reaction times re-
duced. For instance, dramatic improvements have been seen in reactions involving
trans,trans-1,4-diphenylbutadiene (22) [12, 31], and in the reaction of cyclopentadiene
(23) under pressure and solvent-free conditions [44] or, in the latter circumstances, by
using graphite [45] as a support for the tandem retro Diels±Alder/Diels±Alder reaction
starting from dicyclopentadiene. Similarly, anthracene (1) has been reacted under pres-
sure under both solvent-free conditions [12, 31] and in solution in 1,2-xylene [14]. Fi-
nally, cyclohexadiene (24) and a-terpinene (25) have been reacted with diethyl acetylene-
dicarboxylate (26a) [46]. Some Diels±Alder adducts undergo a retro Diels±Alder reaction
to provide, by loss of ethylene and aromatization, substituted benzenes (Scheme 9.5).
Giguere performed tandem ene-intramolecular Diels±Alder reactions between 1,4-
cyclohexadiene (29) and dimethyl acetylenedicarboxylate (26b) in sealed tubes in a
commercial microwave oven (Scheme 9.6) [47].
Berlan found that cycloaddition reactions performed under reflux in xylene or di-
butyl ether (Scheme 9.7) were always faster under microwave conditions than when
R' R'
CO2Et R'
MW CO2 Et
CO2 Et
+
R CO2 Et
CO2Et CO 2Et
R R
24, 25 26a 27 28
24 R = R' = H; 25 R = CH3 , R' = iPr
Scheme 9.5
MeO2 C CO2 Me CO2 Me

26b CO2 Me CO 2Me
CO 2Me
29 30
Conventional heating: DMF, reflux, 40 h, 14%

Scheme 9.6 Microwaves: DMF, 179-184 ºC (90 psi), 20 min, 49%
O O
MW, 95 ºC
+
Xylene or
Dibutyl ether
Scheme 9.7 31 32 33
using classical heating methods [48]. The observed acceleration is more significant
in apolar solvents, for which dielectric losses are weak. On this basis the authors pro-
pose that G{ is changed, possibly as a result of a change in the entropy of the system.
Subsequently, Strauss indicated that the kinetics of these and other reactions are si-
milar under the action of microwave irradiation and classical heating ± hence there
is no specific effect [14].
Similarly, in the cycloaddition of cyclopentadiene (23) with methyl acrylate (34),
described by Gedye, microwave radiation does not alter the endo/exo selectivity and
the observed changes can be explained on the basis of the reactions under micro-
wave conditions occurring at higher temperatures than those occurring under reflux
and under pressure (Scheme 9.8) [49].
Reaction of pyrones under classical conditions requires the use of high tempera-
tures to obtain low to moderate yields. The Diels±Alder reaction of pyrones has been
performed in a commercial microwave oven under solvent-free conditions on solid
supports such as silica gel, montmorillonite, fitrol clay and alumina. The reaction
time was dramatically reduced ± from 4 h to 4 min (Scheme 9.9) [50].
+ CH2 CH CO2CH3 MW, 2.5 min

+
MeOH CO2 CH3
CO2 CH3
23 34 35a 35b
Classical heating, 56 ºC, 85% endo

Scheme 9.8 Microwaves, 110 ºC, 79% endo
R1 O O
MW, SiO2 R1
+
R2 O O 4 min
O R2 O
36 37 38 (73%)
Scheme 9.9
O
MW, 5 min O
O
O OH 1) SiO2 /H 2O (1:1)
2) TBSCl, DMF TBSO
40 41 (64 %)
Scheme 9.10
Cycloaddition of furan (5) has again been performed successfully under pressure
and solvent-free conditions [12, 44]. Usually, however, the cycloaddition of furan and
heterocyclic compounds requires a Lewis-acid catalyst to give good yields.
Reactions of furan (5) under solvent-free conditions, catalyzed by Montmorillonite
K10, have been described by Cintas [27]. The reaction with methyl vinyl ketone (32)
produced Michael addition in positions 2 and 5, whereas reaction with symmetrically
substituted cyclic dienophiles produced a mixture of the endo and exo adducts with
the kinetically favored endo adduct predominating, except when maleic anhydride
(39) was used as the dienophile (Scheme 9.2).
Although the intramolecular Diels±Alder reaction of furan 40 does not occur with
classical heating (Scheme 9.10) [51], the reaction has been performed successfully in
64 % yield by using microwaves and absorbing the product on to silica gel±water.
Moreno described the cycloaddition of 2,5-dimethylfuran (42) catalyzed by silica-
supported Lewis acids under solvent-free conditions in closed Teflon vessels using a
commercial microwave oven (Scheme 9.11) [28, 52]. Under these conditions coordi-
nation of the silica-supported catalyst with the oxygen bridge favors ring opening,
thus leading to the aromatic compounds in one step. The use of Si(Ti) gave the best
results for aromatic compounds.
Most of these compounds gave very low yields when the reactions were performed
using classical heating in an oil bath under comparable reaction conditions and, in
CH 3 O CH 3
CN CH 3 O
MW CH3 CN
M(Si)
O + +
M(Si) CN
H3 C CN H 3C
CH 3 CH 3
Scheme 9.11 42 43 44 45 46 (50-92%)
NMe NMe
NMe
MW
+
COMe MeO MeO
MeO OH OH
OH H COMe
H COMe
32
48 49 50
Scheme 9.12 Microwaves, 32%, 3 : 2 ratio
fact, mixtures of the cycloadducts and aromatic compounds were often obtained.
When the same reactions were performed in a monomode reactor the cycloadducts
could be isolated relatively easily.
Computational results showed that activation barriers for the aromatization pro-
cess are always lower for aluminum-catalyzed reactions and, similarly, lower for tita-
nium-catalyzed than for zinc-catalyzed reactions [52].
Surprisingly, the aromatic product is not obtained in the reaction with fumaroni-
trile (47) ± the Diels±Alder cycloadduct is the only product. The activation barriers
calculated for this aromatization were the highest reported in this work [52].
In an attempt to prepare new diprenorphine analogs, Linders, in one of the first
examples of microwave-induced organic reactions, reported the reaction between
methyl vinyl ketone and 6-demethoxy-b-dihydrothebaine (48) [53]. The Diels±Alder
reaction, when performed under classical conditions, led to extensive polymerization
of the dienophile. A dramatic improvement was achieved when the cycloaddition
was conducted in a modified microwave oven at the reflux temperature of methyl vi-
nyl ketone. By use of these conditions adducts 49 and 50 were obtained in a 3 : 2 ra-
tio, according to HPLC (Scheme 9.12).
The same authors showed that in the cycloaddition of northebaine derivatives the
reaction time with microwave heating was considerably shorter than when conven-
tional heating was used [54]. When, however, cycloadditions were performed in ben-
zene, a poor absorber of microwave irradiation, microwave heating did not result in
a significant increase in the rate of the reaction.
Fallis, in the synthesis of longifolene (53), a bridged sesquiterpene, performed the
intramolecular cycloaddition of compound 51 as a key reaction in the construction
of the bridged system (Scheme 9.13) [55].
The cycloaddition afforded 10 % of cycloadduct 52 after 24 h under reflux in to-
luene in a modified household oven, whereas decomposition predominated at higher
temperatures. When the triene was heated in a sealed glass vessel in a modified mi-
crowave oven the adduct was obtained in 92 % yield.
OR MW
CO2 Me
Toluene
51
52 53
t
R = SiMe2 Bu
52 Conventional heating, 10%
Microwave irradiation, 92%
Scheme 9.13
O
O MW A
H B
MOMO Toluene, reflux, 10 h H C
MOMO
54 55 (40%)
Scheme 9.14
The same author used this strategy to synthesize tricyclic taxoid skeletons 55, an
intramolecular Diels±Alder approach that proceeds in the direction from left to right
(ring A to BC) (Scheme 9.14) [56]. Once again, microwave irradiation was necessary
to perform the required cycloaddition in good yield.
The cycloaddition of ketone 54 could be effected in a sealed glass tube in a modi-
fied microwave oven to afford the tricyclic system stereoselectively. This major ad-
duct arose via the preferred transition state, in which the nonbonded interactions
were minimized, because of the alignment of the dienophile beneath the triene unit
furthest from the MOM substituent. This pattern of p-facial selectivity implies that,
with the ªnaturalº C2 stereoselectivity, the preferred geometry should provide the re-
lative stereochemistry required for taxol itself.
The synthesis of the decalin unit of compactin (59), a potent competitive inhibitor
of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, which acts as an
effective hypocholesterolemic agent, was planned to incorporate an intramolecular
Diels±Alder reaction (Scheme 9.15) [57].
The reaction was performed by heating the reagents at 150 8C for 10 h in o-xylene.
The desired exo adduct was obtained with high stereoselectivity and subsequent for-
mation of the diastereoisomer 58 was considered to occur by isomerization of the
exo adduct. The reaction was dramatically accelerated by use of microwave irradia-
tion in a domestic microwave oven, and the carboxylic acid was obtained after
45 min with a small increase in stereoselectivity (Scheme 9.15) [57].
The Diels±Alder reaction between azonianthracene (61) and bis-substituted olefins
to give 6,11-ethanobenzo-[b]-quinolizinium salts 62 was greatly accelerated by the ac-
tion of microwave irradiation and, consequently, the reaction might be applicable to
O R1 O OH
O O
2 O O
O R O
R1 O
R2
MW R2
R1 +
O
Toluene H
56 58
57
57 R1 = CO2 Et, R 2 = H; Conventional heating: exo/endo: 91/9
Microwave irradiation: exo/endo: 94/6 Compactin 59
58 R1 = CO2 H, R2 = H; Conventional heating: exo/endo: 82/18
Microwave irradiation: exo/endo: 85/15
Scheme 9.15
R1
S
N MW, 500 W, 3 min
+ N S R2
CH 2CH 2F
S S TFE, 10% AcOH
Br Br
60 61 62
a R1 = H; R2 = CH 2CH 2F
Scheme 9.16 b R1 = CH 2CH2 F; R2 = H
labeling with 18F, which has a short half-life (Scheme 9.16) [58]. The most efficient
reaction occurred in 10 % AcOH in TFE in a commercial microwave oven and the re-
action was approximately 200 times faster than that in CH3CN. In the synthesis of
62a, the radiochemical yield was 20 % in a 1 : 1 ratio after a synthesis time of 77 min,
including HPLC purification.
Deshayes described the cycloaddition of 1-amino-1,3-butadienes 63 with ethyl ac-
rylate (34) under the action of microwave irradiation in a monomode reactor with
temperature control [59]. Irradiation for 30 min at 70 8C in the absence of solvent af-
forded a 60 : 40 ratio of an inseparable mixture of the endo and exo isomers in 90 %
yield. Classical heating under the same conditions did not affect the selectivity but
the yield was lower (Scheme 9.17).
Lacova described the cycloaddition of vinylchromones with a variety of dienophiles,
by use of both classical heating and microwave irradiation. Only reaction with maleic
MW +
+ CO 2Et CO 2Et
CO2 Et 30 min, 70ºC
NR2 NR2 NR2
Scheme 9.17 63 34 64 (60%) 65 (40%)
anhydride (39) was successful under classical conditions [60]. The use of microwave
irradiation for the Diels±Alder experiments was unsuccessful in this instance. Silva
and de la Hoz have, however, performed the cycloaddition of styrylchromones 66
with N-methyl- and N-phenylmaleimide (39) and (6), respectively. The reaction per-
formed with conventional heating resulted in cycloaddition then aromatization,
whereas the same reaction under the action of microwaves gave the cycloadduct 68,
which could be isolated without migration of the double bond (Scheme 9.18) [61].
Diels±Alder cycloadditions of vinylpyrazoles under classical conditions require
highly reactive dienophiles and extreme conditions, i. e. high pressures and tempera-
tures (8±10 atm and 120±140 8C) for long reaction times (several days), and usually
afford moderate yields only [62]. The main obstacle to these reactions is extensive
polymerization of the reagents. 1-Phenyl-4-vinylpyrazole (69) reacted with dimethyl
acetylenedicarboxylate (26b) within 6 min under the action of microwave irradiation
to afford the adducts 70 and 71 in 72 % overall yield (Scheme 9.19) [63]. The cycload-
Ph
O
N
O
O O
Cl CH
O Cl
66 O
67
+
MW Ph
O
O N
270 W, 30 min O O
N Ph
O Cl
6 O
Scheme 9.18 68
CO2 CH 3
H3 CO2 C
DMAD CO2 CH 3
N N CO2 CH 3
MW N + N
N CO 2CH3 N
Ph Ph CO 2CH 3
Ph
69 70 (10%) 71 (62%)
H3 CO 2C
H 3CO 2C
CO 2CH3
N
N
CO 2CH 3
Ph
Scheme 9.19 72
dition was performed in a Teflon vessel in a domestic oven. The clean nature of the
reaction enabled characterization of intermediate 72, although this compound is not
detected when classical heating is used, because it rearranges spontaneously in a
few minutes at the reaction temperature to give the aromatic compound.
The reaction proceeds even with a very poor dienophile such as ethyl phenylpro-
piolate (73), which does not react under classical conditions.
C60 (4) reacts as an electron-deficient polyolefin and, consequently, one of the
main ways of functionalizing fullerenes involves cycloaddition reactions [64] in
which C60 (4) is a reactive 2 component. In this context, [1+2], [2+2], [3+2], and [4+2]
cycloadditions have been performed (Scheme 9.20) and the conditions for cycload-
duct formation found to depend strongly on the gap between the controlling orbitals.
For this reason it is frequently necessary to use conditions involving several hours
(or days) under reflux in high boiling solvents. It thus seemed interesting to investi-
gate the potential of microwave irradiation in the preparation of fullerene derivatives
when this type of reaction is involved. The characteristics of [60]fullerene (4), i. e. the
absence of a dipole moment and the need to work on a very small scale, imply the
use of a solvent in these reactions.
[4+2] Cycloadditions selectively afford the adducts on the 6,6-ring junctions [65], and
the products occasionally undergo a facile retro-Diels±Alder reaction as a consequence
of the low thermodynamic stability of the adduct. Very stable Diels±Alder cycloadducts
have, however, been prepared by use of different substituted o-quinodimethanes, prob-
ably because of stabilization by aromatization of the resulting adducts [66].
ER2
R
R
R
R
[1+2] [2+2]
[4+2] 4 [3+2]
R a
b
R c
Scheme 9.20
Langa et al. [67] described the microwave-induced Diels±Alder reaction of o-quino-

dimethane, generated in situ from 4,5-benzo-3,6-dihydro-1,2-oxathiin-2-oxide (74)
(sultine), [68, 69] leading to cycloadduct 75 (Scheme 9.21). This reaction was the first
application of microwave irradiation to the preparation of a functionalized C60 [67].
To avoid explosion hazards [70], a modified domestic microwave oven was used.
Higher yields were obtained in shorter periods of time on use of microwave irradia-
tion (39 % yield after 20 min irradiation) in comparison with thermal conditions.
Longer irradiation times led to a decrease in the yield of 75, because of increased bis
adduct formation.
The scope of the microwave technique in the preparation of fullerene derivatives
was determined in the well known Diels±Alder reaction of C60 with anthracene (1)
[71], which has been reported to occur under thermal conditions (13 % [71 a], reflux,
toluene, three days; 25 % [71 b], reflux, benzene, 12 h) (Scheme 9.22). In addition to
76, multiply-substituted adducts that undergo cycloreversion to the starting materi-
als were formed.
Under the action of microwave irradiation, with toluene as a solvent, cycloadduct
76 was formed in 35 % yield after 15 min at 800 W [72]; this is an improvement on
the yields obtained by conventional heating and probably occurs because of a de-
crease in the reversion of the cycloaddition in the shorter period of time needed for
the irradiated reaction. It is remarkable that under microwave conditions the forma-
tion of bis adducts was not observed in these reactions.
Novel pyrazine-containing cycloadducts 80a±c were synthesized by Diels±Alder re-
action of [60]fullerene with the corresponding 2,3-bis(bromomethyl)pyrazine deriva-
tives 79a±c (Scheme 9.23) [73]; the 2,3-pyrazinoquinodimethanes were trapped as
the Diels±Alder adducts by reaction with [60]fullerene under reflux in o-dichloroben-
zene (ODCB) as solvent with classical heating and under the action of microwave ir-
MW C60
O
S 4
O
74
Scheme 9.21 75 (39%)
MW, 15 min
C60 +
Toluene
4 1
Scheme 9.22 76 (35%)

R2 NH2 O R2 N NaI
Br Br
+
Br Br
R1 NH2 O R1 N 18-Crown-6
77 78 79a-c
R2 N C60, ODCB N R2
R1 N MW
N R1
CH
R1 = R2 = a: CN, b: (-CH=CH) 2, c:
80a-c
CH
Scheme 9.23
radiation in a focused microwave reactor. Once again, the use of microwave irradia-
tion led to higher yields than classical heating for 80a and 80b (up to 4.5-fold) and re-
action times were significantly reduced ± from 24 h to 0.5 h. For 80c, large amounts
of polyadducts were detected when microwave irradiation was used; this reduced the
yield.
Interestingly, in syntheses of thiophene cycloadducts 81 use of microwave irradia-
tion led to lower yields [73] than conventional heating (23 % compared with 43 %),
although reaction times were significantly reduced [74].
9.5.2
Retro Diels±Alder Reactions
Retro Diels±Alder reactions often require severe conditions, high temperatures, and,
sometimes, flash vacuum thermolysis. Microwave irradiation has been used as an al-
ternative to these harsh conditions [12], even using graphite as a support [45]. Simi-
larly, the use of higher input power has enabled retro-Diels±Alder reactions of an-
thracene derivatives to occur in 3±5 min [41]. This method is an alternative to the
use of flash thermolysis. The use of graphite is a prerequisite for obtaining high tem-
peratures in a short time.
Bortolussi described the synthesis of unsaturated amino alcohols 83 by thermoly-
sis of furan adducts 82; use of microwaves resulted in a significant reduction in reac-
tion time (Scheme 9.24) [75].
R
O R' N CH2 Ph H
MW
R' CH2 OH
H +
10-15 min R N CH 2Ph O
CH2 OH
Scheme 9.24 82 83 (98%) 5
9.5.3
Hetero Diels±Alder Reactions
The hetero-Diels±Alder reaction is one of the most important methods of synthesis

of heterocycles, yet as a potentially powerful synthetic tool it has found relatively lit-
tle general use. Microwave irradiation has been used to improve reactions involving
heterodienophiles and heterodienes of low reactivity.
9.5.3.1 Heterodienes
The introduction of a nitrogen atom into a conjugated system will confer electrophi-
lic character on the system. This has led to the development of the inverse-electron-
demand Diels±Alder reaction [1 b, 10]. Substitution of the azadiene with electron-
withdrawing groups accentuates the electron-deficient nature of the azadiene and
enables the use of electron-rich dienophiles. The magnitude of the LUMOdiene±
HOMOdienophile energy separation has been related to the rate of inverse-demand cy-
cloadditions. Alternatively, addition of a strong electron-donating substituent to the
azadiene enables the use of conventional electron-deficient dienophiles in a normal
demand Diels±Alder reaction.
The Diels±Alder reaction of 1-azadienes suffers from low conversion, because of
the low reactivity of these systems. In an attempt to overcome this problem, consider-
able effort has been focused on both inter- and intramolecular versions of the reaction.
Garrigues described the reaction of the 1-azadiene 84 with dimethyl acetylenedi-
carboxylate (26b) on a graphite support [35]. After sequential microwave irradiation
for 10 min in a monomode reactor pyridine 85 was obtained in 60 % yield. This aza-
diene does not react when conventional heating is used (Scheme 9.25).
Similarly, Motorina described the intramolecular hetero-Diels±Alder reaction of N-
alkyl-2-cyano-1-azadienes 86 (Scheme 9.26) [76]; although the reaction had already
been performed by heating the reactants in benzene overnight in a sealed tube at
110 8C, it was found that reaction time could be reduced to 14 min in a microwave oven
at 650 W.
COOMe
Me MW 10 min. Me COOMe
C
+
C Graphite N COOMe
N
COOMe
NMe2
84 26b 85 (60%)
Scheme 9.25
Me Me
NC N ∆ or MW NC N
H
86 87
Scheme 9.26
NH
CO 2Et
N
H
90 NH
R R
R CO2 Et
NH N
CO2 Et 89 R
N
H R
H
88
91 (67-98%)
NH
CO 2Et
N
R
Scheme 9.27
Bazureau described a tandem conjugate addition±intermolecular hetero-Diels±Al-

der reaction of perimidine derivatives under solvent-free conditions with focused mi-
crowave irradiation [77]. The main feature of this reaction was attainment of complete
addition in less than 8 min. When the reaction mixture was heated in an oil bath set at
the same temperature for the same time the results were analogous (Scheme 9.27).
Das has described the cycloaddition of camptothecin (92), an alkaloid with potent
antitumor activity, with maleic anhydride under the action of microwave irradiation
in a commercial microwave oven for 9 min [78]. Two unprecedented adducts, 93 and
94, were produced. The first was formed by involvement of the B-ring in a hetero
Diels±Alder reaction whereas the second was formed by involvement of the C-ring,
probably through Diels±Alder reaction of intermediate 95 (Scheme 9.28).
O
H O
H
HO
OH
O N
N
O
O 93 O
N OH
39 N
N O O
N
O MW, 466 W, 9 min O H
OH H O
OH O 95
92 OH
N
N
Scheme 9.28 94 O
Pyrazole derivatives are very reluctant to participate as dienes in Diels±Alder cy-

cloadditions that involve the pyrazole ring, because of the loss of aromatic character
during the process [79]. Microwave irradiation under solvent-free conditions, how-
ever, induces pyrazolyl 2-azadienes 96 to undergo Diels±Alder cycloadditions with ni-
troalkenes 97 and 98 in 5±10 min to give good yields of pyrazolo-[3,4-b]-pyridines
(Scheme 9.29) [80]. Under the action of classical heating only traces of the corre-
sponding cycloadducts were detected.
This is the first example of a [4+2] cycloaddition involving a pyrazole ring; it is a
new, interesting, and versatile approach to the preparation of pyrazolo-[3,4-b]-pyri-
dines.
Later, Quiroga described a similar reaction ± the cycloaddition of 2-azadienes de-
rived from pyrazoles and pyrimidones with arylvinylketones 103 as dienophiles
(Scheme 9.30) [81].
DÌaz-Ortiz described the cycloaddition of 4,6-dimethyl-1,2,3-triazine (105) with en-
amines to give condensed pyridine systems [82]. These reactions were performed in
a monomode reactor at a power of 270 W for 20 min at 15 8C. The reactions can also
be performed with pyrrolidine, with cyclic ketones used as precursors of the enam-
Ph Ph
NO 2
NO 2 + N
Ph 97 N N N
N N
MW, 5 min Et Et
130 ºC
N NMe2 99 (64%) 100 (8%)
N
N
Et MW, 5 min
96 130 ºC
S
S NO 2 NO2
98
N N
N
Et
Scheme 9.29 101 (84%)
O O O
H 3C O 60 W, 3 min H3 C
N + N Ar
Ar MW
H3 CS N N N(CH3 )2 H3 CS N N
102 103 104

Scheme 9.30
N 33-71%
(CH2 )n
106
MW, 270 W, 20 min

(CH2 )n
N N O N
N
(CH 2) n + 109 17-40%
105 N
107 H
n = 3-10
Scheme 9.31 108
OH MW C60
OH O 4
O
110
Scheme 9.32 111
ines. This methodology is a dramatic improvement on the classical method and en-
ables such heterocyclic derivatives to be obtained in good yield (Scheme 9.31).
The reaction of C60 with o-quinonemethide, prepared from o-hydroxybenzyl alco-
hol (110) (Scheme 9.32), was performed in a modified domestic oven at 800 W and
gave 111 in 27 % yield after only 4 min [72]. Although Eguchi et al. [83] reported the
same reaction with a slightly better yield (31%) by thermolysis in a sealed vessel, the
microwave approach to this adduct has the advantage of simplicity, and avoids the
risks associated with high-pressure conditions.
9.5.3.2 Heterodienophiles
Examples of the use of heterodienophiles under the action of microwave irradiation
are not common. Soufiaoui [84] and Garrigues [37] used carbonyl compounds as die-
nophiles. The first example employed solvent-free conditions; the second is an exam-
ple of the use of graphite as a susceptor. Cycloaddition of a carbonyl compound pro-
vided a 5,6-dihydro-2H-pyran derivative. These types of reaction proceed poorly with
aliphatic and aromatic aldehydes and ketones unless highly reactive dienes and/or
Lewis acid catalysts are used. Reaction of 2,3-dimethyl-1,3-butadiene (31) with ethyl
glyoxylate (112) occurred in 75 % yield in 20 min under the action of microwave irra-
diation. When conventional heating is used it is necessary to heat the mixture at
150 8C for 4 h in a sealed tube to obtain a satisfactory yield (Scheme 9.33).
Jimnez et al. studied the asymmetric Diels±Alder reactions of 1-aryl-1,2-diaza-1,3-
butadienes 114, heterodienes derived from sugars, with diethyl azodicarboxylate
(115), a heterodienophile [85]. The reactions were performed without solvent in a fo-
cused microwave reactor for periods of a few hours. The reaction is stereoselective
H3C H 3C
O MW, 30 W O
+ CO2 Et
H3C H CO2 Et 20 x 1 min H 3C H
31 112 113
Scheme 9.33
Ar Ar
N CO 2Et N CO 2Et
N N [R(1)ReR(4)Re] N N
+
N N
EtO2 C AcO CO 2Et
AcO H HH
R*
R*
114 115 116
Scheme 9.34
and the major diastereoisomers have the (6R)-configuration if the chiral descriptor
of the heterodiene at C-1 is R. The relative induction arises from the preferential re-
action of DEAD with the Re face of the azoalkane (Scheme 9.34). This results in a
like (lk) combination and the stereochemical course can be designated self-consis-
tently as [R(1)ReR(4)Re].
9.5.4
Miscellaneous
Hong described the [6+4] cycloaddition of fulvenes 117 with a-pyrones 118 to give
azulene-indoles 119, which have potential antineoplastic activity [86 a]. Reactions
were performed in DMF solution by use of a monomode reactor (30 W for 60 min).
It is worthy of note that reactions performed using conventional heating require
long reaction times (5 days) and give low yields of the final product, along with re-
covered starting materials and decomposition products (Scheme 9.35).
The same authors showed that microwave irradiation can alter the reaction path-
way. Occasionally with conventional heating the Diels±Alder adducts are favored
whereas the tandem [6+4]±[4+2] cycloaddition products were obtained exclusively un-
der the action of microwaves [86 b].
Me2 N H O
O MW, DMF
30 W, 60 min N
N H
H
117 118 119 (65%)
Scheme 9.35
9.6
1,3-Dipolar Cycloadditions
1,3-Dipolar cycloadditions are one of the best and most widely used procedures to
prepare five-membered heterocycles. The process involves a concerted reaction be-
tween a 1,3-dipole and a multiple-bonded compound.
The 1,3-dipole is often very unstable, its formation requires high temperatures
and the subsequent cycloadditions require often long reaction times. Both of these
conditions result in a decrease in yields and purity of products. The rapid heating in-
duced by microwave irradiation avoids the harsh reaction conditions associated with
classical heating and facilitates 1,3-dipolar cycloadditions that are very difficult (or
impossible) to achieve with classical energy sources.
In the nineteen-nineties, numerous examples of 1,3-dipolar cycloadditions under
microwave heating were reported with a wide variety of dipoles. In many cases the
product yields and/or reaction times were improved and the method was used to pre-
pare valuable compounds that could not be obtained by classical heating and, in
some instances, the regioselectivity of the reaction was modified. Most of these pro-
cesses were performed in the absence of solvent.
In the following section the main 1,3-dipolar cycloadditions under microwaves
will be reviewed according to the nature of the dipole.
9.6.1
Azomethine Ylides
Microwave-induced 1,3-dipolar cycloadditions involving azomethine ylides have

been widely reported in the literature. Bazureau showed that imidates derived from
a-amino esters 120, as potential azomethine ylides, undergo 1,3-dipolar cyclo-
additions with imino-alcohols 121 in the absence of solvent under microwave irradia-
tion. This reaction leads to polyfunctionalized 4-yliden-2-imidazolin-5-ones 122
(Scheme 9.36) [87].
Me H
C N CH
EtO CO 2Me R N A OH
R
120 121 MW / 45-120 W Me N
9-18 min
+
N
HO A O
Me H
NH EtOH, MeOH
A 122 (88-95%)
EtO N CO2 Et
H R O
H
120'
121'
A = Alkyl chain
Scheme 9.36
Comparison of this reaction with that performed using classical heating shows an
acceleration of the 1,3-dipolar cycloaddition upon irradiation and yield enhance-
ments for the synthesis of imidazolones 122. These advantages occur by virtue of di-
minished formation of the byproduct 125 (see Scheme 9.37).
The same authors also investigated the reaction of the imidate 120 and aldehydes
123 with dry acetic acid as a catalyst in the absence of solvent. The mixture was imme-
diately submitted to focused microwave irradiation to afford compounds 125 together
with alcohols, ethyl acetate and a small amount of imine 124 (Scheme 9.37) [88].
Likewise, imidate 126 undergoes highly regioselective cycloadditions with a wide
range of aldehydes ± as dipolarophiles ± in short reaction times to afford ethyl 4-cy-
ano-2-oxazoline-4-carboxylates 127 in good yields (81±98 %) and moderate diastereo-
meric ratios (Scheme 9.38). The use of microwave radiation gave higher yields than
classical heating but the moderate diastereomeric composition was the same [89]. In
a similar way, addition of imidate 126 to the dipolarophile N-benzylidenemethyl-
Me - MeCO2 Et
C N CH 2CO2 Me + R CHO R N CO2 Me
EtO
120 123 124
Me H
C N CH
EtO CO2 Me R
120 Me N
124 / MW
N
MeO2 C O
Me H
EtOH, MeOH 125
EtO N CO2Et
H
120'
Scheme 9.37
Me N CN
Me CO2Et
C N CH O CO2 Et
EtO CN R
EtOH
126 H 127 cis
R CHO Me N CO 2Et
+
MW EtO CN
O
Me CO2Et R Me N CO2Et
EtO N CN O CN
H
R
126' 127 trans
Scheme 9.38
Ph C C CO2Et
73 CO 2Et
N N N Ph
MW / 120 W +
C
NC CN 25 min NC NC
Ph CO2Et
130 131 132
celite 88 12
bentonite 98 2
Scheme 9.39
amine (128) under focused microwaves gave the expected product ethyl 4-cyano-
2-methyl-5-phenyl-2-imidazoline-4-carboxylate (129) in good yield.
Solid supports such as silica gel and alumina have also been used in the genera-
tion of 1,3-dipoles to obtain heterocyclic compounds. However, changes in regios-
electivity were not observed under microwave irradiation conditions. The regioselec-
tivity can be modified by changing the polarity of the solid support [90]. De la Hoz re-
ported the reaction of pyridinium dicyanomethylidene ylide (130) with ethyl phenyl-
propiolate (73), and found that the selectivity changes from 88 : 12 to 98 : 2 when the
support is changed from celite, to neutral bentonite (Scheme 9.39).
4,4-Bipyridinium ylides 133, generated in situ from 4,4-bipyridinium diquaternary
salts 133, undergo 1,3-dipolar cycloaddition with activated alkynes under micro-
waves, on KF±alumina in the absence of solvent, to give 7,7-bis-indolizines 134 in
81±93 % yield (Scheme 9.40) [91]. The same reactions, when performed using ben-
zene as a solvent under classical heating, yielded 7,7-bis-indolizine derivatives in
yields of only 50±60 % [92].
Microwave irradiation in solvent-free conditions induces the cleavage of the 2,3-
bond of 2-aroyl-aziridines 135 to give an azomethine ylide intermediate, which sub-
sequently undergoes cycloadditions to a multiple bond and leads to oxazolidine, imi-
dazoline, naphthooxazole and pyrroline derivatives 136 in good yields (Scheme 9.41)
[32 b]. Reactions were performed at atmospheric pressure in an Erlenmeyer flask
placed in a commercial domestic oven. The reactions were complete in 10±15 min
while the conventional method requires 18±20 h.
Highly stereoselective intramolecular cycloadditions of unsaturated N-substituted
azomethine ylides have been conducted under microwave irradiation. Oritani re-
ported that a mixture of the aldehyde 137 and N-methyl- or N-benzylglycine ethyl es-
ter (138) on the surface of silica gel, irradiated under microwaves for 15 min, gener-
ated azomethine ylides 139 that subsequently underwent in situ intramolecular cy-
cloadditions to afford the corresponding tricyclic compounds 140 in 79 and 81%
yield, respectively (Scheme 9.42) [93].
A general method for the functionalization of C60 (4) is the 1,3-dipolar cycloaddi-
tion of azomethine ylides. This process was first described by Prato [94] and leads to
fulleropyrrolidines. Several fulleropyrrolidines (143a±c) have been prepared under
microwave irradiation by Langa et al. [72]. These authors observed that microwave ir-
radiation again competes favorably with thermal heating and, in this way, 143 a was
R' Br Br R'
R C C N N C C R
H H2
O 2 O
133
MW KF / alumina
R' R'
R C C N N C C R
O H H O
133'
R'' C C COOR'''
73
R' O O R'
C N N C
R R
R'' R''
COOR''' R'''OOC
Scheme 9.40 134
C6H 5OC C 6H 5 C6 H11

MW
+ X Y C6 H5 OC N C6 H5
N 10-15 min
C6 H11 X Y
135 136
Scheme 9.41
H R R
CHO RNHCH2 COOEt N H H
138 CH 2COOEt COOEt
O N O N O
MW / 15 min N H
O O O
137 139a R = Me 140a (79%)
139b R = Bn 140b (81%)
Scheme 9.42
prepared in 37 % using a focused microwave reactor. In addition, 143b and 143c,

which had not been previously been reported, were prepared in 30 % and 15 % yield,
respectively (Scheme 9.43).
Langa also described the cycloaddition of N-methylazomethine ylides to C70 (144)
to give three regioisomers (145a±c) by attack at the 1±2, 5±6, and 7±21 bonds, respec-
CHO
CO2 H R C60
+
N NH
NH2
R
123 141 142

a, R=H; b, R= OMe; c, R= NO2 143a-c
Scheme 9.43
tively (Scheme 9.44) [43]. Under conventional heating the 7±21 isomer (145c) was
formed in only a low proportion and the 1±2 isomer (145a) was found to predomi-
nate. Under microwave irradiation, and on using o-dichlorobenzene (ODCB), a polar
a solvent that absorbs microwaves efficiently, significant changes were observed. In
contrast to classical conditions, 145c was not formed under microwave irradiation re-
gardless of the irradiation power, and isomer 145b was found to be predominant at
higher power (Scheme 9.44 and Fig. 9.1).
A computational study on the mode of cycloaddition showed that the reaction is
stepwise, the first step consisting of a nucleophilic attack on the azomethine ylide.
The most negative charge of the fullerene moiety in the transition states leading to
145 a and 145b are located at the carbon adjacent to the carbon±carbon bond being
formed. In the transition state that affords 145c, however, the negative charge is delo-
calized all around the C70 subunit. The relative ratio of isomers 145a±c is related to
the greatest hardness, and the formation of the product along the harder transition
state should be favored under microwave irradiation. It is noteworthy that purely
Bond Length
b
a 1-2 a: 1.375 Å
c 5-6 b: 1.387 Å
d 7-21 c: 1.414 Å
20-21 d: 1.465 Å
144
CH 3NHCH 2COOH /HCHO
C70 N CH3
C70
∆ or Microwaves
144
Scheme 9.44 145a, b, c

a) b) c)
Fig. 9.1 1H NMR spectra (methyl groups) of cal heating in ODCB; (c) microwave irradiation
the adducts 145a, 145b, and 145c from left to at 180 W in ODCB.
right. (a) classical heating in toluene; (b) classi-
thermal arguments predict the predominance of 145c under microwave irradiation,

which is opposite to the result found experimentally.
Recently, a novel method for the synthesis of a library of substituted prolines with
microwave technology [95] has been described. In the first step, 1 equivalent of an
amine is added to 1.1 equivalents of an aldehyde in 1,2-dichloroethane (DCE), with
subsequent irradiation at 180 8C for 2 min. In the second step, 0.85 equivalents of
the maleimide are added and the resulting solution is heated at 180 8C for an addi-
tional 5 min. This methodology allowed the production of a solution-phase library of
800 compounds with a crude purity between 65 and 82 % (Scheme 9.45). The com-
pounds were purified by solid-supported reagent scavenging to afford the final pro-
ducts with a purity between 90 and 98 % and in 79±85 % yield [96].
Also in 2001, Azizian described a one-pot diastereoselective synthesis of 2-sub-
stituted 1,1,2,3,3aa,3bb,4,5,6,8,8aa-decahydro-8-(spiro-3-indolino-2-one)pyrrolo[3,4-b]
pyrrolizine-1,3-dione (151) in good yield and diastereomeric excess using microwave
irradiation (Scheme 9.46).
Isatin derivatives and proline react to give stereospecific formation of an azo-
methine ylide intermediate via the decarboxylation route. The resulting 1,3-dipole
undergoes a cycloaddition reaction with N-substituted maleimide (6), as a dipolaro-
R3
O
O O N O
O
R1 MW
OCH 3 + + N R3
R2 H DCE MeO2C
NH2 R2
O 7 min R1 N
H
138 123 6
146
Scheme 9.45
O O
R3
O + N R1 + COOH
N N
R2 O H
147 6 148
MW
O
N N
R3 O R3 H
stereoselective
O O
cycloreversion
N N
R2 R2
149 150
1,3-dipolar
cycloaddition
HH O
N H N R1
R3
O O
N
R2
Scheme 9.46 151
phile, to produce the adduct stereoselectively [97]. It is noteworthy that the adduct
has five chiral centers, but the synthesis affords only one diastereoisomer owing to
the dipole configuration and exo-transition state structure.
9.6.2
Nitrones
Inter- and intramolecular 1,3-dipolar cycloadditions of nitrones under microwave ir-

radiation have been reported to give heterocyclic derivatives.
Sandhu reported that conjugated nitrones react with unactivated alkenes under
microwave activation more rapidly (6±15 min) than in the corresponding thermolytic
or sonochemical reactions [32 a].
Likewise, Loupy showed the utility of focused microwaves as an energy source in
the 1,3-dipolar cycloaddition of N-methyl-a-phenylnitrone (152) with fluorinated di-
polarophiles in solvent-free conditions (Scheme 9.47) [98].
Ph
F3 C
Ph O Ph MW / 30 W
N + O Ph
Me F3C 3 min N
Me
152 153
154
Scheme 9.47
Me
pF3 C-C6H 4 N
pF3C-C 6H4 O 135 ºC O
EtO2 C CN + N
3 min N
Me CO 2Et
155 152
microwaves 50% 156
Scheme 9.48 classical heating 17%
Microwave irradiation induces 1,3-dipolar cycloadditions of nitrones, such as 152,

with aliphatic and aromatic nitriles in the absence of solvent. The products of these
reactions are the corresponding 2,3-dihydro-1,2,4-oxadiazoles 156 (Scheme 9.48).
The use of microwaves led to yields that were always higher than those obtained
with classical heating, with the differences being more significant with the less reac-
tive nitriles [99].
3-Methylene-N-substituted isoindolones 157 react with N-arylnitrones, such as 11,
to give the diastereomeric spiro[1H-isoindol-1,5(4H)-isoxazol] -7(6H)-ones 158 and
159 (Scheme 9.49). These cycloadditions can be performed using classical heating,
although both starting materials and spiro adducts are particularly sensitive to over-
heating. This situation explains the fact that the kinetics and yields improve when a
mixture of 157 and 11 were subjected to microwave irradiation [100].
Cycloaddition of the nitrone 161 to the lactone 160 in boiling benzene for 6 h gave
a 53 : 37 : 10 mixture of the three optically active adducts 162±164 in 66 % combined
yield (Scheme 9.50). Formation of the diastereoisomers 162±164 can be rationalized
in terms of a highly preferred anti approach of the nitrone to the hydroxymethyl
group in the transition state. The isomer ratio in the adducts was found to be depen-
dent upon the solvent used in the reaction. Optimization of the reaction or the dia-
stereoselectivity by Lewis acid catalysis failed. However, attempts to accelerate the cy-
cloadditions by microwave irradiation, using 1,4-dioxane as the solvent, were suc-
cessful and the reaction time decreased from hours to less than 10 min with only a
CH 2
Ph MW
Ph O
N R + N + N Ph
Ph O O N O N O N
O R Ph R Ph
157 11
Scheme 9.49 158 159
OH O H CO 2Et O H CO2 Et
O O
O N Bn + O N Bn
O O
H H
160 HO HO
MW 162 (64%) 163 (23%)
+
dioxane
H CO2 Et 10 min O H O H CO2 Et
N O
Bn O O N Bn + O N Bn
O
161 H CO2 Et H
HO HO
Scheme 9.50 164 (10%) 165 (3%)
small change in the stereoselectivity (in favor of the exo-162 isomer). Moreover, the
use of microwaves also led to the formation of a small amount of the unexpected syn
adduct 165 [101].
When the aldehyde 137 and N-methylhydroxylamine (166) were mixed with silica
gel and irradiated with microwaves for 15 min the adduct obtained was 168 (82 %
yield). A mixture of 137 and N-methylhydroxylamine (166) in alcohol, heated at
120 8C in a sealed tube, afforded the products 168 and 169 in an 8 : 1 ratio
(Scheme 9.51) [93]. The authors proposed that the selectivity observed in the micro-
wave-induced reaction results from a faster transformation leading to the kinetically
controlled product.
In a recent study, classical heating, microwave radiation and gamma radiation
have been compared as energy sources to perform 1,3-dipolar reactions between un-
saturated oximes and conventional dipolarophiles. On using gamma radiation the
reactions were clean and yields obtained were similar to those for the thermal reac-
tions. However, microwave radiation reactions were extremely clean, occurred more
rapidly and gave higher yields [102].
Me Me
H CH3 H
H N N
CHO MeNHOH·HCl C N O
166 O O
O + O
O N O N N N
H H
O O O
O
137 167 168 169
Microwaves / silica gel - 15 min 100 0
Scheme 9.51 NaHCO 3 / EtOH 90% reflux 88.9 11.1
9.6.3
Nitrile Oxides
Microwave irradiation has been extensively employed to generate nitrile oxides and
to promote 1,3-dipolar cycloadditions of the previously prepared dipole.
The first application of microwave irradiation in conjunction with dry media in
the generation of nitrile oxide intermediates was reported by Hamelin [29]. In this
example, methyl nitroacetate (170) was mixed with a dipolarophile in the presence
of catalytic amounts of toluene-p-sulfonic acid (PTSA) (10 % weight). Subsequent mi-
crowave irradiation led to the formation of the corresponding heterocyclic adducts
(Scheme 9.52). Reactions were performed in an open vessel from which water was
continuously removed [103]. Likewise, irradiation in a domestic oven of a mixture of
ethyl chloro(hydroxyimino)acetate (173) and a dipolarophile over alumina led to the
same results in only a few minutes (Scheme 9.52) [103].
In 1999 Hamelin and Benhaoua reported a comparative study between dry media
conditions and the procedure in homogeneous solution under microwaves and clas-
sical heating [104]. Reactions undertaken with aromatic oxime chlorides 174 over
alumina, without solvent and under microwaves, showed that alkynes and disubsti-
tuted alkenes give moderate yields of cycloadducts (40±60 %). The corresponding
procedure with trisubstituted alkenes did not give any products. These reactions
were also performed in the presence of N-methylmorpholine (NMM) in xylene at
130 8C during 30 min under focused microwaves. The same products were obtained
in these cases and the yields were better than for the reactions in dry media. The use
of classical heating resulted in worse yields in all cases (Scheme 9.53).
Soufiaoui reported that arylnitrile oxides 10 can be generated under microwaves
not only from aromatic oxime chlorides, such as 174, by the action of alumina
(Method A) but also from aryloximes, such as 176, by the addition of a chlorination
agent, N-chlorosuccinimide (NCS), supported on alumina (Method B) (Scheme 9.54)
[29 a]. Both methods afforded identical cycloadducts in similar yields ± when indene
was used as the dipolarophile the yield was 86 %. In the absence of alumina, meth-
od B fails (reagents are less reactive and decompose) and method A does not yield
any cycloadduct but a dimer of the dipole.
MeO2 C CO 2Me
PTSA / MW DMAD
MeO2 C CH 2NO2 MeO2 C C N O O
30 min MeO2C N
- H2 O
170 171 172 (91%)
MeO 2C CO 2Me
DMAD
Cl alumina / MW O
C N OH EtO2 C C N O 30 min EtO2 C N
EtO2 C - HCl
173 171 172 (56%)
Scheme 9.52
E E
EHC CHE
Ph C N OH Ph C N O O
Cl Ph N
10
174 175
alumina / neat / MW / 30 min 60%
NMM / xylene / MW / 130 ºC, 30 min 65%
Scheme 9.53 classical heating 30%
Cl H
Cl C N OH Cl C N OH
174 176
MW / 700 W alumina MW / 700 W NCS / alumina

10 min METHOD A 10 min
METHOD B
Cl C N O
10
177
Cl
O N
+
N
O
Cl
Scheme 9.54 178 179
The application of microwaves to the cycloaddition reactions of allyl alcohols 180

with nitrile oxides not only achieved a substantial reduction of the reaction time and
an improvement of the adduct yields, but also altered the regioselectivity of
the cycloaddition in favor of the nonhydrogen bond-directed cycloadduct 182
(Scheme 9.55) [105].
Aroylnitrile oxides can also be generated from diaroyl furoxans 183 under micro-
wave irradiation [33]. Formation of the nitrile oxide intermediate 184 and its cycload-
dition with dipolarophiles proceeds at atmospheric pressure within minutes in the
absence of solvent and in good yields (Scheme 9.56). The reaction occurs by the rear-
Cl
C3 H7 -(E) (E)-C 3H 7
Ph NOH Ph
174 OH
(E)-C3H 7 OH + O
NEt3, benzene N O N Ph
OH
180 181 182
classical method:
57 : 43
50 h, r. t. (54% yield)
microwave irradiation:
46 : 54
Scheme 9.55 400 W, 2 min (53% yield)
O OCOAr
N
ArOC COAr
N O C Ar C
MW X Y ArOC
Ar C C C N O X
N N 12-18 min
O O O N Y
O
183 184 185 (55-65%)

Scheme 9.56
rangement of dibenzoylfuroxan 183 and intramolecular transfer of the benzoyl

group to afford the nitrile oxide intermediate 184. The presence of the polar N+±O±
functionality in the furoxans and nitrile oxides increases the efficiency of the micro-
waves.
DÌaz-Ortiz described the microwave-induced 1,3-dipolar cycloadditions of the me-
sitonitrile oxide 10 with aliphatic and aromatic nitriles in solvent-free conditions
[99]. The procedure allowed the corresponding heterocyclic adducts, the 1,2,4-oxadia-
zoles 187, to be obtained in a domestic oven. The reaction times were shorter and
the yields better than those seen with the classical homogeneous reactions
(Scheme 9.57).
Corsaro reported the cycloaddition of previously prepared nitrile oxides 10 with
aromatic polycyclic compounds as dipolarophiles under microwaves and in the ab-
sence of solvent (Scheme 9.58) [106]. The same cycloadducts were obtained as in the
O 2N C N Me Me
Me
186 N
O
Me C N O
MW / 450 W / 8 min Me N
Me
NO 2
10
187 (68%)
Scheme 9.57 classical heating, 48% yield
Ar C N O
10
H
H O
1 N
Ar
188
Ar C N O
10
Ar
N O N
H H Ar
O
H H
H + H
O H O
H
N N
Ar Ar
189 190
Products (yield, %)
Classical heating with solvent
188 (15.7) + 189 (traces) + 190 (4.6)
24 h in refluxing toluene
Microwave irradiation
188 (11) + 189 (10.2) + 190 (32.7)
650 W, 6 min
Scheme 9.58
case with classical heating and, moreover, the symmetrical bis-cycloadduct 189 was
also isolated. Reaction times were shortened from 24 h to 3±10 min and yields of cy-
cloadducts increased by a factor of 3±7 on changing from heating at reflux to micro-
wave irradiation. The highest yields of bis-cycloadducts suggested that these could
be because of the effect of the lowest temperature used in classical heating. An at-
tempt to perform the reaction under reflux in decalin failed, however, because the
1,3-dipole underwent degradation rather than cycloaddition.
Methylmagnesium bromide (191) exerts a great influence on the stereoselectivity
of the reactions between mesitonitrile oxide 10 and the Baylis±Hillman adducts 192.
In the absence of a Grignard reagent, a mixture of isomers is formed in which com-
pounds 194 are the main products. The presence of a Grignard reagent reverses the
stereoselectivity (Scheme 9.59). When FiÉera [107] performed these reactions under
microwave irradiation, the reaction times decreased from days to less than 5 min
without any loss of stereoselectivity for noncatalyzed cycloadditions, but with a small
change in the stereoselectivity in the chelated reactions.
Nitrile oxides have been used in conjunction with microwaves in the field of fuller-
ene chemistry. For example, 3-(N-phenylpyrazolyl)isoxazolo[60]fullerene dyads 198
Mst C N O MeO2C Mst MeO2C O

Ph 10 Ph N
+
CO2Me Ph O N
OH HO Mst
OH
192 193 194
Entry Solvent Lewis acid Reaction Reaction Yield Ratio

time temp. (%) 193 : 194
1 toluene --- 4h 80 ºC 92 42 : 58
2 chlorobenzene --- 1.5 min MW 99 43 : 57
3 dichloromethane MeMgBr 24 h r. t. 57 61 : 39
4 chlorobenzene MeMgBr 4 min MW 40 70 : 30
Scheme 9.59
have been prepared in 22 % yield from the corresponding nitrile oxides

(Scheme 9.60) [108]. Longer reaction times afforded larger amounts of bis adducts.
The same reactions under thermal conditions produced markedly lower yields (14±
17 %). A significant accelerating effect (10 min compared with 24 h) is observed on
using microwave irradiation.
The scope of the reaction has been demonstrated by the preparation of a series of
isoxazolo[60]fullerenes 198 (Scheme 9.61) [109]. The nitrile oxides were prepared
from the corresponding oximes by reaction with NBS or NCS and subsequent treat-
ment of the mixture with triethylamine under microwave irradiation.
N OH Br
N OH
NBS / Benzene
N
N N
Ph N
Ph
195 196
Et 3N
N
N O
N
C60, MW N O
Ph N
10 min, 210 W N
Ph
198 (22%) 197

Scheme 9.60
a N e
N S
N Ph
R
O
N
b N f Me 2 N
Ph
c g Fe
Me
198
d N h
O
Scheme 9.61
9.6.4
Nitrile Imines
Loupy and Soufiaoui described a comparative study of the reactivity of diphenylnitri-

limine 200 with several dipolarophiles under microwave irradiation in the absence
of solvent using a solid mineral support or phase-transfer catalysis (PTC) conditions
(Scheme 9.62) [30 b]. The results showed that the best yields of adducts were
achieved upon impregnating KF±alumina with a mixture of the hydrazynoyl chlor-
ide 199 and the dipolarophile followed by irradiation of the mixture in a focused
oven. Reaction of this mixture under solid±liquid PTC conditions with KF-Aliquat
under microwaves afforded lower yields of cycloadducts, perhaps owing to the partial
decomposition of Aliquat at the reaction temperature (140 8C). In all cases, worse
yields were obtained by classical heating under comparable reaction conditions
(time and temperature).
Spiro[3H-indole-3,5(4H)-(1,2,4)triazoline]-2-one derivatives 204 have been ob-
tained using microwave irradiation in the reaction between imines of isatin 203 and
nitrile imines generated in situ from the corresponding hydrazonyl chlorides 199
(Scheme 9.63). The yields are in the range 85±95 % and the reaction is complete
within 5 min [110]. Similar reactions performed under thermal conditions were
complete in 6±10 h and yields decreased to 20±30 %. However, when the reaction
was performed at ambient temperature, the products were obtained in excellent
yields but only after a prolonged reaction time (30 h).
As mentioned in Sect. 9.6.3., a comparative study between dry media conditions
and reactions in homogeneous solution under microwave irradiation has shown that
Ph N Ph
C N
Ph C N N Ph
Cl H
199 200
177
Ph Ph
N N N
+
N
Ph Ph
201 202
Reaction time Ratio

Entry Technique Yield (%)
(min) 201 : 202
MW
1 20 96 93 : 7
(domestic oven)
MW
2 5 98 94 : 6
(focused oven)
PTC
3 3 68 93 : 7
solid-liquid
classical heating,
4 5 traces ---
165 ºC
Scheme 9.62
N Ar'
N Ar Ph N
Ar' N Ph Et3 N / MW N
N Ar
O +
200 W / 5 min O
N Cl H N
H H
203 199 204 (85-95%)
Scheme 9.63
nitrile imines are generated and react with several dipolarophiles. These reactions
appear better in homogeneous solution in xylene in the presence of N-methylmor-
pholine (NMM) under focused microwaves than in dry media [104]. In any case,
both methods afford better yields of cycloadducts than the corresponding reactions
under classical heating.
The formation of several pyrazolylpyrazolino[60]fullerene adducts (208a±c) from
nitrile imines have been described (Scheme 9.64) [111]. The nitrile imines are gener-
ated in situ from the corresponding hydrazone 205 and NBS in the presence of Et3N
Br
NH NBS / Benzene NH
N N N
N
N N
R R
Ph Ph
205 206
N 1. Et 3N
N Ph 2. C60, MW
N
+ -
N N N
N
N
Ph R
R
208a-c 207
a: R=H, b: R=OMe, c: R=NO2
Scheme 9.64
and reacted with C60 (4) under microwave irradiation. This approach has also been
used to obtain a 2-pyrazoline ring fused to C60 in a one-pot process from the hydra-
zone. The route is simpler than the previously described method, which involved cy-
cloaddition of C60 to nitrile imines prepared from the corresponding N-chlorobenzy-
lidene derivatives [112].
This route has been used to prepare fullerodendrimers in 31±34 % yield [113].
9.6.5
Azides and Azomethine Imines
Other 1,3-dipoles, such are azides and azomethine imines, have also been employed
in microwave-induced cycloadditions. The main results reported are reviewed in this
section.
1,2,3-Triazole derivatives are very interesting compounds that can be prepared by
1,3-dipolar cycloadditions between azides and alkynes. Loupy and Palacios reported
that electron-deficient acetylenes react with azidoethylphosphonate 209 to form the
regioisomeric substituted 1,2,3-triazoles 210 and 211 under microwaves in solvent-
free conditions (Scheme 9.65) [114]. This procedure avoids the harsh reaction condi-
tions associated with thermal cycloadditions (toluene under reflux) and the very long
reaction times.
(EtO)2OP N3
N N
209 (EtO)2OP N N (EtO)2OP N N
+
+ H CO2Et EtO2C H
H C C CO2Et
210 211
89
Reaction temp. Reaction Yield Ratio

Entry Solvent Technique
(ºC) time (%) 210 :211
1 110 30 h toluene classical heating 86 75 : 25
2 100 48 h --- classical heating 98 88 : 12
3 100 5 min --- classical heating 70 75 : 25
4 100 5 min --- MW 92 66 : 34
Scheme 9.65
Aryl and vinyl nitriles have been prepared very efficiently from the corresponding
bromides by palladium-catalyzed reactions under microwaves. This energy source
has been employed for the conversion of these nitriles into aryl and vinyl tetrazoles
by cycloaddition reactions with sodium azide (Scheme 9.66). The direct transforma-
tion of aryl halides to the aryl tetrazoles in a one pot procedure could be accom-
plished both in solution and on a solid support [115]. The reactions were complete in
a few minutes, a reaction time considerably shorter than those previously reported
for the thermal reactions. The cycloadditions were performed with sodium azide and
ammonium chloride in DMF and, although no explosion occurred in the develop-
ment of this work, the authors point out the necessity of taking adequate precautions
against this eventuality.
The thermal hydrazone±azomethine imine isomerization can be easily performed
under microwave irradiation in the absence of solvent. The subsequent 1,3-dipolar
cycloadditions with electron-deficient dipolarophiles occur in only a few minutes to
afford the corresponding cycloadducts. The use of pyrazolyl hydrazones 205 leads to
valuable compounds, such as bipyrazoles 213, in good yields and this provides a new
approach to the preparation of these heterocyclic derivatives [116] (Scheme 9.67). Re-
actions undertaken with classical heating under comparable reaction conditions
(time and temperature) lead to cycloadduct yields that are considerably lower and, in-
deed, several dipolarophiles do not react at all.
HN N
CN
NaN 3, NH 4Cl N
N
H3 CO DMF / MW
25 min / 20 W H3 CO
186
212 (96%)
Scheme 9.66 thermal heating, 24 h, 68% yield
R R'
H R C C R'
N MW N N Ar
N N Ar N N Ar 26 N
N N H N
N
Ph Ph 10-45 min
Ph
205 205' 213 (30-84%)
Scheme 9.67
9.7
[2+2] Cycloadditions
[2+2] Cycloadditions give rise to four-membered rings. Thermal concerted [2+2] cy-
cloadditions have to be antarafacial on one component and the geometrical and orbi-
tal constraints thus imposed ensure that this process is encountered only in special
circumstances. Most thermal [2+2] cycloadditions of alkenes take place by a stepwise
pathway involving diradical or zwitterionic intermediates [1 a]. Considerably fewer
studies have been performed regarding the application of microwave irradiation in
[2+2] cycloadditions than for other kinds of cycloaddition (vide supra). Such reactions
have been commonly used to obtain b-lactam derivatives by cycloaddition of ketenes
with imines [18±20, 117, 118].
In 1991 Bose described the synthesis of a-vinyl b-lactams by reaction of a,b-unsa-
turated acyl chlorides with a Schiff base in chlorobenzene under microwave irradia-
tion (an example of the ªeco-friendlyº MORE chemistry, in which only a limited
amount of solvent is used) [20 b]. Under these conditions, a-vinyl b-lactam formation
can be achieved in 65±70 % in approximately 5 min (classical conditions require sev-
eral hours and lead only to modest yields).
This methodology has also been used by Bose, who described the synthesis of the
thienamycin side chain [119], the first step of which was a [2+2] cycloaddition under
microwave irradiation. Likewise, Khajavi described the reaction of trichloroacetic an-
hydride with imines [120]; with classical heating the reaction requires the use of
Fe2(CO)9 as a catalyst, whereas under microwave irradiation a catalyst is not required.
Bose has described reactions between acid chlorides 214 and Schiff bases 215
where the stereoselectivity depends on the order of addition of the reagents
(Scheme 9.68) [117]. When the condensation was conducted by a ªnormal additionº
sequence (i. e. acid chloride last), only the cis b-lactam (216b) was formed. However,
R2 ZO R2 ZO R2
ZO NMM
+ +
N Chlorobenzene N N
1 1
O Cl R O R O R1
214 215 MWI 216a 216b
Scheme 9.68 Z = COCH 3, Ph, R1 = CH 2Ar, R2 = Ar NMM: N-methylmorpholine

if the ªinverse additionº technique (triethylamine last) was used, 30 % cis and 70 %
trans b-lactams were obtained under the same conditions. When the reaction was
conducted in a microwave oven using chlorobenzene, the ratio of trans and cis b-lac-
tams was 90 : 10 irrespective of the order of addition. Moreover, there was no isomeri-
zation to the thermodynamically more stable trans b-lactam (216a). These data can
be rationalized by assuming that at higher reaction temperatures the rate of forma-
tion of the trans b-lactam is faster than that of the cis b-lactam [20].
This effect has recently been explained by considering that under microwave irra-
diation the route involving direct reaction between the acyl chloride and the imine
competes efficiently with the ketene±imine reaction pathway, a situation highlighted
by theoretical calculations (Scheme 9.69) [42 a].
A rapid approach to a-amino b-lactams has been developed by Bose and uses the
tetrachlorophthalimido group as a masked amino substituent (Scheme 9.70) [118].
The trans b-lactam 218a could be obtained almost exclusively in 98 % yield after 3±
5 min under strong microwave irradiation. Under classical conditions the cis isomer
(218a : 218b = 10 : 90) is obtained in 52 % yield.
N-(4-hydroxycyclohexyl)-3-mercapto-3-cyano-4-arylazetidine-2-ones were synthe-
sized from N-(4-hydroxycyclohexyl)aryldiimine by reaction with ethyl a-mercapto-a-
cyanoacetate on basic alumina under microwaves. The reaction time was reduced
from hours to minutes in comparison to conventional heating and, moreover, the
yield was improved [121].
R1 H R2 R1 R2 R1 R2
R1
. N N
N
O O R3 O R3 O R3
R2
Base
Base
N
R1 R2
R2
R1 R2 Cl Base R 1 Cl
Cl R1
R1 N
N
Cl N O R3 O R3
O O R 3
Scheme 9.69
R2 TCP-N R2 TCP-N R2
TCP-N NMM
+ +
N Chlorobenzene N N
O Cl R1 O R1 O R1
217 MW 218a 218b
215
R1 = R2 = p-methoxyphenyl
NMM: N-methylmorpholine, TCP: Tetrachlorophthaloyl
Scheme 9.70
Several eco-friendly approaches to vinyl-b-lactams (219±221) bearing a vinyl sub-

stituent at various positions on the ring (Scheme 9.71) have recently been described
by Manhas [122]. Vinyl-b-lactams are efficient synthons for a variety of compounds
of biomedical interest, e. g. isocephalosporins, carbapenem intermediates and pyrro-
lidine alkaloids. MORE chemistry techniques allow highly accelerated syntheses
using limited amounts of solvent and with efficient stereocontrol, thus achieving
high ªatom economyº.
The same group has developed the enantiospecific synthesis of a-hydroxy b-lac-
tams 224 from readily available carbohydrates (Scheme 9.72) [123]. Microwave-as-
sisted chemical reactions have been utilized for the preparation of these 3-hydroxy-
2-azetidinones 224 and their subsequent conversion to enantiomeric forms of inter-
mediates for natural products.
The one-pot synthesis of b-lactams containing the ferrocene moiety 226
(Scheme 9.73) was described by Bonini [124]. The reactions were performed under
classical heating (3.5±24 h) and/or by using a focused microwave reactor (4±6 min).
In this case, the stereochemical outcome of the reaction is the same with both proce-
dures and microwave irradiation does not necessarily improve on the yields obtained
by classical heating.
Finally, Podlech has recently reported [125] the transformation of diazoketones
227, derived from a-amino acids, to ketenes that can react further with imines to af-
ford b-lactams 228 (Scheme 9.74). It was found that this route proceeds not only by
R1 R2
R1 R3 Z Y
Y Z
R3 N R1
R2
N N O
O R O R R3 R2
Scheme 9.71 219 220 221
O
O BnOCH2 COCl / NEt 3 H H
BnO HO
H HO 223 H
H NH O
NH O MW, 3 min O
Ph O
Ph O
224 (72%)
Scheme 9.72 222
Fe COX + R1HC=N-R 2 Fe
R1
225 215 N
O R2
Scheme 9.73 X= OH, Cl 226
R1 H R1 R1
Cbz R2
Cbz R2 Cbz R2
N N2 + MWI or hυ N N
H N H H
O N +
N
R3
O R3 O R3
227 215 228a 228b
Scheme 9.74
utilizing photochemical reaction conditions but also under the action of microwave
irradiation. b-Lactams with a trans-substitution pattern on the ring were obtained ex-
clusively in 40±85 % yield.
9.8
Conclusions
We have shown that microwave irradiation is an efficient methodology in cycloaddi-

tion reactions. The special characteristics of the radiation (i. e. dielectric properties,
energy transfer, penetration depth, etc.) are completely different from conventional
heating and have led to the development of new laboratory techniques, equipment,
glassware and a different outlook on chemical reactions. Numerous procedures have
been designed to work in solution or solvent-free conditions and the choice of
method depends on the nature of the reagents and the reaction, although solvent-
free conditions using solid supports are especially suited to microwave conditions.
The application of microwave irradiation to organic synthesis shows that the effect
of microwaves on the yield is particularly important in compounds with low reactiv-
ity and reagents and products with high sensitivity. The particular suitability of mi-
crowave radiation for such reactions stems from the fact that mild reaction condi-
tions, shorter times and/or lower temperatures can be used.
In some cases, modifications in the selectivity, in relation to classical heating, have
been observed. These modifications have been ascribed to changes in the reaction
path; under microwave irradiation the more polar path will be favored. Computa-
tional studies have shown that the harder transition state must be favored under mi-
crowave irradiation. This result opens new possibilities for the application of micro-
wave irradiation to organic and inorganic synthesis as dramatic modifications in the
selectivity of competitive reactions can be expected if the transition states are of dif-
ferent hardness.
Acknowledgments
Financial support from Spanish DGI (projects BQU2001±1095 and BQU2001±

1512) is gratefully acknowledged.
References 339
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10
Microwave Catalysis in Organic Synthesis
Milan Hjek
10.1
Introduction
The aim of this chapter is to draw the attention of experimental organic and catalytic
chemists to a new field of catalysis, especially to catalytic methods which use micro-
wave irradiation as a new means of activation of chemical reactions, called ªmicro-
wave catalysisº. It is intended to advise synthetic organic chemists about the choice of
catalytic steps which might be more efficient than conventional synthetic methods.
This chapter focuses exclusively on microwave heterogeneous catalysis. Microwave
homogeneous catalysis by transition metal complexes is treated in Chapt. 11, phase
transfer catalysis in Chapt. 5, catalytic reactions on graphite in Chapt. 7, photocataly-
tic reactions in Chapt. 14, and catalytic synthesis of labeled compounds in Chapt. 13.
The development of microwave heterogeneous catalysis is, however, impeded be-
cause most synthetic chemists are not well acquainted with factors affecting both
heterogeneous catalysis and microwaves. Although attempts have been made to ac-
celerate reaction rate or to improve yield and selectivity, they have been based on the
rule ªlet's try microwaves and see what happensº.
This chapter is written to help the synthetic chemist to understand the effect of
microwaves on heterogeneously catalyzed reactions. Not only are metal catalysts dis-
cussed, but also metal oxides, zeolites, clays, and similar materials that act either as
catalysts or as potential supports for the catalytically active species. The factors in-
volved in the preparation of catalysts under microwave conditions are summarized
and discussed in terms of their effect on catalyst activity and selectivity. Basic me-
chanistic understanding can frequently be used to modify reaction conditions to
achieve product formation in high yield. Such an approach cannot be readily applied
to heterogeneously catalyzed processes, because the mechanistic understanding
needed by the synthetic chemist is not yet commonly available for this type of reac-
tion. This chapter is intended to call the attention of synthetic chemists to microwave
catalysis, because it has some advantages over conventional heterogeneous catalysis
(there are also some problems). Hopefully, this may encourage synthetic and cataly-
tic chemists to use the process more frequently and thus extend the application of
microwaves to the preparation of a variety of materials.

ISBN: 3-527-30514-9
346 10 Microwave Catalysis in Organic Synthesis
10.1.1
Definitions
A catalyst is a substance that increases rate of a chemical reaction without being

changed in the process. During the reaction it can become a different entity, but after
the catalytic cycle is closed the catalyst is the same as at the start. The function of the
catalyst is to reduce the energy of the reaction pathway. Catalysts can, in general, be
heterogeneous, homogeneous, or biological. Typical types of heterogeneous catalyst
are bulk metals, supported inorganic metallic compounds, and supported organome-
tallic complexes. Catalyst interaction with reactants can occur homogeneously, i. e.
with the reactants and the catalyst in the same phase (usually liquid), or heteroge-
neously at the interface between two phases. The latter type of catalyzed reaction uti-
lizes a solid catalyst, and the interaction occurs at either the liquid/solid or gas/solid
interface.
Microwave catalysis is a catalytic process performed in the presence of a microwave
(electromagnetic) field in which the catalyst acts as an energy ªconvertorº. It uses mi-
crowave irradiation to stimulate catalytic reactions. It is necessary to stress that any
sort of electromagnetic or microwave radiation is not itself a catalyst, as has some-
times erroneously stated [1]. Similarly, it is not correct to say that microwave irradia-
tion catalyzes chemical reactions [1]. The principles of microwave catalysis will be de-
scribed in the following sections.
A catalytic reaction is one in which more than one turnover or event occurs per re-
action center or catalytically active site. If, however, less than one turnover occurs per
active site, it cannot be a true catalytic reaction. This occurs for reactions on sup-
ported reagents in the absence of solvent, when support or catalyst is used in excess
(called also solvent-free, solvent-less, dry media etc.; Chapts. 3 and 6). Catalytic reac-
tors usually contain a small amount of solid catalyst compared with the amounts of
reactants that pass over the catalyst as liquids or gases. For microwave heating to be
successfully applied in catalytic systems the catalyst itself must absorb microwave
energy. Many supported catalysts (metal, metal oxides, etc.) are known to absorb mi-
crowave energy readily to different extents, whereas the support (silica, alumina)
does not. Thus, after conversion, a liquid or gas stream passing over the catalyst
reaches the cooler part of the reactor more quickly, thus preserving the reactive pro-
ducts otherwise destroyed in a conventional system. Microwave catalyzed reactions
thus occur at lower temperatures with substantial energy savings and often with
higher yields of the desired products.
Heterogeneously catalyzed reactions are rather complex processes. In a two-phase
system, either liquid/solid or gas/solid, several steps are needed to complete the cata-
lytic cycle:
. transport of the reactants to the catalyst;

. interaction of the reactants with the catalyst (adsorption);
. reaction of adsorbed species to give the products (surface reaction);
. desorption of the products; and
. transport of the products away from the catalyst.
Microwave radiation can be used to prepare new catalysts, enhance the rates of che-
mical reactions, by microwave activation, and improve their selectivity, by selective
heating. The heating of the catalytic material generally depends on several factors in-
cluding the size and shape of the material and the exact location of the material in the
microwave field. Its location depends on the type of the microwave cavity used [2].
The aim of this chapter is to describe some advances in catalysis achieved by use
of microwave heating. The aspects of microwave catalytic reactions which differ
from traditional thermal methods are emphasized. The input of microwave energy
into a reaction mixture is quite different from conventional (thermal) heating and it
is the task of synthetic chemists to exploit this special situation as fully as possible.
10.2
Preparation of Heterogeneous Catalysts
The interaction of microwaves with solid materials has proven attractive for the pre-
paration and activation of heterogeneous catalysts. It has been suggested that micro-
wave irradiation modifies the catalytic properties of solid catalysts, resulting in in-
creasing rates of chemical reactions. It is evident that microwave irradiation creates
catalysts with different structures, activity, and/or selectivity. Current studies docu-
ment a growing interest in the preparation of microwave-assisted catalysts and in
the favorable influence of microwaves on catalytic reactions.
The preparation of catalysts usually involves the impregnation of a support with a
solution of active metal salts. The impregnated support is then dried, calcined to de-
compose the metal salt and then reduced (activated) to produce the catalyst in its ac-
tive form. Microwaves have been employed at all stages of catalyst preparation. Bene-
ficial effects of microwave heating, compared with conventional methods, have been
observed especially in the drying, calcination, and activation steps.
10.2.1
Drying and Calcination
It is well known that microwave drying of many solid materials is a very efficient
and widely used process even on an industrial scale [3]; it is also an attractive means
of drying of heterogeneous catalysts. Microwave drying of catalysts and supported
sorbents has several advantages:
. reduction of drying time;

. higher surface area and catalytic activity;
. thermal dispersion of active species facilitated by microwave energy, providing
more uniform metal distribution; and
. higher mechanical strength of catalyst pellets.
Microwave heating has been reported to produce materials with particular physi-
cal and chemical properties [4]. Stable solid structures are formed at low reaction
temperatures with unusually high surface areas, making them very useful as cata-
lysts or catalyst supports. Calcination of solid precursors in a microwave field has
significant advantages over conventional heating. The effective synthesis of the cata-
lysts and supporting adsorbents has been reported for the examples below.
Microwave drying of an alumina-supported nickel catalyst reduced the drying time
by a factor of 2±3 [4]. The results indicated that better dispersion of nickel was achieved
by microwave drying, presumably because of minimization of moisture gradients dur-
ing drying. Analysis of the results confirmed, moreover, that the microwave-dried
samples were significantly stronger than those dried conventionally. As a conse-
quence of minimal moisture gradients, the metal ions are not redistributed to the
same extent during the microwave-drying process as they are when the samples are
dried conventionally, because of the moisture leveling [2, 3] process. As a consequence
of minimal moisture gradients, metal ions are not distributed to the same extent dur-
ing MW drying process as under conventional drying. This causes the resulting dry
pellets to be stronger, as shown by analysis of crushing strengths [4]. Because the heat-
ing effect is approximately proportional to the moisture content, microwaves are ideal
for equalizing moisture within the product in which the moisture distribution is initi-
ally nonuniform. Microwave drying also proceeds at relatively low temperatures, and
no part of the product needs be hotter than the evaporating temperature.
The microwave technique has also been found to be a potential method for the
preparation of the catalysts containing highly dispersed metal compounds on high-
porosity materials. The process is based on thermal dispersion of active species, fa-
cilitated by microwave energy, into the internal pore surface of a microporous sup-
port. Dealuminated Y zeolite-supported CuO and CuCl sorbents were prepared by
this method and used for SO2 removal and industrial gas separation, respectively [5].
The results demonstrated the effective preparation of supported sorbents by micro-
wave heating. The method was simple, fast, and energy-efficient, because the synth-
esis of both sorbents required a much lower temperature and much less time com-
pared with conventional thermal dispersion.
The V2O5/SiO2 catalyst for o-xylene oxidation prepared by wet impregnation under
microwave irradiation had several advantages [6] compared with that prepared by the
conventional thermal method:
. dispersion of V2O5 on the surface of SiO2 was more homogeneous;

. the nonisothermal process was minimized;
. dispersion of active phase (V2O5) was highly uniform; and
. in the catalytic microwave process the optimum reaction temperature of o-xylene
oxidation was reduced by 100 K (from 653 to 553 K).
The more active cobalt catalyst for pyrolytic reactions was prepared by microwave
calcination of cobalt nitrate which was converted to cobalt oxide by rapid microwave
heating [7].
The high dispersion of inorganic salts (CuCl2, NiCl2, AuCl3, RuCl3, etc.) on the
surface of zeolites (NaZSM-5, NaY, NaBeta) and alumina with high loading of the ac-
tive components has recently been achieved by microwave techniques [8±10]. The
catalysts were very active in NOx decomposition, even at room temperature, CO and
NO were partially converted to CO2 and N2. It was concluded that microwave treat-
ment is a new route for dispersing a high loading of inorganic compounds onto the
surface of supports to form highly active catalysts.
The microwave technique has been also found to be the best method for preparing
strongly basic zeolites (ZSM-5, L, Beta, etc.) by direct dispersion of MgO and KF.
This novel procedure enabled the preparation of shape-selective, solid, strongly base
catalysts by a simple, cost-effective, and environmentally friendly process [11, 12].
New solid bases formed were efficient catalysts for dehydrogenation of 2-propanol
and isomerization of cis-2-butene.
In the microwave synthesis of zeolites, a mixture of a precursor and a zeolite sup-
port is heated in a microwave oven. The sample is then tested for its catalytic activity
and the results compared with the sample obtained by the conventional method. Mi-
crowave irradiation at the calcination stage led to samples with a more uniform parti-
cle-size distribution and microstructure and to a bimetallic catalyst with different
morphology. Microwave calcination of magnesia-, alumina-, and silica- supported Pd
and Pd±Fe catalysts resulted in their having enhanced catalytic activity in test reac-
tions ± hydrogenation of benzene and hydrodechlorination of chlorobenzene ± com-
pared with conventionally prepared catalysts [13±15]. The higher catalytic activity
was attributed to the prevention of formation of a Pd±Fe alloy of low activity, which
occurs at the high reduction temperature used in conventional heating.
The microwave technique for drying then calcination is an excellent way of obtain-
ing highly porous silica gel with a high surface area (as high as 635 m2 g±1) for use
as a catalyst and as a catalyst support [16].
The dispersion and solid-state ion exchange of ZnCl2 on to the surface of NaY zeo-
lite by use of microwave irradiation [17] and modification of the surface of active car-
bon as catalyst support by means of microwave induced treatment have also been re-
ported [18]. The ion-exchange reactions of both cationic (montmorillonites) and anio-
nic clays (layered double hydroxides) were greatly accelerated under conditions of
microwave heating compared with other techniques currently available [19.]
Microwave irradiation has also been applied to the preparation of Fe2O3/SO2± 4
superacid [20, 21] and high-surface aluminum pillared montmorillonites [20].
The most successful application of microwave energy in the preparation of hetero-
geneous solid catalysts has been the microwave synthesis and modification of zeo-
lites [21, 22]. For example, cracking catalysts in the form of uniformly sized Y zeolite
crystallites were prepared by microwave irradiation in 10 min, whereas 10±50 h were
required by conventional heating techniques. Similarly, ZSM-5 was synthesized in
30 min by use of this technique. The rapid internal heating induced by microwaves
not only led to a shorter synthesis time, and high crystallinity, but also enhanced
substitution and ion exchange [22].
Microwave processing of zeolites and their application in the catalysis of synthetic
organic reactions has recently been excellently reviewed by Cundy [23] and other
authors [24]. The microwave synthesis of zeolites and mesoporous materials was sur-
veyed, with emphasis on those aspects which differ from conventional thermal
methods. The observed rate enhancement of microwave-mediated organic synthesis
achieved by use of these catalysts was caused by a variety of thermal effects, includ-
ing very high rates of temperature increase, bulk superheating, and differential heat-
ing. Examples of microwave activation of chemical reactions catalyzed by zeolites
will be presented in Sect. 10.3.
An efficient oxidation catalyst, OMS-1 (octahedral mol. sieve), was prepared by mi-
crowave heating of a family of layered and tunnel-structured manganese oxide mate-
rials. These materials are known to interact strongly with microwave radiation, and
thus pronounced effects on the microstructure were expected. Their catalytic activity
was tested in the oxidative dehydrogenation of ethylbenzene to styrene [25].
In the preparation of microporous manganese oxide materials different chemical
properties were observed for the microwave and thermal preparations. In the conver-
sion of ethylbenzene to styrene the activity and selectivity of the materials was differ-
ent [26].
An alternative approach for the preparation of supported metal catalysts is based
on the use of a microwave-generated plasma [27]. Several new materials prepared by
this method are unlikely to be obtained by other methods. It is accepted that use of a
microwave plasma results in a unique mechanism, because of the generation of a
nonthermodynamic equilibrium in discharges during catalytic reactions. This can
lead to significant changes in the activity and selectivity of the catalyst.
10.2.2
Catalyst Activation and Reactivation (Regeneration)
Microwave irradiation of catalysts before their use in chemical reactions has been
found to be a new promising tool for catalyst activation. Microwave irradiation has
been found to modify not only the size and distribution of metal particles but prob-
ably also their shape and, consequently, the nature of their active sites. These phe-
nomena might have a significant effect on the activity and selectivity of catalysts, as
found in the isomerization of 2-methylpentene on a Pt catalyst [2].
As an example, the microwave activation of the platinum catalyst under conditions
when it was highly sensitive to thermal treatment resulted in an increase of its cata-
lytic activity and selectivity (from 40 to 80 %) [28].
Durable changes of the catalytic properties of supported platinum induced by mi-
crowave irradiation have been also recorded [29]. A drastic reduction of the time of
activation (from 9 h to 10 min) was observed in the activation of NaY zeolite catalyst
by microwave dehydration in comparison with conventional thermal activation [30].
The very efficient activation and regeneration of zeolites by microwave heating can
be explained by the direct desorption of water molecules from zeolite by the electro-
magnetic field; this process is independent of the temperature of the solid [31]. Inter-
action between the adsorbed molecules and the microwave field does not result sim-
ply in heating of the system. Desorption is much faster than in the conventional
thermal process, because transport of water molecules from the inside of the zeolite
pores is much faster than the usual diffusion process.
Very little is known about the reactivation (regeneration) of used catalysts by mi-
crowave irradiation. Catalyst activity has been shown to decay with increasing carbon
deposition, and several patents disclose the decarbonization of cracking zeolite cata-
lysts by microwaves [32]. Because carbon is a very lossy material (it absorb micro-
waves very efficiently), any carbon deposited on the surface of the catalyst is strongly
heated. In the presence of air or hydrogen the carbon is removed in the form of car-
bon dioxide or methane, respectively. When carbon deposition reaches a certain level
it starts to absorb microwave energy strongly and is, therefore, subsequently re-
moved, leading to an increase in the activity of the catalyst.
Alumina spheres polluted by carbon residues have been also reactivated by use of
microwaves [33]. Their regeneration has been performed in a stream of air and in
the presence of silicon carbide as an auxiliary microwave absorber. Microwave heat
treatment led to full recovery of the catalyst in times varying from a half to a quarter
of the conventional treatments. Regeneration of a commercial Ni catalyst (Ni/Al2O3)
deactivated, presumably, by coke formation, by means of a flow of hydrogen or oxy-
gen and water vapor under the action of microwave irradiation was, however, unsuc-
cessful [34].
Microwaves are frequently used in the laboratory by synthetic organic chemists
for regeneration and activation of solids such as molecular sieves, silica gel or alu-
mina when fast and complete drying is required.
10.3
Microwave Activation of Catalytic Reactions
Heterogeneous catalysts have been employed in a number of organic reactions in

which microwave heating was used. There is, unfortunately, a limited number of
control data, which makes comparison with conventional heating difficult. Neverthe-
less, from the data so far reported it can be concluded that use of microwave radia-
tion has yielded some remarkable results relating to rate enhancement and selectiv-
ity improvement. Activation can be achieved by superheating of the catalyst or by se-
lective heating of active sites (Sect. 10.3.3) which cannot be achieved by conventional
heating. The numerous reactions performed using heterogeneous catalysts can be
divided into two groups ± liquid-phase reactions and gas-phase reactions
10.3.1
Reactions in the Liquid Phase
There has been a limited number of reports of heterogeneously catalyzed reactions

in the liquid phase under the action of microwave irradiation.
10.3.1.1 Esterification, Transesterification

Chemat et al. [35] examined rates of esterification of stearic acid by butanols as a
model reaction to compare differences between homogeneously and heteroge-
neously catalyzed reactions, Scheme 10.1. Particular attention was paid to whether
the effect of microwaves can be advantageously used to improve yields and to acceler-
ate the rate of esterification.
Cat.
CH3(CH2 )14COOH + CH3(CH2)2CH2OH CH3(CH2)14COOCH2(CH2)2CH3 + H2O
Scheme 10.1 Esterification of stearic acid with 1-butanol.
It was found that the reaction under microwave conditions was faster than that
heated conventionally. Yields were greatly improved ± from 50±82 % for conventional
heating to 71±95 % for microwave heating when heterogeneous catalysts were used.
The catalysts Fe2(SO4)3, TiBu4, KF, KSF, and PTSA were used in a continuous-flow
reactor. The results were further improved by use of a heat captor (graphite) and si-
multaneous use of ultrasound. Better results (yield and rate) under microwave condi-
tions were also achieved in other esterification reactions of stearic and acetic acid in
the presence of a heterogeneous catalyst (Fe2(SO4)3) adsorbed on montmorillonite
clay pellets 4±5 mm in diameter [36, 37]. The reaction rate increased by 50±150 %
compared with conventional heating. This increase was most probably because of
superheating of voluminous pellets (5 mm), the temperature of which was calcu-
lated to be 9±18 K above the bulk temperature. When the esterification was homoge-
neously catalyzed by sulfuric acid using the two modes of heating no differences be-
tween yield and reaction rates were observed.
The effect of the mode of heating was also studied in heterogeneously catalyzed
esterification of acetic acid by isopentyl alcohol in the presence of Amberlyst-15 ca-
tion exchange resin catalyst [38], Scheme 10.2.
Amberlyst
CH3COOH + (CH3)2CHCH2CH2OH CH3COOCH2CH2CH(CH3)2 + H2O
Scheme 10.2 Esterification of acetic acid with isopentyl alcohol.
Because the reaction is driven by protonation of the carbonyl functionality, react-

ing species were expected to be localized on the bed of the acid catalyst subjected to
microwave irradiation. Hexane was used as a nonpolar solvent to minimize solvent
absorption and superheating. Elimination of catalyst superheating in a continuous-
flow reactor was most probably the reason why no significant differences were ob-
served between the reaction rates under the action of microwave and conventional
heating.
Similar results were obtained in the esterification of acetic acid with 1-propanol
performed in the presence of a heterogeneous silica catalyst [39]. The results showed
that for this reaction microwave irradiation and conventional heating had similar ef-
fects on the reaction rate.
The rates of transesterification of triglycerides to methyl esters, efficiently cata-
lyzed by boron carbide (B4C), were, on the other hand, faster under microwave condi-
tions, probably because of superheating of the boron carbide catalyst, which is
known to be a very strong absorber of microwaves [40], Scheme 10.3. Yields of
methyl ester of up to 98 % were achieved.
R CO O CH2 CH2 OH
B4C
R COO CH + 3 CH3OH 3 R COOCH3 + CH OH
R COO CH2 CH2 OH
Scheme 10.3 Transesterification of triglycerides with methanol.
10.3.1.2 Hydrogenation, Hydrogenolysis

Another attractive heterogeneous catalytic reaction of great interest in organic synth-
esis is hydrogenation. Catalytic transfer hydrogenation of soybean oil in the presence
of palladium catalyst (10 % Pd/C) was investigated using microwave and conven-
tional heating [41]. Sodium formate was used as hydrogen donor. Kinetic results re-
vealed the reaction rate increased significantly when microwave heating was used.
The rate enhancement was attributed to microwave heating assistance of transport
processes at the catalyst and oil±water interface.
Microwave-assisted catalytic hydrogenation of steroid compounds, e. g. choles-
terol, campesterol, sitosterol, etc., in the presence of Pd/C catalyst and ammonium
formate in glycol solvent was fast and afforded the corresponding products in high
yield (80±95 %) and purity [42].
A simplified and rapid hydrogenation of b-lactams under the action of microwave
irradiation has been described by Bose et al. [43, 44], Scheme 10.4. Pd/C and Raney
nickel were used as catalysts and a high-boiling solvent such as ethylene glycol was
used as the microwave energy transfer agent in the presence of ammonium formate
as the hydrogen donor. The yields of the corresponding amides were 80±90 %.
Y Ph HCOONH4 Y Ph
10% Pd/C
Scheme 10.4 Selective transformation N Ethylene glycol NH

of b-lactams. O R O R
Hydrogenation of C±C double bonds and hydrogenolysis of several functional

groups have been described as a safe, rapid, and efficient method resulting in high
yields (80±90 %) of products. The technique described was recommended as suitable
for research and for undergraduate and high school exercises [43, 44]. Hydrogenoly-
sis and dehalogenation of aromatic compounds with the same catalytic system was
also successful. Thus, several b-lactams and isoquinoline derivatives were smoothly
dehalogenated in a few minutes [44].
10.3.1.3 Miscellaneous Reactions

A heterogeneous Pd catalyst dispersed on supports such as -Al2O3, C, MgO and
CaCO3 was found to be an recyclable and selective catalyst for heterogeneous Heck
arylation (an important method of C±C bond formation ± Chapt. 11) of several ole-
fins (styrene, a-methylstyrene, 1-decene, acrylonitrile, etc.) with iodobenzene [45],
Scheme 10.5.
I
5% Pd/MgO CN
+ CN
E/Z
Scheme 10.5 Arylation of acrylonitrile with iodobenzene.
The E/Z ratio of the isomers formed over a supported Pd catalyst differed from
that obtained with the homogeneous counterpart. The activity of the catalyst under
the action of microwave and conventional conditions was comparable, but micro-
wave irradiation improved yields and reduced reaction times.
Heck C±C coupling reactions were also facilitated by the presence of a palladium
catalyst when Pd was deposited on a tubular membrane of porous glass. Thus, the
coupling of iodobenzene with allyl alcohol affording 3-phenylpropionaldehyde in the
presence of this Pd catalyst had several advantages ± the ease of catalyst manufac-
ture, mechanical strength, thermal stability, and resistance to organic solvents [46].
The hydrolysis of sucrose catalyzed by the strongly acidic cation-exchange resin
Amberlite 200C in RH form was chosen as a model reaction to compare the use of
stirred tank and continuous-flow reactors [47±49], Scheme 10.6.
No rate enhancement was observed when the reaction was performed under mi-
crowave irradiation at the same temperature as in conventional heating [47]. Similar
reaction kinetics were found in both experiments, presumably because mass and
heat effects were eliminated by intense stirring [47]. The model developed enabled
accurate description of microwave heating in the continuous-flow reactor equipped
with specific regulation of microwave power [47, 48]. Calculated conversions and
yields of sucrose based on predicted temperature profiles agreed with experimental
data.
Several other miscellaneous heterogeneously catalyzed reactions have been per-
formed in the liquid phase. Hexane was successfully oxyfunctionalized with aqueous
hydrogen peroxide by use of the zeolite TS-1 catalyst [50] and microwave-promoted
acetalization of a number of aldehydes and ketones with ethylene glycol proceeded
readily (2 min) in the presence both of heterogeneous (acidic alumina) and homoge-
neous (PTSA, Lewis acids) catalysts [51], Scheme 10.7.
Amberlite
C12H22O 11 + H2O C6H12O 6 + C6H12O 6
sucrose glucose fructose
Scheme 10.6 Hydrolysis of sucrose.
O Al2O 3
O O + H2O
R1 R2 HO OH R1 R2
Scheme 10.7 Acetalization of ketones with ethylene glycol.

Cat.
CH3O + COCl CH3O C
- HCl
O
Scheme 10.8 Benzoylation of anisole.
Yields were high (up to 97 %) and comparable with those of homogeneously cata-
lyzed reactions. A much higher catalyst-to-substrate ratio had to be used with hetero-
geneous alumina (10±15) than with the homogeneous catalysts (0.015±0.050), how-
ever. It was concluded that the microwave method led to considerable improvement
of acetalization reactions, compared with conventional methods.
Friedel±Crafts acylation of aromatic ethers has been performed in the presence of
a variety of metal chlorides and oxides (FeCl3, ZnCl2, AlCl3, Fe2O3, Fe3O4, etc.) but
without temperature control [52], Scheme 10.8.
The short reaction time (1 min, 160 8C) in the benzoylation of anisole was prob-
ably a result of large temperature gradients rather than a nonthermal microwave ef-
fect.
Some reactions have been found to proceed with better results in the absence of
solvent, probably because of the creation of temperature gradients which are elimi-
nated in the presence of a stirred solvent. This was observed for the Diels±Alder reac-
tion of a-amino acid precursors with cyclopentadiene catalyzed by heterogeneous cat-
alysts (SiO2±Al, SiO2±Ti), when the reaction was performed in toluene or in the ab-
sence of solvent [53]. Microwave activation increased the rate of reaction without re-
ducing the selectivity of the reaction.
The microwave activation of Michael additions in the preparation of N-substituted
imidazoles afforded excellent yields in very short reaction times under mild reaction
conditions, Scheme 10.9. Basic clays (Li+, Cs+) exchanged montmorillonites were
found to be very active and selective catalysts for the Michael addition of imidazole
and ethyl acrylate [54].
A total of 75 % conversion with 100 % selectivity was obtained in only 5 min in the
absence of solvents.
An efficient method for conversion of a variety of acids into their corresponding
amides in the presence of zeolite±HY under the action of microwave irradiation has
recently been described [55], Scheme 10.10.
N Clay N CO2Et
NH + CO2Et N
Scheme 10.9 Michael addition of imidazole with ethyl acrylate.
O O
Zeolite HY
+ H2N R 2 + H2O
R1 OH R1 NH R 2
Scheme 10.10 Preparation of amides.

Ra-Ni
NH2 + ROH NH R
Scheme 10.11 Alkylation of aniline with alcohols.
OH OH OH
Zeolite Zeolite
+
H2O 2 H2 O2
HO OH
Scheme 10.12 Oxidation of benzene with hydrogen peroxide.
The reactions proceeded at atmospheric pressure with high yields (80±97 %) in

the absence of solvent.
Facile N-alkylation of anilines with alcohols in the presence of Raney nickel proved
the high efficiency of the catalyst, which is a highly absorptive material for micro-
waves [56], Scheme 10.11.
A 6- to 48-fold rate enhancement was observed for this reaction. The authors sug-
gested that a nonthermal effect might account for this enhancement [56].
Hydroxylation of benzene with hydrogen peroxide in the presence of solid zeolite
catalyst (titan±silicate±zeolite) was chosen by Radoiu et al. [57] as a model heteroge-
neous liquid-phase reaction for study of microwave effects, Scheme 10.12.
Titanium-containing zeolite was an efficient catalyst for oxidation of benzene with
hydrogen peroxide in a microwave field, affording phenol with high selectivity. It
was reported that microwaves had a strong effect on the selectivity of the reaction.
A detailed study of microwave activation of catalytic reactions in the liquid phase
has recently been performed by Hjek et al. [58±60], Scheme 10.13.
It was found that in the catalytic transformation of 2- and 4-t-butylphenol in the li-
quid phase on heterogeneous KSF and K10 montmorillonite catalysts under micro-
wave and conventional conditions the microwaves affected both the rate and the se-
lectivity of the reaction.
The rate was enhanced up to 2.6-fold for reaction of the 2-isomer and up to 14-fold
for the 4-isomer. The product distribution in the final reaction mixtures was always
somewhat different when microwave heating was used. The results were explained
in terms of efficient interaction of microwaves with a highly polarized reagent mole-
cule adsorbed on the acidic active site. Possible superheating of the active sites was
difficult to detect (Sect. 10.3.3).
OH OH OH OH
KSF
+ + +
(K10)
Scheme 10.13 Catalytic transformation of t-butylphenols.

To elucidate the cause of the microwave-induced enhancement of the rate of this

reaction in more detail the transformation of 2-t-butylphenol was performed at low
temperatures (up to ±176 8C). At temperatures below zero the reaction did not pro-
ceed under conventional conditions. When the reaction was performed under micro-
wave conditions in this low temperature region, however, product formation was al-
ways detected (conversion ranged from 0.5 to 31.4 %). It was assumed that the cata-
lyst was superheated or selectively heated by microwaves to a temperature calculated
to be more than 105±115 8C above the low bulk temperature. Limited heat transfer
in the solidified reaction mixture caused superheating of the catalyst particles and
this was responsible for initiation of the reaction even at very low temperatures. If
superheating of the catalyst was eliminated by the use of a nonpolar solvent, no reac-
tion products were detected at temperatures below zero (see also Sect. 10.3.3).
10.3.2
Reactions in the Gas Phase
Heterogeneous catalytic gas-phase reactions are most important in industrial pro-

cesses, especially in petrochemistry and related fields, in which most petrochemical
and chemical products are manufactured by this method. These reactions are cur-
rently being studied in many laboratories, and the results of this research can be
also used for synthetic purposes. The reactions are usually performed [61] in a con-
tinuous system on a fixed catalyst bed (exceptionally a fluidized bed).
In catalytic reactions sufficient heat is usually required to overcome the activation
energy barrier. In kinetic terms, the activation energy is the minimum energy re-
quired to form an activated complex undergoing transformation to the reaction pro-
ducts. Microwaves can be used as the source of thermal energy to induce catalytic re-
actions. The advantage of microwaves is that they can heat microwave-absorptive cat-
alysts selectively to a temperature well above the bulk temperature of the reactants.
The ability to heat the catalyst in microwave field enables heating of the bed from
the interior and not from a hot exterior, as by conventional thermal means. Thus,
the gas stream passing over the catalyst enters the cooler part of the reactor more
quickly, so preserving the reactive products which would otherwise be destroyed in a
conventional system. During microwave irradiation the catalyst active sites are, ide-
ally, heated to the required temperature well before the adsorbed reactants have time
to desorb. In general, because the bond breaking step occurs on the catalyst surface
(the surface reaction is the rate-determining step) it is understandable that the reac-
tion is enhanced. Because the temperature of the bulk reactants (and nonabsorptive
support) is lower, the back, side or consecutive reactions can occur to a lesser extent,
i. e. the selectivity of the reaction can be significantly improved. For example, in the
formation of ethane and ethylene from methane in the presence of doped catalysts,
oxygen, and microwave irradiation, the undesirable reactions producing gaseous car-
bon dioxide and carbon monoxide were slower by one to three orders of magnitude,
because the temperature of the bulk gas was lower than when conventional heating
was used [62].
10.3.2.1 Reactions of Methane

The most studied catalytic gas-phase reaction has been the transformation of
methane to the higher hydrocarbons or oxygenated products. This reflects the large
effort being made by catalytic chemists to find a simple process by which world's
large resources of natural gas can be utilized.
The existence of vast worldwide reserves of the natural gas, of which methane is
the main component, has focused attention on the possibility of converting it directly
to more valuable chemicals. A single-step conversion of methane to more valuable
products is of immense industrial significance and economic importance.
The activation of methane by microwaves has long been a goal of scientists in at-
tempts to convert this natural gas component into higher hydrocarbons valuable in
petrochemistry and the chemical industry. Two pathways are being extensively inves-
tigated by research groups all over the world:
. oxidative coupling of methane to yield C2 and higher hydrocarbons; and

. direct partial oxidation of methane to produce methanol and other oxygenates.
Oxidative coupling of methane to yield C2 and higher hydrocarbons

The oxidative coupling of methane has been studied by several authors. The most
elusive transformation has been the oxidative coupling of methane into C2 hydrocar-
bons (ethene, ethane), because the reaction is more endothermic than other transfor-
mations [2]. The application of fast and efficient microwave heating to endothermic
reactions is particular interest.
Many attempts had been made to solve this problem. One is partial oxidation of
methane over a special catalyst capable of inhibiting further oxidation into CO
and CO2 during the transformation. The reactions in question are shown in
Scheme 10.14.
The most efficient catalysts for the desired transformation are metal oxides such
as MgO, CaO, La2O3, Sm2O3, and LiO2. The problem is, however, far from being
solved. The best C2 selectivity so far obtained is only 60 % [2].
In conventional experiments the gas and catalyst are maintained at the same tem-
perature. In microwave experiments the power is deposited within the catalyst,
which is cooled by the gas flow and thermal conduction to the surroundings. If the
catalyst bed is not thick, the gas is always at a lower temperature than the solid cata-
lyst. The increased loss factor of the catalyst favors the formation of CH3 radicals be-
cause they are produced at active ªO2º sites and these specific sites are preferentially
excited by the microwave field. Hence the observed enhancement of C2 selectivity is,
2 CH4 + O2 C2H4 + 2 H2O or CH4 C2H6 C2H4

2 CH4 + 1/2 O2 C2H6 + H2O
CO x
CH4 + 3/2 O2 CO + 2 H2O
CH4 + 2 O2 CO2 + 2 H2O
Scheme 10.14 Oxidative coupling of methane.

in fact, a ªthermalº phenomenon in that it can be completely explained by tempera-

ture gradients within catalyst particles, i. e. by locally excited catalytic sites. This ob-
served effect can be explained by assuming that under microwave irradiation the
temperature of the reaction sites is higher than the mean temperature of the catalyst
bed (see also Sect. 10.3.3).
Similarly, Bond et al. [4] confirmed that the microwave stimulation of methane
transformation reactions in the presence of a number of rare earth basic oxides to
form C2 hydrocarbons (ethene, ethane) was achieved at a lower temperature and
with the increased selectivity. Microwave irradiation resulted in an increase of the
ethene/ethane ratio, which was desirable. The results obtained were explained by the
formation of hot spots (Sect. 10.3.3) of higher temperature than the bulk catalyst.
This means that methane is activated at these hot spots.
Microwave-induced, catalytic gas-phase reactions have primary been pursued by
Wan [63, 64]. Wan et al. [65] have used pulsed-microwave radiation (millisecond
high-energy pulses) to study the reaction of methane in the absence of oxygen. The
reaction was performed by use of a series of nickel catalysts. The structure of the pro-
ducts seemed to be function of both the catalyst and the power and frequency of mi-
crowave pulses. A Ni/SiO2 catalyst has been reported to produce 93 % ethyne,
whereas under the same irradiation conditions a Ni powder catalyst produced 83 %
ethene and 8.5 % ethane, but no ethyne.
Wan et al. [61] also reported the highly effective conversion of methane to aromatic
hydrocarbons over Cu, Ni, Fe, and Al catalysts. The effects of the type of catalyst, its
configuration, and the microwave irradiation conditions on reaction path and pro-
duct selectivity were examined under both batch and continuous-flow conditions.
Catalytic microwave heating has been used to oligomerize methane to higher hy-
drocarbons in the presence of Ni and Fe powder and activated carbon as the most ac-
tive and efficient catalysts [66]. Oligomers ranging from C2 to C6 hydrocarbons, in-
cluding benzene, have been prepared with good selectivity, depending on the nature
of the diluent (helium) which favors the oligomerization of methane by microwave
heating.
Mechanistic details of the microwave-induced oligomerization of methane on a
microporous MnO2 catalyst were studied by Suib et al. [67], with emphasis on funda-
mental aspects such as reactor configuration, additives (chain propagators, dielec-
trics), temperature measurements, magnetic field effect, and reaction conditions.
Oxidative coupling of methane has also been examined by other authors [2, 68±
70], who have used different catalysts.
Pyrolysis of methane under the action of pulsed microwave radiation in the pre-
sence of solid catalysts has been reported by Russian authors [71, 72]. The applica-
tion of pulse microwave power was shown to be a promising means of production of
hydrogen syngas, ethyne, and filament carbon.
Partial oxidation of methane to syngas over Ni and Co catalysts was effected by
use of microwave irradiation, and compared with conventional heating [73].
Although the same conversion levels and H2/CO ratio (2.0 ± 0.2) were observed, the
temperature of the catalyst bed was much lower (200 K) when microwave irradiation
was used than with conventional heating. Under both activation modes the Ni-based
catalyst (Ni/ZrO2, Ni/La2O3) had higher activity and selectivity than the Co catalyst
(Co/ZrO2, Co/La2O3). It was proposed that nonuniform distribution of the micro-
wave energy on the catalyst surface created ªhot spotsº (Sect. 10.3.3) as active centers
for the catalytic reaction.
Microwaves have been used to generate plasma in methane at 5±50 Torr. The radi-
cals produced in such a system were then allowed to react over a nickel catalyst, af-
fording a mixture of ethane, ethene, and ethyne [74].
Methane has also been used as the reducing agent in the catalytic conversion of
NO to N2 over Co-ZSM-5 zeolites [75] in the presence of oxygen. The high NO con-
versions (>70 %) were achieved by microwave irradiation at 250±400 8C, whereas un-
der similar conditions thermal runs failed to convert either NO or methane in signif-
icant amounts. The high activity and selectivity of the reduction of NO by methane
achieved with microwave irradiation was probably because of the activation of
methane to form methyl radicals at relatively low reaction temperatures.
Direct partial oxidation of methane to produce methanol and other oxygenates

The formation of oxygenates by reaction of methane with oxygen and vapor under
the action of conventional heating has received considerably less attention than the
methane coupling reaction. The problem was poor selectivity and the formation of
large amounts of COx . The use of microwave radiation for formation of the oxyge-
nates from methane has, nevertheless, yielded some encouraging results. Wan et al.
[76] used the vapor as the oxidant in preference to oxygen. The authors showed that
acetone, 2-propanol, methanol, and dimethyl ether can be produced by this method.
Suib et al. [77] used microwaves to generate plasma in an atmosphere containing
methane and oxygen. The plasma passing over a metal or metal oxide catalyst led to
formation of C2 hydrocarbons and some oxygenates.
Wan and Koch [78] also developed a method for producing HCN on a small scale
by reaction of methane with ammonia, Scheme 10.15.
M / Al 2O3
CH4 + NH3 HCN + 3 H2
Scheme 10.15 Synthesis of hydrogen cyanide.
The reaction was performed over a series of Pt/Al2O3, Ru/Al2O3, and carbon-sup-
ported catalysts under the action of pulsed microwave radiation; conversions ex-
ceeded 90 % and acetonitrile was formed as the byproduct.
10.3.2.2 Reactions of Higher Hydrocarbons

Microwave activation of alkane transformations was studied in detail by Roussy et
al., who summarized their results in several papers [2, 28, 29, 79]. Isomerization of
hexane, 2-methylpentane, 2-methyl-2-pentene, and hydrogenolysis of methylcyclo-
pentane have been investigated, and the diversity of possible effects has been speci-
fied [2]. The course of 2-methylpentane isomerization on a 0.3 % Pt/Al2O3 catalyst
depended on the mode of heating ± the distribution of hexane products was different
under the action of conventional and microwave heating [28, 79]. The isomer selec-
tivity of transformation of 2-methylpentane to 3-methylpentane, methylcyclopen-
tane, and hexane on this catalyst increased from 40 to 80 % when the catalyst was
pretreated with microwave energy [79]. The beneficial change in selectivity was
found to be permanent. Microwave irradiation has been found to be a new, original
means of activation of supported metal catalysts, in particular reforming catalysts
[28, 29]. Hydrogenolysis of methylcyclopentane was studied mechanistically, because
methylcyclopentane is one of the four molecules in equilibrium with the intermedi-
ate cyclopentane in the cyclic mechanism [2]. Four possible effects of the electromag-
netic field on catalytic reactions were identified.
1. Microwave treatment can permanently modify the catalyst.

2. Heterogeneous phases (solid and gas) may give rise to inter-phase temperature
gradients.
3. The electromagnetic field can act directly on the reaction sites to activate adsorbed
organic molecules.
4. The electromagnetic field can act on polar intermediate species, e. g. carbenium
ions.
Hydrogenolysis of 2-methylpentane, hexane, and methylcyclopentane has been

also studied on tungsten carbide, WC, a highly absorptive catalyst, at 150±350 8C in a
flow reactor [80]. These reforming reactions were mainly cracking reactions leading
to lower molar mass hydrocarbons. At the highest temperature (350 8C) all the car-
bon±carbon bonds were broken, and only methane was formed. At lower tempera-
tures (150±200 8C) product molecules contained several carbon atoms.
The effect of microwave irradiation on the catalytic hydrogenation, dehydrogena-
tion, and hydrogenolysis of cyclohexene was studied by Wolf et al. [81]. Optimum
conditions for benzene formation were a hydrogen flow, N±CaNi5 catalyst, atmo-
spheric pressure, and 70 s irradiation time. Cyclohexane was the main product when
the irradiation time was 20 s, or in a batch/static system.
The oxidation of toluene to benzaldehyde and benzoic acid over V2O5/TiO2 as-
sisted by microwaves was studied by Liu et al. [82]. The authors concluded that mi-
crowave energy can greatly improve the process of selective toluene oxidation. The
highest yields of benzoic acid were, however, only 38±41% and the highest selectivity
was 51% at 80 % conversion to benzoic acid.
In the cracking of benzene to acetylene over alumina- and silica-supported nickel
catalysts it was observed that the selectivity of the reaction, expressed as the ethyne/
ethene ratio, was dramatically affected (from 1 : 9 to 9 : 1) by controlling the micro-
wave energy input (i. e. 90 % selectivity) [83].
Other catalytic hydrocarbon reactions include decomposition of olefins over a
powdered nickel catalyst [84], hydrogenation of alkenes, hydrocracking of cycloalk-
enes, and water-gas shift reactions [64].
10.3.2.3 Miscellaneous Reactions

Several reactions have already been mentioned in Sect. 10.2 ± NOx decomposition
over modified zeolites [8±10], dehydrogenation of 2-propanol, isomerization of cis-
butene over basic zeolites [11, 12], hydrogenation of benzene and hydrodechlorina-
tion of chlorobenzene [13±15], and oxidative dehydrogenation of ethylbenzene to
styrene [26, 27]. Microwave-assisted decomposition of NOx or its mixture with SO2
was reported by Tse [76] and other authors [75, 85±87]. Oxygen, nitrogen, and solid
sulfur were the major products of the decomposition performed over a range of
nickel and copper catalysts [76]. The reaction of nitrogen oxides under an oxidative
atmosphere is a very extensively studied reaction, but the true reaction pathways
are still very difficult to understand. The high activity and selectivity of Co-ZSM-5
zeolite catalysts for reduction of NO by methane is probably because of activation
of methane to form methyl radicals at relatively low temperatures [75], as already
mentioned. Wan et al. [88] have also shown that carbon dioxide can be reacted over
a supported metal catalyst in the presence of water vapor to yield alcohols and
other oxygenates if the catalyst is irradiated with microwaves. The reaction pro-
ceeded at relatively low temperatures (220±350 8C). It seems likely that the surface
temperature of the metal is several hundred degrees higher than the bulk tempera-
ture of the catalyst. Decomposition of chloromethane over a metal catalyst irra-
diated by pulsed-microwave radiation afforded methane, although the metal catalyst
was inhibited by partial formation of the metal chloride by reaction with hydrogen
chloride [89].
The reaction of 2-propanol to propanone and propene over a series of alkali-metal-
doped catalysts with use of microwave irradiation has been studied by Bond et al.
[90]. The nature of the carbon support was shown to affect the selectivity of the cata-
lyst. Under microwave irradiation the threshold reaction temperature (i. e. the lowest
temperature at which the reaction proceeded) was substantially reduced; this was ex-
plained in terms of ªhot spotsº (Sect. 10.3.3) formed within the catalyst bed.
The effect of microwave irradiation on the catalytic properties of a silver catalyst
(Ag/Al2O3) in ethane epoxidation was studied by Klimov et al. [91]. It was found that
on catalyst previously reduced with hydrogen the rates of both epoxidation and car-
bon dioxide formation increased considerably on exposure to a microwave field. This
effect gradually decreased or even disappeared as the catalyst attained the steady
state. It was suggested that this was very likely because of modification of electronic
properties of the catalyst exposed to microwave irradiation.
10.3.3
Mechanistic Aspects
Although microwave activation of catalytic reactions has been the subject of many
studies (Sects. 10.3.1 and 10.3.2), the mechanism of these reactions is not yet fully
understood. In heterogeneous catalytic liquid/solid and gas/solid systems many re-
sults have revealed significant differences between the rates of conventionally and
microwave heated reactions. As a rule, at the same temperature microwave heated
reactions were faster than conventional and their rate enhancement was over one or-
der of magnitude. Such rate differences have not been reported for other catalytic re-
actions, so how should they be interpreted? The reactions can be divided into two ca-
tegories according to the rate enhancement effect observed under microwave condi-
tions compared to conventional heating ± those accelerated by application of micro-
waves and those which are not.
Reactions accelerated by microwaves

1. Esterification of stearic acid and acetic acid with propanol and butanol in the pre-
sence of Fe2(SO4)3/KSF montmorillonite [37]. The rate enhancement observed
(1.5±2.5 times) was ascribed to the higher temperature of the catalyst bed (calcu-
lated to be 9±18 K above the bulk temperature). Reaction conditions: batch (no
stirring) and a stirred single-mode tank reactor, catalyst particle size 5 mm, 10-
fold excess of alcohol.
2. Transesterification of triglycerides in the presence of B4C [40]. The rate enhance-
ment was not assessed quantitatively. Reaction conditions: a stirred multi-mode
tank reactor, no solvent.
3. Acylation of aromatic ethers in the presence of a variety of metal chlorides and
oxides [52]. The rate enhancement was probably caused by large temperature gra-
dients but was not evaluated quantitatively. Reaction conditions: a single-mode
stirred tank reactor, fourfold excess of anisole, no solvent.
4. Transformation of 2- and 4-t-butylphenols in the presence of KSF catalyst [58].
Rate enhancement up to 21.6 was recorded. Reaction conditions: a stirred multi-
mode tank reactor, no solvent or polar and nonpolar solvents.
5. Diels±Alder reaction of methyl 2-acetamidoacrylate with cyclopentadiene in the
presence of SiO2±Al and SiO2±Ti catalysts [53]. Rate enhancement was not ex-
pressed quantitatively. Reaction conditions: a stirred multi-mode tank microreac-
tor, no solvent.
6. Oxidation of o-xylene over V2O5/SiO2 [6]. The rate enhancement was because of a
temperature gradient of approx. 100 K in the catalyst bed. Reaction conditions: a
flow fixed-bed multi-mode reactor.
7. Decomposition of H2S over MoS2 [92]. The rate enhancement, quantitatively un-
specified, was attributed to the creation of ªhot spotsº with temperatures 100±
200 K above that of the bulk. Reaction conditions: a flow fixed-bed single-mode
reactor.
Reactions not accelerated by microwaves

8. Esterification of acetic acid by isopentanol in the presence of Amberlyst-15 [38].
Reaction conditions: hexane solvent, continuous-flow reactor.
9. Esterification of acetic acid with 1-propanol in the presence of SiO2 [39]. Reac-
tion conditions: reflux, tenfold molar excess of 1-propanol, batch reactor.
10. Arylation of alkenes with iodobenzene in the presence of supported Pd catalyst
[45]. Reaction conditions: acetonitrile as solvent, pressure CEM reactor.
11. Hydrolysis of sucrose in the presence of Amberlite 200C [47±49]. Reaction con-
ditions: 9 % aqueous solution of sucrose, a stirred tank [47] or continuous-flow
fixed-bed reactor [48, 49].
12. Cyclization of citronellal in the presence of KSF catalyst [93]. Reaction condi-
tions: reflux, CCl4 as solvent, single-mode reactor¹
13. CO oxidation over Pd/g-Al2O3 and Pt/g-Al2O3 [94, 95]. Reaction conditions: sin-
gle-mode packed bed microwave reactor operated on continuous basis at
915 MHz.
Several reasons have been proposed to account for the effect of microwave heating
on chemical reactions and catalytic systems. The results summarized in 1 to 7,
above, show that under specific conditions microwave irradiation favorably affects re-
action rates of both the liquid- and gas-phase processes. This phenomenon has been
explained in terms of microwave effects, i. e. effects which cannot be achieved by con-
ventional heating. These include superheating, selective heating, and formation of hot
spots (and possibly nonthermal effects).
. Superheating can occur as superheating of a liquid reaction mixture in liquid/solid

reactions or as localized superheating in gas/solid reactions.
. Selective heating can occur as selective heating of catalyst particles or in the ex-
treme case as selective heating of active sites.
. Hot spots are either macroscopic hot spots (measurable) or microscopic hot spots
(on a molecular level, immeasurable and similar to those in sonochemistry).
These microwave effects can be regarded as thermal. The proposal of some authors
on the operation of nonthermal effects is still controversial (see Chapt. 3).
In the literature, thermal microwave effects are still the subject of some misunder-
standings. For that reason, let us discuss the matter in more detail.
Superheating of liquid reaction mixture

Superheating of liquid reaction mixture above the boiling point [96, 97] and localized
superheating of solid samples generating temperature gradients [98] is very often re-
sponsible for enhancement of reaction rates in both homogeneous and heteroge-
neous reactions. It is generally known that the irradiation of a heterogeneous system
(e. g. suspension) by means of a electromagnetic field leads to nonuniform tempera-
ture distribution. If the reaction is performed under reflux, the reaction temperature
can be significantly higher under the action of microwaves than under conventional
conditions, because of the superheating effect of microwaves on the polar reaction
mixture. Superheating occurs because the sample is heated so quickly that convec-
tion to the surface of the liquid and vaporization cannot adequately dissipate the ex-
cess energy. Organic chemists can use the superheating effect to accelerate both het-
erogeneous and homogeneous liquid-phase reactions. Under these conditions the re-
actions proceed at temperatures higher than the boiling point of the liquid mixture,
without the need to work under pressure. The superheating of liquids can be re-
duced or suppressed by addition of a boiling stone or by efficient stirring. Localized
superheating accompanied by the creation of hot zones is more significant for solids
than for liquids.
Localized superheating in the solid phase

In gas/solid phase reactions enhancement of the rate by microwaves can be caused by
the localized superheating of a solid catalyst bed to a much larger extent than in the li-
quid phase. Both differential coupling abilities of materials and distribution of electro-
magnetic fields can result in localized temperature distribution in the catalytic bed, but
the contribution of these effects is difficult to quantify. Localized superheating creates
hot zones, and consequently, leads to temperature gradients in solid materials. It also
increases the frequency of collision of reactants. The preferential alignment of dipolar
or ionic functional group, because of the microwave field can create a favorable situa-
tion for collisions to occur at the active sites of catalyst, thus increasing the collision ef-
ficiency. The large difference between temperature profiles of the catalyst bed under
microwave and conventional heating can result in a different product distribution for
catalytic reactions. Stuerga et al. [98] have suggested that localized rate enhancement
might be responsible for nonisothermal and heterogeneous kinetic phenomena.
Measurement and estimation of temperature distributions induced by microwave
heating in solid materials is, however, very difficult. Consequently, most local tem-
perature fluctuations are greater than those measured. Under stronger microwave ir-
radiation it is, therefore, very easy to obtain local temperature gradients. Temperature
measurements usually yield an average temperature, because temperature gradients
induce convective motions. Despite these difficulties, some methods, e. g. IR ther-
mography, can reveal the surface temperature distribution without any contact with
the sample studied. By this method the temperature gradients between 7 and
70 8 cm±1 were detected in an alumina layer [98] and 50 8 mm±1 in a magnetite sam-
ple [99]. Similar temperature gradients ± 30±50 8 cm±1 ± have also been found by Ha-
jek et al. [100] for a cylindrical sample of alumina.
A systematic theoretical study of temperature profiles in microwave-heated solids
has been performed by Dolande et al. [101]. According to these results, differences
between reaction rates and/or yields observed for conventional and microwave heat-
ing can be explained in terms of localized superheating. The main interest in the
use of microwave heating is its ability to produce very steep thermal gradients and
very fast heating rates. One can also induce localized superheating, which leads to lo-
calized rate enhancement [98±100]. Localized superheating can be advantageously
used by synthetic chemists, especially for reactions performed on inorganic supports
under solvent-free conditions (Chapt. 6). In conclusion, it should be stressed that lo-
calized superheating can have a beneficial effect on heterogeneous catalytic reactions
because of both rate enhancement and selectivity improvement.
Selective heating
Selective heating generally means that in a sample containing more than one com-
ponent, only that component which couples with microwaves is selectively heated.
The nonabsorbing components are not thus heated directly but only by heat transfer
from the heated component. For example:
. liquid±liquid ± polar reactants in nonpolar solvents (e. g. mixture of H2O with

CCl4).
. solid±liquid ± solid reactants or solid catalysts in nonpolar reaction mixtures (e. g.

KSF in CCl4).
. solid±solid ± mixtures of strong microwave absorbers (e. g. C, SiC, CuO, etc.) with
transparent materials (e. g. SiO2, MgO etc.) or supported catalysts (e. g. Pt/SiO2,
Pd/Al2O3 etc.).
The selective heating is more enhanced when the catalyst contains a low micro-
wave absorbing support (e. g. a-Al2O3 rather than g-Al2O3). Metal or metal oxides
supported on transparent support may be therefore selectively heated. Thus for ex-
ample, Pt sites in Pt/SiO2 catalyst can be selectively heated, in contrast to the trans-
parent, unheated SiO2 support. Hence, selective heating of the active sites to the
temperature higher than that of the support may occur if heat loss from the metal
particles is not too fast. Microwave field does not couple with transparent ceramic
support, but it may strongly couple with metal particles because of their high electri-
cal conductivity. Unfortunately, to get a direct experimental proof of this concept
seems very unlikely, since to measure the temperature of individual active sites is be-
yond current experimental possibilities. Until now, the possibility to heat selectively
the active sites without rising the temperature of the catalyst bed has been only mod-
eled [102] and found to be strongly dependent on the size of catalyst particles and mi-
crowave frequency [103]. A number of experimental studies on catalytic reactions un-
der microwave conditions were concerned with kinetic aspects and showed that the
reaction rates and product distribution correspond to a higher reaction temperature
than was that measured for the bulk of catalyst bed. Both reaction characteristics
were often explained in terms of the higher local temperature of certain active cen-
ters within the catalyst bulk. It is worth mentioning that the results of theoretical cal-
culation reported by Thomas [102] did not substantiate the possibility of achieving
selective heating of supported metal catalysts by microwaves. However, a recent de-
tailed modeling of small-scale, microwave-heated, packed bed and fluidized bed cata-
lytic reactors indicated that under specific conditions, the active sites may be selec-
tively heated in both types of catalyst bed [103, 104].
Hot spots
Hot spots are created by a nonlinear dependence of thermal and electromagnetic
properties of the material being heated on temperature. If the rate at which microwave
energy is absorbed by the material increases faster than linearly with temperature,
then heating does not take place uniformly, and the regions of very high temperature
can create hot spots. Nonhomogenity of electromagnetic field contributes to the crea-
tion of hot zones significantly. Generally, hot spots can be created by localized super-
heating, selective heating as well as by nonhomogenity of electromagnetic field.
In a microwave-heated packed catalyst bed, two different forms of hot spots can be
created.
1. Hot spots as large scale nonisothermalities, which can be detected and measured
by optical pyrometers, fiber optic or IR pyrometers, i. e. these are macro scale hot
zones.
2. Hot spots as a temperature gradient between the metal particles and the support,
which cannot be detected and measured because they are close to micro scale, i. e.
they possess molecular dimensions, they are closed to selective heating of active
sites.
Unfortunately, the microwave radiation effects on molecular level are not well un-
derstood.
Zhang et al. [92] presented a certain evidence for the formation of hot spots in the
microwave experiments and demonstrated that these hot spots need not be exclu-
sively localized on the active sites but may also involve the support material
(g-Al2O3). They also estimated the dimensions of these hot spots to be in the region
of 90±1000 mm. Development of hot spots in the catalyst bed in the course of the gas
phase decomposition of H2S catalyzed by MoS2/Al2O3 was probably the reason for a
significant apparent shift in the equilibrium constant. The temperature of these hot
spots was probably by 100±200 K above the bulk temperature. The formation of hot
spots in the support could be due to the absorptive properties of g-Al2O3 (compared
to low absorptive a-Al2O3). It was concluded that these hot spots also induce a con-
siderable reorganization of the catalyst under microwave conditions. Such selective
or localized superheating to create hot spots as effected with microwave heating can-
not be achieved by conventional heating methods.
If microwave heating leads to enhanced reactions rates, it is plausible to assume
that the active sites on the surface of the catalyst (micro hot spots) are exposed to se-
lective heating which causes some pathways to predominate. In the case of metal
supported catalysts, the metal can be heated without heating of the support due to
different dielectric properties of both catalyst components. The nonisothermal nat-
ure of the microwave-heated catalyst and the lower reaction temperature affects fa-
vorably not only reaction rate but also selectivity of such reactions.
Chen et al. [70] suggested that temperature gradients may have been responsible
for the more than 90 % selectivity of the formation of acetylene from methane in a
microwave heated activated carbon bed. The authors believed that the highly non-
isothermal nature of the packed bed might allow reaction intermediates formed on
the surface to desorb into a relatively cool gas stream where they are transformed via
a different reaction pathway than in a conventional isothermal reactor. The results
indicated that temperature gradients were approximately 20 K. The nonisothermal
nature of this packed bed resulted in an apparent rate enhancement and altered the
activation energy and pre-exponential factor [94]. Formation of hot spots was mod-
eled by calculation and, in the case of solid materials, studied by several authors
[105±108].
It is obvious that nonisothermal conditions induced by microwave heating lead to
very different results from those obtained under conventional heating conditions. In
summary microwave effects like superheating, selective heating and hot spots, can
all be characterized by temperature gradients ranging from macroscopic to molecu-
lar scale dimensions.
Let us now return to the question ªHow to interpret or explain the fact that some
reactions are affected by microwaves and some reactions do notº, as documented by
examples 1±7 and 8±13, above. A detailed study of this subject has been performed
by Hjek et al. [58±60] for heterogeneous catalytic liquid phase reactions. Transfor-
mation of 2-t-butylphenol into phenol, 4-t-butylphenol, 2,4-di-t-butylphenol and iso-
butene on montmorillonites as catalysts (KSF, K10) was chosen as a model reaction.
Both the reactant and the catalysts coupled very well with microwaves. KSF and K10
catalysts in the form of a fine powder (10±15 mm) were used to avoid creation of hot
spots (as in the presence of voluminous catalyst pellets, e. g. 5 mm [36, 37]). The re-
sults can be summarized as follows.
Effect of microwaves on selectivity

The product distribution determined for the reactions performed over a broad tem-
perature range (from ±176 to 199 8C) under microwave heating was always more or
less different from that obtained by conventional method. Thus, a vigorous forma-
tion of isobutene under reflux using microwave heating indicates superheating of
the catalyst to a higher temperature. This facilitates the dealkylation reaction, which
is promoted by elevated temperature.
Effect of microwaves on rate enhancement

Temperature and solvent effects were examined with the following results. When
the reaction temperature was gradually decreased from the reflux temperature
(199 8C), the rate enhancement factor increased from 1.0 at 199 8C to 1.4 at 105 8C,
and to 2.6 at 75 8C. These results may indicate that the superheating of the catalyst is
more pronounced at lower temperatures. In the presence of nonpolar solvents like
hexane and heptane, the more efficient heat transfer from the superheated catalyst
particles can explain the lower value of the rate enhancement 1.2 at 105 8C (heptane)
and 1.6 at 75 8C (hexane). In order to suppress the reaction under conventional heat-
ing, the reaction was performed at very low temperatures ranging from ±176 to 0 8C,
i. e. in the temperature region in which conventional conditions [60] do not lead to
any reaction. The efficient cooling of the reaction mixture by liquid nitrogen or dry
ice was used to perform the reaction at the above mentioned low temperatures. The
reaction was taking place in the solid state because 2-t-butylphenol solidified at these
temperatures (m.p. is ±7 8C). It seems likely that under these conditions the heat
transfer from the superheated catalyst particles in the solid reaction mixture at ±176
to 0 8C was not so efficient, and rather significant conversions (0.5±31.4 %) were re-
corded. The superheating of catalyst particles (or acidic active sites?) was calculated
to be 105±115 8C over the bulk. When the reaction mixture was diluted by a nonpolar
solvent (hexane + tetrachloromethane) under efficient stirring, no reaction was ob-
served to take place, similarly as under conventional conditions [60]. This finding
can be accounted for an efficient heat transfer from the catalyst particles due to effi-
cient stirring of the liquid reaction mixture. The question is the extent of catalyst
superheating. Are catalyst particles of 10±15 mm or polar acidic sites superheated,
participating in the interaction of microwave energy with highly polarized reagent
molecules via adsorption of these molecules on their active sites? The above finding
related to selective heating of active acidic sites was not excluded but also no direct
evidence has been found for this assertion.
When the results obtained in the liquid phase are applied to the reactions 1±7 and
8±13, above, both for the liquid and gas phase, one can conclude that if reactions are
performed under conditions where temperature gradients can be completely elimi-
nated, e. g. on using efficient stirring, nonpolar solvents, a high flow of reactants in
continuous flow system, fluidized bed and then any differences between microwave
and conventional heating conditions may disappear. However, from the synthetic
point of view it is more attractive to perform synthetic reactions using microwaves
under conditions favorable to the production of temperature gradients, because
higher reaction rate and improved selectivities can be obtained more easily com-
pared to conventional heating methods.
10.3.4
Microwave Catalytic Reactors
10.3.4.1 Batch Reactors

The instrumentation which has been used for microwave catalytic reactions varied
from domestic multi-mode ovens to continuous-flow single-mode reactors. In do-
mestic microwave ovens the microwave output is changed by varying the patterns of
on±off cycles. Thus, for example, a half microwave output does not mean real half
output power but only that the full power is switched on and off for a certain period
(e. g. half power corresponds to 10 s full power and 10 s of no power). In this case
the catalyst and/or reaction mixture suffer thermal shocks, which is not desirable.
Moreover, in domestic microwave ovens the microwaves are randomly distributed in
oven space, thereby yielding ill-defined regions of the high and low intensities inside
the oven. The second disadvantage of domestic ovens is the problem of temperature
measurement, because in the absence of correct temperature profile in the reaction
mixture, the reaction is not comparable with conventional heating and may not be
reproducible when performed in two different microwave systems.
The problem of switch on±off system of the most domestic ovens has been over-
come by an inverter circuit that allows power levels to be adjusted in increments
(e. g. 10 % of output) [109]. The desired power is continuous at different levels, as
compared to the long pulsed operations of the magnetrons in most domestic ovens.
The advantage of this system for laboratory applications, where small loads are nor-
mally used, is that lower power levels can be applied, which minimizes the amount
of the reflected power reaching the magnetrons. Therefore, a simple unmodified mi-
crowave domestic oven operating on multi-mode system cannot be recommended
for catalytic reactions (and generally for organic synthesis) induced by microwaves.
Disadvantages are quite evident:
. no possibility of temperature measurement and no temperature control.

. reaction mixtures subjected to thermal shocks by switch on±off cycles.
. nonhomogenity of microwave field.
However, an inexpensive and safe modification of domestic ovens can be made,

which almost eliminates these disadvantages and allows independent temperature
Fig. 10.1 Microwave batch reactor: 1. micro-

wave cavity, 2. magnetron, 3. stirring bar, 4. alu-
minum plate, 5. magnetic stirrer, 6. IR pyrom-
eter, 7. switch on/off, 8. water cooler.
measurement as well as reasonable temperature control. For temperature measure-

ment IR thermometer or better fiber optic thermometer [58±60] have been recom-
mended. Such a batch microwave reactor made by modification of microwave do-
mestic oven is represented in Fig. 10.1 and was described in some papers [40, 58±60,
109±112] and references cited therein.
A complementary, more advanced, laboratory-scale microwave batch reactor for
synthesis and kinetics studies was developed by Strauss et al. [113] (Fig. 10.2).
The reactor is equipped with magnetic stirrer, microwave power and temperature
control by computer and can operate under pressure. Even though it was developed
for homogeneous organic synthetic reactions, it can be used also for heterogeneous
catalytic reactions in the liquid phase.
The first continuous-flow reactor was developed by Strauss [113, 115, 116] and has
recently been commercialized.
The reactor (Fig. 10.3) consists of microwave cavity fitted with a tubular coil
(3 × 3 mm) of microwave-transparent, inert material. The coin is attached to a meter-
Fig. 10.2 Schematic diagram of the microwave

batch reactor: 1. reaction vessel, 2. retaining
cylinder, 3. top flange, 4. cold finger, 5. pressure
meter, 6. magnetron, 7. power meters, 8. power
supply, 9. stirrer, 10. fiber optic thermometer,
11. computer, 12. load-matching device, 13. wa-
veguide, 14. microwave cavity. Reproduced from
Ref. [114] by permission of CSIRO Publishing.
Fig. 10.3 Schematic diagram of the

continuous-flow microwave reactor:
1. reactants for processing, 2. metering
pump, 3. pressure transducer, 4. micro-
wave cavity, 5. reaction coil, 6. tempera-
ture sensor, 7. heat exchanger, 8. pres-
sure regulator, 9. microprocessor regula-
tor, 10. product vessel. Reproduced
from Ref. [114] by permission of CSIRO
Publishing.
ing pump and pressure gauge at the inlet end and to a heat exchanger and pressure-
regulating valve at the effluent end. Temperature is monitored outside the cavity at
the inlet and the outlet.
The reactor has facilitated a diverse range of synthetic reactions at temperatures
up to 200 8C and 1.4 Pa. The temperature measurements taken at the microwave
zone exit indicate that the maximum temperature is attained, but they give insuffi-
cient information about thermal gradients within the coil. Accurate kinetic data for
studied reactions are thus difficult to obtain. This problem has recently been avoided
by using fiber optic thermometer. The advantage of continuous-flow reactor is the
possibility to process large amounts of starting material in a small volume reactor
(50 mL, flow rate 1 L h±1). A similar reactor, but of smaller volume (10 mL), has been
described by Chen et al. [117].
It was noted that hydrolysis of sucrose using a strong acidic cation-exchange resin
as heterogeneous catalyst gives better results than with soluble mineral acids [118].
The hydrolysis of sucrose catalyzed by the strong acidic cation-exchange resin Am-
berlite 200C was used by Plazl et al. [48, 49] to test successfully a continuous-flow cat-
alytic reactor with packed catalyst bed made by a modification of a commercial mi-
crowave oven (Panasonic NE-1780). The continuous-flow catalytic reactor was built
by modification of domestic ovens (Panasonic, General Electric) also by other
authors [38, 40]. The continuous-flow microwave reactor based on single-mode sys-
tem was described by Chemat [37] and Marqui [118]. Better isothermal conditions,
the possibility of selective heating of catalyst bed and scaling-up are the main advan-
tages of single-mode continuous-flow reactors compared to multi-mode systems for
catalytic reactions in the liquid phase.
For gas phase heterogeneous catalytic reactions, the continuous-flow integral
catalytic reactors with packed catalyst bed have been exclusively used [61±91]. Con-
tinuous or short pulsed-radiation (milliseconds) was applied in catalytic studies
(see Sect. 10.3.2). To avoid the creation of temperature gradients in the catalyst
bed, a single-mode radiation system can be recommended. A typical example of
the most advanced laboratory-scale microwave, continuous single-mode catalytic
reactor has been described by Roussy et al. [79] and is shown in Figs. 10.4 and
10.5.
The principle aspects of this microwave irradiation system are, briefly:
. continuously variable microwave power from 20 to 200 W;

. temperature of the catalyst bed is measured by use of two thermocouples; and
. homogeneous distribution of electromagnetic field.
In addition to packed catalyst bed, a fluidized bed irradiated by single and multi-
mode microwave field, respectively, was also modeled by Roussy et al. [120]. It was
proved that the equality of solid and gas temperatures could be accepted in the sta-
tionary state and during cooling in a single-mode system. The single-mode cavity
eliminates the influence of particle movements on the electric field distribution.
When the bed was irradiated in the multimode cavity, the model has failed. Never-
Fig. 10.4 Schematic diagram of the microwave system for cata-

lytic study: 1. generator, 2. water load, 3. circulator, 4. switch,
5. input power, 6. power meter, 7. coupling iris, 8. microcompu-
ter, 9. catalyst, 10. chromatograph, 11. gas production setup,
12. thermocouple, 13. short-circuit, 14. stepping motor. Reprinted
from Ref. [119] with permission from Elsevier Science.
Fig. 10.5 Schematic diagram of the microwave

applicator: 1. reactor, 2. wave guide, 3. fritted
silica disc, 4. thermal insulation, 5. catalyst, 6,
7. thermocouples. Reprinted from Ref. [119] with
permission from Elsevier Science.
theless, the combination of the fluidization technique with microwave heating pro-
vides significant benefits such as reduced energy costs, appreciable reduction in pro-
cessing time, and higher product quality. A fluidized bed reactor has been success-
fully applied in the destruction of hazardous/toxic organic compounds as trichlor-
oethylene, p-xylene, naphthalene, and some gasoline-like hydrocarbon materials
[121]. Granulated activation charcoal was used as the catalyst. All these organic com-
pounds could be completely decomposed by the combination of these two technolo-
gies.
10.4
Industrial Applications
Since the early 1980s there has been a great deal of interest in the development of in-
dustrial applications of microwave irradiation in catalytic processes. This interest has
been driven by the unique attributes of the selective interactions of microwave radia-
tion with different materials as the basis for the initiation and control of catalytic che-
mical reactions. The microwave mode of energy conversion has many attractive fea-
tures for the chemist because some liquids and solids can absorb in situ and trans-
form electromagnetic energy into heat very effectively [2]. However, microwave tech-
nology has so far only rarely attracted industrial attention. A number of potential che-
mical processes using this technique have been established in research laboratories,
but the large scale-up to commercial practice remains elusive. Microwave technology
is not new to physicists and electrical engineers, but the concept of using microwaves
as an energy source for chemical reactions has only recently been appreciated by che-
mists. In the subsequent stage of the scale-up of the process, some of potential advan-
tages of the microwave induced catalysis proved in laboratory experiments might not
be easy to realize in a commercial scale production. This is because of the necessity
to identify many difficulties and modifications, technical and economical, before the
final choice of a proper system can be designed and installed [122].
Wan et al. [122] demonstrated problems of the scaling-up in the case of the cataly-
tic conversion ethane into ethyne by finding that the optimization of the process for
the large-scale reaction system was quite different from the laboratory experiment. It
is not practical to construct a huge quartz reactor enclosed by a huge microwave
oven. Rather, the microwave radiation can be introduced into a stainless steel reactor.
There are obviously many other engineering problems to be encountered, such as
penetration depth, uniformity of temperature profile of catalyst bed and the like,
which are specific to a microwave reactor. In large scale processes the spatial unifor-
mity may be often critical. Engineering and scale-up aspects of microwave induced
catalytic reactions were summarized by Mehdisadeh [123] of DuPont de Memours
Co. It was recommended that the choice of the catalyst should be made not only for
its chemical merits, but also for its microwave properties. For example, a catalyst
with too low a dielectric loss would be inefficient, and could cause control difficul-
ties. On the other hand, a catalyst with too high a dielectric loss can cause low pene-
tration and uniformity problems.
Despite the scaling-up problems, the following industrial processes have been pro-
posed, and disclosed mainly in the patent literature:
. microwave induced catalytic conversion of methane to ethene and hydrogen [63];

. microwave induced catalytic conversion of methane to C3 oxygenates [124];
. oxidative coupling of methane to C2±C4 oxygenates [125];
. oxidative coupling of methane to ethane and ethene [126];
. cracking of heavy hydrocarbon feeds [127];
. reforming of hydrocarbons [128];
. production of terminal alkenes from long chain alkanes [129±131];
. formation of shorter-chain hydrocarbons from higher hydrocarbons [132];
. preparation of vinyl acetate [133]; and
. production of organic nitrogen compounds by direct conversion of elemental ni-
trogen [134].
In conclusion, one can ask the question ªWhich microwave catalytic process is op-
erated on industrial scaleº? The answer has been frequently looked for at AMPERE
meetings, in particular at conferences in Prague (1998), Valencia (1999), or Antibes
(2000) and Bayreuth (2001). It was stated that relevant information concerning this
matter was missing, because an industrial microwave catalytic process put in opera-
tion had not been disclosed. The reason could be either that such a process has not
yet been successfully realized or that the disclosure of new technology has been
strictly protected by industry. Nevertheless, the potential of the microwave catalysis
for industrial application is quite great, both for gas phase processes and continu-
ous-flow liquid phase reactors where even a small equipment can produce signifi-
cant amounts of products. Moreover, another potential application exists in environ-
mental catalysis, since recent legislative measures have stimulated the development
of new technologies to reduce toxic emissions or to remove and dispose of hazardous
wastes.
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379
11
Transition Metal Catalysis and Microwave Flash Heating in
Organic Chemistry
Kristofer Olofsson, Anders Hallberg, and Mats Larhed
11.1
Introduction
The combination of homogeneous catalysis and microwave heating is not only a hot
topic but also a research area that is likely to have an impact on several fields of modern
chemistry [1±11]. Transition metal-catalyzed reactions that typically needed hours or
days to reach completion with standard, thermal heating can now with high reproduc-
ibility be brought to full conversion in only seconds or minutes, consuming only a frac-
tion of the energy normally needed for a standard, oil-bath-heated reaction. What is
more, the application of microwave heating is in many cases associated with advan-
tages not easily achieved by the use of traditional heating. Indeed, transition metal-ca-
talyzed chemistry has on several occasions been proven to be even more efficient under
the action of microwaves than with standard heating [9]. In addition, the preparative
value of this heating method has increased with the attentive development of catalytic
systems that can withstand the sometimes extreme temperatures that are induced
under irradiation [12]. This chapter will discuss some of the factors which make the
combination of organometallic chemistry and microwave heating one of the most pro-
mising research areas in the field of modern synthetic chemistry.
We review herein progress in microwave-assisted homogeneous metal catalysis in
the liquid phase. Most of the work published in this field is, as the reader will see, as-
sociated with palladium chemistry, and this will, by necessity, also be reflected in the
text.
11.2
Safety
The use of microwave techniques introduces unique challenges in safety considera-

tions. Guidelines for the use of microwave systems in the analytical laboratory have
been published and most of these also apply to microwave-assisted organic chemis-
try [13]. The health hazards of microwave radiation are also still under investigation,
and it is not yet known whether or not low level exposure is detrimental. Recom-

ISBN: 3-527-30514-9
380 11 Transition Metal Catalysis and Microwave Flash Heating in Organic Chemistry
mended safety levels tend to move in the direction of lower doses of radiation, so
great care should be taken to minimize microwave leakage.
Although microwave-heated organic reactions can be smoothly conducted in open
vessels, it is often of interest to work with closed systems, especially if superheating
and high-pressure conditions are desired. When working under pressure it is
strongly recommended to use reactors equipped with efficient temperature feedback
coupled to the power control and/or to use pressure-relief devices in the reaction ves-
sels to avoid vessel rupture. Another potential hazard is the formation of electric arcs
in the cavity [2]. Closed vessels can be sealed under an inert gas atmosphere to re-
duce the risk of explosions.
11.3
Metal-catalyzed Reactions
The first examples of the use of palladium as a catalyst for carbon±carbon coupling
reactions were reported almost thirty years ago [14], and over recent decades a mas-
sive effort has been devoted to the extension of the scope of palladium-catalyzed reac-
tions. Organic and organometallic chemists have received extensive input from pal-
ladium-coordination chemistry in the task of understanding the mechanisms behind
these efficient synthetic procedures [14].
Palladium(0)-catalyzed coupling reactions ± i. e. the Heck and Sonogashira reac-
tions, the carbonylative coupling reactions, the Suzuki and Stille cross-coupling reac-
tions, and allylic substitutions (Fig. 11.1) ± have enabled the formation of many
kinds of carbon±carbon attachments that were previously very difficult to make.
These reactions are usually robust and occur in the presence of a wide variety of
functional groups. The reactions are, furthermore, autocatalytic (i. e. the substrate
regenerates the required oxidation state of the palladium) and a vast number of dif-
ferent ligands can be used to fine-tune the reactivity and selectivity of the reactions.
The long reaction times (ranging from hours to days) frequently required for full
conversions have, however, limited the exploitation of homogeneous catalysis in
R
Heck coupling R X +
R' R'
Sonogashira coupling R X + R' R R'
Carbonylative coupling R X + CO + Nu R CO Nu
Cross-coupling R X + R' M(R'')n R R'
X Nu
Allylic substitution + Nu
R R R R
Fig. 11.1 Examples of important palladium(0)-catalyzed transformations.
high-throughput synthesis. Rapid and reliable microwave applications are therefore

desired not only for the fast production of new chemical entities but also for homo-
geneous catalysis in general. In addition, if flash-heated metal-catalyzed reactions
can be combined with modern high-speed purification techniques the large reper-
toire of smooth transformations available will make this methodology highly attrac-
tive for the rapid creation of compound libraries [9].
11.3.1
Heck Reactions
The Heck reaction, a palladium-catalyzed vinylic substitution, is conducted with ole-

fins and organohalides or pseudohalides are frequently used as reactants [15, 16].
One of the strengths of the method is that it enables the direct monofunctionaliza-
tion of a vinylic carbon, which is difficult to achieve by other means. Numerous ele-
gant transformations based on Heck chemistry have been developed in natural and
non-natural product synthesis. Intermolecular reactions with cyclic and acyclic al-
kenes, and intramolecular cyclization procedures, have led to the assembly of a va-
riety of complex and sterically congested molecules.
Reaction temperatures of 60±120 8C are routinely used with standard catalysts and
conventional heating sources [16]. Attempts to reduce reaction times by the use of
higher temperatures are seldom effective, because the catalytic systems are often
sensitive to heat [17]. As a consequence, access to new methods that enable fast cou-
pling reactions has been highly desirable.
The Heck arylations in Eqs. (11.1)±(11.4), were reported in 1996 and constitute the
first examples of microwave-promoted, palladium-catalyzed C±C bond formations [17].
The power of the flash-heating methodology is amply illustrated by the short reaction
times and high yields of these couplings. The reactions were conducted in a single-
mode cavity in septum-sealed Pyrex vessels without temperature control. The Heck re-
action in Eq. (11.1) (and in four additional Heck coupling examples) was originally per-
formed in the absence of solvent. To enhance yields and reduce reaction times 0.5 mL
DMF was added to increase the polarity and the dielectric loss tangent of the reaction
mixture. This small modification of the original reaction conditions enabled isolation
of the products in high purity after very short reaction times (2.8±4.8 min). The same
high chemo- and regioselectivity experienced in classical, oil-bath heating was found to
apply to these microwave promoted reactions. 4-Bromostilbene was conveniently
synthesized within 4.8 min with high chemoselectivity in complete agreement with the
literature procedure if a relatively low microwave power was employed (Eq. 11.1).
Microwave promoted, palladium-catalyzed, DPPP-controlled arylation of butyl vi-
nyl ether with 4-tert-butylphenyl triflate afforded the branched arylation product and
the corresponding methyl ketone, indicating the occurrence of selective internal
a-arylation. Addition of water to the reaction mixture and microwave-heating for
2.8 min at 55 W smoothly produced the hydrolyzed product, 4-tert-butylacetophe-
none, with an isolated yield of 77 % (Eq. 11.2) [17].
Equally high terminal selectivity was achieved by application of low-power micro-
wave dielectric heating in Eq. (11.3); 87 % of the b-product was isolated. This high re-
I
Pd(OAc)2
Et3N, (DMF)
Br Br
Yield
o
∆ 17 h, 100 C 64%
MW 4.8 min, 60 W 63%
Equation 11.1 Heck-coupling of 4-bromoiodobenzene and styrene.
β
Hydrolyzed
α
O product
OTf
Pd(OAc)2, DPPP O
Et3 N, DMF/H2O
t-Bu t-Bu
Yield Selectivity
MW 2.8 min, 55 W 77% α/β = 99/1
Equation 11.2 Heck-coupling of 4-tert-butylphenyl triflate and butyl vinyl
ether in the presence of water (DPPP = 1,3-bis(diphenylphosphino)propane).
β O
α NMe2
OTf O
Pd(OAc)2, PPh3 NMe 2
Et3N, DMF
Yield Selectivity
o
∆ 9 h, 60 C 93% α/β = 1/99
MW 7 min, 35 W 87% α/β = 1/99
Equation 11.3 Chelation-controlled Heck coupling of 2-naphthyl triflate.
gioselectivity corroborates the applicability of chelation-controlled Heck reactions un-

der microwave heating conditions [17].
One exception to the preservation of selectivity in microwave reactions was the
C2 arylation of 2,3-dihydrofuran, which yielded an isomeric byproduct under the ac-
tion of microwaves (2-phenyl-2,3-dihydrofuran/byproduct = 71/29), in contrast with
the reported procedure using conventional heating (Eq. 11.4). The desired product
could be isolated in 58 % yield. Attempts to reduce the reaction time by using oil
baths (125 8C or 150 8C) did not result in similar yields, but instead furnished com-
plicated reaction mixtures, in definite contrast with the microwave procedure [17].
Regioselectivities that are usually high to excellent have been reported in novel
palladium-catalyzed Heck arylation reactions with a variety of allylic substrates. The
b-stabilizing effect of silicon enhanced regiocontrol in the internal arylation of allyl-
trimethylsilane (Eq. 11.5) [18], and coordination between palladium and nitrogen
O
I
Pd(OAc)2, PPh3 O
KOAc, Bu4NCl, DMF
Yield
o
∆ 24 h, 80 C 76%
MW 6 min, 30 W 58%
Equation 11.4 Heck-coupling of iodobenzene and 2,3-dihydrofuran.
γ
β SiMe3
OTf SiMe 3
Pd(OAc)2, DPPF
K 2CO3, CH3CN
Yield Selectivity
∆ 20 h, 80 oC 60% β/γ = 100/0
MW 5 min, 50 W (GC-MS Yield) 66% β/γ = 93/7
Equation 11.5 Internal arylation of allyltrimethylsilane (DPPF = 1,1-bis(di-
phenylphosphino)ferrocene).
γ
β NMe2
OTf NMe2
Pd(OAc)2, DPPF
K2CO3
Yield Selectivity
o
∆ 20 h, 80 C 71% β/γ = 99.5/0.5
MW 5 min, 15 W 42% β/γ = 99.5/0.5
Equation 11.6 Internal arylation of N,N-dimethylallylamine.
resulted in very high regioselectivity in the arylation of N,N-dialkylallylamines

(Eq. 11.6) [19] and the Boc-protected allylamine, producing b-arylated arylethyla-
mines (Eq. 11.7) [20]. These internal arylations can be completed in less than 10 min
under the action of single-mode microwave irradiation, compared with overnight re-
actions with conventional heating. Slightly lower selectivity and yields were, how-
ever, often obtained in the high-temperature microwave-mediated couplings com-
pared with the corresponding thermal reactions.
In the Heck reactions discussed above it was essential to use polar aprotic solvents
such as acetonitrile or DMF if high regioselectivity was to be achieved. In other Heck
couplings the use of water as a solvent has recently gained attention. The advantages
of water compared with standard organic solvents are many ± it is, for example, cheap
and nontoxic ± but its usefulness extends only over a number of well-defined applica-
tions, partly because of problems with the solubility of the reactants and catalysts. The
development of aqueous catalytic systems is, consequently, an important field [21].
γ
OMe β NHBoc OMe
OTf NHBoc
Pd(OAc)2, DPPF
K2CO3
Yield Selectivity
o
∆ 20 h, 90 C 74% β/γ = 99.5/0.5
MW 6 min, 20 W 64% β/γ = 95/5
Equation 11.7 Internal arylation of the Boc-protected allylamine.
OMe O
I
Pd(PPh 3)2Cl2, TBAB OMe
K2CO3, H2O Yield
HOOC HOOC
MW 10 min, 375 W 92%
Equation 11.8 Arylation of methyl acrylate under phase-transfer conditions.
(TBAB = tetrabutyl ammonium bromide)
In a recent report by Wang, microwave-mediated Heck couplings were rapidly per-

formed in water under phase-transfer conditions (Eq. 11.8) [22]. Villemin has also re-
ported the use of water and acetonitrile in the context of using water-soluble ligands
in microwave-assisted Heck couplings [23].
Even though the excellent internal regioselectivity reported in Eqs. (11.5)±(11.7) is
restricted to the use of aryl triflates as aryl precursors, many similar reactions can
use aryl bromides in combination with thallium salts. These salts are thought to act
as halide scavengers and can thus mimic the leaving group properties of the triflate
group by promoting abstraction of the halide [16]. Preparatively, this modification of
the Heck coupling is somewhat perilous as the thallium salts are known for their
toxicity. With this in mind, the discovery that thallium derivatives could be replaced
by the simple addition of water as a cosolvent was conceptually stimulating. Internal
arylations of butyl vinyl ether followed by acid workup, resulted in a good yield of
acetophenone after 60 min of microwave-heating at the optimized temperature of
122 8C, compared with a reaction time of 16 h with classical heating (Eq. 11.9) [24].
A perhaps more exotic substrate for the Heck reaction is 1,2-cyclohexanedione
[25]. The reactivity of this molecule under Heck coupling conditions can probably be
attributed to its resonance enol form. This reaction is attractive, because the litera-
ture contains relatively few examples of the preparation of 3-aryl-1,2-cyclohexane-
diones. Yields varied from good to modest when classic heating and electron-rich
aryl bromides were used, and reaction times typically ranged from 16 to 48 h. Simi-
lar yields were obtained under continuous microwave irradiation with a single-mode
microwave reactor for 10 min at 40±50 W (Eq. 11.10) [25].
β
α
O
1. Pd(OAc)2, DPPP Hydrolyzed
Br product
K2CO3, H2 O, DMF O
2. HCl
Yield Selectivity
∆ 16 h, 80 oC 82% α/β = 99/1
MW 60 min, 122 oC 62% α/β = 99/1
Equation 11.9 Internal arylation of butyl vinyl ether with bromo-

benzene.
O
HO O
HO
Br Pd(OAc)2, PPh3
i-Pr2EtN, H2O, DMF
Yield
∆ 16 h, 100 oC 66%
MW 10 min, 40 W 69%
Equation 11.10 Arylation of the enol form of 1,2-cyclohexanedione.
O
EtO O
EtO
Br Pd(OAc)2, PPh3
i-Pr2EtN, H2O, DMF
Yield
o
∆ 16 h, 100 C 83%
MW 12 min, 40 W 57%
Equation 11.11 Arylation of the ethyl vinyl ether of 1,2-cyclo-
hexanedione.
Traditional Heck arylation of the corresponding ethyl vinyl ether afforded high yields
with most of the aryl bromides investigated (Eq. 11.11). Under continuous single-
mode microwave treatment the transformations were complete within 10±12 min [25].
Heck reactions without solvent in a domestic microwave oven have been examined
by DÌaz-Ortiz [26]. The reactions were conducted in closed vessels with reported tem-
peratures of 150 8C. A study was performed in which reactions performed with mi-
crowave irradiation were compared with oil-bath-heated reactions with identical reac-
tion times and temperatures. The isolated yields tended to substantially favor the mi-
crowave-heated reactions (Eq. 11.12).
Ph
N Ph
N N
N
Br
Pd(OAc)2, P(o-tol)3
Et3N
Yield
o
∆ 22 min, 160 C 39%
MW 22 min, 450 W 78%
Equation 11.12 Heck reaction with phenyl bromide.
O α
O O
β
Pd(OAc)2, DPPP
Et3N, DMSO
O
TfO
Yield Selectivity
o
∆ 6 h, 60 C 79% α/β = 99/1
MW 5 min, 5 W 64% α/β = 99/1
Equation 11.13 Internal vinylation of butyl vinyl ether with a vinyl triflate.
O
α
O β O
HO
Pd(OAc)2, DPPP
Et3N, DMSO
O
TfO O
Yield Selectivity
o
∆ 20 h, 40 C 59% α/β = 99/1
MW 7 min, 5 W 53% α/β = 99/1
Equation 11.14 Internal vinylation of 2-hydroxyethyl vinyl ether with a vinyl triflate.
A challenge of a different kind was encountered in the internal vinylation of var-

ious vinyl triflates and bromides as depicted in Eq. (11.13) [27]. The electron-rich
structures obtained from the reactions were of interest for further use in Diels±Alder
reactions, but the risk of degrading the products in the hot reaction medium posed a
problem and a prudent choice of energy input was imperative. It turned out that sin-
gle-mode microwave heating for 5 min at the very low power of 5 W was sufficient to
yield 64 % of the product with excellent regioselectivity. Measurements with a fluor-
optic probe revealed an unexpectedly high temperature of 76 8C [27].
230 25 W x 5 min
20 W x 7 min
200
170
T/ oC
140 10 W x 5 min
110
80
50
5 W x 5 min
20
0 1 2 3 4 5 6 7 8 9
t/min
Fig. 11.2 Selected temperature profiles for the DMSO at different power inputs (fluoroptic ther-
single-mode heating of internal vinylations in mometer, Smith prototype).
Exchange of the butyl vinyl ether for 2-hydroxyethyl vinyl ether enabled the facile
transformation of vinyl triflates or bromides into protected a,b-unsaturated methyl
ketones (Eq. 11.14) [27]. One interesting aspect of this reaction is that a masked
methyl ketone can easily be introduced into a structure even in the presence of other
free ketone groups.
Selected temperature profiles for the reactions represented in Eqs (11.13) and
(11.14) are shown in Fig. 11.2. Note that the high tan d value of DMSO (0.825) [5]
results in extensive heating even at a relatively modest power input of single-mode
irradiation.
11.3.2
Carbonylative Couplings
The palladium-catalyzed Heck carbonylation reaction is a powerful means of gener-

ating amides, esters, and carboxylic acids from aryl halides or pseudohalides [28].
The development of rapid, reliable, and convenient procedures for the introduction
of carbonyl groups is important for the development of high throughput chemistry
in general and high-speed microwave-mediated chemistry in particular. Unfortu-
nately, the traditional method of introducing carbon monoxide into a reaction mix-
ture via a balloon or gas tube is not practical because of the special requirements of
microwave synthesis.
The molybdenum hexacarbonyl complex was recently introduced as a condensed
source of carbon monoxide for Heck carbonylations [29]. This easily handled and in-
expensive solid delivers a fixed amount of carbon monoxide when heated to approxi-
O
Br
BINAP/Herrmann's catalyst N Bu
O + n-BuNH2 O H
Mo(CO)6, K2CO 3 (aq), Diglyme
Yield
o
MW 15 min, 150 C 79%
Equation 11.15 Carbonylative coupling with molybdenum hexacarbonyl.
O
I Pd/(C), Mo(CO) 6, K2CO 3 (aq) OH
Diglyme/Ethylene glycol
Me Me Yield
o
MW 15 min, 150 C 87%
Equation 11.16 Carbonylative synthesis of benzoic acid in the presence

of ethylene glycol.
mately 150 8C. This enables the in situ generation of carbon monoxide directly in the
reaction mixture, without the need for external devices.
A variety of amides has been formed in moderate to high yields with aryl bromides
or iodides as aryl precursors and single-mode microwave heating for 15 min at
150 8C (Eq. 11.15) [29]. Under these conditions, aliphatic, unhindered primary, and
secondary amines reacted readily, whereas sterically hindered amines or amines of
low nucleophilicity, e. g. anilines, afforded low yields and incomplete conversions.
Among the homogeneous catalytic systems tested the most suitable for the use with
aryl bromides was a 2 : 1 mixture of BINAP and Herrmann's palladacycle.
Addition of ethylene glycol as cosolvent, as in Eq. (11.16), resulted in efficient for-
mation of the corresponding benzoic acid, instead of the amide [29].
11.3.3
Sonogashira Coupling Reactions
The palladium-catalyzed Sonogashira coupling enjoys considerable popularity as a

reliable and general method for the preparation of unsymmetrical acetylenes [30]. Er-
dlyi and Gogoll recently highlighted the potential of controlled microwave heating
to promote homogeneous Sonogashira couplings under single-mode reaction condi-
tions [31]. Problems with thermal runaway effects had been reported after previous
attempts to execute similar reactions with microwaves, a difficulty that seemingly
could be dealt with more easily with a single-mode apparatus with temperature con-
trol. An illustration is shown in Eq. (11.17), where 4-cyanophenyl triflate was com-
pletely consumed after only 5 min of irradiation. Several different examples of reac-
tions with aryl halides were also reported.
Wang also reported efficient Sonogashira-type reactions in DMF (Eq. 11.18) [32].
Interestingly, the generally most efficient palladium catalysts did not have to be
SiMe3
OTf
Pd(PPh 3)2Cl2, CuI
+ H SiMe3
NC Et2NH, DMF, LiCl NMR Yield
NC
o
MW 5 min, 120 C 99%
Equation 11.17 Sonogashira coupling of 4-cyanophenyl triflate.
CuI, PPh3, K2 CO 3 OH
I + H
OH DMF Yield
MW 10 min, 375 W 80%
Equation 11.18 Sonogashira coupling of allyl iodide.
O O
Cl CuI, Et3 N
+ Ph
Ph
Br Br Yield
MW 10 min, 525 W 93%
Equation 11.19 Synthesis of conjugated acetylenic ketones with CuI-catalysis.
used, because the cheaper CuI could be employed with reasonable yields. The cop-
per-catalyzed aroylation reactions were performed in triethylamine and in the ab-
sence of any added solvent (Eq. 11.19) [33]
11.3.4
Cross-coupling Reactions
A cross-coupling can be described as a transition metal-catalyzed reaction of a nucleo-

philic organometallic reagent with an organic halide or pseudohalide, leading to a new
carbon±carbon s-bond and a metal halide. The most preparatively useful reagents in-
clude organoboron, organotin, and organozinc compounds. An attractive feature of
many cross-coupling reactions is that the most commonly used functional groups, in
either or both of the coupling partners, are unreactive under the reaction conditions
used, which means that the use of protection groups is often unnecessary. Organo-
boron and organotin reactants have the benefit of being comparatively stable to air
and moisture and organoboron compounds have the added advantage of low toxicity.
11.3.4.1 Suzuki Couplings

Organoboron compounds were first thought to be poor coupling partners in cross-
coupling reactions, because the organic groups on boron are only weakly nucleophi-
lic. Suzuki, however, discovered that coupling reactions of organoboron compounds
proceeded in the presence of ordinary bases such as hydroxide or alkoxide ions [34].
This modification proved generally applicable and the Suzuki reaction is arguably
the most versatile of modern cross-coupling reactions. The reaction has, for example,
attracted the interest of groups involved in high-throughput chemistry, because a
large variety of boronic acids are commercially available.
The first microwave-promoted Suzuki couplings were reported in 1996 (Eq. 11.20)
[17]. Phenyl boronic acid was coupled with 4-bromotoluene to give a fair yield of pro-
duct after a reaction time of less than 3 min under single-mode irradiation. The
same reaction had previously been conducted with a reported reaction time of 4 h.
Equation (11.21) is an example of a single-mode microwave-promoted Suzuki cou-
pling, delivering a cyclic HIV-protease inhibitor after a subsequent hydrolysis of the
ketal group [35]. Half a dozen compounds were synthesized with the help of micro-
waves and some of the compounds had Ki values in the nanomolar range.
Interestingly, the Suzuki reaction worked smoothly on solid supports and high
yields of a variety of products were reported under these reaction conditions
(Eq. 11.22) [36]. 4-Bromo- and 4-iodobenzoic acid linked to Rink-amide TentaGel re-
Br
Pd(PPh 3)4, EtOH
+
DME, H2O Yield
Me (HO)2B
Me 55%
MW 2.8 min, 55 W
Equation 11.20 Suzuki coupling of phenyl boronic acid with 4-bromotoluene.
Br S S
Br
S B(OH)2
O O O O
S S
N N N N
PhO OPh Pd(PPh3 )4 PhO OPh
Yield
O O O O
MW 4 min, 45 W 48%
Equation 11.21 Double Suzuki coupling generating a precursor to an HIV-protease inhibitor.
(HO)2B
N
SO2Ph
1. Pd(PPh 3)4, Na2CO3 (aq)
H EtOH, DME
RAM N H2N
MW 3.8 min, 45 W
Br
O 2. TFA N
O SO2Ph
Yield
88%
Equation 11.22 Suzuki coupling on a solid support.
O
S Pd(OAc)2 , K2CO3
O Br +
PEG
H2O
(HO)2B OMe MW 2 min, 75 W
O
S
PEG O
OMe
Equation 11.23 PEG-supported, aqueous Suzuki coupling.
Me
I Me
PEG-400, PdCl2, KF
+
OH (HO)2B Yield
MW 50 s, 240 W OH 79%
Equation 11.24 Suzuki coupling in PEG as a nontoxic reaction medium.
sulted in more than 99 % conversion of the starting material, and the whole reaction
was brought to completion within 4 min. The high yields suggest the high potential
of the use of microwave-assisted reactions on polymer supports [37].
Another interesting report by Kænig deals with rapid parallel Suzuki reactions in
water with phase-transfer catalysts [38]. The polymeric support used in these reac-
tions was PEG and a variety of aryl-palladium precursors was evaluated (halides, tri-
flates, and nonaflates, Eq. 11.23). The soluble polymer-supported liquid phase strat-
egy with PEG is appealing because, apart from facilitating the purification proce-
dure, PEG also helps solubilize the reagents and it has been suggested that PEG sta-
bilizes the palladium catalyst in the absence of phosphine ligands. The reactions ty-
pically reached full conversion in only 2 min of 75 W heating in a multimode oven,
whereas the parallel reactions needed 4 min to reach completion. The standard heat-
ing techniques required 2 h for the same reactions. The polymers and the esters
were both reported to withstand 10 min of 900 W microwave heating whereas con-
ventional thermal conditions induced substantial (up to 45 %) ester cleavage [38].
Similar Suzuki couplings performed with PEG as a nontoxic reaction medium
have been reported by Varma (Eq. 11.24) [39]. A domestic microwave oven with inver-
ter technology was used for these experiments and it was suggested that this technol-
ogy enabled more realistic control of the microwave power input.
Villemin has reported the use of sodium tetraphenylborate as a stable reactant for
Suzuki couplings performed in water or N-methylformamide (NMF) as solvents
(Eq. 11.25) [40].
A series of potent, linear C2-symmetric HIV-1 protease inhibitors with Ki values in
the nanomolar range was prepared from a diaryl bromide precursor emanating from
a carbohydrate scaffold, by application of Heck, Suzuki, Stille, and cyanation reac-
tions. Included in this series was the first reported microwave-promoted Suzuki
coupling with an alkyl borane [41]. A very high-yielding Suzuki coupling is presented
O O
I
HN Pd(OAc)2, Na2CO3 HN
NaBPh4, CH3NHCHO
O N O N Yield
H H
MW 8 min, 100 W 70%
Equation 11.25 Suzuki coupling with sodium tetraphenylborate.
Br
S
(HO)2B
H O OH O H O
Pd(PPh3)4 , Na2CO3
N N S
N N DME, EtOH, H 2O
O H O OH O H MW 4 min, 45 W
H O OH O H O
Br N N
N N
O H O OH O H
Yield
96%
S
Equation 11.26 Synthesis of a linear HIV-protease inhibitor by a double Suzuki coupling.
in Eq. (11.26) and demonstrates that even relatively complex structures, such as these
peptidomimetics, do not decompose or are in any other way unsuitable for applica-
tions with flash heating chemistry. These syntheses of HIV-protease inhibitors were
reported to be the first examples in medicinal chemistry of the application of homo-
geneous palladium-catalyzed reactions conducted with flash heating [41].
11.3.4.2 Stille Couplings

The defining feature of the Stille cross-coupling reaction (or the Migita±Kosugi±
Stille coupling) is the use of an organotin moiety in combination with palladium cat-
alysts [42]. This reaction is, in the same way as the Suzuki reaction, very reliable,
high yielding, and tolerant of many functionalities. The main drawback is the mod-
est reactivity of the organotin reactants, but this limitation can often be overcome by
judicious choice of experimental conditions. The nonreacting ligands are usually
methyl or butyl, although newer dummy ligands have been proposed. Typically, the
transferable fourth ligand on tin is an unsaturated moiety. The group transfer order
is believed to be alkynyl > vinyl > aryl > alkyl.
The Stille reaction was one of the earliest transition-metal-catalyzed reactions to
be reported with microwave-heating, and single-mode irradiation with very short re-
action times was easily applied to Stille reactions in solution (Eq. 11.27) [17] and on
polymer supports (Eq. 11.28) [36].
We [43] and, more recently, Maleczka [44] have reported one-pot microwave-as-
sisted hydrostannylations and Stille coupling sequences. Eq. (11.29) depicts one of
Maleczka's reactions (see also Eq. 11.32).
Some of the disadvantages of the Stille reaction, e. g. the low reactivity of some sub-
strates, separation difficulties in chromatography, and the toxicity of tin compounds,
have been ameliorated by recent efforts to improve the procedure. Curran has, in a ser-
ies of papers, reported the development of the concept of fluorous chemistry, in which
the special solubility properties of perfluorinated or partly fluorinated reagents and
solvents are put to good use [45]. In short, fluorinated solvents are well known for their
insolubility in standard organic solvents or water. If a compound contains a sufficient
number of fluorine atoms it will partition to the fluorous phase, if such a phase is pre-
sent. An extraction procedure would thus give rise to a three-phase solution enabling
ready separation of fluorinated from nonfluorinated compounds.
Among the many applications of fluorous chemistry is the Stille coupling of tin re-
agents with fluorinated tags in which the products and excess of the tin-containing
reagents can be conveniently removed from the reaction mixture, and recycled. Un-
OTf
Pd2dba3, Ph3As
+
O LiCl, NMP
Bu 3Sn O Yield
∆ 70 h, rt 82%
MW 2.8 min, 50 W 68%
Equation 11.27 Stille coupling in solution with 4-acetylphenyl triflate.
Bu 3Sn
H 1. Pd 2dba3, Ph3As
RAM N MW 3.8 min, 40 W H 2N
I
O 2. TFA O
Yield
85%
Equation 11.28 Stille coupling utilizing a RAM-linker on a polymer support.
1.SnBu3Cl, KF (aq), PMHS

TBAF, Pd(PPh3)4,THF
t-Bu
MW 3 min, 140 W
H t-Bu
2. PhCH=CHBr, Pd(PPh3)4 Yield
MW 10 min, 140 W
91%
Equation 11.29 One-pot hydrostannylation and Stille coupling
(PMHS = polymethylhydrosiloxane).
O
OTf O PdCl2(PPh3)2
+ Sn(CH2CH2 C6F13)3
O LiCl, DMF O
OMe OMe Yield

MW 2 min, 60 W 63%
Equation 11.30 Stille reaction with the F-13-tagged furyltin reagent.
OTf PdCl2 (PPh 3)2

+
O LiCl, DMF O
Sn(CH2CH2C10F21)3 Yield
MW 6 min, 50 W 71%
Equation 11.31 Stille reaction with the F-21-tagged phenyltin reagent.
fortunately, fluorous Stille reactions require long reaction times, typically one day at
80 8C and the solubilities of fluorous compounds in most of the common solvents
used in synthesis are low, which limits the scope of the procedure.
The long reaction times under the action of classic heating were reduced to only a
few minutes with single-mode heating at a power of 50±70 W. One example of the
use of CH2CH2C6F13 (denoted F-13) -tagged organostannanes is presented in
Eq. (11.30) [46].
Occasionally it was apparent that the fluoricity provided with the F-13 tags was not
sufficient to enable full partitioning of the products to the fluorous phase. The use
of more heavily fluorinated tags, e. g. the ±CH2CH2C10F21 (F-21) tag, was investi-
gated, but proved to be preparatively elusive, because the solubility of these com-
pounds was very poor. Heating the reactions to 80 8C in fluorinated solvents resulted
in very sluggish and irreproducible reactions. The use of single-mode heating en-
abled rapid and efficient reactions (Eq. 11.31) [43]. Superheating of the solvent made
solution of the reactants possible and a one-phase system was generated by the heat-
ing procedure. On cooling, the fluorous reagents and products separated from the
mixture again and separation of fluorous from nonfluorous compounds ensued
without complications. The use of highly fluorinated tags could be said to combine
the attractive features of both solid- and liquid phase chemistry, because the ease of
separation is reminiscent of the former and the versatility and reactivity of the
soluble reagents is typical of the latter.
The fluorous Stille procedure has also been applied to a one-pot hydrostannylation
of an acetylenic compound in the hybrid fluorous/organic solvent benzotrifluoride
(BTF). Subsequent Stille coupling of the product in BTF/DMF, as shown in Eq. (11.32),
was easily achieved in 8 min with 60 W single-mode microwave irradiation [43].
To take advantage of the fluorous extraction procedure, or the use of the prepara-
tively simple filtration, the use of highly fluorous reagents is crucial. The usefulness
of the microwave heating technique is obvious in these examples.
1. AIBN, BTF O
O O Ph OEt
MW 10 min, 60 W
+ HSn(CH2CH2C10F21)3
EtO OEt 2. PhI, Pd(OAc)2, CuO
EtO E/Z = 5:1
DMF/BTF
O
MW 8 min, 60 W Yield
44%
Equation 11.32 One-pot hydrostannylation and Stille reaction with
F-21-tagged reagents.
The first examples of microwave-assisted cross-couplings with organozinc com-

pounds were recently reported [47]. In addition, the first high-speed synthesis of aryl
boronates (Suzuki coupling reactants) has been performed under the action of sin-
gle-mode irradiation with an in-situ-generated palladium carbene catalyst [48].
11.3.5
Other Palladium-catalyzed Reactions
The synthesis of nitriles from halides is valuable in medicinal chemistry because nitriles
are flexible building blocks readily converted into carboxylic acids, amides, amines, or a
variety of heterocycles, e. g. thiazoles, oxazolidones, triazoles, and tetrazoles. The impor-
tance of the tetrazole group in medicinal chemistry is easily understood if we consider
that it is the most commonly used bioisostere of the carboxyl group.
An improvement of the palladium-catalyzed cyanation of aryl bromides, in which
zinc cyanide was used as the cyanide source, was reported in the middle of the nine-
ties [49]. Typically, the conversion from halide to nitrile takes at least 5 h by this route
and the subsequent cycloaddition to the tetrazole is known to require even longer re-
action times.
A single-mode microwave procedure has been reported for the palladium-cata-
lyzed preparation of both aryl and vinyl nitriles from the corresponding bromides.
The reaction times were short and full conversions were achieved in just a few min-
utes (Eq. 11.33) [50]. The cycloadditions to yield the tetrazoles needed slightly longer
reaction times, from 10 to 25 min, but only 20 W of power was required as a tem-
perature of 220 8C was reached after 10 min heating. The yields in this step ranged
from 36 % to 96 %. This method for transforming halides into tetrazoles has been
used for the synthesis of a novel HIV-protease inhibitor [50].
The coupling and cycloaddition could also be achieved as a one-pot procedure on a
polymer support, as shown in Eq. (11.34), in which a Rink linker on TentaGel was
used. Negligible decomposition of the solid support was reported [50].
Br Zn(CN)2, Pd(PPh3)4 CN
DMF
N N Yield
Equation 11.33 Palladium-cata-
o
lyzed conversion of aryl bromides ∆ 4 h, 97 C 71%
into aryl nitriles. MW 2 min, 60 W 88%
H 1. Zn(CN)2, Pd(PPh3 )4, DMF H

N MW 2 min, 60 W H2N N N
I
O 2. NaN3, NH4Cl, DMF O N N
MW 15 min, 20 W Yield
3. TFA, H2O
72%
Equation 11.34 One-pot procedure for tetrazole synthesis on a polymer support.
O O O
I O P(OEt) 2
MeO PdCl2(PPh3) 2, HSiEt3 MeO
+ HP(OEt)2
Et 3N, Toluene Yield
MW 9 min, 490 W 80%

Equation 11.35 Conversion of aryl iodides into aryl phosphonates.
OMe
OMe OMe OMe
I
PdCl2(PPh3)2, NaOAc
DMA
OMe OMe O OMe OMe O Yield

∆ 18 h, 130 oC 29%
MW 60 s, 450 W 53%
Equation 11.36 Intramolecular ring-closure to kinafluorenones.
The conversion of aryl iodides into aryl phosphonates, a useful precursor to aryl
phosphonic acids, was performed in a Teflon autoclave by Villemin [51]. A domestic
microwave oven was used for these experiments and the reaction times for classic
heating were effectively reduced from 10 h to 4±22 min. The reactivity of iodides
was good whereas the use of bromides resulted in lower yields and reactions with tri-
flates were very slow (Eq. 11.35). It is notable that the reactions were brought to com-
pletion with short reaction times in a non-polar solvent.
The synthesis of kinafluorenones, which are of interest for the synthesis of Strepto-
myces-related antibiotics, has been investigated by Jones [52]. The palladium-
mediated ring closure depicted in Eq. (11.36) resulted in poor yields under conven-
tional heating but irradiation with a domestic microwave oven for 60 s improved the
yield substantially.
11.3.6
Asymmetric Catalysis
Palladium-catalyzed allylic substitution reactions are popular in the chemical com-

munity and the number of applications of the reaction, perhaps in particular for
asymmetric procedures, continues to grow [53]. The efficiency of asymmetric chem-
istry is best described in terms of the enantiomeric excess (ee) of the reaction, and it
has been shown that microwave heating can dramatically reduce the reaction times
in asymmetric catalysis without significantly affecting ee values [54].
This particular field of palladium chemistry has been responsible for attempts to
develop temperature-stable catalyst systems, sometimes with very fascinating re-
sults. The high temperatures of microwave synthesis can be a double-edged sword ±
the high temperatures result in high reaction rates but also increase the risk of cata-
lyst breakdown. It is often the metal ligands that are temperature sensitive, and be-
cause these ligands induce the asymmetry in the reactions, catalyst breakdown is as-
sociated with loss of ee. The development of temperature-stable ligands for asym-
metric reactions has thus been of great importance.
A highly thermostable palladium±phosphine oxazoline catalytic system, shown in
Eq. (11.37), has recently been reported to yield high ee under single-mode micro-
wave irradiation [54, 55]. The use of this P,N-ligand catalytic system resulted in even
higher ee than the P,P-ligand BINAP [56]. The reactions were performed in acetoni-
trile (b.p. 81±82 8C) and superheating increased the temperatures up to 145 8C, as
measured by means of a fluoroptic probe.
The palladium-catalyzed substitution of the less reactive racemic ethyl 3-cyclohexe-
nyl carbonate could, in a similar fashion, be completed with dimethyl malonate,
p-methoxyphenol, or phthalimide as nucleophiles, with satisfactory ee (Eq. 11.38)
[55]. These reactions, when irradiated for 1 min with temperatures up to 100 8C, de-
livered yields (91±96 %) and ee values (94±95 %) identical with those performed in
O O O
OAc Ph2 P N MeO OMe
(Pd(η3-C3H5)µ-Cl)2
Dimethyl malonate
BSA, CH3CN HPLC Yield ee
MW 30 s, 120 W
98% >99%
Equation 11.37 Asymmetric palladium-catalyzed allylic alkylation
(BSA = N,O-bis(trimethylsilyl)acetamide).
O O
NH HN
PPh2 PPh 2 OMe
OMe
O OEt + O
HO (Pd(η3-C3H5)µ-Cl)2
O Yield ee
MW 1 min, 120 W 96% 95%
Equation 11.38 Asymmetric substitution of racemic ethyl-3-cyclohexenyl carbonate.

closed vessels in an oil bath at 100 8C for 5 min. A related experiment, conducted in
acetonitrile with phthalimide as nucleophile in which the temperature was increased
to 140 8C, resulted in much higher yields when microwave heating was used,
although the enantiomeric excesses remained the same (95±96 %) [55].
The molybdenum-catalyzed asymmetric reaction differs from the palladium-cata-
lyzed reaction in several ways, the most important of which is the different regios-
electivity achieved. Molybdenum-catalyzed reactions favor the most sterically hin-
dered position (Eq. 11.39), in contrast with palladium catalysis. The molybdenum-
catalyzed allylations also suffer from significantly lower reactivity.
It was found by Trost that the low reactivity could be circumvented by the employ-
ment of labile ligands, such as the propionitrile in the Mo(CO)3(EtCN)3 precatalyst
[57]. Instead of directly transferring this procedure to microwave heating applica-
tions, a useful and easily handled microwave procedure was developed for rapid and
selective molybdenum-catalyzed allylic alkylations under noninert conditions
(Eq. 11.39) [12]. The former, more sensitive, two-step reaction was fine-tuned into a
robust one-step procedure employing the inexpensive and stable precatalyst
Mo(CO)6, used in low concentrations. The alkylations were conducted in air and re-
sulted in complete conversions, high yields, and an impressive enantiomeric excess
(98 %) in only 5±6 min. Despite the daunting temperatures, up to 250 8C with THF
O O
NH HN O O
O N N MeO OMe
O OMe
Mo(CO)6 , THF, BSA
Dimethyl malonate Yield ee
MW 5 min, 250 W 87% 98%
Equation 11.39 Asymmetric molybdenum-catalyzed allylic alkylation.
O O
NH HN O O
O N N MeO OMe
O OMe MeO OMe

Mo(CO)6 , THF, BSA
Dimethyl malonate Yield ee
MW 4 min, 200 W 88% >99%

Equation 11.40 Asymmetric molybdenum-catalyzed allylic alkylation
with an optimized ligand.
as solvent (b.p. 65±67 8C), the high enantiomeric purity remained constant, which
suggests that the coordination of the ligand to the metal is not broken, despite of
these stressing reaction conditions [12].
After preparation of several different chiral trans-1,2-bis-(2-carboxyamidopyridine)
cyclohexane ligands, a 4-methoxypyridine derivative (Eq. 11.40) was discovered to
have superior qualities and to deliver a high yield (88 %) of the branched product
with >99 % ee and a regioisomer ratio of 41 : 1 (alkylation at the most, rather than
least, substituted position) [58]. Single-mode microwave irradiation was applied at
the very high power of 200 W for 4 min and superheating caused THF to reach tem-
peratures of 150±180 8C.
11.3.7
Other Metal-catalyzed Reactions
The copper-catalyzed hydrosilylation of 2-vinylpyridine is reported to be a very dirty

reaction associated with low yields and a tedious workup procedure. As early as 1991
Abramovitch used well-defined heating cycles of microwave irradiation to improve
this reaction and reported a 360-fold decrease in reaction time and a considerable
improvement in yield (Eq. 11.41) [59].
Shortly thereafter Hjek investigated the related CuCl/2-propylamine-catalyzed
addition of tetrachloromethane or ethyltrichloroacetate to styrene (Eq. 11.42) and re-
ported a more modest increase in the reaction rate [60]. The reactions were per-
formed under both microwave and classic heating conditions, and the temperatures
in the samples were measured by a quick-response digital thermometer.
Gordon used a household microwave oven for the transfer hydrogenation of benz-
aldehyde with (carbonyl)-chlorohydridotris-(triphenylphosphine)ruthenium(II) as
catalyst and formic acid as hydrogen donor (Eq. 11.43) [61]. An improvement in the
average catalytic activity from 280 to 6700 turnovers h±1 was achieved when the tradi-
tional reflux conditions were replaced by microwave heating.
More recently a Ru-catalyzed hydrogen transfer of acetophenone under microwave
conditions with monotosylated (S,S)-diphenylethylenamine as a chiral source, has
SiMeCl2
MeSiCl2H, CuCl
N TMEDA N
MW 6 x 30 s, 750 W
Equation 11.41 Hydrosilylation of 2-vinylpyridine.
Cl O
O CCl2COEt
Cu(2-propylamine)2Cl2
+ CCl3COEt
CH3CN
MW 600 W
Equation 11.42 Addition of ethyltrichloroacetate to styrene.
O
O
H RuHCl(CO)(PPh3 )3 OH
+
H OH MW
Equation 11.43 Transfer hydrogenation of benzaldehyde with ruthenium catalysis.
afforded (R)-1-phenylethanol in over 90 % yield and 82 % ee within 9 min [62]. t-Butyl

phenyl ketone was reduced in almost quantitative yield, although with low ee. Micro-
wave-assisted hydrogenation of electron-deficient alkenes with Wilkinson's catalyst
and a polymer-supported hydrogen donor has also been described [63].
Combs recently reported the first examples of a microwave induced copper-cata-
lyzed aryl-heteroaryl C±N coupling reaction in which libraries of N-arylated hetero-
cycles were produced for biological screening [64]. An aryl boronic acid was used as
a coupling partner and the heterocyclic carboxylic acids were coupled to a PS±PEG
resin via a PAL-linker. The yields of the reactions were poor at 80 8C for 48 h with
conventional heating. The heating time was reduced to 5 min with a domestic, 1000-
W oven at full power after five cycles of 3 × 10 s of irradiation, with manual agitation
and addition of fresh reagents between each interval (Eq. 11.44). The reactions
worked equally well with a polystyrene resin.
Aziridines comprise a useful group of organic compounds. Chanda and Bedekar
reported the microwave-assisted synthesis of aziridines from a variety of olefins with
the reagent Bromamine-T (TsN±NaBr). The reaction was catalyzed by metal halides
and CuCl2 and CuBr2 were found to give the best yields among the compounds
tested (Eq. 11.45) [65]. Microwave heating was reported to increase the reactivity of
compounds not reactive under classic heating conditions, although the reported
yields were modest.
O
1. Cu(OAc)2
N (HO)2B O N
N Molecular sieves
+
H N Pyridine/NMP H2N N
H MW 3 x 10 s, 1000 W
2. TFA:CH 2Cl2 Yield
56%
1:1 mixture
of isomers
Equation 11.44 Solid support aryl/heteroaryl C±N coupling reactions.
Ts
N
O Br CuBr2, CH3CN
+ S N
Na Yield
O
MW 12 min 88%
Equation 11.45 Transition metal-catalyzed aziridation of olefins.
References 401
11.4
Summary
The development in microwave chemistry has been remarkable during the last few
years; from the first reports in which, typically, domestic ovens were used to modern
applications with state-of-the-art single-mode cavities. We believe that it is today pos-
sible today to develop robust microwave-assisted methods for nearly any reaction
that needs an external heat source and we have proved it is possible to perform tran-
sition-metal catalyzed reactions very cleanly and selectively.
Heating by means of single-mode microwave irradiation enables readily adjustable
and controlled bulk heating which can be performed safely and with very low energy
consumption. The synthetic chemist of today can take advantage of the unique car-
bon±carbon bond formation reactions afforded by organometallic chemistry and
make the reaction happen in seconds or minutes, an important feat, because many
transition-metal-catalyzed reactions are time-consuming.
The examples presented indicate that the combined approach of microwave heat-
ing and homogeneous catalysis can be an almost synergistic strategy, in the sense
that the combination in itself has more potential than its two separate parts in isola-
tion. There are, furthermore, still many other catalytic reactions with great potential
for microwave heating [66]. It might, for example, be expected that increasing num-
bers of aqueous biocatalytic reactions might respond well to microwave heating. It is
already clear that modern automatic microwave synthesizers have much to offer in
the high-speed generation of combinatorial libraries.
Acknowledgment
We thank the Swedish Natural Science Research Council, the Swedish Foundation
for Strategic Research, Knut and Alice Wallenberg's Foundation, PersonalChemistry
AB, Medivir AB and Gunnar Wikman.
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12
Microwave-Assisted Combinatorial Chemistry
C. Oliver Kappe and Alexander Stadler
12.1
Introduction
Combinatorial chemistry, the art and science of synthesizing and testing compounds
for bioactivity en masse, has emerged as one of the most promising approaches to drug
discovery [1±5]. Because of the enormous progress made in genomic sciences, molecu-
lar biology, and biochemistry, a large number of biologically important target proteins
has now become available for screening purposes. This has led to an ever-growing de-
mand for large libraries of novel compounds that are being evaluated for their biological
properties by use of appropriate screening procedures. The discovery of novel biological
targets was paralleled by the development of novel assays and high-throughput screen-
ing (HTS) technologies including miniaturized formats, enabling the testing of thou-
sands of individual compounds per day. Traditional methods of organic synthesis are or-
ders of magnitude too slow to satisfy the increasing demand for these compounds.
Combinatorial chemistry officially dates back to the mid-1980s and since then has
experienced enormous growth and has steadily attracted the interest of researchers
from a variety of different fields. The essence of combinatorial synthesis is the ability
to generate large numbers of chemical compounds very quickly [1±5]. Chemistry in
the past has been characterized by slow, steady, and painstaking work; combinatorial
chemistry has broken many of the preconceptions and resulted in a level of chemical
productivity thought impossible a few years ago. In the past chemists made one com-
pound at a time, in one reaction at a time. For example, compound A would have
been reacted with compound B to give product AB, which would have been isolated
after reaction, workup, and purification by chromatography. In contrast with this ap-
proach combinatorial chemistry offers the potential to make every combination of
compound A1 to An with compound B1 to Bn (Fig. 12.1). The range of combinatorial
techniques is highly diverse and the products could be made individually in a parallel
fashion or in mixtures, by use of either solution or solid-phase techniques [1±6].
Parallel to these developments in combinatorial chemistry, microwave-enhanced
organic synthesis has attracted a substantial amount of attention in recent years. As
evidenced from the other chapters in this book and the large number of review arti-
cles available on this subject [7±14], high-speed microwave-assisted synthesis has

ISBN: 3-527-30514-9
406 12 Microwave-assisted Combinatorial Chemistry
A1 B1
A2 B2
A3 B3
A4 B4 A1-nB1-n
A+B AB
. .
. .
An Bn
(A) (B)
Fig. 12.1 (A) In a conventional synth- ferent building blocks of type A1 ±An are
esis, one starting material A reacts with treated with different building blocks of
one reagent B resulting in one product type B1±n according to combinatorial
AB. (B). In a combinatorial synthesis, dif- principles.
been applied successfully in many fields of synthetic organic chemistry. It is, in fact,
becoming evident that microwave approaches can probably be developed for most
chemical transformations requiring heat, and/or for processes in which small polar
molecules are removed from a chemical equilibrium. Although different hypotheses
have been proposed to account for the rate-enhancements observed under micro-
wave irradiation, a generally accepted rationalization remains elusive (Chapt. 3) [13,
14]. Irrespective of the origin and/or existence of a special microwave effect, rapid
microwave dielectric heating (microwave flash heating) is extremely efficient and ap-
plicable to a broad range of practical synthesis [7±12].
The main benefits of performing reactions under microwave irradiation condi-
tions are the significant rate-enhancements and the higher product yields that can
frequently be observed. Not surprisingly, these features have recently also attracted
interest from the combinatorial and/or medicinal chemistry community, for whom
reaction speed is of great importance [15±18]. Combination of microwave heating
technology and combinatorial chemistry applications is, therefore, a logical conse-
quence of the increased speed and effectiveness afforded by microwave heating. In
that respect, all chemical transformations that can be speeded up by microwave irra-
diation should, by definition, be of interest to practitioners in the field of combinator-
ial and medicinal chemistry [15±18].
This attractive linking of combinatorial processing with microwave heating was re-
cognized in a 1995 summary of microwave-assisted organic reactions [8]. This review
is limited to microwave-assisted processes and techniques that are of direct relevance
to combinatorial chemistry applications, including solid-phase organic synthesis, the
use of polymer-bound scavengers or reagents, synthesis on soluble polymer sup-
ports, fluorous phase techniques, parallel synthesis, and the construction of libraries
in automated format by use of microwave technology. Because some of these applica-
tions require specialized equipment, a section will be devoted to microwave reactor
technology for high-throughput synthesis. In many of the examples of microwave
chemistry presented in this review we mention reported ªrate-enhancementsº in the
microwave-heated reactions compared with conventional heating. The reader should
be aware that such comparisons are inherently troublesome (Chapt. 3) [13, 14] and
do not a priori imply the existence of nonthermal or specific microwave effects.
12.2
Solid-Phase Organic Synthesis
One of the cornerstones of combinatorial synthesis has been the development of so-
lid-phase organic synthesis (SPOS) based on the original Merrifield method for pep-
tide preparation [19]. Because transformations on insoluble polymer supports should
enable chemical reactions to be driven to completion and enable simple product pur-
ification by filtration, combinatorial chemistry has been primarily performed by
SPOS [19±23]. Nonetheless, solid-phase synthesis has several shortcomings, because
of the nature of heterogeneous reaction conditions. Nonlinear kinetic behavior, slow
reaction, solvation problems, and degradation of the polymer support, because of the
long reactions, are some of the problems typically experienced in SPOS. It is, there-
fore, not surprising that the first applications of microwave-assisted solid-phase
synthesis were reported as early 1992 [24].
The earliest published example of microwave-assisted SPOS involved diisopropyl-
carbodiimide (DIC)-mediated solid-phase peptide couplings [24]. Numerous Fmoc-
protected amino acids and peptide fragments were coupled with glycine-preloaded
polystyrene Wang resin (PS-Wang) in DMF, using either the symmetric anhydride or
preformed N-hydroxybenzotriazole active esters (HOBt) as precursors (Scheme 12.1).
Reactions were performed in an unmodified domestic microwave oven employing
a custom-made solid-phase reaction vessel under atmospheric pressure. Efficiencies
were significantly improved by use of microwave irradiation for all the peptide cou-
plings tested, the rate enhancement being at least 2±3-fold compared with conven-
tional couplings at room temperature. In general, peptide bond formations were
completed within 2±6 min, compared to 30 min for reactions without microwave ir-
radiation at room temperature. As with so many of the early publications in micro-
wave-assisted chemistry, the exact reaction temperature during the irradiation period
was not determined, presumably because of lack of suitable instrumentation
(although the temperature at the end of the reaction could have been measured).
The reasons for the observed rate-enhancements, and the possible involvement of
so-called nonthermal microwave effects (Chapt. 3) [13, 14] therefore remain unclear.
In a more recent study using dedicated multimode microwave reactors for chemical
synthesis, which enable temperature and power control, it was demonstrated that mi-
crowave irradiation could be effectively employed to couple aromatic carboxylic acids
to polystyrene Wang resin [25], if the symmetrical anhydride procedure was used, and
not the three-component O-acylisourea activation method [19]. Almost quantitative
loading was achieved in 1-methyl-2-pyrrolidone (NMP) at 200 8C within 10 min under
O e.g. Fmoc-Ile, DIC, HOBt

MW, 6 min O H
NH2
O N Fmoc
DMF O N
O H
PS-Wang
Scheme 12.1 Peptide couplings on solid support.

(PhCO)2O, O
a) OH MW, 10 min
O Ph
PS-Wang NMP, 200 °C
RCO2 H, Cs2CO3 O
b) Cl MW, 5-15 min
O R
PS-Merrifield/Wang NMP, 200 °C
33 examples
Scheme 12.2 Attachment of carboxylic acids to Wang and Merrifield resins.
atmospheric pressure, as opposed to 2±3 days by use of conventional coupling proce-

dures at room temperature (Scheme 12.2 a). In a related study, the attachment of car-
boxylic acids to chloromethylated polystyrene resins (Merrifield or Wang linker) via
the cesium carbonate method was also investigated (Scheme 12.2 b) [26].
Significant rate-accelerations and higher loadings were observed when the micro-
wave-assisted procedure was compared with the conventional thermal method. Reac-
tion times were reduced from 12±48 h with conventional heating at 80 8C to 5±
15 min with microwave flash heating at temperatures up to 200 8C. Detailed kinetic
comparison studies using fluoroptic temperature measurements have, however,
shown that the rate enhancements observed were because of rapid direct heating of
the solvent by microwaves rather than a specific nonthermal microwave effect [26].
Importantly, no degradation of the polystyrene resins was observed, even under pro-
longed exposure to microwave irradiation at 200 8C.
Transition-metal catalyzed carbon±carbon and carbon±heteroatom bond-forming
reactions are processes in which microwave irradiation has often been demonstrated
to reduce reaction times from many hours to only a few minutes (Chapt. 11). Several
of those important microwave-induced coupling procedures have also been success-
fully adapted to work on polymeric supports. These include, for example, the palla-
dium-catalyzed Stille and Suzuki couplings shown in Scheme 12.3 (reactions a and
b) [27]. A TentaGel resin (poly(ethylene glycol)-grafted polystyrene) was used as the
polymeric support, and incorporated the acid labile Rink linker. Microwave irradia-
tion of the reaction mixtures in sealed Pyrex tubes using dedicated monomode reac-
tors (without temperature monitoring) provided the coupled products after only
4 min reaction. Standard acidic cleavage with trifluoroacetic acid (TFA) furnished the
corresponding biaryls in good to excellent yield. In both reactions minimal decompo-
sition of the polymeric support was observed, resulting in the isolation of minor
amounts of free polyethylene glycol. In a related example using the same type of re-
sin/linker system and identical microwave equipment an aryl nitrile was prepared by
microwave-assisted palladium-catalyzed cyanation of the corresponding polymer-
bound aryl iodide. Subsequent conversion of the nitrile into the tetrazole was again
performed by microwave irradiation, in a one-pot reaction (Scheme 12.3 c) [28].
N-Arylated heterocycles are an important class of compounds often associated
with biological activity. It has been shown that yields and reaction rates in copper(II)-
mediated C±N cross coupling reactions on a solid support could be dramatically im-
I Ph
H Bu3SnPh, [Pd] H
N MW, 3.8 min N
a)
O NMP
O
TentaGel-Rink
X Ar
H ArB(OH)2, Na2CO3, [Pd] H
N MW, 3.8 min
N
b)
O X = Br, I DME, EtOH, H2O
O 14 examples
TentaGel-Rink
1. Zn(CN)2, [Pd] N
N
MW, 2 min N
I
H 2. NaN3, NH4Cl H N
MW, 20 min H
N N
c)
NMP
O O
TentaGel-Rink
p-Tol
H
H N H N
N p-TolB(OH)2, Cu(OAc)2, [Pd] N
N MW, 0.5 min N
d)
pyridine-NMP
O O
TentaGel-PAL
Scheme 12.3 Palladium-catalyzed solid-phase organic synthesis.
proved by use of microwave irradiation (e. g. Scheme 12.3 d) [29]. These experiments
were performed with a domestic microwave oven and use of several intermittent ir-
radiation cycles and multiple additions of excess reagent. Compared with the con-
ventional thermal procedure (80 8C) the reaction time was effectively reduced from
48 h (overall) to less than 5 min and afforded a variety of N-arylated heterocycles in
high yield and purity after cleavage from the solid support.
Another metal-catalyzed microwave-assisted transformation performed on a poly-
mer support involves the asymmetric allylic malonate alkylation reaction shown in
Scheme 12.4. The rapid molybdenum(0)-catalyzed process involving thermostable
chiral ligands proceeded with 99 % ee on a solid support. When TentaGel was used
as as support, however, the yields after cleavage were low (8±34 %) compared with
the corresponding solution phase microwave-assisted process (monomode cavity)
which generally proceeded in high yields (>85 %) [30].
Multicomponent reactions (MCR), in which three or more reactions combine to
give a single product, have lately received much attention. The Ugi four-component
condensation in which an amine, an aldehyde or ketone, a carboxylic acid, and an iso-
cyanide combine to yield an a-acylamino amide, is particularly interesting, because
O
O O O O
Ph O OMe
O OMe Mo(CO)6, ligand O OMe
MW, 10 min
TentaGel-OH Ph
THF
Scheme 12.4 Solid-phase molybdenum(0)-catalyzed allylic alkylation.
of the wide range of products obtainable by variation of the starting materials [31].
Although conventional solid-phase Ugi reactions require several days for completion,
it has been demonstrated that by use of microwave irradiation (monomode instru-
ment, sealed Pyrex vessel), products of high purity were obtained in moderate to ex-
cellent yields (24±96% yield) within 5 min irradiation time (Scheme 12.5) [32].
A polymer-bound amino component was used and a mixture of dichloromethane
and methanol (DCM±MeOH 2 : 1) as solvent which both absorbed microwave energy
and solvated the resin. A library comprising 18 members was obtained after cleavage
of the resin-bound material from the support with TFA : DCM 19 : 1.
Another condensation process that has been performed by microwave heating is
the Knoevenagel reaction (Scheme 12.6). Resin-bound nitroalkenes, for example,
R1CHO,
R2CO2H, R 3NC R1 H
MW, 5 min N
NH2 N R3
DCM/MeOH Scheme 12.5 Ugi 4-component
O
TentaGel-RAM O R2 reactions on a solid support.
O
NO2
HO
ArCHO, NH4OAc
DIC, HOBt, rt, 17 h O O
MW, 20 min
NO 2 NO2
THF O THF O
Ar
5 examples
OH
PS-Wang
O O
ArCHO
R1O R
O O piperidinium acetate O O
MW, 170 °C, 1-10 min MW, 125 °C, 60 min
O R O R
1,2-Dichlorobenzene 1,2-Dichlorobenzene
7 examples Ar
21 examples
Scheme 12.6 Knoevenagel condensations on solid support.
were prepared by microwave-assisted Knoevenagel condensation of resin-bound ni-

troacetic acid with a variety of aldehydes. The formation of the resin-bound enones
was realized by microwave-assisted condensation of the aldehyde to the resin within
20 min, by use of a domestic microwave oven. The resin-bound nitroalkenes were
subsequently used in high pressure Diels±Alder and three-component tandem
[4+2]/[3+2] cycloaddition reactions [33]. In a related example, synthesis of Knoeve-
nagel products involving resin-bound b-ketoesters has been reported. Here, the re-
quired resin-bound 1,3-dicarbonyl compounds were generated by rapid, microwave-
mediated acetoacetylation of Wang resin with a variety of b-ketoesters. By use of
microwave flash heating at 170 8C complete conversions were achieved within
1±10 min, a significant improvement over the conventional thermal method, which
required several hours for completion [34]. Significant rate enhancements were also
observed for the subsequent microwave-heated Knoevenagel condensations with a
set of different aldehydes. Reaction times were reduced to 30±60 min at 125 8C, the
optimized reaction temperature in the microwave procedure, compared with
1±2 days using the literature procedures. Kinetic comparison studies indicated that
the observed rate-enhancements could be attributed to the rapid direct heating of the
solvent (1,2-dichlorobenzene) by microwaves rather than to any specific microwave
effect [34]. Both reaction steps were performed in dedicated multimode microwave
reactors in open Teflon vessels with on-line temperature measurement. A library of
21 polymer-bound enones was obtained in a single microwave irradiation experi-
ment by use of parallel synthesis techniques (Sect. 12.7).
An 8000-member library of trisamino- and aminooxy-1,3,5-triazines has been pre-
pared by use of highly effective, microwave-assisted nucleophilic substitution of poly-
propylene (PP) or cellulose membrane-bound monochlorotriazines. The key step re-
lied on the microwave-promoted substitution of the chlorine atom in monochloro-
triazines (Scheme 12.7) [35]. Whereas the conventional procedure required relatively
harsh conditions such as 80 8C for 5 h or very long reaction times (4 days), all substi-
tution reactions were found to proceed within 6 min, with both amines and solutions
of cesium salts of phenols, and use of microwave irradiation in a domestic oven un-
der atmospheric reaction conditions. The reactions were conducted by applying a
SPOT-synthesis technique [36] on 18 × 26 cm cellulose membranes leading to a spa-
tially addressed parallel assembly of the desired triazines after cleavage with TFA
vapor. This concept was later also extended to other halogenated heterocycles, such
as 2,4,6-trichloropyrimidine, 4,6-dichloro-5-nitropyrimidine, and 2,6,8-trichloro-
7-methylpurine, and applied to the synthesis of macrocyclic peptidomimetics [37].
R R2XH (X = O, NR) R
N N Cl MW, 6 min N N X
L L R2
N N NMP or DMSO N N
PP or cellulose
membrane X X
R1 R1
Scheme 12.7 High-speed nucleophilic substitution reactions on polypropylene
or cellulose membranes.
Other microwave-assisted SPOS processes reported in the literature are summar-

ized in Scheme 12.8. The addition of isocyanates to amines bound to Wang resin, for
example, was studied both under conventional conditions at room temperature and
under the action of microwave irradiation in open vessels by use of a monomode in-
strument. By monitoring the progress of the addition by on-bead FTIR it was de-
monstrated that the microwave procedure proceeded significantly faster than the re-
action at room temperature (12 compared with 210 min) [38]. The temperature dur-
ing the microwave irradiation experiment was not determined, however, so it is un-
clear if any nonthermal microwave effects were responsible for the observed rate-en-
hancements (Scheme 12.8 a) [38].
A very unusual microwave-assisted procedure involving the preparation of N-alkyl
imides from anhydrides and polymer-bound g-aminobutyric acid has been described
(Scheme 12.8 b) [39]. This transformation is reported to proceed in the absence of sol-
vent, and involves TaCl5-doped silica gel as reaction medium. After cleavage with TFA,
the corresponding carboxylic acids were obtained in 58±72 % yield. These results, in-
volving dry, unswollen resin, are somewhat unexpected and deserve further in-depth
investigation [40]. Very rapid Claisen rearrangements on the solid-phase have also
been described; they involve microwave heating of the resin in DMF (Scheme 12.8 c).
Compared with classical heating in an oil bath at 140 8C the reaction times were re-
duced from 10±16 h to 4±6 min and led to similar or higher yields of products after
TFA cleavage [41]. Unfortunately, no temperature measurements were documented.
In another application of microwave heating for SPOS, several functionalized resins
(Wang resin, piperazinomethyl resin) were prepared from standard PS-Merrifield re-
sin by rapid nucleophilic substitution of the chloride [42].
O ArNCO O O
a) MW, 12 min
H Ar
O N O N N
DCM
R R H
PS-Wang
5 examples
O O O
e.g.
O
O SiO2 /TaCl5 O
b) MW, 5-7 min
NH2 N
O O
no solvent
PS-Merrifield O
6 examples
O O O OH
MW, 4-6 min
c) O
O R
R DMF
PS-Merrifield
8 examples
Scheme 12.8 Miscellaneous solid-phase reactions performed under
the action of microwave irradiation.
In addition to the aforementioned microwave-assisted reactions on solid supports,

several publications also describe microwave-assisted resin cleavage. In this context
it has been demonstrated that carboxylic acids could be cleaved from conventional
Merrifield resin, using the standard TFA±DCM 1 : 1 mixture, by exposure of the poly-
mer-bound ester and the cleavage reagent to microwave irradiation in a dedicated
Teflon autoclave (multimode instrument). After 30 min at 120 8C, complete recovery
of the carboxylic acid was achieved (Scheme 12.9) [26]. At room temperature, how-
ever, virtually no cleavage was detected after 2 h in 1 : 1 TFA±DCM.
In another application of microwave-assisted resin cleavage, N-benzoylated ala-
nine attached to 4-sulfamylbutyryl resin was cleaved (after activation of the linker to
bromoacetonitrile by use of Kenner's safety-catch principle) with a variety of amines
(Scheme 12.10 a) [43, 44]. Cleavage rates in DMSO were investigated for diisopropyl-
amine and aniline under different reaction conditions using both microwave (do-
mestic oven) and traditional oil-bath heating. It was determined that microwave
heating did not accelerate reaction rates compared with traditional heating when ex-
periments were run at the same temperature (ca. 80 8C). When microwaves were
used, however, even cleavage with normally unreactive aniline could be accom-
plished within 15 min at ca. 140 8C. This principle was extended to the parallel
synthesis (Sect. 12.7) of an 880-member library by utilizing 96 well plates, employing
10 different amino acids each bearing a different acyl group, and using 88 different
amines for cleavage. In closely related work, similar SPOS chemistry was employed
by the same research group to prepare biaryl urea libraries, via microwave-assisted
Suzuki couplings, followed by cleavage with amines (Scheme 12.10 b) [44].
O TFA/DCM 1:1 O
MW, 120 °C (7 bar), 30 min
Scheme 12.9 Microwave- O Ph
assisted cleavage of benzoic HO Ph
acid from Merrifield resin. PS-Merrifield
O2 O2 O R1R2NH O
H H
a) S S N Ph MW ,~140 °C, 15 min R1 N Ph
NH2 N N
O DMSO R2 O
Me Me
PS NC
b) O2 O ArB(OH)2, Na2CO3, [Pd] O2 O

I Ar
S MW , 5 min S
N N N N
H H DME, H2O H H
PS
O
activation, then RNH 2 Ar
R
N N
H H
Scheme 12.10 Microwave-assisted aminolysis (Kenner safety-catch linker).
1) p-NO2C6H4OCOCl
S DCM, 0°C S
2) RNH2, DMF O
R
PS OH O N
H
R1R2NH O
MW, 1-20 min R2 R1
N N
NMP H
R1
Scheme 12.11 Microwave-assisted aminolysis (Marshall linker).
In a related approach ureas were generated by microwave-assisted aminolysis of

resin-bound carbamates (Scheme 12.11) [45]. The carbamates were formed by treat-
ment of thiophenoxy resin (Marshall linker) with p-nitrophenylchloroformate, fol-
lowed by reaction with a primary amine in DMF. A variety of conditions were tested
for subsequent cleavage with amines. Significantly improved reaction times and pro-
duct purity, compared with those obtained by use of the standard thermal procedure,
were achieved by use of NMP or excess amine as the solvent and irradiating the mix-
ture (multimode oven) for 1±20 min. A single example of a microwave-assisted cycla-
tive cleavage procedure leading to hydantoins has also been reported [46].
In all the examples of microwave-assisted SPOS summarized above, the choice of
solvent deserves special attention [47]. Ideally, the solvent should have:
. good swelling properties for the resin involved;

. a high boiling point if reactions are to be performed at atmospheric pressure;
. a high loss tangent (tan d) for good interaction with the microwaves [48]; and
. high chemical stability and inertness, to minimize side reactions.
Solvents such as NMP, DMF, DMSO, or 1,2-dichlorobenzene have therefore been

used frequently. As far as the polymer supports are concerned, the use of cross-
linked polystyrene resin has been most prevalent. These resins have been shown to
withstand microwave irradiation for prolonged periods of time, even at 200 8C [26].
TentaGel resins [27±30, 32] and cellulose membranes [35, 37] have also been used
successfully in microwave-assisted SPOS, although some degradation of TentaGel re-
sins has been observed during irradiation [27]. In most reported studies involving
SPOS, temperature was not, unfortunately, measured during the microwave irradia-
tion period. Consequently, the reasons for the observed rate enhancements in these
transformations, which are potentially highly useful in the field of combinatorial
chemistry, remain unclear. When kinetic comparison studies of differences between
conventional and microwave heating experiments were conducted [26, 27, 34, 43,
44], so-called non-thermal or specific microwave effects (Chapt. 3) [13, 14] were not
observed.
12.3 Polymer-supported Reagents, Scavengers, and Catalysts 415
12.3
Polymer-supported Reagents, Scavengers, and Catalysts
Apart from traditional solid-phase organic synthesis (SPOS), the use of polymer-sup-
ported reagents (PSR) has gained increasing attention from practitioners in the field of
combinatorial chemistry [49±52]. The use of PSR combines the benefits of SPOS with
the advantages of solution-phase synthesis. The most important advantages of these re-
agents are simplification of reaction workup and product isolation, the workup being
reduced to simple filtration. PSR can also be used in excess without affecting the purifi-
cation step. By using this technique, reactions can be driven to completion more easily
than in conventional solution-phase chemistry. So far only a few applications of micro-
wave-assisted PSR strategies have been reported in the literature.
One recent process involves the use of a polymer-supported Burgess reagent for
the synthesis of 1,3,4-oxadiazoles from 1,2-diacylhydrazines (Scheme 12.12). Irradia-
tion of a variety of 1,2-diacylhydrazines with a polyethylene glycol (PEG 750)-sup-
ported Burgess reagent in THF provided the corresponding 1,3,4-oxadiazoles in
75±96 % yield and high purity after only 2±8 min irradiation [53]. Under conventional
reflux conditions a 40 % conversion was obtained after 3 h. Apart from filtration
through silica gel to remove the soluble polymer-supported reagent, and evaporation
of the solvent, no purification was necessary. Reactions were performed in dedicated
monomode instruments under sealed vessel conditions (no temperatures given). In
a variation of this procedure the same authors also described the cyclodehydration of
diacylhydrazines to oxadiazoles by use of the insoluble polystyrene-supported re-
agents A and B (Scheme 12.12) [54]. Similar reduced reaction times as with the solu-
ble polymer support (5±10 min) were also achieved by use of either of the two poly-
styrene-supported reagents in THF with microwave irradiation in sealed vessels.
Another example of microwave-assisted PSR chemistry involves the rapid conver-
sion of amides to thioamides by use of a polystyrene-supported Lawesson-type thio-
nating reagent. By use of microwave irradiation at 200 8C in sealed vessels (mono-
mode reactor), a range of secondary and tertiary amides was converted within
O2 O
S
Et3N N O
PEG R1 O R2
O O
R2 MW, 2-8 min
R1
N N N N
THF
H H 16 examples
O2 O Et2N NtBu
S Me P
N N O N N
Me2N PS PS
A B
Scheme 12.12 Synthesis of 1,3,4-oxadiazoles by use of polymer-supported
reagents.
S OEt Scheme 12.13 Microwave-mediated

PS P thionation of amides.
N NH
O S
MW, 200 °C, 15 min
R NR1R2 R NR1R2
toluene, ionic liquid
9 examples
15 min to the corresponding thioamides, in high yield and purity (Scheme 12.13)
[55]. Compared with classical reflux conditions, these thionation reactions were
much faster and reaction times were reduced from 30 h to 10±15 min. Interestingly,
even heating at these elevated temperatures caused no damage to the polymeric sup-
port. Because toluene is not an optimum solvent for absorption and dissipation of
microwave energy [48], a small amount of ionic liquid (1-ethyl-3-methyl-1H-imidazo-
lium hexafluorophosphate) was added to the reaction mixture to ensure even and ef-
ficient distribution of heat.
In a related example, the catalytic transfer hydrogenation of olefinic substrates
using a polymer-supported hydrogen donor has been reported. By use of microwave
irradiation (monomode reactor) high yields of products (80±95 %) could be obtained
by irradiation of a mixture of an Amberlite-derived supported formate, Wilkinson's
catalyst (RhCl(PPh3)3), and the olefinic substrate in the minimum quantity of
DMSO (Scheme 12.14) [56]. After separation of the Amberlite at the end of the reac-
tion the polymer-supported formate salt could easily be regenerated and used in
further hydrogenation reactions. In total, five reaction±regeneration cycles were pos-
sible before an appreciable decrease in the reaction yield was noted.
Very recently a novel one-pot three-step Wittig reaction using microwave irradia-
tion and polymer-supported triphenylphosphine has been reported [57]. By use of
PS
N HCOO
RhCl(PPh 3)3
E MW, 30 s E Scheme 12.14 Microwave-medi-
R R ated hydrogenation using a polymer-
DMSO
supported hydrogen
8 examples donor.
PS Ph
P
Ph
O MW, 150 °C, 5 min R2
R1 + Br R2 R1
H MeOH, K2CO3
15 examples
Scheme 12.15 Microwave-mediated one-pot, three-component Wittig

olefinations utilizing polymer-supported triphenylphosphine.
12.4 Soluble Polymer-supported Synthesis 417
monomode irradiation in closed vessels olefins could be formed efficiently in just a

few minutes, by use of a three-component coupling process (Scheme 12.15). Yields
of the olefinic products were moderate to good (11±95 %, 15 examples), and the pur-
ity of olefins after automated chromatographic purification was always high.
One of the disadvantages of using polymer-supported scavengers to remove excess re-
agents is the long reaction times frequently encountered. It has been shown that excess
primary amine can be successfully scavenged from a reaction mixture by use of PS alde-
hyde Wang resin under microwave conditions. Compared with 24±36 h at room tem-
perature, the amine was completely scavenged by 3.5 equivalents of the aldehyde resin
within 20±40 min by use of microwave irradiation and dioxane as solvent [58].
12.4
Soluble Polymer-supported Synthesis
Besides solid-phase organic synthesis (SPOS) involving insoluble cross-linked poly-

mer supports, chemistry on soluble polymer-matrixes, sometimes called liquid-phase
organic synthesis, has recently emerged as a viable alternative [59±62]. Problems as-
sociated with the heterogeneous nature of the ensuing chemistry and on-bead spec-
troscopic characterization in SPOS have led to the development of soluble polymers
as alternative matrixes for combinatorial library production. Synthetic approaches
that utilize soluble polymers couple the advantages of homogeneous solution chem-
istry (high reactivity, lack of diffusion phenomena, and ease of analysis) with those of
solid-phase methods (use of excess reagents and easy isolation and purification of
products). Separation of the functionalized matrix was achieved by solvent or heat
precipitation, membrane filtration, or size-exclusion chromatography [59±62].
Several microwave-assisted procedures have been described for soluble polymer-
supported syntheses. Poly(ethylene glycol) (PEG)-supported aryl bromides have been
shown to undergo rapid palladium(0)-catalyzed Suzuki couplings with aryl boronic
acids in water (Scheme 12.16) [63]. The reaction proceeded without organic cosolvent
ArB(OH)2
Pd(OAc)2, K2CO3 O
O
MW, 2 min S
S Ar
O Br O
H2O
PEG
5 examples
ArB(OH)2
Pd(OAc)2, K2CO3 O
O
MW, 2-4 min
O O
H2O
PEG
X Ar
X = I, OTf, ONf 12 examples
Scheme 12.16 Microwave-assisted aqueous Suzuki couplings with PEG-bound aryl

halides or sulfonates.
under thermal conditions or microwave conditions. Compared with classical heating

(70 8C), microwave irradiation shortened the reaction times with representative boro-
nic acids from 2 h to 2±4 min, with conversions typically >95 %. Even at high irradia-
tion energy levels (domestic oven, septum-sealed vessels), the polymer support and
the ester remained stable. Whereas the use of conventional thermal conditions in-
duced ester cleavage, this side reaction was apparently suppressed under microwave
conditions. The reaction proceeded well also for PEG-bound aryl iodides, triflates
(OTf), and nonaflates (ONf) and could be performed in a parallel format [63].
In a related example, the microwave-promoted alkylation of Schiff base-protected
PEG-bound glycine was investigated (Scheme 12.17) [64]. Here PEG (molecular
weight 3400) was used simultaneously as polymeric support, solvent, and phase-
transfer catalyst. The best results were obtained when alkylations with alkyl bro-
mides or iodides (RX) were performed neat in the presence of a base such as
Cs2CO3 or K2CO3 in a domestic microwave oven in open glass vessels. Comparison
experiments involving thermal heating (85 8C) revealed little evidence of any non-
thermal or specific microwave effects (Chapt. 3); the microwave technique was
found to be more practical than conventional heating, especially for performing reac-
tions in a parallel format.
Microwave-mediated transesterification of commercially available neat poly(styr-
ene±co-allyl alcohol) with ethyl 3-oxobutanoate, ethyl 3-phenyl-3-oxopropanoate, and
diethyl malonate provided the desired polymer-supported b-dicarbonyl compounds
(Scheme 12.18) [65]. Multigram quantities of these interesting building blocks for
heterocycle synthesis were obtained simply by exposing the neat mixture of reagents
to microwave irradiation in a domestic microwave oven for 10 min.
The first use of room temperature ionic liquids as potential novel soluble phases
for combinatorial synthesis has recently been described. As model reaction the
Knoevenagel condensation of salicyl aldehyde grafted on to an imidazolium-derived
ionic liquid was studied under the action of microwave irradiation (Scheme 12.19)
[66]. Reactions were performed without additional solvent in the presence of a basic
catalyst, utilizing microwave irradiation in a designated monomode microwave reac-
O RX, Cs2CO3 O
MW, 30-60 min
N Ph N Ph
O no solvent O
PEG Ph R Ph
8 examples
Scheme 12.17 Microwave-assisted alkylations on PEG support.
O O
AlkO R
O O
MW, 10 min
O R Scheme 12.18 Derivatization of
OH no solvent
poly(styrene-co-allyl alcohol) with
R = Me, Ph, OEt b-dicarbonyl compounds.
12.5 Fluorous-phase Synthesis 419
O E2 E1
H E1CH2 E2, piperidine

MW, 15-60 min, 80 °C H
Me N O O
N O no solvent Me N N O
O O
BF4 BF4
E2 E1
NaOMe, rt, 18 h
H
MeOH MeO
O
O
5 examples
Scheme 12.19 Ionic liquid-phase supported synthesis performed with

microwave irradiation.
tor at 80 8C. Knoevenagel condensations proceeded quantitatively within 15±60 min

and furnished, after cleavage from the ionic liquid (reusable), the desired products
in high yield without the need for further purification [66]. In a second example of
this unconventional methodology imines were successfully prepared from the
grafted formyl functionality by reaction with a variety of amines, again using micro-
wave irradiation (80 8C, 20 min) [66].
12.5
Fluorous-phase Synthesis
In so-called fluorous-phase synthesis, an organic molecule is rendered soluble in

fluorocarbon solvents by attachment of a suitable fluorocarbon group (ªfluorous
tagº). Fluorocarbon solvents are usually immiscible with organic solutions and water
at room temperature, and fluorous molecules partition out of an organic phase and
into a fluorous phase by standard liquid±liquid extraction. At the desired stage of the
synthesis, the fluorous label is cleaved and the product is rendered ªorganicº again
[67]. Fluorous techniques (in particular fluorous chromatography) are rapidly be-
coming a means of integrating synthesis and purification strategies in combinatorial
chemistry [68].
One example of microwave-assisted fluorous synthesis involves palladium-cata-
lyzed Stille couplings of fluorous tin reagents with aryl halides or triflates
(Scheme 12.20) [69]. While the comparable thermal process required one day for com-
pletion, the microwave-heated reactions (sealed vessels in monomode reactors) were
completed within 2 min, with the additional benefit of reduced homocoupling of the
tin reagent leading to Ara ±Arb. The desired biaryl products were isolated in good
yields and purities after three-phase extraction. Similar results were also achieved by
utilizing so-called F-21 fluorous tags (CH2CH2C10F21) on the tin reagent [70].
In an additional application of fluorous chemistry, radical-mediated cyclizations
were performed in benzotrifluoride using microwave irradiation [70]. In the pre-
[Pd], LiCl
MW, 1.5-2 min
Ara X + (C6F13CH2CH2)3Sn-Arb Ara Arb
DMF
X = Br, I, OTf (14 examples)
Scheme 12.20 Fluorous Stille couplings under the action of microwave irradiation.
I (C10F 21CH2CH2)3SnH, AIBN

MW, 5 min
N benzotrifluoride (BTF) N
Cbz CBz
Scheme 12.21 Microwave-mediated radical cyclizations.
sence of 2,2-azobizisobutyronitrile (AIBN) as radical initiator, the aryl iodide shown

in Scheme 12.21 for example smoothly underwent microwave-mediated cyclization
to the corresponding indole derivative in 93 % isolated yield. The reaction time using
sealed Pyrex vessels (monomode reactor) was 5 min. The ability to promote highly
fluorous reactions with microwave heating deserves special attention. With these
highly fluorous tin reagents, microwave irradiation is more than an expedient to re-
duce reaction times. Reactions conducted under traditional heating either did not
work at all or did not work nearly as well. The advantage of microwave heating may
be the rapid coalescence of the organic and fluorous phase to form a homogeneous
solution [70].
12.6.
Parallel Synthesis
Parallel processing of synthetic operations has been one of the cornerstones in com-
binatorial chemistry for years [1±6]. In the parallel synthesis of combinatorial li-
braries, compounds are synthesized using ordered arrays of spatially separated reac-
tion vessels adhering to the traditional ªone vessel-one compoundº philosophy. The
defined location of the compound in the array provides the structure of the com-
pound. A commonly used format for parallel synthesis is the 96-well microtiter plate,
and today combinatorial libraries comprising hundreds to thousands of compounds
can be synthesized by parallel synthesis, often in an automated fashion [6].
As demonstrated in the previous sections of this review, microwave-assisted reac-
tions allow rapid product generation in high yield under uniform conditions. There-
fore, they should be ideally suited for parallel synthesis and/or combinatorial chem-
istry applications. The first example of parallel reactions performed under micro-
wave irradiation conditions involved the nucleophilic substitution of an alkyl iodide
with 60 diverse piperidine or piperazine derivatives (Scheme 12.22) [71]. Reactions
were performed in a multimode microwave reactor in individual sealed polypropy-
X
I X NH
N
N MW, 4 h
NH2 N
S MeCN X = NR, CR1R2 NH2
S
60 examples
Scheme 12.22 Nucleophilic substitution reactions performed in parallel.
O O Ar O
Ar bentonite clay
R2 MW, 5 min R2 R2
+ + NH4NO3
O H no solvent
R1 O R1 N R1
> 96 examples
Scheme 12.23 Microwave-assisted Hantzsch pyridine synthesis.
lene vials using acetonitrile as solvent (no further details given). Screening of the re-
sulting 2-aminothiazole library in a herpes simplex virus-1 (HSV-1) assay led to three
confirmed hits, demonstrating the potential of this method for rapid lead optimiza-
tion.
In a key 1998 publication, the concept of microwave-assisted combinatorial chem-
istry was introduced for the first time. Using the three-component Hantzsch pyri-
dine synthesis as a model reaction, libraries of substituted pyridines were prepared
in a high-throughput parallel fashion. In this variation of the Hantzsch multicompo-
nent reaction, ammonium nitrate was used as the ammonium source as well as oxi-
dizing agent, employing bentonite clay as inorganic support (Scheme 12.23) [72]. Mi-
crowave irradiation was performed in 96-well filter-bottom polypropylene plates, in
which the corresponding eight 1,3-dicarbonyl compounds and twelve aldehyde build-
ing blocks were dispensed using a robotic liquid handler. Microwave irradiation of
the 96-well plate containing aldehydes, 1,3-dicarbonyl compounds, and ammonium
nitrate±clay in a domestic microwave oven for 5 min produced the expected pyridine
library directly, after the desired products were extracted from the solid support by
organic solvent and collected in a receiving plate. HPLC±MS analysis showed that
the reactions were uniformly successful across the 96-well reactor plate, without any
starting material being present. The diversity of this method was further extended
when mixtures of two different 1,3-dicarbonyl compounds were used in the same
Hantzsch synthesis, potentially leading to three distinct pyridine derivatives (not
shown).
Using a similar format, dihydropyrimidines were obtained in a microwave-expe-
dited version of the classical Biginelli three-component condensation (Scheme 12.24)
[73]. Neat mixtures of b-ketoesters, aryl aldehydes and (thio)ureas with polyphosphate
ester (PPE) as reaction mediator were irradiated in a domestic microwave oven for
1.5 min. The desired dihydropyrimidines were obtained in 61±95 % yield after aqu-
Ar O Ar
O
PPE H
O H R1O N
R1O NH2 MW, 1.5 min
+
R2 O HN X no solvent R2 N X
R3 R3
15 examples
Scheme 12.24 Microwave-assisted Biginelli dihydropyrimidine
synthesis.
eous workup. Furthermore, it was shown that, for example, 10 dihydropyrimidine

analogs could be prepared in parallel fashion in a single microwave irradiation experi-
ment when 10 Pyrex beakers containing the individual building blocks±reagent mix-
tures were immersed in an alumina bath (acting as a heat sink) and subsequently irra-
diated. This strategy is therefore clearly applicable for the parallel synthesis of single
compound libraries. In a related approach hydantoins were obtained by parallel mi-
crowave-assisted condensation of arylglyoxals and phenylurea using PPE as reaction
mediator [74].
Related applications of solvent-free microwave-enhanced parallel processes are
summarized in Scheme 12.25. Imidazo-annulated pyridines, pyrazines, and pyrimi-
dines were rapidly prepared in high yield by an Ugi-type multicomponent reaction
using montmorillonite K-10 clay as inorganic support (reaction a) [75]. A diverse set
of 1,2,4,5-substituted imidazoles was similarly synthesized by condensation of 1,2-di-
carbonyl compounds with aldehydes, amines, and ammonium acetate on acidic alu-
mina as support (reaction b) [76]. After chromatographic workup, the imidazoles
were obtained in 68±80 % yield. Related 2,4,5-substituted imidazoles were synthe-
sized analogously from 1,2-dicarbonyl compounds and aldehydes using ammonium
acetate as ammonium source (4 examples, 67±82 % yield). A 25-member thioamide
library containing additional basic amine functionalities (R1R2) was prepared by oxy-
gen±sulfur exchange utilizing Lawesson's reagent. Microwave irradiation of the thor-
oughly mixed amide±thionation reagent mixture for 8 min produced the correspond-
ing thioamides in good yields and high purities after solid-phase extraction (reac-
tion c) [77]. In another example, the regiospecific three-component cyclocondensa-
tion of equimolar amounts of aminopyrimidin-4-ones, benzoylacetonitrile, and aryl-
aldehydes furnished the densely functionalized pyrido[2,3-d]pyrimidinones in
70±75 % yield (Scheme 12.25 d) [78]. The process was conducted in a domestic micro-
wave oven using Pyrex glass vials in the absence of any solvent or support.
Most of the parallel reactions described in Schs. 12.23±12.25 were performed as
dry-media reactions, in the absence of any solvent. In many cases, the starting mate-
rials and/or reagents were supported on an inorganic solid support, such as silica
gel, alumina, or clay that absorbs microwave energy or acts as a catalyst for the reac-
tion (see also Chapt. 6) [10, 11]. In this context, an interesting method for optimiza-
tion of silica supported reactions has been described [79]. The reagents were co-
spotted neat or in solution on to a thin-layer chromatographic (TLC) plate. The glass
plate was exposed to microwave irradiation, eluted and viewed by standard TLC vi-
R1
R1
O
H NH 2 Montmorillonite K-10 clay N
a) + MW, 4 min R2
R2 NC N X N X
no solvent
Y Y
X = Y = CH 14 examples
X = CH, Y = N
X = N, Y = CH
R2
R2
R1 O H2N NH4OAc, Al2O3 R1 N
b) MW, 20 min
+ O R3
R1 O no solvent R1 N
R3
H
4 examples
O Lawesson's reagent S
R1 MW, 8 min R1
Ar N Ar N
c) R2 no solvent R2
25 examples
Ar O Ar
O
R H O CN R CN
MW,15-20 min N
d) N
+ Me
Me no solvent X N N Ph
X N NH2 O Ph H
X = O, S; R = H, Me 9 examples
Scheme 12.25 Rapid dry-media reactions under microwave conditions.
sualization procedures for the results of the reaction. In this particular example, the
synthesis of an arylpiperazine library (Scheme 12.26) was described, but the simpli-
city and general utility of the approach for the rapid screening of solvent-free micro-
wave reactions may make this a powerful screening and reaction optimization tool.
Other microwave-assisted parallel processes, for example, involving solid-phase or-
ganic synthesis (SPOS) have already been discussed in Sect. 12.2. (Schs. 12.6, 12.7,
and 12.10). In the majority of cases described so far, however, domestic multimode
microwave ovens have been used as heating devices, without utilizing specialized re-
actor equipment. Since reactions in household multimode ovens are notoriously dif-
ficult to reproduce due to the lack of temperature and pressure control, pulsed irra-
silica gel TLC plate

MW, 5 min
Ar1 N NH + Ar2ZCl Ar1 N N Z Ar2
no solvent
Z = SO2, CH2, CO 9 examples
Scheme 12.26 Microwave chemistry on a TLC plate.
diation, uneven electromagnetic field distribution, and the unpredictable formation

of hotspots [10, 43], a recent trend has been to use dedicated, commercially available
reactor systems that make microwave-assisted chemistry more reproducible
(Sect. 12.7).
12.7
Equipment for High-throughput Microwave-assisted Synthesis
Although the examples of microwave-assisted reactions presented in this and other

chapters demonstrate that rapid synthetic transformations can in many cases be
achieved using microwave irradiation, the possibility of high-speed synthesis does
not necessarily mean that these processes can also be adapted to a truly high-
throughput format. As of the year 2000, virtually all commercial suppliers of micro-
wave instrumentation for organic synthesis [80±82] have moved toward combinator-
ial and/or high-throughput platforms. In this section, specialized equipment for
either parallel or rapid sequential microwave-assisted chemistry is presented. How-
ever, due to space restrictions no attempt can be made to discuss basic microwave re-
actor design and technology (see Chapts. 1 and 2).
Several articles in the area of microwave-assisted parallel synthesis have described
irradiation of 96-well filter-bottom polypropylene plates in conventional household
microwave ovens for high-throughput synthesis [29, 43, 44, 72]. While some authors
did not report any difficulties associated with use of such equipment (see
Scheme 12.23) [72], others have experienced problems in connection with the ther-
mal instability of the polypropylene material itself [43], and with respect to tempera-
ture gradients developing between individual wells upon microwave heating [43, 44].
Fig. 12.2 shows the temperature gradients after 1 min irradiation of a conventional
96-well plate in a domestic microwave oven. For the particular chemistry involved
(Scheme 12.10), the 20 8C difference between inner and outer wells was, however,
not critical.
Apart from domestic household microwave ovens, a number of commercial mi-
crowave synthesis systems have been available for a number of years that can be
adapted to high-throughput format [80±82]. Currently, two different cavity designs
are being used. In so-called multimode cavities (conceptually similar to a domestic
oven), the microwaves that enter the cavity are being reflected by the walls and the
load over the typically large cavity. A mode stirrer ensures that the field distribution
is as homogeneous as possible. In the much smaller mono- or single-mode cavities,
Fig. 12.2 Temperature gra-

dients within a microwave-
heated microtiter plate. 1 mL
per well heated continuously
for 1 min at full power in a
conventional microwave oven
(adapted from Ref. [44]).
only one mode is present and the electromagnetic irradiation is focused directly
through an accurately designed wave guide on to the reaction vessel mounted in a
fixed distance from the radiation source. For combinatorial chemistry applications,
the key difference between the two types of reactor systems is that in multimode cav-
ities several reaction vessels can be irradiated simultaneously, whereas in monomode
systems, only one vessel can be irradiated at a time. One instrument designed for
high-throughput organic synthesis is the Ethos SYNTH microwave labstation (Mile-
stone Inc.) [80, 83]. This multimode instrument features a built-in magnetic stirrer,
direct temperature control of the reaction mixture with the aid of fiber-optic probes
and software that enables online temperature and/or pressure control by regulation
of microwave power output (1000 W maximum). The flexible modular platform al-
lows the use of standard glassware for reactions performed at atmospheric pressure,
sealed reaction vessels for performing synthetic transformations at elevated tempera-
ture and pressure, and the application of various parallel reactors [80, 83]. For all con-
figurations, the operator has full on-line access to all control parameters such as tem-
perature, pressure, microwave power, and irradiation time. For this reactor so-called
multiPREP rotors have been developed that house 36, 50, or 80 reaction vessels that
fit into the large multimode cavity. These continuously moving rotors operate at at-
mospheric pressure with ca. 20 mL glass, TFM, or PFA vessels. For applications re-
quiring sealed vessel conditions a rotor system with 36 glass vessels (Ethos multi-
PREP-36/P, Fig. 12.3) with a maximum operating temperature and pressure of
200 8C and 15 bar, respectively, has also been developed. In general, the temperature
in a parallel reaction is measured in one reference vessel either by fiber-optic sensor
or with the aid of a shielded thermocouple. During the reaction the temperature can
additionally be controlled by an external IR sensor in the wall of the instrument,
monitoring the surface temperature of the individual vessels as they move by the
sensor. Magnetic stirring of each vessel ensures homogeneous mixing of the sample
and even temperature distribution. Published applications of the multiPREP 50-ro-
tor system (open vessels) have included the generation of a 21-member library by
parallel solid-phase Knoevenagel condensations (Scheme 12.6) [34]. Here the tem-
perature was monitored with the aid of a shielded thermocouple inserted into one of
the reaction containers. It has been confirmed by standard temperature measure-
ments performed immediately after the irradiation period that the resulting end
temperature in each vessel was the same within ±2 8C [34]. In a different study invol-
ving the multiPREP 36/P rotor (Fig. 12.3) utilizing sealed glass vessels, the unifor-
mity of the reaction conditions in such a parallel set-up was investigated. For that
Fig. 12.3 MultiPREP 36/P rotor used in an ETHOS mul-

timode microwave reactor. Temperature measurement
with a shielded thermocouple in one reference vessel
(Milestone, Inc.) [80].
purpose, 36 identical Biginelli condensations using benzaldehyde, ethyl acetoacetate,

and ureas as building blocks (see Scheme 12.24) were run employing ethanol as sol-
vent and HCl as catalyst [84]. All 36 individual vessels provided identical yields of di-
hydropyrimidine product (65±70 %) within experimental error (no reaction details
provided). In a subsequent experiment, six different aldehyde components
(Fig. 12.4) were used to construct a small library of dihydropyrimidine analogs.
Again, the yields of isolated products did not vary significantly depending on the po-
sition in the rotor, although slightly increased yields were obtained for mixtures that
were placed in the inner circle, which would indicate a somewhat higher tempera-
ture in those reaction vessels (Fig. 12.4) [84].
An even higher throughput can be achieved using, for example, specifically de-
signed 96 deep-well format plates (1 mL volume/vial) (Fig. 12.5) that can be mounted
100 b
80 b Aldehydes a-f
c
Yield (%)
60 a c a f
e f d e
40 d
20
0
1 6 11 16 21 26 31 36
Reaction Vessel
Fig. 12.4 Isolated yields of Biginelli dihydro- b, 2-hydroxybenzaldehyde; c, 3,4-dimethoxy-

pyrimidine products (Scheme 12.24) in different benzaldehyde; d, 3-nitrobenzaldehyde;
reaction vessels of the MultiPREP 36/P rotor e, 2-chlorobenzaldehyde; f, 4-(N,N-dimethyl-
(Fig. 12.3). Outer ring, vessels 1±20; inner ring, amino)benzaldehyde. Adapted from Ref. [84].
vessels 21±36). Aldehydes: a, benzaldehyde;
Fig. 12.5 Ethos combCHEM system (Milestone, Inc.);

left: 96 deep-well plates; right: overhead rotor with two plates [80, 84, 85].
in an overhead rotor system in the large multimode microwave cavity (ETHOS

combCHEM system, Fig. 12.5). Since several of such devices can be mounted on top
of each other, several hundred reactions may potentially be performed in one irradia-
tion cycle [85]. It is important to note that with this system, the material used for the
preparation of the plates (Weflon) absorbs microwave energy which means that the
sealed glass vials will be heated by microwave irradiation regardless of the dielectric
properties [47] of the reactants and/or solvents (Chapt. 1). The system is designed to
interface with conventional liquid handler and/or dispensers to achieve a high de-
gree of automation in the whole process. At the time of writing this review no pub-
lished material on the performance of this setup in combinatorial synthesis was
available [85].
Similar parallel reactors as described above for the ETHOS multimode microwave
reactor (Milestone, Inc.) are also available for the MARS-S multimode reactor from
CEM Corp. [81]. Recently the construction of a parallel reactor with expandable reac-
tion vessels that accommodate the pressure build-up during a microwave irradiation
experiment has been reported [87]. The system was used for the parallel synthesis of
a 24-membered library of substituted 4-sulfanyl-1H-imidazoles [87].
A different strategy to achieve high throughput in microwave-assisted reactions
has been realized for monomode instruments such as the Emrys Synthesizer (Perso-
nalChemistry AB, Fig. 12.6) [82, 86]. Since it is not feasible to have more than one re-
action vessel in a monomode microwave cavity, a robotic system has been integrated
into the platform that moves individual reaction vessels in and out of a specifically
designed cavity that operates with continuous microwave irradiation and a maxi-
mum power of 300 W. A liquid handler allows dispensing of reagents into the Te-
flon-sealed reaction vials, while the gripper moves each sealed vial in and out of the
microwave cavity after irradiation. The temperature is monitored by an IR sensor on
Fig. 12.6 Monomode microwave reactor with and reaction vials (bottom right) are also dis-
integrated robotics interface for automated use played (Emrys Synthesizer, Personal Chemistry
(left). Details of the cavity/gripper (top right) AB) [86].
the outside of the reaction vessel. The instrument processes up to 120 reactions per
run with a typical throughput of 12±15 reactions h±1. Magnetic stirring of each indi-
vidual process vial (250 8C, 20 bar maximum temperature and pressure, respectively)
and unattended operation are some of the features of this microwave reactor. In con-
trast to the parallel synthesis application in multimode cavities this, approach allows
the user to perform a series of optimization reactions with each reaction separately
programmed.
The use of this setup for automated sequential microwave-assisted library synth-
esis was first reported in the context of preparing a series of dihydropyrimidines by
the Biginelli reaction (see Scheme 12.24). A diverse set of 17 CH-acidic carbonyl
compounds, 25 aldehydes, and 8 urea and/or thioureas was used in the preparation
of a dihydropyrimidine library [88]. Of the 3400 theoretically possible dihydropyrimi-
dine derivatives, a representative subset of 48 analogs was prepared using automated
addition of building blocks and subsequent sequential microwave irradiation of each
process vial. For most building block combinations, 10 min of microwave flash heat-
ing at 120 8C using AcOH±EtOH, 3 : 1, and 10 mol % Yb(OTf)3 as solvent±catalyst
system proved to be successful, leading to an average isolated yield of 52 % of
DHPM with > 90 % purity. For some building block combinations the general condi-
tions were modified, by changing the solvent, catalyst, reaction temperature, or irra-
diation time. The unattended automation capabilities of the microwave synthesizer
enables a library of this size to be prepared within 12 h.
In a related example involving the use of the same instrument (Fig. 12.6) in the
Hantzsch multicomponent condensation, the serial synthesis of 24 dihydropyridine
R O R O
O O
O H MW, 140-150 °C, 10-15 min R1 R1
R1 R1
+
R2 O O R2 aqueous NH3 (25%) R2 N R2
H
24 examples
Scheme 12.27 Generation of a dihydropyridine library using automated sequential
microwave processing.
derivatives was reported, involving the microwave assisted reaction of 6 different al-
dehydes with 4 different b-ketoesters or 1,3-dicarbonyl compounds and aqueous am-
monia (Scheme 12.27) [89]. Reactions were run in sealed vessels (see above) at
140±150 8C for 10±15 min, providing the desired products in 39±89 % yield and low
to excellent purities (53±99 %).
Additional applications of this technology for rapid lead discovery and lead optimi-
zation have been reported [87, 90±93]. It should also be noted that a variety of chemi-
cal transformations, in particular in the area of transition-metal catalyzed reactions,
have been performed with this or related equipment (Chapt. 11) [25]. Other mono-
mode microwave reactors using related concepts to introduce high-throughput were
recently introduced by CEM Corp. (Discover or Explorer line of products, Fig. 12.7.)
[81]. At the time of writing this review no published synthetic applications using this
microwave reactor were available.
The issue of parallel versus sequential synthesis using multimode or monomode
cavities, respectively deserves special comment. While the parallel setup allows for
considerable throughput that can be achieved in the relatively short timeframe of a
microwave-enhanced chemical reaction, the individual control over each reaction
vessel in terms of reaction temperature and/or pressure is limited. In the parallel
Figure 12.7 Monomode

microwave reactor Discover
(without automation) for use
with open or sealed vessels of
different volumes (CEM Corp.)
[81]. A related instrument with
automation (Explorer) has re-
cently been introduced.
mode, all reaction vessels are exposed to the same irradiation conditions. In order to
ensure similar temperatures in each vessel, the same amount of the identical solvent
should be used in each reaction vessel because of the dielectric properties involved
[48]. An alternative to parallel processing the automated sequential synthesis of li-
braries can be a viable strategy. Irradiating each individual reaction vessel separately
gives better control over the reaction parameters, and allows for the rapid optimiza-
tion of reaction conditions. For the preparation of relatively small libraries, where de-
licate chemistries are to be performed, the sequential format may be preferable.
12.8
Conclusion
The combination of modern microwave reactor technology and combinatorial chem-

istry applications is a logical consequence of the increased speed and effectiveness
offered by microwave dielectric heating. While this technology is heavily used in
pharmaceutical and agrochemical research laboratories already, a further increase in
the use of microwave-assisted combinatorial chemistry applications both in industry
and in academic laboratories can be expected. This will depend also on the availabil-
ity of modern instrumentation, either for parallel or for sequential processing mode
[94, 95]. Unfortunately, the number of publications reporting combinatorial chemis-
try applications involving microwave heating technology is still comparatively small.
One has to realize that most of the examples so far have been conducted in industrial
laboratories where only a very small fraction of work is getting published. Despite
this fact, it is clear that microwave-assisted combinatorial chemistry has a great po-
tential and will likely become a standard tool in most combinatorial chemistry la-
boratories in a few years [96±98].
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435
13
Microwave-Enhanced Radiochemistry
John R. Jones and Shui-Yu Lu
13.1
Introduction
The synthesis, analysis and applications of labeled compounds is an area in which

basic and applied research go hand-in-hand. Over the last quarter of a century the
field has seen considerable expansion as reflected in the emergence of a specific jour-
nal ( Journal of Labeled Compounds and Radiopharmaceuticals) and the publication of
the proceedings of international conferences held at three-yearly intervals. The for-
mation of the International Isotope Society is also an indication of the increasing im-
portance of isotopes and isotopically labeled compounds.
Within the pharmaceutical industry labeled compounds are used for a variety of
purposes e. g. screening new targets, for binding experiments, for identification of
metabolites, in absorption, distribution and excretion studies and for quantifying
concentrations in target organs [1]. Understanding reaction mechanisms are greatly
assisted by the availability of suitably labeled compounds.
As most of the compounds used in the above areas are organic it follows that most
of the isotopes used are those of hydrogen and carbon with oxygen, nitrogen and the
halogens being used in a minority of cases [2, 3]. Whilst radioisotopes are preferred in
terms of sensitivity the problems associated with the use of radioactivity (separate la-
boratory facilities required as well as trained personnel) and the production of radioac-
tive waste (costs of storage and disposal) means that increasing use is being made of
compounds labeled with stable isotopes, especially as some of the analytical methods,
notably nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry are
becoming more sensitive and versatile [4±7]. Indeed more and more pharmaceutical
companies are developing policies which require drug candidates to be labeled (sepa-
rately) with both stable and radioactive isotopes. Consequently there is the added ben-
efit to those interested in the preparation of radiolabeled compounds that the informa-
tion obtained can be used for preparing the corresponding compounds labeled with a
stable isotope. Indeed for those in academic centers it is customary practice to label
the target compound, first with a stable isotope, and then with the radioactive isotope.
In labeling a compound with a stable isotope and with a radioactive isotope there
are several differences. The former tends to be done on the mg g±1 scale whereas the

ISBN: 3-527-30514-9
436 13 Microwave-Enhanced Radiochemistry
radiolabeled compound is usually prepared on the mg to mg scale. Purification of the

former can be achieved by recrystallization or distillation as well as by one or more
chromatographic methods whereas radiolabeled compounds are invariably purified
by radiochromatographic methods.
Within the pharmaceutical industry there is pressure to produce more drug candi-
dates in a shorter time (greater efficiency). This trend makes it necessary to devise
new and more efficient methods for preparing labeled compounds. There is also a
growing need for a drug candidate to be labeled with several isotopes i. e. multideut-
erated or multitritiated rather than monodeuterated or monotritiated. Finally, and as
mentioned already, there is a need at the end of a particular study, to convert the
radioactive waste to a form which can then be reused, even though the specific activ-
ity may not be as high as in the original study. The movement towards a more envir-
onmentally friendly chemical industry, with faster, more selective and efficient synth-
esis, with greatly reduced levels of waste, both radioactive and otherwise, is gathering
momentum and it is one in which microwaves are destined to play an important
role. Whilst the work that we focus on in this chapter concerns the preparation of tri-
tium and inevitably deuterium labeled compounds examples are given where the
benefits can also be applied to the carbon (11C, 13C and 14C)-labeled area [8]. Finally
we refer to the use of microwaves in the synthesis of 18F-labeled radiopharmaceuti-
cals. The latter area has been the subject of a recent review [9].
13.1.1
Methods for Incorporating Tritium into Organic Compounds
The standard work of Evans [2] as well as a survey of the papers produced in the Jour-
nal of Labeled Compounds and Radiopharmaceuticals over the last 20 years shows that
the main tritiation routes are as given in Tab. 13.1. One can immediately see that un-
like most 14C-labeling routes they consist of one step and frequently involve a cata-
lyst, which can be either homogeneous or heterogeneous. One should therefore be
able to exploit the tremendous developments that have been made in catalysis in re-
cent years to benefit tritiation procedures. Chirally catalyzed hydrogenation reactions
(Knowles and Noyori were recently awarded the Nobel prize for chemistry for their
work in this area, sharing it with Sharpless for his work on the equivalent oxidation
reactions) immediately come to mind. Already optically active compounds such as
tritiated l-alanine, l-tyrosine, l-dopa, etc. have been prepared in this way.
The development of phase transfer catalysis, of supercritical fluids, of ionic liquids
and of course, new reagents, should also have considerable potential in the labeling
area. Furthermore there is the possibility of combining these approaches with en-
ergy-enhanced conditions ± in this way marked improvements can be expected.
13.1.2
Problems and Possible Solutions
The tritiation procedures given in Tab. 13.1 all have serious limitations/disadvan-
tages. Thus for all three hydrogen isotope exchange reactions HTO is used as the do-
Tab. 13.1 Main tritiation procedures.
Reaction Example
1 Hydrogen isotope exchange

HTO
(a) Base-catalyzed C6 H5 COCH3 + OH- C 6 H5 COCH2 T
(b) Acid-catalyzed CH3 CH3

+
H3 O
T
HTO
(c) Metal-catalyzed PtO2

T
HTO
2 Hydrogenation CH CHCOOH CHTCHTCOOH

(a) Homogeneous T2
(b) Heterogeneous
catalyst
3 Aromatic dehalogenation CH3 CH3

T2
catalyst
X T X = Br, Cl, I
4 Methylation N N
NaH
N CT3 I N
H CT3
5 Borohydride reduction O H HO H
NaBT4 T
nor. For health and safety reasons 50 Ci mL±1 (1 Ci = 37 GBq), corresponding to

close on 2 % isotopic abundance, is the highest specific activity that we have used
and this inevitably limits the maximum specific activity of the products that can be
obtained by these routes.
The success of the base-catalyzed hydrogen isotope exchange reaction very much
depends on the acidity of the carbon acid ± the weaker it is (higher pKa ) the stronger
the base required to abstract the proton to form the reactive carbanion [10]. Within
the pharmaceutical industry there is a reluctance to use tritium labeled compounds
produced by this route ± this is because of the dangers of ªback exchangeº. If the
compound to be labeled contains several acidic sites then the label will no longer be
incorporated at one site. This may or may not be a disadvantage depending on what
use is to be made of the labeled compound.
Although many pharmaceutical compounds are unable to withstand harsh acidic
conditions a surprisingly large number of compounds have been labeled by this
route. Werstiuk [11], for example, has reduced the acid concentration but increased
the temperature, one effect more than compensating for the other ± however, the
time required is frequently very long, extending into days. Ion exchange resins, both
acid and base forms, can be used to overcome separation problems [12, 13].
Since the pioneering work of Garnett and Long [14, 15] much progress has been
made in increasing the selectivity of one-step metal-catalyzed hydrogen isotope ex-
change reactions. RhCl3, and iridium(I) catalysts of the type [Ir(COD)(L)2]PF6 (COD:
cis,cis-1,5-cyclooctadiene) have been successfully used by, amongst others, Heys,
Hesk, Lockley, Salter and their coworkers [16±19]. In some of these studies HTO has
been replaced by T2 as donor so that compounds of very high specific activity can be
obtained. Myasoedov and colleagues [20, 21] have also made extensive use of high
temperature solid state catalytic isotope exchange (HSCIE) for the tritiation of a wide
range of organic compounds at high specific activity.
Until recently hydrogenation reactions with T2 were performed on glass gas lines
but this is now frowned upon by the environmental and health and safety inspecto-
rate. Fortunately there are two commercial instruments available, one manufactured
in Switzerland and the other in the USA, which are entirely metallic and use an ura-
nium ªgetterº for storing T2 gas; gentle heating allows a predetermined volume of gas
to be transferred to the reaction vessel and on completion of the reaction any excess
can be returned to a secondary bed for storage and reuse. T2 gas is relatively inexpen-
sive and available at 100 % isotopic incorporation (specific activity of 56 Ci mmol±1).
The main disadvantage now is that it is sparingly soluble in many organic solvents
with the result that the catalyzed reactions, under both homogeneous and heteroge-
neous conditions, are frequently very slow.
Aromatic dehalogenation suffers from the disadvantage that only 50 % of the tri-
tium is incorporated, the rest appearing as waste. This situation is even more
marked for borotritide reductions but the problem can be overcome by using some
of the new tritide reagents that have recently become available as a result of the
synthesis of carrier-free lithium tritide (Scheme 13.1) [22]. Their reactivity can be
fine-tuned through the elements (e. g. B, Al, Sn) to which the tritium is attached and
by the electronic and steric nature of the substituents at the central atom.
TMEDA
n-BuLi + T2 LiT + n-BuT
hexane
Li(s-Bu)3BT LiPh3BT
s-Bu3B Ph3B
Et3B Bu3SnCl
LiEt3BT LiT Bu3SnT
B(OMe)3 Al(OBu-t)3
Scheme 13.1 Preparation of
LiB(OMe)3T Li(OBu-t)3AlT tritide reagents from LiT.
Tritiated methyl iodide has the advantage that three tritiums can be incorporated
in one step so that compounds with a specific activity close to 80 Ci mmol±1 can be
prepared. CT3I is available from commercial sources and being a low boiling liquid
needs very careful handling. It is stable for short periods, consequently there is a
need for new methylating agents that offer greater flexibility.
13.1.3
The Use of Microwaves
The possibility of accelerating chemical reactions through the application of a source

of energy, be it in the form of external radiation or an electric or magnetic field, has
a long history. The first radiation induced method of labeling was reported by Wilz-
bach [23] in 1957 and was subsequently described as the Wilzbach gas exposure
method. Typically 0.5±4.0 g substrate was exposed to 7±14 Ci of T2 gas for between 3
and 10 days, leading to 20±600 mCi incorporation with specific activities of the pro-
duct being in the 1±100 mCi g±1 region. This work was done long before the develop-
ment of 3H NMR spectroscopy [24] so that the pattern of labeling could not be ascer-
tained. Furthermore purification of the products by techniques such as high perfor-
mance liquid chromatography (HPLC) was not possible. The hopes of the author
that ªthe availability of T2 gas at low cost and the high levels of radioactivity attain-
able, even in materials of complex structure, combine to make exposure to tritium
gas an attractive method for the preparation of tritium labeled compoundsº were not
therefore fully realized and, in the course of time, more attractive tritiation methods
were developed. Nevertheless the work stimulated a great deal of interest with the
objective of minimizing radiation damage and increasing the specific activity of the
labeled substrate. Many improved versions of the Wilzbach method were reported,
of which the following are best known:
. recoil labeling
. electrical discharge method
. low pressure method
. ion beam method
. microwave discharge activation (MDA) method
. adsorbed tritium method
The recoil method does in fact predate the Wilzbach method.

Although chemists very frequently refer to two papers [25, 26] published in 1986
as the start of the ªmicrowave-enhanced eraº as an efficient new procedure for or-
ganic synthesis, it was Westermark et al. [27], way back in 1960, who first suggested
that input of microwave power into a system containing tritium could accelerate the
tritiation kinetics. A number of antibiotics, local anesthetics and amino acids were
amongst the early compounds labeled. Wolf et al. [28±30] improved the technique by
circulating the tritium gas within the labeling system and successfully tritiated a
number of tripeptides, amongst other compounds. Essentially the same system was
used by Peng et al. [31, 32] to tritiate a number of steroids. The apparatus was rela-
tively simple to construct and the MDA method was seen to be superior to the other
radiation-induced methods of labeling, requiring a short reaction time and using a
small amount of tritium gas. However, the chemistry within this kind of microwave
plasma is complex with various tritium species being formed e. g. T +, T3+, T and T ±.
Consequently there are several reaction mechanisms taking place concurrently so
that the overall tritiation is characterized by low selectivity; extensive purification is
also necessary. Being a radiation-induced method the work can not be applied to
deuteration studies, in sharp contrast to the more recently developed microwave-en-
hanced methods. An excellent account of radiation-induced methods of labeling has
been given by Peng [33].
The exponential growth in microwave-enhanced synthetic organic chemistry (see
Fig. 1 in Refs. [8] and [34]) which Gedye and Giguere and their colleagues initiated
in 1986 may come to represent one of the most significant events in the develop-
ment of chemistry over the last half-century. Whilst microwave dielectric heating has
been widely used in the food processing area for many years chemists have been
slow in recognizing the potential, partly because the necessary theory is usually
taught as part of a physics degree course and partly because of the lack of suitable in-
strumentation for making quantitative, as distinct from qualitative, measurements.
This second problem will soon not exist as several powerful computer-controlled in-
struments have come to market within the last year.
A detailed account of the theory behind the interaction of microwaves with matter
is beyond the scope of this chapter but there are several excellent and recent reviews
available [35±37 and Chapt. 1], especially by Mingos and coworkers. Whilst micro-
waves are known to be electromagnetic waves in the frequency region 0.3 to
300 GHz current instrumentation tends to operate at a fixed frequency of
2450 MHz, corresponding to a wavelength of 12.2 cm, as the major part of the mi-
crowave region is assigned to radar and telecommunications. In the absence of free
electric charges the interaction between the microwave field and a molecule can be
expressed in terms of an interaction between an electric field and an electric dipole.
The polarization, P, represents the response:
P e0 we E
where E is the electric field, we the electrical susceptibility and e0 the electrical permit-
tivity in vacuum. The applied field creates a current which is the vector sum of the
polarization current and the conduction current. At high frequencies the molecular
inertia causes the polarization vector P to lag behind the applied field E and this is
the origin of the term ªdielectric lossº, expressed as tan d. Microwave energy is not
therefore transferred by convection or conduction but by dielectric loss ± a high value
for tan d indicates a high susceptibility to microwave energy. Polar solvents and so-
lids have high tan d values and are therefore favored for microwave-enhanced reac-
tions. Increasing the ionic strength of the reaction medium can also provide bene-
fits. In the case of nonpolar solvents, or under solvent-free conditions, it is claimed
[34] that when polar mechanisms are involved that nonthermal and specific micro-
wave effects may arise.
Microwave irradiation, in contrast to thermal heating, produces very efficient heat

transfer resulting in even heating throughout the sample. The process can be opti-
mized by giving careful thought to the dimensions of the reaction vessel and volume
of reactants [9]; it is fortunate that radiochemical syntheses are usually performed on
a very small scale (< 5 cm3) where a high and stable E-field intensity is easier to main-
tain, especially if a monomodal cavity, rather than a multimodal mode, is adopted.
13.1.4
Instrumentation
The instruments used for microwave-enhanced chemistry fall into two categories:
the multimode type that we commonly use in the kitchen and the mono-mode (or
single-mode) type that is specially designed for chemistry laboratories. The main dif-
ference between them comes down to how the microwave power is delivered and
controlled. In the multimode oven a time pulse at a fixed power level is used and the
waves within the cavity are not directed in any particular direction. The ovens do not
possess well defined electric fields and consequently the heating pattern within the
areas of the cavity is not homogeneous. In contrast, the mono-mode instrument has
a waveguide which focuses the microwave field on the sample. The power control
enables more precise energy to be delivered and this can be varied according to the
needs of the reaction. It also has a temperature sensor, and some are equipped with
a pressure sensor, which allow chemists to monitor or to control the heating process.
These devices give better reproducibility, shorter reaction time and sometimes better
chemical yields because the interaction between the microwave field and the sample
can be optimized.
Most of the early work was carried out using the multimode oven or commercial
domestic microwave oven. At Surrey we first used a Matsui M169BTunit (750 W), la-
ter on a Prolabo Synthewave S402 focused microwave reactor (300 W) was acquired.
In our earlier studies, the reagents were contained in a thick walled glass tube sealed
at the top but experience showed that a small conical flask (20 cm3) fitted with a sep-
tum stopper was well suited for most of the reactions. It was placed in a beaker con-
taining vermiculite and slowly rotated during the course of the irradiation. To avoid
undue pressure buildup the vessel can also be left unstoppered. For parallel reac-
tions, the Radley's RDT 24 place PTFE carousel reaction station together with Pyrex
glass tubes (25 cm3, o.d. = 15 mm) was placed on the turntable of the microwave
oven. The reaction vessels for the Synthelabo S402 are quartz tubes of different sizes.
For smaller scale reaction specially designed Pyrex tubes (o.d. = 9 mm) can be in-
serted inside the standard quartz tube (o.d. = 25 mm).
More and more researchers are using the mono-mode instruments and the manu-
facturers are bringing the second generation of microwave reactors (e. g. The Smith-
Synthesizer or the SmithCreator by Personal Chemistry, the Discover focused micro-
wave synthesis system by CEM, and the Ethos Synth microwave labstations by Mile-
stone) to the market; these are more effective and user friendly. New standard glass-
ware, capable of withstanding high temperature and pressure is also being devel-
oped and marketed.
13.2
Microwave-enhanced Tritiation Reactions
13.2.1
Hydrogen Isotope Exchange
This is one of the most versatile reactions known as it can be catalyzed by acids,
bases and metals as well as induced by photochemical and other means. It is also
amongst the simplest of organic reactions so that studies in this area have greatly
improved our understanding of reaction mechanisms. It is also one of the best meth-
ods for introducing deuterium/tritium into organic compounds. The knowledge
gained from basic research studies can therefore be put to good use within a fairly
short time interval.
Koves [38±40] was the first to show that acid-catalyzed aromatic hydrogen isotope
exchange could benefit from the use of microwaves and shortly afterwards we
showed that both heterogeneous and homogeneous metal-catalyzed reactions could
also be greatly accelerated [41, 42]. It was during these studies that we recognized
that further benefits could accrue by converting the organic compound (usually neu-
tral) to an ionic form e. g. by protonating the ±NH2 group. These preliminary studies
were then extended to take in a large number of nitrogen-containing heterocyclic
compounds ± here protonation on an NH2 group or the ring-based nitrogen was pos-
sible. This work was prompted by the earlier findings of Werstiuk employing a high
temperature, dilute acid, approach to the deuteration of many organic compounds.
Extensive labeling could be obtained provided the heating times were long (typically
12±50 h). Rarely can compounds of pharmaceutical interest withstand such demand-
ing conditions. Furthermore, the development of new, combinatorial chemistry, re-
quires that labeling reactions should be rapid so that high sample throughput can be
achieved.
The results for mono-, di- and fused ring substituted pyridines showed, as for the
earlier study on the microwave-enhanced deuteration of o-toluidine, that by first
forming the hydrochloride salt extensive labeling could be achieved within 20 min.
Furthermore the reaction products were easily isolated and of high purity, a fre-
quently noticed feature of these reactions. The reaction mechanism is represented in
Scheme 13.2, the deuterium being inserted in the ortho and para positions. The time
taken to reach a predetermined temperature depends greatly on the polarity of the
solvent used and as the results in Fig. 13.1 show this can be altered either by chan-
ging the solvent or adding a cosolvent. For labeling purposes a D2O (or HTO)±
NH3 Cl-
NH2 +
ND3 Cl-
+
ND3 Cl-
+
CH3
HCl CH3 D O CH3 D2O D CH3
2 microwaves
H2O
D
Scheme 13.2 Deuteration of o-toluidine hydrochloride under microwave conditions.
250
1 Solvent b.p (oC) ε s δ
Tanδ
200
Temperature ('C)
2
1 DMSO 189 47 0.825
150 3
2 DMF 153 36.7 0.161
4, 5 3 BuOH 118 n/a n/a
100
6
4 H2 O 100 80.4 0.123
50 7
8 5 EtOH 78 24.6 0.941
0
6 CHCl3 61 4.8 0.091
0 50 100 150 200 250
7 CH2Cl2 40 9.1 0.042
Microwave irradiation time (sec) 8 1,4-dioxane 101 n/a n/a
Fig. 13.1 Microwave heating profile of organic solvents using a

Prolabo Synthewave S402 microwave instrument (5 cm3 at 300 W)
DMSO mixture has great attraction as the heating time can now be reduced to a mat-
ter of 1±2 min.
The choice of solvent can also be beneficial in another respect. This possibility
was highlighted by the findings of Cioffi on the Raney Nickel catalyzed hydrogen±
deuterium exchange of a model carbohydrate [1-O-methyl-b-d-galactopyranoside]
but under ultrasonic irradiation (Tab. 13.2) [43]. Extensive deuteration at C-4 position
occurred for a series of ethereal solvents, the C-3 position was deuterated by seven
solvent systems and the C-2 position deuterated less extensively, also by seven sol-
vent systems. For 1,4-dioxane-D2O no labeling at the C-2 position occurred and for
1,2-dimethoxyethane-D2O no C-3 labeling was observed.
We chose the microwave-enhanced Raney Nickel catalyzed hydrogen isotope ex-
change of indole and N-methylindole as our substrates and D2O, CD3COCD3,
CD3OD and CDCl3 as the solvents. The thermal reaction had already been the sub-
ject of a recent study [44]. The microwave-enhanced method was some 500-fold fas-
ter than the corresponding thermal reaction (at 40 8C). Furthermore the pattern of la-
beling (Scheme 13.3) varied with the choice of solvent. Thus in the case of indole it-
Tab. 13.2 Pattern of labeling for a model carbohydrate under ultrasonic irradiation.
CH2OH CH2OH
OH O OMe Ni / ultrasound OH O OMe
OH H OH R
Solvent / R2O
H H R H
H OH R OH R = 2H, 3H
Position THF DMTHF THP 1,3-Dioxane 1,4-Dioxane DME
C2 27 28 20 25 <1 15
C3 73 84 59 60 62 <1
C4 89 93 59 76 75 29
THF = tetrahydrofuran, DMTHF = 2,5-dimethyltetrahydrofuran, THP = tetrahydropyran, DME = 1,2-di-

methoxyethane
D (36%)
D (97%)
(40%) D
D 2O
D (98%)
(44%) D N
D (94%)H
D (5%)
Raney Ni CD3COCD3
(47%) D
N microwaves D (93%)
H N
D (80%)H
D (26%)
CDCl3
N
H
Scheme 13.3 Pattern of deuteration at different sites for indole
using various solvents and microwave irradiation.
self the more polar solvents such as D2O and CD3OD give rise to general labeling
whilst CDCl3, for example, gave very regiospecific labeling. There is at this stage no
indication that the pattern of labeling in the microwave-enhanced reactions is differ-
ent in any way from that observed for the thermal reactions. However inherent in
both sets of results are mechanistic features worthy of more detailed investigation.
The benefits of using ionic compounds in microwave-enhanced reactions led us to
explore the possibility of using ionic solvents i. e. ionic liquids, as donors for both
deuterium and tritium. Whilst D2O is now relatively inexpensive and available at
high isotopic enrichment, tritiated water is usually employed, for safety reasons, at
low isotopic incorporation (we typically use HTO at 5 or 50 Ci mL±1 specific activity
corresponding to 0.2±2 % isotopic incorporation). This is a serious limitation when
there is a need to provide compounds at high specific activity.
Ionic liquids [45±47] are liquids containing only ions, and are fluid at or close to,
room temperature; those with higher melting points are called molten (or fused)
salts. They are nonvolatile and many are both air- and moisture-stable as well as
being good solvents for a wide range of both inorganic and organic molecules; they
frequently permit unusual combinations of reagents to be brought into the same
phase.
Many ionic liquids are based on N,N-dialkylimidazolium cations (BMI) which
form salts that exist as liquids at, or below, room temperature. Their properties are
also influenced by the nature of the anion e. g. BF4±, PF6±. The C-2(H) in imidazole is
fairly labile but the C-4(H) and the C-5(H) are less so. Under microwave-enhanced
conditions it is therefore possible to introduce three deuterium atoms (Scheme 13.4).
As hydrogen isotope exchange is a reversible reaction this means that the three deu-
terium atoms can be readily exchanged under microwave irradiation. For storage pur-
pose it might be best to back-exchange the C-2(D) so that the 4,5-[2H2] isotopomer
can be safely stored as the solid without any dangers of deuterium loss. The recently
toluene
N N + n-BuCl N + N
-
Cl NaBF4
acetone
D D
CD3OD
N + N N + N
-
- Raney Ni BF4
D BF4 microwaves
Scheme 13.4 Preparation of 2,4,5-[2H3]-BMI-BF4 ionic liquid.
reported microwave-assisted preparation of a series of ambient temperature ionic li-

quids may well accelerate their use in this area [48]. We have already carried out some
deuteration studies with the 2,4,5-[2H3]-BMI-BF4 ionic liquid and found that for rea-
sonably volatile organic compounds these can be separated off by simple evaporation
leaving the deuterated ionic liquid available for repeated use i. e. until all the deuter-
ium has been replaced by hydrogen [49]. Extension of the investigations to the tritium
area will require the analog to be prepared using Raney Nickel and T2 gas under ther-
mal conditions.
Ease of separation of tritiated products from a reaction medium is an important
feature in the choice of labeling procedure. Sometime ago we used polymer-sup-
ported acid and base catalysts [12, 13] to good effect and with the current interest in
Green Chemistry one can expect to see more studies where the rate accelerations ob-
served under microwave-enhanced conditions are combined with the use of solid cat-
alysts such as Nafion, or zeolites.
13.2.2
Hydrogenation
Neither tritium or deuterium gas, with zero dipole moments, can be expected to in-
teract positively with microwave radiation. Their low solubilities are seen as a
further disadvantage. Our thoughts therefore turned towards an alternative proce-
dure, of using solid tritium donors and the one that has found most favor with us
is formate, usually as the potassium, sodium or ammonium salt. Catalytic hydro-
gen transfer of this kind is remarkably efficient as the results for a-methylcinnamic
acid show [50]. The thermal reaction, when performed at a temperature of 50 8C,
takes over 2 h to come to equilibrium whereas the microwave-enhanced reaction is
complete within 5 min. A further advantage is that more sterically hindered al-
kenes such as a-phenylcinnamic acid which are reduced with extreme difficulty
when using H2 gas and Wilkinson's catalyst are easily reduced under microwave-
enhanced conditions.
Formate can only donate one hydrogen, the other presumably coming from traces
of water present in the solvent or on the surface of the reaction vessel. With the need
to increase the specific activity of the product our thoughts turned to the preparation
of a diformate salt and as a first example we synthesized the diformic acid salt of
tetramethylethylenediamine (TMEDA).
The tritiated version could be prepared from tritiated formic acid which we had
prepared at high specific activity (2.5 Ci mmol±1) by a metal-catalyzed hydrogen±tri-
tium exchange procedure using T2 gas. The material can be stored either as a solid
or as a solution; if the latter any release of tritium by back exchange can be easily
monitored by 3H NMR spectroscopy. In our experience very little exchange occurs
over several weeks of storage [51].
The use of tritiated formates have further benefits. Firstly the exact amount neces-
sary for 100 % hydrogenation can be added so the problems associated with the use
of excess T2 gas are avoided and virtually no radioactive waste is produced. Secondly,
the pattern of labeling can be easily varied, as illustrated for the case of cinnamic
acid (using deuterium rather than tritium). When formate is used in D2O there are
three possible combinations: H2O + DCO±2, D2O + HCO±2 and D2O + DCO±2 (or the
DCO2D salt of TMEDA on its own). The 2H NMR spectra show that three iso-
topomers can be prepared ± C6H5CHDCH2COOH, C6H5CH2CHDCOOH, and
C6H5CHDCHDCOOH.
As of now no details of the synthesis of optically active tritiated compounds produced
under microwave-enhanced conditions have been published. Another area of consider-
able interest would be the study of solvent effects on the hydrogenation of aromatic
compounds using noble-metal catalysts as considerable data on the thermal reactions is
available [52]. Comparison between the microwave and thermal results could then pro-
vide useful information on the role of the solvent, not readily available by other means.
13.2.3
Aromatic Dehalogenation
As far as preparing tritiated (and deuterated) compounds are concerned aromatic de-
halogenation is second only to hydrogenation in importance. Furthermore it suffers
from the same disadvantages e. g. slow rates which are caused in part by the poor so-
lubility of the T2 gas in many organic solvents. The situation is however worse as
only 50 % of the tritium is introduced into the desired product. Once again we modi-
fied the classical dehalogenation by replacing D2/T2 gas with labeled formates [53].
There were some previous examples [54±56] of the use of formates in dehalogena-
tion reactions but none of these describe the utility of these agents for labeling or-
ganic compounds under the influence of microwave irradiation.
The N-4-picolyl-4-halogenobenzamide system (Scheme 13.5) was chosen as the ba-
sic substrate structure because:
. the Cl, Br and I derivatives were all easily synthesized;

. satisfactory purification procedures were to hand;
H O H O
N R1COOK N
N N
microwaves
solvents 1
X R
X = Cl, Br, I
R1 = 2H, 3H
Scheme 13.5 Dehalogenation of N-4-picolyl-4-halobenzamide compounds.
. they yield strong pseudomolecular ions in both positive and negative ion HPLC/
MS; and
. they have simple NMR spectra.
Under the experimental conditions dehalogenation proved to be extremely rapid

and was complete within 1 min. This contrasts with the 90±270 min at 100 8C re-
quired for thermal debromination of 2-bromonapthalene. No dehalogenation takes
place in the absence of the formate donor and when the deuterium is located in the
cosolvent rather than the donor (i. e. HCOOK + D2O) hardly any deuterium incor-
poration takes place. Another interesting observation was that the amount (%) deu-
terium incorporation was always lower when protic solvents such as alcohols were
used than aprotic solvents such as dimethyl sulfoxide (DMSO). These are both inter-
esting and useful findings which are valuable for proposed tritiation studies.
13.2.4
Borohydride Reductions
One of the most attractive features of borohydride reductions is that under micro-
wave-enhanced conditions they can be performed in the solid state, and rapidly. We
were attracted by the work of Loupy [57], and in particular Varma [58, 59] who has
shown that irradiation of a number of aldehydes and ketones in a microwave oven in
the presence of alumina doped NaBH4 for short periods of time led to rapid reduc-
tion (0.5±2 min) in good yields (62±93 %). In our study [60] seven aldehydes and four
ketones were reduced (Tab. 13.3). Again reduction was complete within 1 min, the
products were of high purity (> 95 %), of high isotopic incorporation (95 %, same as
the NaBD4) and the reactions completely selective.
So far this remains the only microwave-enhanced borohydride deuteration study.
Corresponding tritiation studies can be anticipated in due course, especially with the
wider range of tritiated reducing agents, referred to previously, becoming available.
Significant reductions in radioactive waste can be anticipated.
Many borohydrides are highly unstable and have to be used as freshly prepared
ethereal solutions. However there are instances where the polymer-supported ver-
sions are more stable e. g. an Amberlyst anion exchange resin supported borohydride
and cyanoborohydride [61], polyvinylpyridine supported zinc borohydride [62] and
the corresponding zirconium borohydride [63]. Such compounds, in their labeled
forms, should turn out to be very useful.
Tab. 13.3 Borodeuteride reduction of carbonyl compounds under microwave conditions (750W,
1 min).
NaBD4/alumina
R
1
750 W, 1 min R1 OH
O
2 R
2 D
R
O NaBD4/alumina HO D
750W, 1 min
Aldehydes, R2 = H
R1 Ph 4-NO2C6H4 trans- 2,4,6-(OMe)3C6H2 1-Naphthyl 2-Naphthyl PhCH2

PhCH=CH
Yield (%) 37 37 77 83 85 89 68
Ketones
R1 Ph 4-NO2C6H4 3-ClC6H4 5-methyltetralone
R2 Me Me Me ±
Yield (%) 82 68 86 87
13.2.5
Methylation Reactions
Methyl iodide is the most widely used methylating agent and is the favored route to
CT3- and CD3- containing compounds. As it can be rapidly synthesized (from CH4)
the [11C]-isotopomer also finds wide application (Sect. 13.4) in the rapidly expanding
positron emission tomography (PET) area [64]. Nevertheless it is generally agreed
that [11C]-methyl triflate is a better methylating agent ± it is more reactive and less
volatile so that one does not require cooling for trapping or heating for reaction to
take place.
We realized that using a low boiling liquid in a microwave environment, even on a
small scale, did not constitute ªbest practiceº and as for hydrogenations our thoughts
turned to using formates in a modified Eshweiler±Clarke reaction [65±67] and suc-
cessfully methylated a number of primary and secondary amines under microwave
conditions (Scheme 13.6) [68].
The methylation of secondary amines works better than for primary amines be-
cause there is no competition between the formation of mono- or dimethylated pro-
ducts. The best results for the microwave-enhanced conditions were obtained when
the molar ratios of substrate/formaldehyde/formic acid were 1 : 1 : 1, so that the
amount of radioactive waste produced is minimal. The reaction can be carried out in
neat form if the substrate is reasonably miscible with formic acid/aldehyde or in
DMSO solution if not. Again the reaction is rapid ± it is complete within 2 min at
120 W microwave irradiation compared to longer than 4 h under reflux. The reaction
mechanism and source of label is ascertained by alternatively labeling the formalde-
hyde and formic acid with deuterium. The results indicate that formaldehyde contri-
CH2D
N
HCHO N
DCOOD
H CHD2
N N
DCDO N
N 120W, 1 min HCOOH
CD3
N
DCDO
DCOOD N
Scheme 13.6 Microwave-enhanced methylation using

Eshweiler±Clarke reaction.
butes two deuterium atoms and the carbon whilst formic acid contributes one deu-
terium atom; there is no exchange between the formaldehyde and formic acid.
13.2.6
Aromatic Decarboxylation
As previous examples have shown the development of microwave-enhanced labeling

technology means more than accelerating reactions ± it provides alternative opportu-
nities. It follows therefore that some previously used methods now become much
more attractive and this is the case for certain aromatic decarboxylations which can
now be used for tritiations as well as in the treatment of tritiated waste. In previous
studies [69] of the reaction the overriding feature was the harsh experimental condi-
tions required.
2-Unsubstituted indoles, widely used intermediates in organic chemistry, are com-
monly synthesized through decarboxylation of the parent acid [70]. This is achieved
by prolonged heating in the presence of Cu (metal/salt) as catalyst and a basic sol-
vent such as quinoline. In our studies [71] prior washing of the acid with CH3OD to
exchange the carboxyl proton with deuterium, followed by brief microwave activa-
tion, is sufficient to achieve decarboxylation/deuteration in ~100 % yield. Other stu-
dies employing a commercial reactor and thick wall glass tubes capable of withstand-
ing high pressure show that the decarboxylation proceeds in the absence of the envir-
onmentally undesirable copper catalysts and that quinoline can be replaced with
water (Scheme 13.7) [72±74].
For a number of benzylformic acids we used N-ethylmorpholine as catalyst and
D2O as solvent/donor. Once again decarboxylation/deuteration occurs very rapidly
and is complete within 4 min. The range of compounds that can be labeled in this
manner has been further widened by the recent observation [75±77] that tributylpho-
sphine and other trivalent phosphorus compounds (R3P, R = Bu, Ph, Me2N, OEt)
catalyze the decarboxylation of a-iminoacids. By using deuterated/tritiated acetic
CuCO3 Cu(OH)2 D (67%)

quinoline
COOD
D (33%)
N 560W, 16min N
D
H
O O
N-ethylmorpholine
D 2O
COOD D (100%)
750W(level II), 4min
MeO MeO
Scheme 13.7 Examples of microwave-enhanced decarboxylation.
acid as a D+/T+ donor several labeled imines have been prepared. Under microwave-
enhanced conditions the reactions would be expected to be much faster which again
would be very useful as tritiated imines are frequently used to label b-lactams and
other biologically interesting compounds such as a-aminophosphate [78]. It is also
worth mentioning that the corresponding phosphites (R2HP=O, R = OEt, OMe) are
cheap, nontoxic hydrogen-atom donors and attractive alternatives to organic tin hy-
drides [79] and have been identified as effective radical reducing agents for organic
halides, thioesters and isocyanides. The tritiated version of these reagents thus pro-
vide new opportunities, especially when coupled to microwave irradiation.
The potential of the microwave-enhanced decarboxylation route in the radioactive
waste area is immediately apparent ± washing the tritium waste with a protic solvent
leads to exchange of the labile tritium. The solvent can then be used with one of the
carboxylic acids mentioned above and after the microwave-enhanced decarboxylation
the waste is now in the form of a solid (greatly reduced volume) which may have
some further use.
13.2.7
The Development of Parallel Procedures
Chemistry as a subject has developed through the synthesis of individual com-

pounds in a number of distinct steps. Recently it has benefited from the introduction
of combinatorial/parallel chemistry techniques as well as microwave-enhanced tech-
nology but so far these studies have not been combined [80]. Lockley and coworkers
[81±83] have shown very nicely how parallel chemistry techniques can be used for
the rapid screening and ranking of catalysts using the hydrogenation of 3-methyl-
3-butenylisonicotinate as the model reaction (Scheme 13.8).
The authors constructed an 80-well hydrogenator. Fifteen catalysts were screened
and the isotopic incorporation assessed by LC/MS. The regiospecificity was deter-
mined by VAST Direct Injection NMR [82] in conjunction with SPADEZ [83], a mul-
tispectrum analysis tool ± this is capable of displaying and quantifying up to 96 spec-
tra. So far it has not been possible to vary the solvents as, under the experimental
conditions, the more volatile distil over into the less volatile solvents.
D
D D
O O
D2, catalysts
CH3COOEt D
O O
D D
N N D
15 catalysts screened
Scheme 13.8 Parallel screening and ranking of catalysts for the
reduction of isobutenyl groups.
A similar study [84, 85] was performed for ortho-directing hydrogen isotope ex-
change reactions of substituted aromatics. The initial screening showed catalytic ac-
tivity to reside exclusively with the Group VIII metals, especially the salts and com-
plexes of Ru, Rh and Ir. Iridium based catalysts are superior to those previously used
± they are more active, operate at lower temperatures and are applicable to a wider
range of substrates. Eventually CODIrAcac (acac = acetylacetone or 2,4-pentane-
dione) was identified as the catalyst displaying the best activity; further optimization
of activity was achieved by varying the ligand structure.
In our own preliminary studies [86] on parallel procedures under microwave-en-
hanced conditions, we have used the Radley's RDT 24 place PTFE carousel reaction
station on the turntable of the Matsui M 169BT microwave oven. In this way, we have
studied the catalytic activity of RhCl3 and Pd(OAc)2 towards the reduction or dehalo-
genation of 4-bromocinnamic acid and structurally similar compounds. A nine-reac-
tion matrix was used under microwave-enhanced conditions as illustrated in
Scheme 13.9 ± greatly reduced reaction times and easy optimization of reaction con-
ditions are immediate benefits. As robotics come to play an increasingly important
role in chemistry, one can immediately see more sophisticated labeling experiments
being undertaken.
13.2.8
Combined Methodology
In the search for labeled compounds at higher specific activity/isotope incorporation,

we were aware of the fact that the most widely used methods (Tab. 13.1) are invari-
ably performed separately. Consequently we embarked on a study to see whether, by
choosing an appropriate compound, we could not combine e. g. hydrogenation and
dehalogenation, or methylation and dehalogenation, or isotope exchange/hydrogena-
tion/dehalogenation. Whilst the investigations are at an early stage, there are suffi-
cient successful examples to indicate that in future more attention will be paid to
using combined methodologies to improve isotopic incorporation.
As an example, p-bromocinnamic acid undergoes debromination in the presence
of HCOOK/H2O/DMSO using Pd(OAc)2 as catalyst. The reaction is complete in 60±
90 s. On the other hand, the same compound undergoes hydrogenation under the
same conditions using RhCl3 as catalyst; again reaction is complete within 60 s. The
combined debromination/hydrogenation of 4-bromocinnamic acid was complete
D H
R2 R
1 2
Hydrogenation
R
Dehalogenation
H D
X X D
b c
metathesis
or no reaction
X = I, Br, Cl R2
R1 = H, COOH
R2 = H, COOK
X
a
Reaction conditions: DCOOK/D2O, DMSO, level II of 750 W, 40 sec
COOH
Br
b (98%)
a (100%) c (95%)
RhCl3
No Cat Pd(OAc)2
c (95%) Pd(OAc)2 No Cat a (100%)
RhCl3 RhCl3
b (98%) b (98%)
No Cat Pd(OAc)2
a (100%) c (95%)
COOH
CH2
Br
Br
Scheme 13.9 A 9-reaction parallel matrix under microwave-enhanced
conditions and schematic representation of carousel arrangement.
within 1 min when the reaction was performed under microwave-enhanced condi-
tions (Scheme 13.10) [87]. Therefore one-pot M+3 deuterium labeling in a multi-
functional molecule is achieved using a microwave-enhanced combined hydrogena-
tion/aromatic dehalogenation procedure. Isotopic purity in all three positions was
>95 %.
The screening of the catalytic activity in these reactions is made possible by the
readily available library of various heterogeneous and homogeneous transition metal
catalysts. The use of microwaves ensures that two reactions, each requiring different
times to reach equilibrium under thermal conditions, can now be completed within
a very short interval.
13.3 Microwave-enhanced Detritiation Reactions 453
H D
COOH COOH
RhCl3
D H
Br Br
RhCl3
Pd(OAc)2
Pd(OAc)2
H D
COOH COOH
D H
D D
Conditions for all reactions: catalysts, DCOOK/D2O, DMSO, level II of 750W, 60sec.
Scheme 13.10 Example of multiple deuterium labeling using combined methodology.
13.3
Microwave-enhanced Detritiation Reactions
In the preparation of tritium-labeled compounds there are four stages:
. purchase of the tritiated reagent

. radiochemical synthesis
. storage of reagent/product followed by
. removal of radioactive waste
The first of these can be expensive as also can the last, consequently there is in-
creasing interest in developing procedures which are more efficient than hitherto so
that less radioactive waste is produced in the first place. Some radioactive waste can
be disposed of via the drains but less so to the atmosphere, consequently there is
also increasing interest in the possibility of converting the waste to a suitable reagent
which can then be used in subsequent syntheses even though it is likely that the spe-
cific activity will be somewhat reduced. This philosophy can clearly be seen in the
operation of both the Trisorber and Tritech tritium gas units which have replaced the
old glass gas lines. In both instruments, the tritium gas is stored on an uranium
ªgetterº which on warming, releases a predetermined amount of T2 into the reaction
vessel. On completion of the reaction, any surplus gas is returned to a secondary bed
where it can be stored before use in a subsequent reaction.
Of all the methods used to tritiate organic compounds hydrogen isotope exchange
stands on its own by virtue of the fact that it is the only truly reversible reaction. Con-
sequently the benefits that have emerged from the study of microwave-enhanced hy-
drogen±tritium exchange should be immediately transferable to tritium±hydrogen
exchange. By performing the reaction in a good microwave solvent such as water, a
tritiated compound or mixture of compounds could be ªdecontaminatedº and the
HTO formed used in further tritiation studies, albeit at a lower level of specific activ-
Tab. 13.4 Microwave-enhanced and thermal detritiation of [ 3H]-oils.

Raney Nickel
CH2T H2O CH2H
Microwaves
T H
T H
HTO
[ 3H]-Oil Original activity Thermal detritiation Microwave detritiationa

(kBq mg±1) % detritiation Time (h) % Detritiation Time (min)
1 140 62 b 48 60 562
2 1128 89 c 48 87 562
3 2.1 60 c 66 43 562
4 2.2 70 c 66 71 562
a
Microwave power set at level I (25 %) of 750 W
b
at 120 8C
c
at 180 8C
ity. If the specific activity requirements are not too demanding the whole tritiation/
detritiation cycle could be repeated several times, thereby making much better use of
the tritiated water.
The first example [88] that we encountered was of an oil that had been exposed to
a harsh tritium rich environment for a considerable time and had a level of radioac-
tivity in the 2.1±2.2 kBq mg±1 range. An inactive oil, as represented by its 1H NMR
spectrum, had an identical composition and was used as a model compound. Based
on previous work on shale oils [89] and engine basestocks [90] we knew that Raney
Nickel could catalyze the hydrogen±tritium exchange reactions although the thermal
reactions required high temperature (>180 8C) and long reaction times (48±66 h).
However under microwave-enhanced conditions 5 6 2 min pulses was sufficient to
exchange 60±90 % of the tritium in the oils; repeating the procedure led to further
detritiation (Tab. 13.4). Although these studies were performed on a small scale there
is no reason why, as for other microwave-enhanced reactions, the scale of the opera-
tion can not be increased, or, alternatively a flow system designed.
13.4
Microwave-enhanced PET Radiochemistry
Positron emission tomography (PET) employs radiotracers and radioligands contain-

ing positron emitters e. g. 11C, 13N and 18F in organic molecules, to study physiologi-
cal, biochemical and pharmacological functions in humans at the molecular level
[64, 91]. All of the three above-mentioned radionuclides have very short half-lives ±
11
C (20.4 min), 13N (10 min) and 18F (110 min); consequently in order to achieve
high radiochemical yields and specific activities the labeling procedures need to be
rapid, simple to perform and the products easy to purify. Automation provides
further benefits whilst the need to use reactants on a micro scale requires a good ap-
preciation of both the reaction stoichiometry and the factors that influence the rates
of chemical reactions.
Because of these requirements, and in particular, the need to perform the reac-
tions rapidly, it is not surprising that microwaves were used in the PET synthesis
area at a very early stage [92]. However, the subsequent increase has not been as dra-
matic as one might have anticipated. Two recent reviews [8, 9] give an up-to-date pic-
ture whilst here we present some noteworthy examples.
13.4.1
11
C-Labeled Compounds
The most widely used synthetic routes follow on closely from those adopted for 14C
syntheses ± a small number of key precursors such as 11CO2, 11CN±, 11CH3I and
H11CHO are sufficient to label a wide range of compounds. O-, N- and S-alkylation
can be achieved using 11CH3X (X = I, OTf) [93, 94]. Through the use of microwaves
the time required to synthesize [N-methyl-11C]Flumazenil can be reduced from 5 to
0.5 min, accompanied by a 20 % improvement in yield. Further improvements can
be achieved by changing the solvent, in this case from acetone to dimethylforma-
mide (Scheme 13.11) [93].
[11C]-Cyanide is a secondary precursor, produced from 11CO2, but nevertheless as
a result of microwave-enhanced accelerations can be used to label a wide range of
amines, acids, esters and alcohols. Such an example is illustrated in Scheme 13.12
[95±98]. Reactions with less reactive substrates can be achieved by increasing the po-
larity of the reaction medium through the addition of various salts.
[11C]-formaldehyde has been widely used for reductive methylation reaction but
because of the marked fluctuation in the reported yields as well as impurities formed
in its preparation from 11CO2 the tendency has been to use 11CH3I for direct methy-
lation. However, the recent development [99, 100] of a low temperature no-carrier-
added method for preparing H11CHO, coupled to the microwave-enhanced Eschwei-
ler±Clarke reaction [65±68] has led to a resurgence of interest in the use of H11CHO.
N N N
CO2Et CO2Et CO2H
N 11
N N
CH3I NaOH
F N F N F N
H 11 11
O O CH3 O CH3
In acetone
5 min, 70 C, 45% 2 min, 70 C, 40%
0.5 min, 100W, 65% 0.5 min, 100W, 60%
in DMF
0.5 min, 50W, 80% 0.5 min, 50W, >95%
11
Scheme 13.11 Synthesis of [N-methyl- C]flumazenil acid.
O Cl
11
CN- LAH, THF
EtOH HO 11
CH2NH2 2 min, r.t. 90%
O
H2SO4
O 11 HO 11 0.25 min, 75W
CN COOH
or 5 min, 120 °C
0.25 min, 100W 90%
or 2 min, 80 °C HCl(g), EtOH
91% HO 11
COOEt 0.5 min, 75 W
or 10, 80 °C
LAH, THF 93%
HO 11 2 min, r.t. 89%

CH2OH
11
Scheme 13.12 Synthesis of various C-labeled amines, acids, esters and alcohols.
In their study Roeda and Crouzel shower that the LAH reduction of 11CO2 produced
34 % H11CHO plus 59 % H11COOH. Our experience in using a mixture of DCHO
and DCOOH for the N-methylation of both primary and secondary amines suggests
that the corresponding [11C]-mixture would be ideal for the 11C-labeling of amines
under microwave-enhanced conditions.
13.4.2
18
F-labeled Compounds
Substitution of fluorine for hydrogen in an organic compound causes little or no steric

perturbation. However, as a result of its greater electronegativity and high C±F bond
energy, the chemical and biological properties will be different. The much longer half-
life, relative to 11C, provides much greater scope for microwave-enhanced reactions, of
which nucleophilic substitution, either aromatic or aliphatic, is the most widely used.
Three examples of the former are given in Scheme 13.13 [101±103].
In a series of comparative studies Dolle et al. examined the nucleophilic aromatic
substitution of a number of nitropyridine derivatives [104±106]. The results, as sum-
marized in Scheme 13.14, show that under microwave-enhanced conditions the
2-NO2 and 2-+NMe3 groups led to excellent fluorine incorporation whilst the 2-iodo
compound was virtually unreactive. Under thermal conditions no fluorination was
observed for the 2-chloro and 2-bromo compounds. In a separate study Banks et al.
[107] again observed the beneficial effects of nitro and trimethylamino substitution
(Scheme 13.15). The authors also developed a novel microwave-enhanced method of
producing [18F]-fluoromethane [108].
The use of microwaves, together with the involvement of a suitable protection
group, can also be beneficial in reducing isotopic dilution as shown in Scheme 13.16
Scheme 13.13 Examples of aromatic

nucleophilic substitutions used in the
synthesis of 18F-labeled radiopharmaceu-
ticals. H
O
H H
O
O2N 18
(CH3(CH2)4N F
DMSO
H
O
H H
O
18F Oil bath 148 °C 45 min 75%
Microwave 250W 45s 70-83%
OCH3 N
N
N N NO2
O
+18 -
[K2.2.2] F
DMSO
OCH3 N
N
N N 18 F
O
Heating block 150 °C 20 min 16%
Microwave 500W 3 min 40%
H
N S
N NO2
N
O
1 8 F-/DMF O
K2.2.2/K 2 CO3
H
N S
N 1 8F
N
O
O
microwave 575 W 3min 23%
Oil bath 130 °C 30 min
[18F]KF-K2.2.2 Scheme 13.14 Substituent ef-

DMSO fects in the microwave-enhanced
nucleophilic fluorination of a num-
N X N 18F
ber of pyridine derivatives.
+
X= Cl Br I NO2 N (CH3)3
50W, 4 min 26% 68% 8% 76% 96%
100W, 2 min 22% 71% 14% 88% 90%
O
O
R
[18F]KF-K2.2.2 R
DMSO
X 18
F
700W, 2.5 min
+ - + - + -
X= 4-NO2 2-NO2 4-N (CH3)3TfO 2-N (CH3)3TfO 4-I 4-N (CH3)3TfO
R= H H H H H CH3
63% 77% 3%
Scheme 13.15 Substituent effects in the microwave-enhanced
nucleophilic fluorination of bifunctional radiopharmaceutical
intermediates.
18F-
O O K2CO3/K2.2.2 O
X X DMF 18F
OEt N N
F F F
F F F
X = Br, F H+
O
18F
OEt
F
F
Heating block 20 min 110 °C

Microwave 15-30s 50W
Scheme 13.16. Protection±deprotection strategy in
microwave-enhanced fluoro-debromination reaction.
[109]. Formation of the oxazoline reduced undesirable 18F±19F exchange and the de-
sired product was rapidly (15s) isolated in good yield (45±55 %) with a specific activ-
ity (1.1 GBq mmol±1) that was 20 times higher than that obtained when using direct
debromination route. In another example, the synthesis of 2-deoxy-2-18F-fluoro-d-
glucose [110] the high purity of the product and the improved specific activity is at-
tributed to the short reaction times that are made possible via the use of micro-
waves.
References 459
13.5
Conclusion
From an early stage in the development of modern chemistry, it has been customary
practice to simplify complex problems by the selective use of isotopes. For example,
in the area of catalysis, relatively simple reactions such as hydrogen isotope ex-
change or hydrogenation reactions, have been investigated in order to delineate
some of the finer details of reaction mechanisms. This information has then been
applied so as to optimize the procedures that have been developed for labeling or-
ganic compounds. The last fifty years has seen the emergence of several, now large
companies, specializing in these areas, as well as many smaller versions.
Now, with the emergence of new, microwave-enhanced technology, the process is
destined to be repeated. In this case, faster, more selective and efficient procedures
will emerge, where levels of radioactive waste will be greatly reduced and a more fa-
vorable, environmentally friendlier image of the chemical industry achieved. The
products so produced can then go on to be used, in the words of Gordon Dean,
sometime Chairman of the US Atomic Energy Commission, ªto treat the sick, to
learn more about disease, to improve manufacturing processes, to increase the pro-
ductivity of crops and livestock, and to help man to understand the basic processes
of his body, the living things about him, and the physical world in which he exists.º
Acknowledgments
The tritium work at Surrey has been generously funded over many years by EPSRC
(previously SERC and at the beginning, SRC), the EU, NATO and the chemical in-
dustry. The task of writing the current chapter was undertaken as part of the EU
sponsored D10 COST Program (Innovative Methods and Techniques for Chemical
Transformations). We are also grateful to Dr Norman De'ath (Radleys Discovery
Technologies) for the loan of the RDT 24 place PTFE carousel reaction station.
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14
Microwave Photochemistry
Petr Kln and VladimÌr CÌrkva
14.1
Introduction
Chemistry under extreme or nonclassical conditions is currently a dynamically devel-

oping issue in applied research and industry. Alternatives to conventional synthetic
or waste-treatment procedures might increase production efficiency or save the en-
vironment by reducing the use or generation of hazardous substances in chemical
production.
Microwave energy is a nonclassical energy source, with ultrasound, high pressure,
mechanical activation, or plasma discharge [1]. Since first reports of the use of MW
heating to accelerate organic chemical transformations [2, 3] over 1000 articles have
been published on the subject of microwave-assisted synthesis and related topics ±
microwave chemistry has certainly become an important field of modern organic
chemistry [4±13]. Microwave activation increases the efficiency of many chemical
processes and can simultaneously reduce formation of the byproducts obtained from
conventionally heated reactions. Chemical processes performed under the action of
microwave radiation are believed to be affected in part by superheating, formation of
hot-spots, polarization, and spin alignment [7, 8, 13]. The existence of a ªspecific mi-
crowave effectº, i. e. a nonthermal effect, in homogeneous reactions has been a mat-
ter of controversy during the past decade [11, 14±17].
Microwave heating has already been used in combination with some other (un)-
conventional activation processes. Such a combination might have a synergic effect
on reaction efficiencies or, at least, enhance them by combining their individual ef-
fects. Application of MW radiation to ultrasound-assisted chemical processes has
been recently described by some authors [18, 19]. Mechanical activation has also
been successfully combined with MW heating to increase chemical yields of several
reactions [1].
There have also been attempts to affect photochemical reactions by use of other
sources of nonclassical activation, for example ultrasound [20, 21]. Combined chemi-
cal activation by use of two different types of electromagnetic radiation, microwave
(MW) and ultraviolet (UV)/visible (VIS), is covered by the field broadly called micro-
wave photochemistry. The energy of MW radiation is considerably lower than that of

ISBN: 3-527-30514-9
464 14 Microwave Photochemistry
UV radiation, certainly not sufficient to disrupt the bonds of common organic mole-
cules. We therefore assume that, essentially, photoinitiation is responsible for a che-
mical change and MW radiation subsequently affects the course of the reaction. The
objective of microwave photochemistry is frequently, but not necessarily, connected
to the electrodeless discharge lamp (EDL) which generates UV radiation when
placed in the MW field.
This chapter presents a complete picture of current knowledge about microwave
photochemistry. It provides the necessary theoretical background and some details
about synthetic and other applications, the technique itself, and safety precautions.
Although microwave photochemistry is a newly developing discipline of chemistry,
recent advances suggest it has a promising future.
14.2
Ultraviolet Discharge in Electrodeless Lamps
The electrodeless discharge lamp (EDL) [22] consists of a glass tube (ªenvelopeº)
filled with an inert gas and an excitable substance and sealed under a lower pressure
of a noble gas. A high-frequency electromagnetic field (radiofrequency or MW: 300±
3000 MHz) can trigger gas discharge causing the emission of electromagnetic radia-
tion. This phenomenon has been studied for many years [23] and was already well
understood in the nineteen-sixties [24]. The term ªelectrodelessº means that the
lamps lack the electrodes within the envelope. Meggers [24] developed the first EDL
using the mercury isotope 198Hg in 1942 (Fig. 14.1) and its earliest application was
in absorption spectroscopy [25]. EDL is usually characterized by a higher emission
intensity than that of hollow cathode lamps, lower contamination, because of the ab-
sence of the electrodes [26], and a longer lifetime [27].
Fig. 14.1 The electrodeless mercury lamp made by William

F. Meggers. With permission from the National Institute of
Standards and Technology, Technology Administration,
US Department of Commerce.
14.2 Ultraviolet Discharge in Electrodeless Lamps 465
electrostatic EDL
plasma waves
(b) (d)
electromagnetic (c) hot electrons

MW power hν
waves of plasma of plasma
(a) (e)
Fig. 14.2 Block diagram illustrating wave absorption; (d) collisional or colli-
the operation of EDL: (a) energy flows sionless dumping; (e) collisional excita-
from a MW source into the plasma tion of atoms and ions followed by
chamber; (b) collisional or collisionless emission. Adapted from Ref. [28].
transformation; (c) normal or nonlinear
14.2.1
Theoretical Aspects of the Discharge in EDL
The theory of EDL operation, as it is currently understood, is shown in the block dia-
gram in Fig. 14.2 [28]. Free electrons in the fill (i. e. electrons that have become sepa-
rated from the environment because of the ambient energy) accelerate as a result of
the electromagnetic (EM) field energy. They collide with the gas atoms and ionize
them to release more electrons. The repetitive effect causes the number of electrons to
increase significantly over a short period of time, an effect known as an ªavalancheº.
The electrons are generated by processes including collisional or collisionless transfor-
mation of EM waves, and normal or nonlinear wave absorption [26]. The energetic elec-
trons collide with the heavy-atom particles present in the plasma, exciting them from
a ground state to higher energy levels. The excitation energy is then released as EM
radiation with spectral characteristics which depend on the composition of the envel-
ope. The excited molecular or atomic species in the plasma can emit photons over
very broad region of the EM spectrum, ranging from X-rays to the IR [29].
14.2.2
The Fundamentals of EDL Construction and Performance
The EDL system is modular and consists of two basic parts, a gas filled bulb and a
power supply with waveguides or external electrodes. A typical EDL consists of a
scaled (usually quartz) tube envelope, which contains an inert gas (such as a noble
gas) and an excitable substance (e. g. Hg, Cd, Na, Ga, In, Tl, Sc, S, Se, or Te) [30]. The
envelope material must be impermeable to gases, an electrical insulator, and chemi-
cally resistant to the filling compounds at the temperature of operation.
Historically four basic methods have been used to excite discharges without elec-
trodes [31±35]. In the first method, referred as the capacitive coupling, the electric
field lines of the applied EM signal (usually 915 MHz) originate from one external
electrode, pass through the gas-filled bulb containing the discharge, and terminate
at a second external (coaxial) electrode. This discharge is similar to arc discharge in
an electrode lamp, but needs a higher current. The second method of exciting EDL
with MW power (typically 2450 MHz) is to place the bulb in the path of radiation
from a directional antenna. The microwave discharge is excited by both electric and
magnetic components of the EM field. Because free propagation of the MW power
occurs, however, emission is often inherently inefficient. This method is used for ex-
citation of EDL inside a MW oven. The third method is called the traveling wave dis-
charge ± a gap between the external electrodes provides the electric field that
launches a surface wave discharge. The fourth method uses the inductive coupling of
EDL and the system can be compared with an electrical transformer. An alternating
current in the coil generates a changing magnetic field inducing the electric field
that drives a current into the plasma. The operating frequency is limited to approxi-
mately 50 kHz [36].
The operating conditions affecting electrodeless lamp performance are a combina-
tion of many factors [30]:
. The inert gas. The arc chamber contains a buffer noble gas (usually Kr, Xe, or Ar)
which is inert to the extent that it does not adversely affect the lamp operation. He-
lium has a higher thermal conductivity than other noble gases and, therefore,
higher thermal conduction loss is observed [37]. The inert gas easily ionizes at low
pressure but its transition to the thermal arc is slower and the lamp requires a
longer warm-up time. Ionization is more difficult at higher pressures and it re-
quires a higher input power to establish the discharge. The pressure in the EDL at
the operating temperature is usually much higher (5±20 atm) than that of a con-
ventional electrode lamp.
. The choice of the fill material initiating the discharge is very important. Together
with a standard mercury fill it is often desirable to incorporate an additive in the
fill material that has a low ionization potential [38, 39]. One category of low-ioniza-
tion-potential materials is the group of alkali metals or their halides (LiI, NaI) but
some other elements, such as Al, Ga, In, Tl [40, 41], Be, Mg, Ca, Sr, La, Pr, or Nd
[23, 37, 42], can be used.
. The dimensions and properties of the lamp envelope are based on the discovery that
the volume of Hg is critical for the effective UV operation [43]. Higher Hg pres-
sures result in the need to use higher MW power levels. To focus the MW field effi-
ciently into the EDL a special Cd low-pressure lamp with a metal antenna (a mo-
lybdenum foil) was developed by Florian and Knapp [44].
. The nature and characteristics of the EM energy-coupling device are discussed in
Sect. 14.2.3.
. The frequency and intensity of EM energy is determined by the type of a device.
A standard MW power source operates around 915 or 2450 MHz.
14.2.3
Spectral Characteristics of EDL
The spectral characteristics of EDL are of a general interest in microwave photo-

chemistry. The right choice of filling material can provide a desirable ultraviolet ra-
diation. Atomic fills usually furnish line emission spectra (e. g. that of an Hg-EDL is
Fig. 14.3 Emission spectrum of MW-powered Hg-EDL [44].

With permission from the American Chemical Society.
shown in Fig. 14.3) and molecular fills give continuous spectra [45]. The total emis-
sion output of Hg-EDL in the region of 200±600 nm is approximately the same as
that of the electrode lamp with the same power input [46]. The distribution of radia-
tion is, however, markedly different, as a result of much higher Hg pressure and the
greater number of atoms that can participate in the plasma. EDL emit over three
times as much UV and less than a half as much IR as a conventional lamp [47]. It
has been noted that EDL and electrode lamps furnish different spectra when the fill
includes a rare-earth material but similar spectra when a nonrare-earth fills are used
[48]. Addition of some elements (Sn, Pb, Ga) has a very significant effect on the spec-
tral distributions of the EDL [46]. Most lamps emit less efficiently below 280 nm
than a standard Hg lamp (Tab. 14.1). The advantages of EDL for microwave photo-
chemical applications are discussed in the Sect. 14.3.
14.3
Microwave Photochemical Reactor
The microwave photochemical reactor is an essential tool for experimental work in

this field. Such equipment enables simultaneous irradiation of the sample with both
MW and UV/VIS radiation. The idea of using an electrodeless lamp (EDL), in which
the discharge is powered by the MW field, for photochemistry was born half a cen-
tury ago [46, 68]. The lamp was originally proposed as a source of UV radiation only,
Tab. 14.1 Filling compounds and the wavelength of EDL emission.
Filling material Excited species Main emission bands, k (nm) References

(filling gas)
Hg (Ar) Hg 185, 254, 365, 405, 436, 546 30, 31, 43, 44, 48±50
Cd (Ar) Cd 229, 326 30, 44, 51
SnI2 (Ar) SnI2 400±850, 610 52
FeCl2 (Ar) Fe 248 30
Zn (Ar) Zn 214 30, 44, 53
CuCl (Ar) Cu 325 30
NaI (Xe, Kr) Na 589 54, 55
Mg, H2 (Ar) MgH 518, 521, 480±560 56
AlBr3 (Ne) AlBr 278 57
AlCl3 (Ne) AlCl 261 58, 59
Ga, GaI3 (Ar) Ga 403, 417, 380±450 49, 53
InI3 (Ar) In 410, 451 53
TlI (Ar) Tl 277, 535 30, 53
PCl4 (Kr) P2 380 60
S (Ar) S 350±850, 525 40, 61, 62
Se (Ar, Xe) Se 370±850, 545 62±64
Te (Xe) Te 390±850, 565 62, 64
Ar (Ar) Ar2 126, 107±165 29, 65
Ar, Cl2 (Ar) ArCl 175 29, 65
Xe, Cl2 (Xe) XeCl 308 29, 65
B2O3, S (Kr) B2S3 812 66
I2, HgI2 (Ar) I 206 67
without considering the effects of microwaves on photochemical reactions. The first

applications of EDL were connected with the construction of a high-intensity source
of UV radiation for atomic fluorescence flame spectrometry [69±71].
Gunning, Pertel and their coworkers reported the photochemical separation of mer-
cury isotopes [72±75] in a flow reactor which consisted of a microwave-operated dis-
charge lamp [76, 77] cooled by a flowing film of water. A filter cell and a circulation sys-
tem, preventing the filter solution and the cell from being heated, were placed concen-
trically and coaxially with the lamp. A similar reactor, for small-scale laboratory photo-
lysis of organic compounds in the solution or gas phase, has been proposed by Den
Besten and Tracy [78]. In this arrangement, EDL was placed in a reaction solution and
was operated by means of an external microwave field from a radio- or microwave-fre-
quency transmitter (Fig. 14.4). The lamp quantum output was controlled by changing
the output of the transmitter or by using a dilute ionic solution circulating through
the cooling jacket. For maximum lamp output a weakly conducting solution has been
proposed. Placing the EDL into the solution was quite advantageous, because the full
quantum output was utilized. The authors recommended keeping the sample tem-
perature low, because EDL produce a substantial amount of heat.
Use of a domestic microwave oven has appeared in a patent [79], according to
which gaseous reactants were irradiated with microwave and UV/VIS radiation to
Fig. 14.4 Apparatus for electrodeless photochemical irradiation.

A. antenna, B. transmitter, C1. capacitor, C2. variable capacitor,
D. jacketed flask, E. EDL, F. reaction mixture, G. circulating cool-
ant. Adapted from Ref. [78].
produce desired photoproducts (the EDL was positioned inside the MW cavity,
although outside the reaction vessel). Several similar reactors have been proposed
for UV sterilization [80±82] or for treatment of waste water containing organic pollu-
tants [83±85].
CÌrkva and Hjek have proposed a simple application of a domestic microwave
oven for microwave photochemistry experiments [86]. In this arrangement, the EDL
(the MW-powered lamp for this application was specified as a microwave lamp or
MWL) was placed in a reaction vessel located in the cavity of an oven. The MW field
generated a UV discharge inside the lamp that resulted in simultaneous UV and
MW irradiation of the sample. This arrangement provided the unique possibility of
studying photochemical reactions under extreme thermal conditions (e. g. Ref. [87]).
Kln et al. published a series of papers that described the scope and limitations of
this reactor [88±91]. In a typical design (Figs. 14.5 and 14.6) four holes were drilled
Fig. 14.5 A modified MW oven for mi-

crowave photochemistry experiments.
A. magnetron, B. reaction mixture with
the EDL and a magnetic stir bar, C. alu-
minum plate, D. magnetic stirrer, E. in-
frared pyrometer, F. circulating water in
a glass tube, G. dummy load inside the
oven cavity [88]. With permission from
Elsevier Science.
Fig. 14.6 Photochemistry in a

microwave oven (the EDL floats
on the liquid surface).
into the walls of a domestic oven ± one for a condenser tube in the oven top, another
in the side for an IR pyrometer, and two ports for a glass tube with circulating water.
Part of the oven bottom was replaced with an aluminum plate to enable magnetic
stirring. The opening for the IR pyrometer could also serve for an external (addi-
tional) source of UV radiation. The vessel was connected to a very efficient water-
cooled condenser by means of a long glass tube. The circulating cool water or a MW-
absorbing solid material (dummy load ± basic Al2O3, molecular sieve, etc.) were
used when a small quantity of a non- or poorly absorbing sample was used for mi-
crowave photochemical experiments. The material removed excess microwave power
and prevented the magnetron from being destroyed by overheating.
The EDL had always to be placed in a position, in which the solvent cooled it effi-
ciently, because lamp overheating might cause failure of lamp emission. Intense IR
output from the lamp triggered immediate boiling of all solvents including nonpolar
(MW-transparent) liquids [89, 90]. Polar solvents, on the other hand, absorbed most
of MW radiation, resulting in reduction of UV output efficiency. Tab. 14.2 depicts the
most important advantages and disadvantages of EDL applications.
Chemat and his coworkers [92] have proposed an innovative MW±UV combined
reactor (Fig. 14.7) based on the construction of a commercially available MW reactor,
the Synthewave 402 (Prolabo) [9]. It is a monomode microwave oven cavity operating
at 2.45 GHz designed for both solvent and dry media reactions. A sample in the
quartz reaction vessel could be magnetically stirred and its temperature was moni-
tored by means of an IR pyrometer. The reaction systems were irradiated from an ex-
ternal source of UV radiation (a 240-W medium-pressure mercury lamp). Similar
photochemical applications in a Synthewave reactor using either an external or inter-
nal UV source have been reported by Louerat and Loupy [93].
A microwave-assisted, high-temperature, and high-pressure UV digestion reactor
has been developed by Florian and Knapp [44] for analytical purposes. The appara-
tus consists of the immersed electrodeless discharge lamp operating as a result of
the MW field in the oven cavity (Fig. 14.8). An antenna fixed to the top of EDL en-
hanced the EDL excitation efficiency. Another interesting MW±UV reactor has
Tab. 14.2 Advantages and disadvantages of EDL applications in photochemistry. Adapted from
Ref. [90].
Advantages
Simultaneous UV and MW irradiation of the sample

Possibility of performing photochemistry at high temperature
Good photochemical efficiency ± the EDL is ªinsideº the sample
Simplicity of the experiment and the low cost of the EDL
Use of a commercially available microwave oven
ªWirelessº EDL operation
Choice of the EDL material might modify its spectral output
Disadvantages
Technical difficulties of performing experiments at temperatures below the solvent b.p.

Greater safety precautions
EDL overheating causes lamp emission failure
Polar solvents absorb MW radiation, thus reducing the UV output efficiency of the EDL
Fig. 14.7 A reactor for microwave

photochemistry derived from the
Synthewave 402 (Prolabo). A. medium-
pressure Hg lamp, B. window hermetic
to MW radiation, C. reaction mixture, D.
magnetron, E. regulator, F. IR sensor.
Adapted from Ref. [92].
been designed by Howard and his coworkers [94]. A beaker-shaped electrodeless

discharge lamp, placed in a modified domestic MW oven has been used for miner-
alization of organophosphate compounds. The samples in quartz tubes were posi-
tioned in a carousel inside an open UV beaker; they were thus efficiently photo-
lyzed from the whole surface of the beaker.
Microwave-enhanced chemistry introduces unique safety considerations that are
not encountered by the chemist in other fields of chemistry [95]. Careful planning of
all experiments is strongly advised, especially when the results are uncertain, be-
cause control of reaction temperature might be complicated by rapid heat-transfer
mechanisms. It is, furthermore, well known that electronically excited singlet oxy-
gen, capable of causing serious physiological damage, is generated by microwave dis-
Fig. 14.8 Simplified schematic diagram of a high-pressure digestion ves-

sel with an EDL. A. plug and seal, B. quartz pressure reaction vessel with
a sample solution, C. EDL with an antenna, D. vessel jacket with a screw
cap, E. air flow. Adapted from Ref. [44].
charge through an oxygen stream [96]. The combined effect of MW and UV irradia-
tion could increase the singlet oxygen concentration in the MW cavity, particularly in
the presence of a photosensitizer.
14.4
Microwave Photochemistry
14.4.1
Interactions of Ultraviolet and Microwave Radiation with Matter
Although microwave chemistry has already received widespread attention from the
chemical community, considerably less information is available about the effect of mi-
crowave radiation on photochemical reactions. Photochemistry is the study of the in-
teraction of ultraviolet or visible radiation (E = 600±170 kJ mol±1 at l = 200±700 nm)
with matter. The excess energy of electronically excited states significantly alters spe-
cies reactivity ± it corresponds, approximately, to typical reaction activation energies
helping the molecules overcome activation barriers. The microwave region of the elec-
tromagnetic spectrum, on the other hand, lies between infrared radiation and radio
frequencies. Its energy (E = 1±100 J mol±1 at n = 1±100 GHz) is approximately 3±6 or-
ders of magnitude lower than that of UV radiation (a typical MW kitchen oven oper-
ates at 2.45 GHz). Microwave heating is not identical with classical external heating,
at least at the molecular level. Molecules with a permanent (or induced) dipole re-
spond to an electromagnetic field by rotating, which results in friction with neighbor-
ing molecules (thus generating heat). Additional (secondary) effects of microwaves in-
clude ionic conduction (ionic migration in the presence of an electric field) and spin
alignment.
Fig. 14.9 Simplified model of nonsynergic effects of UV and MW

MW radiation on a chemical reaction. M R
MW
UV
M* I P
Simultaneous UV/VIS and MW irradiation of molecules, which does not necessa-

rily cause any chemical change, might affect the course of a reaction by a variety of
mechanisms at each stage of the transformation. From many possibilities, let us pre-
sent a simplified model describing two main distinct pathways (Fig. 14.9). The first
route, more probable, is a photochemical reaction starting with a ground state mole-
cule, M, which is excited electronically to M*, transformed into an intermediate (or a
transition state) I, and, finally, a product, P. Virtually each step may be complicated
by a parallel microwave-assisted reaction enabling a different chemical history. There
is a theoretical possibility that MW radiation affects the electronically excited mole-
cule M* or a short-lived transition state. In such circumstances the lifetime of the
species should be long enough to provide a sufficient time for interaction with this
low-frequency radiation. The second pathway becomes important when MW initiate
a ªdarkº chemical reaction (essentially through polar mechanisms), competitive or
exclusive to a photochemical pathway, yielding a different (R) or the same (P) pro-
duct. Fig. 14.9 depicts a model in which MW and UV effects are easily distinguish-
able ± it is assumed there is no synergic effect during a single step of the transforma-
tion.
Let us, on the other hand, assume that the efficiency of a photoreaction is altered
by microwave induction. In an example shown in Fig. 14.10, microwave heating af-
fects the excitation energy of the starting ground state molecule. The individual ef-
fects of both types of electromagnetic radiation simultaneously influence a single
chemical step in which the ground state molecules M and MD (a MW-heated mole-
cule) are being excited. If, furthermore, the intermediates I and ID react with differ-
ent rate constants, the total observed rate constant kobs of the reaction is proportional
to the sum (wkr + wDkDr ), where w and wD represent the populations of I and ID.
M hν
Fig. 14.10 A simplified model of the ∆T (MW)
synergic effect of UV and MW radia- ∆T (MW) M* I I∆
tion on a chemical reaction, where
depicts ªhotº molecules, and kr and kr M∆ hν' kr kr∆
are the rate constants of the pro- P
14.4.2
Photochemical Reactions in the Microwave Field ± Thermal Effects
Baghurst and Mingos have hypothesized that superheating of polar solvents at atmo-
spheric pressure, so that their average temperatures are higher than the correspond-
ing boiling points, occurs as a consequence of dissipation of the microwaves
throughout the whole volume of a liquid [97]. With the absence of nucleation points
necessary for boiling heat loss occurs at the liquid/reactor wall or at liquid/air inter-
faces. Many reaction efficiency enhancements reported in the literature have been
explained as the effect of superheating when the reactions were essentially per-
formed in sealed vessels without stirring [98±102]; this effect is also expected in mi-
crowave photochemistry experiments in condensed media. Gedye and Wei [15], for
example, have observed enhancement of the rate of several different thermal reac-
tions by factors of 1.05±1.44 in experiments accomplished in a domestic-type MW
oven but not in a variable-frequency microwave reactor. The enhancement was inter-
preted as a consequence of solvent superheating or hot-spot formation rather than
nonthermal effects. Stadler and Kappe reported similar results in an interesting
study of the MW-mediated Biginelli reaction [14].
Kln et al. [91] successfully evaluated MW superheating effects in polar solvents
by use of a temperature dependent photochemical reaction. It is known that quan-
tum efficiencies of the Norrish type II reaction [103] for a mixture of some p-substi-
tuted valerophenones depend on the presence of a weak base, because of specific hy-
drogen-bonding to the biradical OH group (BR; Sch. 14.1) [88, 91]. This reaction pro-
vided linear temperature dependence of the efficiency over a broad temperature re-
gion and the system served as a photochemical thermometer at the molecular level,
even for the MW-heated mixtures. The magnitude of the photochemical change in
the MW field suggested the existence of superheating effect (4±11 8C) for three ali-
1. h ν
O H H 2. ISC
* O H H
3
R CH3 R CH3
R = H, CH3 solvent
H
O H OH H
∆T
R CH3 R CH3
solvated BR BR
HO
O
R +
R
Scheme 14.1
Scheme 14.2
O
UV or MW OH
O
bentonite
O O
O
Fig. 14.11 Reaction yields in the rearrangement of 2-benzoyloxyaceto-

phenone induced by microwave heating (*), ultraviolet irradiation (*),
or simultaneous UV and MW irradiation (~). Adapted from Ref. [92].
phatic alcohols and acetonitrile. The results were in a perfect agreement with mea-
surements by use of a fiber-optic thermometer.
Chemat and his collaborators [92] reported the UV- and MW-induced rearrange-
ment of 2-benzoyloxyacetophenone, in the presence of bentonite, into 1-(o-hydroxy-
phenyl)-3-phenylpropane-1,3-dione in methanol at atmospheric pressure (Sch. 14.2).
The reaction, performed in the reactor shown in Fig. 14.7, was subject to a signifi-
cant activation effect under simultaneous UV and MW irradiation; this corresponded
at least to the sum of the individual effects (Fig. 14.11). The rearrangement, however,
was not studied in further detail. Such competitive processes can be described by the
diagram in Fig. 14.9, because the product obtained from both types of activation was
the same.
CÌrkva and Hjek [86] studied a photochemically or microwave-induced addition
of tetrahydrofuran to perfluorohexylethene (Sch. 14.3). Whereas the thermal reaction
was too slow, photochemical activation was very efficient, with no apparent thermal
effects of MW radiation. Combined UV and MW radiation has principally been used
to initiate EDL operation in the reaction mixture (Fig. 14.5). Another illustration of
the MW±UV-assisted reaction has been demonstrated by Nçchter et al. [1] on dehy-
drodimerization reactions of some hydrocarbons. Zheng et al. [104, 105] reported
microwave-assisted heterogeneous photocatalytic oxidation of ethylene using porous
TiO2 and SO2± 4 /TiO2 catalysts. Significant enhancement of the photocatalytic activity
was attributed to the polarization effect of the highly defected catalysts in the MW
field. Louerat and Loupy studied some photochemical reactions (e. g. stilbene iso-
merization) in homogenous solutions and on solid supports such as alumina [93].
UV (MW )
H2C CH (CF2) 5-CF3 + CH2 CH2 (CF2) 5-CF3
O O
Scheme 14.3
Product distributions and reaction conversions of several different photochemical

systems, irradiated by conventional UV source and by EDL in a MW±UV reactor
(Fig. 14.5), were compared to elucidate the advantages and disadvantages of a micro-
wave photochemical reactor [90]. Some reactions, e. g. photolysis of phenacyl benzo-
ate in the presence of triethylamine or photoreduction of acetophenone by 2-propa-
nol, were moderately enhanced by MW heating. The efficiency of chlorobenzene
photosubstitution in methanol, on the other hand, increased dramatically with in-
creasing reaction temperature.
14.4.3
Nonthermal Microwave Effects ± Intersystem Crossing in Radical-recombination
Reactions
Radical pairs and biradicals are extremely common intermediates in many organic
photochemical (and some thermal) reactions. A singlet state intermediate is
formed from the singlet excited state in reactions that conserve spin angular mo-
mentum whereas the triplet intermediate is obtained via the triplet excited state.
Radical pairs in solution coherently fluctuate between singlet and triplet electronic
states [106, 107] and the recombination reactions are often controlled by electron±
nuclear hyperfine interactions (HFI) on a nanosecond time scale [108, 109]. Only
a pair of the neutral radicals with singlet multiplicity recombines. A triplet pair
intersystem crosses into the singlet pair or the radicals escape the solvent cage
and react independently at a later stage (Fig. 14.12) [110]. The increasing effi-
ciency of triplet-to-singlet interconversion (`mixing' of states) leads to a more rapid
recombination reaction and vice versa. It is now well established that a static mag-
netic field can effect intersystem crossing in biradicals (magnetic field effect,
MFE) and the effect has been successfully interpreted in terms of the radical pair
mechanism [111, 112]. This concept enabled explanation of nuclear and electronic
spin polarization phenomena during chemical reactions, e. g. chemically induced
dynamic nuclear polarization (CIDNP) or reaction yield-detected magnetic reso-
nance (RYDMAR).
An external magnetic field that is stronger than the hyperfine couplings inhibits
(because of Zeeman splitting) singlet±triplet interconversions by isolating the tri-
plets T+1 and T±1 from the singlet (S), which can, therefore, mix only with T0
(Fig. 14.12 a, b). For the triplet-born pair, the magnetic field reduces the probability of
radical recombination. The microwave field, which is in resonance with the energy
gaps between the triplet levels (T+1 or T±1) and T0, transfers the excess population
from the T+1 or T±1 states back to a mixed state. Application of a strong magnetic
field to the singlet-born radical pair leads to an increase in the probability of recombi-
nation that can, however, be also controlled by microwave irradiation [112].
'in cage'
R-R recombination
UV
* [R-R]1 [R R]
ISC ISC
radical
* [R-R] 3 [R R] escape
MW
T+1
X
ISC T+1
S T0 S T0
T-1 X
T-1
'in cage' radical
recombination escape
(a) zero external magnetic field (b) applied external magnetic field
Fig. 14.12 Schematic illustration of magnetic field and

microwave effects in radical-pair chemistry.
These microwave-induced spin dynamics can be considered as an archetype of a

nonthermal MW effect. Because the radical pair (biradical) is usually created by a
photochemical pathway, the topic certainly deserves to be included in the field of mi-
crowave photochemistry. The literature offers many examples that span photobiol-
ogy, photochemistry, and photophysics. Wasielewski et al. [113], for instance, showed
that the duration of photosynthetic charge separation could be controlled with micro-
wave radiation. It was, moreover, possible to observe the dynamics of radical pair
processes that involve primary bacterial photochemistry [114]. Okazaki and his colla-
borators [115] reported the possibility of controlling chemical reactions by inducing
the ESR transition of the intermediate radical pair in the photoreduction of anthra-
quinone micellar solution under the action of an external magnetic field and simul-
taneous MW irradiation. A similar study with a bifunctional molecule was reported
by Mukai et al. [116]. Research in this field is very well covered by several reviews
and books [111, 112, 117, 118]. Weak static magnetic fields, smaller than an average
hyperfine coupling, also affect radical pair recombination yields [119, 120]. This ef-
fect is opposite to that of a strong field [121, 122].
Little attention has been devoted to the effects of time-dependent magnetic fields
(created by electromagnetic waves) in the absence of a strong magnetic field. Hore
and his coworkers [123±125] recently described this effect as the oscillating magnetic
field effect (OMFE) on the fluorescence of an exciplex formed in the photochemical re-
action of anthracene with 1,3-dicyanobenzene over the frequency range 1±80 MHz.
Another study of the electron-hole recombination of radical ion pairs (pyrene anion
and dimethylaniline cation) in solution has appeared recently [126]. Triplet±singlet in-
terconversions as a result of HFI are relatively efficient in a zero magnetic field (to be
more precise, in the Earth's field of ~50 mT). All the states are almost degenerate, as-
suming separation of the radicals is such that their electronic exchange interaction is
negligible [111]. Jackson and his coworkers [127] suggested that the resonance energy
of the oscillating field should be tuned to the HFI in one of the radicals. With a typical
value of HFI in the radicals of 0.1±3.0 mT, the oscillating magnetic field effect, enhan-
cing the conversion of the singlet state to the triplet (as was observed for weak static
fields) is expected in the radiofrequency region (3±80 MHz) [124]. Canfield et al. [128±
130] calculated the effects and proved them experimentally for the radical pairs in-
volved in coenzyme B12-dependent enzyme systems. Other theoretical studies have
appeared in the past 5 years [126, 131, 132]. Whether electromagnetic fields influence
animal and human physiology is still an open question. It has, for example, been sug-
gested that radiofrequency fields might disorient birds [133]. Detailed experimental
studies of OMFE in the microwave region have not yet been performed. Hoff and Cor-
nelissen [134] reasoned in their paper that triplet state kinetics could be affected rather
by a pulse of resonant microwaves than by equilibrium methods in the zero static
field.
According to the OMFE model a weak oscillating magnetic field (the magnetic in-
teractions are much smaller than the thermal energy of the molecule [131]) has no
impact on equilibrium constants or activation energies; it can, however, have im-
mense kinetic control over the reaction of the radicals [131]. The simplified kinetic
scheme in Fig. 14.13 shows the excitation of a starting material R±R' into the singlet
state, which intersystem crosses to the triplet (kisc) and is followed by cleavage (kcl) to
the triplet radical pair. The oscillating magnetic field influences the state of mixing
of the radical pair (kTS and kST). The probability that the triplet radical pair will form
the products is given by the efficiency of radical escape from the solvent cage (kesc)
and of triplet-to-singlet intersystem crossing (kTS). The recombination reaction is
very fast when the tight radical pair reaches the singlet state.
hν
* [R-R'] 1 R-R'
kisc
3
* [R-R'] krec
kcl
kesc kTS
products [R R'] [R R']
kST Fig. 14.13 The oscillating magnetic field
OMFE effect (OMFE) in the triplet state radical pair
reaction.
14.4.4
Analytical and Environmental Applications of Microwave Photochemistry
In addition to analytical applications in which microwaves serve as a power source

for electrodeless discharge lamps, the first successful use of combined MW/UV irra-
diation for efficient degradation of a variety of samples before application of an ana-
lytical method has been reported. Florian and Knapp [44] proposed a novel MW±UV,
high-temperature±high-pressure, digestion procedure for the decomposition of inter-
fering dissolved organic carbon as a part of the trace element analysis of industrial
and municipal wastewater or other liquid samples. Very efficient and fast minerali-
zation was achieved in an original reactor (Fig. 14.8), because of the very high tem-
perature (250±280 8C). The high temperature also enabled dissolution of solid or-
ganic matrixes by use of diluted mineral acids. A Cd low-pressure electrodeless dis-
charge microwave lamp, strongly emitting at l = 228 nm, guaranteed even more effi-
cient degradation than standard mercury UV lamps. The pressurized sealed vessel
did not require a separate cooling device to prevent sample evaporation. Efficient de-
composition of organophosphate compounds, with the aim of colorimetric phos-
phate determination, has been achieved by Howard et al. in a novel beaker-shaped
electrodeless MW±UV lamp [94]. Although no details of the organophosphate de-
composition mechanism were presented, the authors suggested two possible path-
ways. In addition to direct photodegradation, much of the decomposition resulted
from the photochemical generation of hydroxyl and oxygen radicals generated from
dissolved O2 in the samples. The concentration of OH radicals could be enhanced by
addition of hydrogen peroxide.
Photodegradation [135] and microwave thermolysis [136] of pollutants and toxic
agents in waste water, often in combination with a solid catalyst (e. g. TiO2), are two
important methods for their removal. It is, therefore, expected that combined MW±
UV will be even more efficient. Results from the first environmentally relevant stu-
dies have already appeared in the scientific literature and the topic is also covered by
several patents [79, 83±85]. Campanella et al. [137] reported minor but positive en-
hancement of the efficiency of photodegradation of o- and p-chlorophenol by micro-
wave heating. The success of these model chemical systems suggests extension to
other environmentally interesting compounds, e. g. sodium dodecylbenzenesulfo-
nate or organophosphate pesticides. It has been suggested that microwave-assisted
photodegradation of pollutants might be of great interest in the future. Heteroge-
neous catalytic degradation of humic acid in aqueous titanium dioxide suspension
under MW±UV conditions was studied by Chemat et al. [92]. Enhancement in this
application was reported as substantial ± i. e. greater than simple addition of both ef-
fects. Zheng and his collaborators [105] investigated the microwave-assisted photoca-
talytic oxidation of ethylene and trichloroethylene in the presence of water. The reac-
tions also served as a model study for photodegradation of organic pollutants in the
microwave field.
14.5
Industrial Applications
Simultaneous application of UV and MW irradiation has found widespread use in in-

dustry. The techniques are based on the conventional UV lamps and MW-powered
electrodeless lamps and MW devices [28]. The following paragraphs discuss several
patents and papers that describe industrial microwave photochemistry, such as treat-
ment of waste water, sterilization, or industrial photoinduced organic synthesis.
Photolithography is a technique for manufacturing semiconductor devices (i. e.
transistors or integrated circuits). In the process the pattern of an optical mask is
imaged with UV radiation on to a semiconductor wafer coated with a UV-sensitive
photoresist. The main goal is to reduce the size of the components and to increase
their densities. Application of shorter wavelengths (190±260 nm) results in a
greater depth of the focus, i. e. sharper printing. The first EDL applied were made
from a material known as commercial water-containing natural quartz [138]. It was
found that the transmission of the envelope at vacuum UV wavelengths falls off
sharply with time. The lamps developed later from water-free quartz [50] were
much more transparent. Excimer lamps used for photoetching and microstructur-
ing of the polymer surface have been developed for applications in standard MW
ovens [65].
A photochemical apparatus for generating superoxide radicals (O2±) in an oxygen-
saturated aqueous sodium formate solution by means of EDL has been described
[139]. An interesting method of initiating and promoting chemical processes by irra-
diation of starting gaseous materials in the EM field under a lower pressure has
been proposed by Lautenschlåger [79]. EDL (containing GaI3, InI3, or AlI3) with a
ªblueº output are now often used for dental purposes or curing polymers. The very
small size of the lamps makes them particularly useful for supplying light to an opti-
cal fiber or a light pipe [140]. Another example of microwave photochemical treat-
ment of solutions at different wavelengths has been described by Moruzzi [141].
Photooxidation of humic acids caused changes in their absorption and luminescence
properties that might be of a great importance for environmental photophysics and
photochemistry [142]. Aqueous aerated alkaline solutions of the acids were irradiated
with an Hg-EDL in a flow system and analyzed by means of fluorescence, absorp-
tion, and chemiluminescence techniques.
Microwave photochemistry is generally quite advantageous for removal of a toxic
material or pathogens from wastewater. Photochemical oxidation is a process in
which a strong oxidizing reagent (ozone or hydrogen peroxide) is added to water in a
UV-ionizing reactor, resulting in the generation of highly reactive hydroxyl radicals
(OH). The first-generation techniques used commercial EDL (high pressure Hg±Xe
lamps) immersed in the water tanks. The lamps rapidly deteriorated, however, lead-
ing to poor production of hydroxyl radicals. The second generation technique incor-
porated manual cleaning mechanisms and use of a polymer coating (PTFE) on the
quartz sleeve, additional oxidizers (ozone), and catalyzing additives (TiO2) to en-
hance the rate of the OH radical production [143]. A novel UV±oxidation system
used a highly efficient EDL combined with a simple coaxial flow-through reactor de-
14.6 Concluding Remarks 481
sign [85]. In this reactor, a liquid containing contaminants (MTBE, 2-propanol, or

phenol) was pumped from the bottom and flowed vertically upward through the re-
actor vessel against gravity. The mercury UV source was mounted above the reactor
vessel and the radiation was directed downward through the reactor vessel. An H2O2
solution was injected into the liquid being treated and thoroughly mixed by means
of an in-line mixer just before the mixture entered the reactor vessel.
Sterilization techniques for intermittent or continuous destruction of pathogens in
solid films or in organic and biological fluids, without significantly affecting the
properties or physiological characteristics of the medium, have been based on the
biocidal synergism of UV and MW irradiation. UV radiation induces a chemical
modification of DNA in bacteria (usually because of thymine dimerization). The first
apparatus involved a commercial UV-emitting lamp with a separate power source in-
side the chamber of a MW oven and was used for simple sterilization of biological
fluids [144]. An apparatus using an Hg-EDL for surface sterilization or disinfection
of objects such as bottles, nipples, contact lenses, or food, has been proposed by Le-
Vay [81]. A continuous sterilizing apparatus has also been described [145, 146]. In ad-
dition, ozone treatment can be used in combination with UV exposure to sanitize or
disinfect a variety of substances [80, 82, 147±149]. Another application of EDL (con-
taining Hg, Cd/Ar or Kr) for disinfecting aqueous solutions has been recently re-
ported by Michael [150].
14.6
Concluding Remarks
Understanding, on the molecular scale, of processes relevant to microwave photo-

chemistry has not yet reached the degree of maturity of other topics in chemistry.
Such a challenge is somewhat ambitious because of several difficulties. Although
some obstacles have been overcome, study of the effects of microwaves on a photo-
chemical reaction requires a special approach. Microwave photochemistry involves
highly reactive, electronically excited molecules which are exposed to a different
kind of reactivity-enhancing stimulation. Microwave heating strongly interferes with
possible nonthermal effects that cannot be easily separated in the mechanistic stu-
dies. One solution seems to be investigation of the spin dynamics of photochemi-
cally generated biradicals. Many photochemical reactions might be accelerated by
MW treatment if they pass through polar transition states and intermediates, e. g.
ions or ion-radicals. Application of an EDL simplifies the technical procedure, espe-
cially in the field of organic synthesis, environmental chemistry, or analysis. Because
of the lower reproducibility of the experimental results, however, an external UV
source would serve better in kinetic studies.
In this review we have discussed how the concept of microwave photochemistry
has already become an important issue in chemistry. Although still in the beginning,
detailed analysis of past and present literature confirms explicitly the usefulness of
this method of chemical activation. The field has been already established in indus-
try and we hope it will also find its way into conventional chemical laboratories.
Acknowledgments
We would like to thank Milan Hjek and JaromÌr Literk for their participation in
our research projects, and Andr Loupy for fruitful discussions. We also acknowl-
edge the Grant Agency of the Czech Republic (203/02/0879) for financial support.
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487
Index
a alkylation of potassium benzoate 92

acetalization 268, 355 N-alkylation of 2-halopyridines 85
acetanilide 160 O-alkylation 150, 159, 164 f.
acetonitrile 383, 397, 475 C-alkylation of active methylenes 163
acidic cation-exchange resin 371 alkylation with dihalogenoalkanes 164
N-acrylated heterocycles 408 O-alkylcarbamates 228
activated aromatic substrates 86 N-alkylimidazolium cations 212
activated charcoal 220 alkynes 333
activated manganese dioxide±silica 196 allylic alkylations 398
activation barriers 305 allylic aromatic compounds 169
activation energy 64 allylic substitution 380
activation energy barrier 357 a-Al2O3 367
active metal salts 347 alumina 20, 69, 84, 151, 164, 184, 190, 346
active sites 364 alumina doped NaBH4 447
acylation of aromatic compounds 235, 239 alumina-supported nickel catalyst 348
acylative cleavage of ethers 240 alumina-supported potassium permanganate
N-acylimidates 283 200
acylium ion 97 aluminosilicate support 197
addition of CCl3X to styrene 141 amberlite 354
addition of 2-aminothiophenol 137 Amberlyst-15 352, 363
addition of vinylpyrazoles to imine systems ambident 2-naphthoxide anion 93
104 amidation of carboxylic acids 78
addition to a carbonyl group 72 amide 160, 387 f., 388
adsorbed tritium method 439 amines 448
agrochemical research laboratories 430 ortho-aminochalcones 102
Alder reaction 225 aminocoumarins 231
Alder±Bong reaction 119 aminolysis 413
aldimines 163 2-amino-substituted isoflav-3-enes 204
aldol condensation 166 aminothiophenes 260
aliphatic ethers 153 ammonium acetate 193
aliquat 151 ammonium formate 201, 255, 353
aliquat 336 150 ammonium persulfate on silica 188
alkyl 232 amorphous carbon 219, 246
alkyl acetates 150 amorphous graphite 219
alkyl glycosides 274 anilines 356, 388
alkyl halides 155 anionic activation 171, 280
alkyl 2-(hydroxymethyl)acrylates 44 anionic bimolecular reactions 73
N-alkyl imides 412 anionic b-elimination 91
N-alkylation 158, 177, 184, 288, 356 annelated pyridines 277
alkylation of dianhydrohexitols 89 anthracene 310, 477
C-alkylation of b-naphthol 94 MW apparatus 244

ISBN: 3-527-30514-9
488 Index
apparent activation energy 100 benzoxazinones and benzothiazinones 159

applicator 19 benzoxazoles 195
aqueous hydrotope solution 262 benzoylation of benzene 238
aqueous media 182 benzyl halides 152
aromatic amines 161 benzylation of 2-pyridone 104
aromatic decarboxylation 449 betonite 421
aromatic dehalogenation 446 Biginelli condensation 208, 421, 426
aromatic esters 152 Biginelli cyclocondensation 264
aromatic ethers 155 Biginelli dihydropyrimidine synthesis 65, 422
aromatic nucleophilic substitution 170 Biginelli synthesis of dihydropyrimidines 128
Arrhenius law 63 bimolecular reactions between neutral reac-
aryl iodides 396 tants 72, 76
aryl phosphonates 396 bimolecular reactions with one charged reac-
N-arylated heterocycles 400 tant 87
aryldiazepinone synthesis 67 bioactivity 405
arylimidazole synthesis 269 biological properties 405
asymmetric catalysis 396 biomimetic reactions 51
asymmetric Diels±Alder reactions 315 biradicals 476
1,2 asymmetric induction 84 bismuth trichloride 189
asynchronous mechanism 71 Boc-protected allylamine 383 f.
athermal effects 17 borohydride reductions 447
aza Diels-Alder additions 49 bromoacetals 169
azadiene 312 Brownian motion 3, 9
azadienes 222 building blocks 406
azaheterocycles 162 bulk temperature 4, 183, 357
azeotropic removal 192
azetidinones 337 c
azides 333 C70 321
aziridation of olefins 400 C±C bond formation 209
aziridination of olefins 255 Cannizzaro reaction 203
aziridine synthesis 255, 268 capacitive coupling 465
aziridines 269, 319, 400 carbamates 414
azolic fungicides 107 carbene generation (a-elimination) 169
azomethine imines 333 carbohydrate glycosylations 274
azomethine ylides 317 carbohydrates 94
carbon lattice 234
b carbon monoxide 387
barbitone 160 carbon±carbon coupling reactions 380
base-catalyzed isomerization 169 carbonylative coupling 380, 387
base-catalyzed transesterification 168 carboxylic acids 387, 395
basic alumina 86 carboxylic amides 395
basic clays 355 carboxylic amines 395
basic zeolites 349, 362 catalyst 149
batch 359 catalyst activation and reactivation 350
batch reactor 28, 369 catalyst active sites 357
Baylis-Hillman 50 catalytic activity 347
Baylis±Hillman adducts 329 catalytic conversion of methane 374
Baylis-Hillman reaction 44 catalytic cycle 346
Beckmann rearrangement 188, 194 f. catalytic effect 242
bentonite 319 catalytic effect of graphite 237
benzimidazole 122, 269 catalytic gas-phase reactions 357
benzodiazepine 260 catalytic hydrogenation 361
benzoic acid 388 catalytic sites 359
benzotrifluoride 419 cation 168
Index 489
cellulose membranes 414 coumarins 229, 261, 272

CEM Corp. 427 coupling of aryl halides 55
CEM products 23 coupling reactions 54
chalcone 175 cracking 361
charge-delocalized anions 92 creatinine 265, 282
charge-localized anions 88 cross-coupling 380, 389
chelation-controlled Heck reactions 382 cross-coupling reactions 389
chemical equilibrium 15, 406 crossed-aldol condensations 125
chemoselectivity 295, 381 cross-linked polymer 417
chloroquinoline ring 101 cross-linking of polymers 143
chromatography 405 18-crown-6 275
chromium trioxide±wet alumina 196 crown ethers 147
cineole derivatives 166, 278 cyanation of aryl bromides 395
cineole ketone 83 cyanuric acid 233
ortho-Claisen rearrangement 119, 261 cyclic b-ketoesters 90, 171
Claisen rearrangements 412 cyclization of monotrifluoroacetylated o-arylene-
Claisen±Schmidt condensation 53 diamines 100
classical heating 15 cycloaddition 71, 76, 295, 302, 316, 335
claycop±hydrogen peroxide 198 cycloaddition reactions 295
clayfen 189, 197, 209 cycloaddition to C70 fullerene 106
clays 69 cyclocondensation 101
cleavage of aldehyde diacetates 185 1,2-cyclohexanedione 384
cleavage of benzoic acid 413 cyclopentadiene 224
cleavage of methoxyphenyl methyl ethers
190 d
cleavage of semicarbazones and phenylhydra- Danishefsky's diene 139
zones 188 deacylation reactions 184
closed system 36 dealkoxycarbonylations of activated esters
closed Teflon vessels 115 (Krapcho Reaction) 90, 171
coconut reactor 28 Dean±Stark apparatus 192
combinatorial chemistry 41, 143, 405, 442 debenzylation of carboxylic esters 185
combinatorial library 263 Debye 8
combinatorial synthesis 208 decarboxylation 52, 322
combined MW/UV irradiation 479 decomplexation of metal complexes 231
comparison of homogeneous and heteroge- deethylation 173
neous conditions 140 dehydration of aldoxime 208
complex dielectric permittivity 4 demethylation 88, 173
concerning the absence of microwave effects deoximation 188
108 deoximation reactions 186
condensation reactions 191 depolymerization of cellulose 43
condensed phases 11 deprotection 186
conduction losses 13 deprotection of N-Cbz and N-Bn derivatives
continuous flow 24, 28 266
continuous microwave reactor 37 deprotection of allyl esters 102
continuous process 27 deprotonations 169
continuous-flow process 247 desilylation reactions 186
continuous-flow reactor 352, 371 dethioacetalization reaction 186
convection 364 dethiocarbonylation 189
conventional heating 62 detritiation reactions 453
Cope rearrangement 70 deuterated ionic liquid 445
copper sulfate or oxone±alumina 198 deuteration 442
cosmetic compounds 156 deuteration and tritiation reactions 210
cosmetic products 278 deuterium labeled compounds 436
coumarin synthesis 67 deuterium labeling 267
490 Index
diacylhydrazines 415 drying and calcination 347

N,N-dialkylimidazolium cations 444 dry-media reactions 422
1,3-dialkylimidazoliums 287 dummy load 470
dianhydrohexitols 154, 281
diaroyl furoxans 327 e
diastereoisomeric excess 84 eco-friendly green procedures 182
diastereoisomers 324 effect of selectivity 75
diazepines 130 effects of reaction mechanisms 69
diazoketones 337 effects of the medium 65
1,3-dicarbonyl compounds 411, 421 electrodeless 464
dielectric constant 57 electrodeless discharge lamp (EDL) 464
dielectric heating 1 electrodeless mercury lamp 464
dielectric loss 7, 10 electromagnetic energy 4
dielectric permittivity 4, 8 f., 11 electromagnetic spectrum 2
dielectric relaxation 65 electron-deficient dienophiles 312
Diels-Alder additions 49 electrophilic aromatic substitution 99
Diels±Alder cycloadditions 70 electrostatic interactions 70
Diels±Alder reaction 67, 105, 123, 136, 221, eletrodeless MW±UV lamp 479
299, 386 b-elimination 73, 165, 169, 280
digestion 40 enamines 76
3,5-dihydroimidazol-4-one derivatives 277 enantiomeric excess 396, 398
dihydropyridine 277, 428 enantiomeric purity 399
dihydropyridine library 429 enantioselectivity 211
dihydropyrimidines 421 endo and exo isomers 307
dimethyl acetylenedicarboxylate 308, 312 endo/exo selectivity 303
dimethyl malonate 397 ene reactions 115, 131, 225
dimethyl sulfoxide (DMSO) 181, 447 energy 14
dimethylformamide (DMF) 168, 181 energy of activation 17
dioxolane 273 energy transfer 67
diphenylnitrilimine 172, 331 enthalpy of activation 17
1,3-dipolar cycloaddition 70, 71, 172, 289, 299, entropy 303
317 entropy of activation 17
dipolar polarization 62, 69 environment 35
dipolar transition states 74 environmentally benign 57
dipolar TS 86 enzymatic catalysis 279
dipolarophiles 172 enzyme-catalyzed reactions 211
1,3-dipole 317 epichlorohydrin 50, 157
dipole moment 6 epoxidation 177, 362
dipole orientation 8 epoxide 157
dipole rotation 39 epoxide ring-opening 164
dipole±dipole interactions 62 equipment 424
diradical intermediates 335 Eshweiler-Clarke reaction 448
Discover 244, 441 ester aminolysis 95
Discover I 429 ester saponification 167
dissipation 14 ester synthesis 150
dissipation factor 39 esterification 42, 56, 65, 141, 351
dissolution of solid samples 40 esterification of acetic acid 131
distribution of dipoles 6 esterification of benzoic acid 131
dithiolanes 274 esterification of carboxylic acids 115
DMF 259, 383, 388, 395 esterification of stearic acid by n-butanol
DMSO 387 234
domestic ovens 18 esters 387
doped catalysts 357 ether synthesis 153
dry media 35, 56 etherification 44
Index 491
Ethos SYNTH 425, 441 g

ethylene glycol 388 Gabriel amine synthesis 160
eugenol±isoeugenol isomerization 195 Gabriel synthesis 191
exo/endo 307 gamma radiation 325
explosions 35 gaseous reactants and media 50
gas-phase reactions 219, 351
f Gedye 37, 56, 61
fatty compounds 168 generators 27
fatty oxirane 276 germanium tetrahalides 232
fatty sulfides 200 Giguere 37
Ferrier rearrangement 196 glass transition temperature 134
ferrocene 337 glyoxal monohydrazones 276
fiber optic thermometer 370 f. grafted ionic liquid phase 289
fiber-optic probes 425 graphite 177, 299, 311 f., 315, 352
field distribution 424 graphite as a sensitizer 220
Fischer indole synthesis 52 graphite as sensitizer and catalyst 234
five-membered heterocycles 317 graphite-supported catalysts 227
five-membered nitrogen heterocycles 162 graphitization of carbon 246
flash heating 254 green chemistry 61, 240, 298, 445
flash thermolysis 299, 311 Grignard reagent 329
flavones 204 ground state 70
fluidization technique 373
fluidized bed 369 h
fluorinated dipolarophiles 323 halogenated acetals 91, 280
fluorocarbon solvents 419 halogenated heterocycles 411
fluoroptic probe 397 halogermanes 232
fluorous chemistry 393 Hammond postulate 74
fluorous phase 406 Hantzsch procedure 205
fluorous Stille reactions 394 Hantzsch pyridine synthesis 421
fluorous-phase synthesis 419 Hantzsch-1,4-dihydropyridine synthesis 262
Fmoc-protected amino acids 407 hard ions 74
focused microwave 23 hardness 321
focused waves 126 harsh conditions 81
formate 445 heat transfer 368
formation of acetals and dioxolanes 183 heat-transfer mechanisms 471
formylation using Vilsmeier reagent 98 Heck arylation 353
fractal dimension 220 Heck coupling 380
free energy change 17 Heck coupling reactions 354
free or conduction electrons 5 Heck cross-coupling reaction 176
frequency 3 Heck reaction 54
Friedel±Crafts acylation 235, 355 Heck vinylation 254
Friedel±Crafts acylation of aromatic ethers Henry reaction 193
97 hetero Diels±Alder reactions 312
frontier orbital interactions 302 heterobicycles 265
C70 fullerene 76, 246 heterobicyclic lactams 275
fullerene derivatives 309 heterocycles 122, 395
fullerenes 309 heterocyclic chemistry 204, 253
fulleropyrrolidines 319 heterocyclic ketene aminals 282
fulvenes 316 hetero-Diels±Alder reaction 222, 299
functionalized tartramides 79 heterodienes 312
furan 304 heterodienophiles 315
furan diethers 153 heterogeneous catalyst 54, 346
furanic diethers 281 heterogeneous media 69
furfuryl alcohol 164 high pressures 22
492 Index
high-boiling solvents 36 infrared 21

higher hydrocarbons 358 infrared sensor 118
high-pressure conditions 315, 380 inner electrons 5
high-temperature water 51 inorganic chemistry 295
HIV protease inhibitor 139, 390, 392, 395 intercalated compounds 220
Hofmann elimination 43 intercalating guest 234
homogeneous and heterogeneous catalysis intercalation 246
141 interfacial reactions 69, 148
homogeneous catalysis 379 internal arylation 383
homogeneous electromagnetic field 126 internal pressure 36
homogeneous media 115 intramolecular addition 74
hot spots 63, 227, 359, 362, 364 intramolecular cyclization 175, 226
Hughes±Ingold model 70 intramolecular Diels±Alder reaction 304
hydrazines 194 intramolecular hetero-Diels±Alder reaction
hydrazone synthesis 77 312
hydrazones 193 intramolecular Michael addition 102, 204
hydrazonyl chlorides 331 intramolecular nucleophilic aromatic substi-
hydroacylation of 1-alkenes with aldehyde tution 101
110 iodine 190, 199
hydrogen cyanide 360 iodobenzene diacetate (IBD)-impregnated
hydrogen isotope exchange 442 alumina 199
hydrogen peroxide 176 f., 356 ionic and radical pathways 108
hydrogenation 353, 438, 445 ionic conduction 39, 472
hydrogenation reactions using formates 211 ionic conductivity 13
hydrogen±deuterium exchange 443 ionic equilibrium 16
hydrogenolysis 353, 361 ionic liquid 182, 212, 253, 416, 436, 444
hydrogen-transfer reduction 46 ionization 74, 466
hydrolysis of amides 42, 115 ion-pair exchange 148 f.
hydrolysis of sucrose 354, 363, 371 ion-radicals 481
hydrosilylation 399 IR pyrometer 470
hydrostannylation 393 IR thermometer 370
a-hydroxy b-lactams 337 isatin 331
o-hydroxychalcones 204 isatin derivatives 322
a-hydroxyketones 198 isocyanates 282
Hyflo Super Cell 211, 279 isocyanides 207
isomerization 139
i isomerization and rearrangement reactions
imidazole 272, 355, 422, 444 194
imidazoline 319 isomerization of carvone 131
imidazolones 318 isophorone 164, 175
imidization 64 isopolar transition-state reactions 70
imidization reaction 64 isosorbide 154
imidization reactions of a polyamic acid 99 isotopes 435
imine 76 isotopic incorporation 451
a-iminoacids 449
impregnated reagents 69 j
impregnation 347 Jacobs±Gould reactions 47
incident power 20 jasminaldehyde 166
increased selectivity 75
indole 52, 272, 443, 449 k
indolizines 319 K 10 356
industrial applications 373, 480 K 10 clay 185
industrial equipment 18 ketene acetals 169
industrial scale 27 ketene±imine reaction pathway 336
Index 493
ketodecarboxylation of carboxylic diacids 235, methods for incorporating tritium 436

241 methylation reactions 448
b-ketoester 128, 129, 411 N-methylformamide (NMF) 391
KF±alumina 319 N-methylmorpholine (NMM) 326, 332
kinetic products 49 Michael additions 49, 84
KMnO4±Al2O3 200 Michael condensation 175
Knoevenagel condensation 67, 191, 282 Michael reaction 160
Knoevenagel reaction 127, 166, 410 microscopic high temperatures 65
Krapcho reaction 90 microwave absorption 63
KSF 356 microwave batch reactor 38
microwave catalysis 345
l microwave cavity 13
labeled compounds 435, 455 f. microwave discharge 466
labeling with 18F 307 microwave flash heating 379, 408
b-lactam chemistry 255 microwave heating 15 f.
b-lactam derivatives 335 microwave heterogeneous catalysis 345
lactam synthesis 269, 275 microwave homogeneous catalysis 345
b-lactams 66, 160, 353, 450 microwave instrumentation 424
lactone 183 microwave organic reaction enhancement
lactone preparation 276 (MORE) 297
Langevin function 7 microwave photochemical reactor 467
Langevin theory 8 microwave photochemistry 463
Lawesson's reagent 206, 422 microwave plasma 350
Lawesson-type thionating reagent 415 microwave reactor design 18
layer structure 220 microwave-accelerated solvent-free organic
leaving groups 151 reactions 182
Leuckart reductive amination 81 microwave-assisted combinatorial chemistry
Lewis acid 186, 194 430
liquid±liquid PTC 147 f. microwave-assisted digestion 40
liquid-phase reactions 351 microwave-assisted library synthesis 428
liquids 470 microwave-enhanced tritiation reactions 442
localized hot-spots 124 microwave-generated plasma 350
localized superheating in the solid phase 365 microwave±matter interactions 1
long chain alkyl bromides 156 microwave±ultrasound reactor 56
long-chain esters 151 Milestone 425
loose ion pairs 73 f. Milestone ETHOS 1600 series 128
loss tangent 414 Milestone products 24
mineral oxides 63, 182
m mineral supports 149
magnetic losses 13 mineralization 471
magnetic susceptibility 4 modification of zeolites 349
magnetite (Fe3O4) 236, 242 modified commercial microwave ovens 296
magnetron 19 modified domestic oven 56
Marshall linker 414 modified MW 469
MARS-S multimode reactor 427 modified zeolites 362
Maxwell equations 3 molecular collisions 11
medicinal chemistry 395, 406 molecular sieves 351, 400
Meerwein-Ponndorf-Verley reduction 46 molybdenum hexacarbonyl complex 387
Merrifield 407 molybdenum-catalyzed asymmetric reac-
Merrifield resin 193 tion 398
MES company 29 f. monoalkylation 163
metal inclusions of graphite 220 monobenzylated isosorbide 90
metal-catalyzed processes 54 monobenzyloxy isosorbide 165
metal-catalyzed reactions 380 monomodal cavity 441
494 Index
monomode cavity 245 on±off cycles 369

monomode instrument 412 optical fiber thermometer 21, 245
monomode reactor 167, 416 organoboron compounds 389
montmorillonite 76, 84, 349, 352 organometallic chemistry 379
montmorillonite K 10 100, 103, 183, 188, 202, organometallic compounds 120
422 organometallic reactions 209
montmorillonite KSF 87 organotin reactants 389
MORE 256 orientation polarization 8
MORE chemistry 35 orienting effect 6, 17
multi-component reactions 207, 409 orienting effect of electric field 6
multimodal mode 441 orienting effects 4
multimode 20 origin of microwave effects 62
multimode cavities 19, 424 orthoesters 269
multiple component condensation 207 oscillating magnetic field effect 477
multiPREP rotors 425 1,3,4-oxadiazole synthesis 264
multistep synthesis of polyheterocyclic sys- oxadiazoles 324, 328, 415
tems 258 oxathiolanes 274
mutarotation of glucose 138 oxazolidine 319
mutual orientation 64 oxazolidones 395
MW±UV combined reactor 470 oxazoline 397, 458
MW±UV-assisted reaction 475 oxidation of alkyl benzenes 115
oxidation of arenes and enamines 200
n oxidation of benzene 356
Nafion 445 oxidation of enamines 200
NaY zeolite 349 oxidation of propan-2-ol 227
near-synchronous mechanism 72 oxidation of sulfides 199
neutral alumina 184 oxidation of toluene 361
nickel catalysts 359 oxidation reactions 176, 196
Niementowski reaction 77 oxidation using KMnO4±Al2O3 278
nitration of styrenes 209 oxidative cleavage 186
nitrile imines 331 oxidative coupling of methane 358, 374
nitrile oxides 326 oximes 195
nitriles 395
nitroalkanes 193 p
nitrones 71, 323 palladium 54, 176, 379, 409
NMM 335 palladium catalyst 353 f., 388
nonpolar 470 palladium complexes 209
nonpolar molecules 63 palladium-catalyzed reactions 334
nonpolar solvents 10, 67, 368 palladium-catalyzed Stille couplings 419
nonthermal effects 17, 61 palladium(0)-catalyzed transformations 380
Norrish type II reaction 474 palladium-doped alumina 210
nucleation 474 parallel synthesis 406, 420
nucleation regulator 63 partial oxidation of methane 360
nucleophilic additions 73 Pechmann reaction 83, 229
nucleophilic additions to carbonyl com- PEG 391, 400
pounds 76, 94, 166 PEG-bound aryl iodides 418
nucleophilic aromatic substitution 86, 456 PEG-400 174, 177
nucleophilic substitution 412, 420 penetration depth 27
peptide bond 407
o pericyclic reactions 296
oligomerization of methane 359 perimidine derivatives 313
oligomers 359 personal chemistry products 25
one-pot conditions 225 PersonalChemistry 427
one-pot procedure 299 pesticides 479
Index 495
petrochemistry 357 potassium fluoride 206

pharmaceutical 430 potassium hydroxide 155, 160, 162
pharmaceutical industry 436 pre-exponential factor 64
phase transfer agent 96 preparation of Benzo[b]furans 281
phase transfer catalysis 69, 147, 436 preparation of heterogeneous catalysts 347
phase transfer catalyst 152, 391 pressure control 23
phase-transfer conditions 384 pressure increases 121
phenacylations of 1,2,4-triazole 107 pressure-controlling device 56
phenethylation of pyrazole 84 pressure-release Savillex 118
phenol 481 pressurized reactors 35
phenolic acetates 184 product distribution 368
phenolic ethers 155 Prolabo products 22
phenolic polyethers 158 Prolabo Synthewave S402 441
phenylethanol 400 protected carbohydrates 168
N-phenylmaleimide 308 protection group 456
phenylpyrrolidino[60]fullerene 161 protection of amines 266
phosphine alkylation 72 protection±deprotection reactions 183
phosphine ligands 391 protection±deprotection strategy 458
phosphonium salts 191 PTC 331
phosphorus ylides 191 pulsar system 29
photocatalytic activity 475 purine derivatives 162
photocatalytic oxidation 475 pyrazine 270, 310
photochemical reactions 463 pyrazole 257, 284, 314
photochemistry 3 pyrazole alkylation in basic media 93
photodegradation of pollutants 479 pyrazole derivatives 314
photolithography 480 2-pyrazoline 333
photolysis of organic compounds 468 pyridazinones 276
phthalimide 397 pyridine 270, 285, 314, 442, 456
phthalimide synthesis 283 pyridone 285
pinacol±pinacolone rearrangement 195 pyrimidine 162, 270, 283
Planck's law 63 pyrimidone 314
plasma discharge 463 pyrolysis of urea 56, 233
Plazmatronika products 26 pyrolytic sublimation 231
polar mechanisms 70, 440 IR pyrometer 245
polar molecules 10, 63 a-pyrones 316
polar solvents 115, 470 pyrroles 272
polar transition state 192, 481
polarization 4 f. q
pollutants 479 quantum mechanics 3
polyethers 154 quaternary onium salts 147
polyheterocyclic compounds 133 quinazolines 133
polymer-bound 406 quinolines 271
polymer-bound ester 413 quinolinyl ethers 157
polymerization 136 quinolone antibacterials 47
polymer-supported building blocks 264 quinoxalines 271
polymer-supported Burgess reagent 264, 415
polymer-supported reagents 415 r
polystyrene resins 408 racemization of amino acids 124
polystyrene Wang resin 407 racemization of L-proline 125
porous silica gel 349 radar applications 2
position of the transition state 74 radical pairs 476
positron emission tomography 454 radical-mediated cyclizations 419
possible explanations of MW acceleration 135 radical-pair chemistry 477
potassium carbonate 152, 160, 162 radical-recombination 476
496 Index
radioactive waste 453 resonant cavities 19

radiochemical syntheses 441 retardation of nucleation 63
radiochemistry 295, 435 retention mechanism of reactants on gra-
radioisotopes 435 phite 246
radiopharmaceuticals 120, 435 retro-Diels±Alder reaction 221, 299, 309, 311
radiopharmaceuticals labeled 56 retro-ene reaction 228
RAMO system 26 reversibility 295
Raney nickel 188 rhodium dimer 123
rare earth basic oxides 359 ring opening of an epoxide by amines 85
rate enhancement 35, 118 ring-expansion 195
rates of homogeneous reactions 123 ring-opening 157
rationalization of microwave effects 109 Robinson annulation 175
reaction mechanisms 67 room temperature ionic liquids 287, 418
reaction medium 65 rotating reactor 245
reaction of pyrazole with phenethyl bro- rotational states 11
mide 84 ruthenium catalysis 400
reaction under pressure 296
reaction vessels 48 s
SN2 reactions 84 saccharin 159
reactions at atmospheric pressure 121 safety 35, 116
reactions at elevated pressures 116 safety considerations 471
reactions in aqueous acid and base 53 safety measures 244
reactions in nonpolar solvents 129 salicylaldehydes 281
reactions involving positively charged reac- saponification 75
tants 97 saponification of hindered aromatic esters 94
reactions of biologically important mole- scaling-up 36, 373
cules 124 Schiff base 418
reactions of methane 358 selective alkylation of b-naphthol 93
reactions under reflux 296 selective alkylation of 1,2,4-triazole 106
reactions with a distillation step 48 selective cleavage of the N-tert-butoxycarbonyl
SN2 reactions with tetraalkylammonium group 186
salts 99 selective dealkylation of aromatic alkoxylated
reactons on graphite 219 compounds 88
reagents 406 selective dealkylations of aromatic ethers 173
rearrangement of ammonium ylides 108 selective deprotection 190
rearrangement of geraniol 126 selective heating 41, 347, 364
recoil labeling 439 selective heating of active sites 351
recombination reaction 476 selective heating of the catalyst 141
recyclability 182 selective hydrolysis of nitriles to amides 174
reduction reactions 201 selectivity 61, 135, 301, 361, 381
reductive amination of carbonyls 202 selectivity effects 103
reductive decyanation of alkyldiphenyl- selenium 174
methanes 177 semiconductor devices 480
regeneration of carbonyl compounds 186 sensitizer 220
regeneration of zeolites 350 sequential MW irradiation 224
regioselective esterification of glycopyrano- silica 69, 346, 352
sides 279 silica gel 82, 102, 159, 193
regioselectivity 75, 85, 104, 295, 381, 383 silyl protecting groups 186
relaxation frequency 12 single-mode 20
relaxation time 8 f. single-mode cavities 20
reproducibility 117, 197 single-mode continuous-flow reactors 371
resin cleavage 413 singlet excited state 476
resin-based adsorption processes 54 singlet state 476
resin-bound nitroalkenes 410 slow-reacting system 92
Index 497
small-molecule libraries 207 substituted thiazoles 205

SmithSynthesizer 25, 427, 441 substitution and elimination reactions 136
sodium borohydride±alumina 201 SN2 substitutions 73
sodium cyanoborohydride 202 sulfonation of naphthalene 137
sodium periodate 188 sulfonylation of mesitylene 98
sodium periodate±silica 199 N-sulfonylimines 193
soft ions 74 supercritical fluids 436
solid mineral supports 69 supercritical microwave reactor 27
solid phase 54 superheating 364, 397
solid supports 30, 390 superheating effect 63, 123, 297
solid±liquid PTC 147 f. superheating of liquid 364
solid-phase organic synthesis 406 f., 415 superheating of polar solvents 474
solid-phase Ugi reactions 410 superheating of the catalyst 351
solid-state deuteration 202 superheating of the solvent 394
soluble polymer-supported synthesis 417 superoxide radicals 480
solution-phase library 322 supported catalysts 346
solvent effects 65 supported reagents 181, 299
solvent-free 61 surface area 347
solvent-free conditions 35, 297 surface reaction 346
solvent-free esterification of fusel oil 82 Suzuki couplings 389, 417
solvent-free synthesis 267 Suzuki cross-coupling reaction 210
solvolytic processes 45 synchronous mechanisms 108
Sommelet±Hauser sigmatropic rearrange- synergic effect 463, 473
ment 108 synthesis 76
sonication 169 synthesis of a thiazoquinazoline 133
sonochemistry 65 synthesis of alkyl-p-toluenesulfinates 82
Sonogashira coupling 380 synthesis of aminocoumarins 83
Sonogashira coupling reaction 210, 388 synthesis of aminotoluenesulfonamides 80
soybean oil 353 synthesis of 2-aroylbenzofurans 206
SP 435 Novozym 211, 279 synthesis of 1,5-aryldiazepines-2-ones 129
spatial distribution 21 synthesis of chalcones 125
specific absorption 67 synthesis of coumarins 191
specific effects 17, 301 synthesis of cyclic acetals 83
specific microwave effects 63 synthesis of diaryl-a-tetralones 175
specific selectivity 298 synthesis of dibenzyl diselenides 174
specific surface 246 synthesis of enamines 192
Spencer 2 synthesis of heterocycles 253
stabilization of the transition state 70 synthesis of imines 192
stearic acid 351, 363 synthesis of b-lactams 172
stereo control of b-lactam formation 105 synthesis of nitroalkenes 192
stereochemistry 139 synthesis of b-nitrostyrenes 209
stereoselectivity 295, 301 synthesis of phosphonium salts 86
steric constraints 42 synthesis of phthalimides 130
sterilization techniques 481 synthesis of phthalimidoacetic acid 122
steroid compounds 353 synthesis of quinolones 206
Stevens rearrangement 108 synthesis of radiolabeled compounds 210
Stille coupling reactions 253 synthesis of N-sulfonylimines 192
Stille couplings 392 synthesis of thiazoloquinazoline 258
structure of reactive ion pairs 73 synthesis of trifluoromethyl aryldiazepines
structuring effect 10 129
styrene 399 synthesis of 1,4-dithiocarbonyl piperazines
substituted amides 96 81
N-substituted imidazoles and imidazolines synthesis of 2-oxazolines 79
276 synthetic commercial graphites 235
498 Index
Synthewave 402 23, 256, 274, 285 p-toluenesulfinate esters 82

Synthewave 1000 23, 151, 244 p-toluenesulfonic acid 101, 132, 183
Synthewave 402 (Prolabo) 470 a-tosyloxyketones 206
transesterification 94, 168, 351, 363, 418
t transfer of microwave energy 39
tandem Claisen rearrangement±cyclization transformation of arylaldehydes to nitriles
261 208
TantaGel resins 414 transglycosylation 211, 280
technical considerations and safety 56 transition metal catalysis 379
Teflon 21 transition states 321
Teflon flask 26 transition-metal catalyzed reactions 429
temperature gradients 69, 364, 424 transmission electron microscopy 235
temperature homogeneity 69 triazine 314, 411
temperature level 109 1,2,4-triazole 285, 333
temperature measurement 21, 23, 245, 425 triazoles 66, 257, 395
temperature-profile 62 triazoline-2-one derivatives 331
TentaGel resin 408 tricyclic taxoid skeletons 306
TE033 propagation mode 31 triglycerides 352, 363
tetraalkylammonium salts 69 triphenylphosphine 416
tetraarylgermanes tetrahalides 232 triplet excited state 476
tetrabutylammonium bromide (TBAB) 149, triplet radical pair 478
184 tritiated formates 446
tetrahydropyranyl ethers 190 tritiation procedures 437
tetrahydroquinolones 102 Turbosphere 28
tetraphenyl porphyrin 267
tetrazines 222 u
tetrazole 334, 395, 408 Ugi-type multicomponent reaction 422
thalidomide 284 ultrasonic 200
theoretical calculations 71, 336 ultrasound 91, 170, 189, 280, 352, 463
thermal conversion 14 ultraviolet discharge in electrodeless lamps
thermal conversion of electromagnetic energy 464
7 ultraviolet radiation 56, 466
thermal cure of epoxy resins 134 unimolecular reactions 74, 99
thermal effects 474 unnatural D-amino acids 124
thermal gradients 47 unsymmetrical acetylenes 388
thermal reactions in heterocyclic syntheses
229 v
thermal runaway 20, 56, 388 valence electrons 5
thermally labile products 43 valerophenones 474
thermodynamic effects 15 van der Waals interactions 246
thermolysis ammonium 78 vibrational states 11
thermolysis of esters 227 vinylation 386
thermostar system 30 vinyl-b-lactams 337
thia-Fries rearrangement 194 vinylpyrazoles 308
thiazoles 395 2-vinylpyridine 399
thienamycin side chain 335 viscous reaction mixtures 47
thioacetals 184 volume of the vessel 118
thioamides 415 V2O5/SiO2 catalyst 348
thiocarbonyls 189
thiohydantoin 265 w
thionation of amides 416 Wang and Merrifield resins 408
thiophene 311 Wang resin 407
tight ion pairs 74, 89 water 51
TMEDA 446 waveguides 19
Index 499
wavelength 3 x
Weflon 427 X-ray diffraction 235
Wilkinson's catalyst 400, 416, 445
Willgerodt 50 z
Willgerodt reactions 46 zeolite 197, 219, 445
Williamson synthesis 44, 153 zeolite±HY 355
Wittig olefination reactions 191 zinc chloride 194
Wolff±Kishner reduction 78, 193 zwitterionic intermediates 335

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Microwaves in Organic Synthesis

Microwaves in Organic Synthesis. Edited by Andr Loupy

R. van Eldik, F.-G. Klårner (eds.)

High Pressure Chemistry

F. Zaragoza Dærwald (ed.)

Organic Synthesis on Solid Phase

P. Wasserscheid, T. Welton (eds.)

Ionic Liquids in Synthesis

Solvent-free Organic Synthesis

Library of Congress Card No.: applied for

Bibliographic information published by

 Wiley-VCH Verlag GmbH & Co. KGaA,

Printed in the Federal Republic of Germany.

Composition ProSatz Unger, Weinheim

1 Wave±Material Interactions, Microwave Technology and Equipment 1

Microwaves in Organic Synthesis. Edited by Andr Loupy

1.2.2.1 The Prolabo Products 22

2 Microwave-assisted Organic Chemistry in Pressurized Reactors 35

2.7.3 Reactions in Aqueous Acid and Base 53

3 Nonthermal Effects of Microwaves in Organic Synthesis 61

4 Organic Synthesis using Microwaves in Homogeneous Media 115

4.4 Effect of Microwaves on the Rates of Homogeneous Reactions

5 Microwave and Phase-transfer Catalysis 147

5.2.5.2 Ester Saponification 167

6 Organic Synthesis Using Microwaves and Supported Reagents 181

6.2.3 Isomerization and Rearrangement Reactions 194

7 Microwave-assisted Reactions on Graphite 219

8 Microwaves in Heterocyclic Chemistry 253

8.3.1 Solvent-free Synthesis under Acidic Conditions 267

8.4 Room-temperature Ionic Liquids (RTIL) ± Synthesis and Applications in

9 Microwaves in Cycloadditions 295

10 Microwave Catalysis in Organic Synthesis 345

10.3 Microwave Activation of Catalytic Reactions 351

11 Transition Metal Catalysis and Microwave Flash Heating in

12 Microwave-assisted Combinatorial Chemistry 405

13 Microwave-Enhanced Radiochemistry 435

14 Microwave Photochemistry 463

14.4.1 Interactions of Ultraviolet and Microwave Radiation with Matter 472

Microwaves in Organic Synthesis. Edited by Andr Loupy

Orsay, March 25th, 2002 Andr Loupy

Editor Dariusz Bogdal

Jean-Pierre Bazureau Michel Delmotte

Microwaves in Organic Synthesis. Edited by Andr Loupy

Jacques Dubac Jack Hamelin

Anders Hallberg C. Oliver Kappe

Petr Kln Julien Marqui

Andr Laporterie Laurence Perreux

Christopher R. Strauss Franoise Texier-Boullet

Microwaves in Organic Synthesis. Edited by Andr Loupy

1.1.1.2 The Electromagnetic Spectrum

Fig. 1.1 The electromagnetic spectrum.

The fundamental relationship between energy, E, frequency, n, wavelength, l, and

To avoid interference with telecommunications and cellular phone frequencies,

Tab. 1.1 Brownian motion and bonds energies.

Brownian motion Hydrogen bonds Covalent bonds Ionic bonds

According to these values, the microwave photon is not sufficiently energetic to

Insulating materials can be heated by applying high-frequency electromagnetic en-

e~  e0 j e00  e0 e0r j e0 e00r 2

1.1.2.1 Polarization and Storage of Electromagnetic Energy

The physical origin of polarization

Microwaves in Organic Synthesis. Edited by Andr Loupy

Microwaves in Organic Synthesis. Edited by Andr Loupy

Microwaves in Organic Synthesis. Edited by Andr Loupy

Orsay, March 25th, 2002 Andr Loupy

Microwaves in Organic Synthesis. Edited by Andr Loupy

Petr Kln Julien Marqui

Andr Laporterie Laurence Perreux

Christopher R. Strauss Franoise Texier-Boullet

Microwaves in Organic Synthesis. Edited by Andr Loupy

e~ e0 j e00 e0 e0r j e0 e00r 2

t T tSteric tInter T 13

Microwaves in Organic Synthesis. Edited by Andr Loupy