Green Chemistry & Catalysis for Sustainable Organic Synthesis

Roger A. Sheldon Delft University of Technology [email protected]

Lecture given at University Pierre et Marie Curie, Paris, May 12, 2004

Sustainability: Meeting the needs of the present generation without compromising the needs of future generations

is the goal
Green Chemistry: Technologies that are energy efficient,minimise or preferably eliminate the formation of waste,avoid the use of toxic and/or hazardous solvents and reagents and, where possible,utilise renewable raw materials.

is the means
Primary Pollution Prevention not (End-of Pipe)Remediation

Do politicians understand the issues?

Its not pollution that is the problem its the impurities in our air and water. Dan Quayle

The E Factor
Amount of waste/kg product: Product tonnage E Factor Bulk Chemicals Fine chemical Industry Pharmaceutical Industry 104-106 102-104 10-103 <1 - 5 5 - >50 25 - >100

R.A. Sheldon, Chem & Ind,1997,12; 1992,903

The E Factor
Is the actual amount of waste formed in the process, including solvent losses, acids and bases used in work-up,process aids, and,in principle,waste from energy production (c.f. atom efficiency is a theoretical nr.) Can be derived from amount of raw materials purchased /amount of product sold,i.e., from the mass balance: E= [raw materials-product]/product A good way to quickly show (e.g.,to students)the enormity of the waste problem

WHERE DOES ALL THIS WASTE ORIGINATE?

1. STOICHIOMETRIC BRONSTED ACIDS & BASES - Aromatic nitrations with H2SO4 / HNO3 - Acid promoted rearrangements, e.g. Beckmann (H2SO4) - Base promoted condensations, e.g. Aldol (NaOH, NaOMe) 2. STOICHIOMETRIC LEWIS ACIDS - Friedel-Crafts acylation (AlCl3, ZnCl2, BF3) 3. STOICHIOMETRIC OXIDANTS & REDUCTANTS - Na2Cr2O7, KMnO4, MnO2 - LiAlH4, NaBH4, Zn, Fe/HCl 4. HALOGENATION & HALOGEN REPLACEMENT - Nucleophilic substitutions 5. SOLVENT LOSSES

ATOM EFFICIENCY: STOICHIOMETRIC VS CATALYTIC OXIDATION

Stoichiometric: The Jones Reagent (Sir Ewart Jones)

3 PhCH(OH)CH 3 + 2 CrO 3 + 3 H 2SO 4 3 PhCOCH 3 + Cr 2(SO 4)3 + 6 H 2O

Atom efficiency = 360 / 860 = 42% Catalytic:

PhCH(OH)CH 3 + 1/2 O 2 Catalyst PhCOCH 3 + H 2O

Etheor = ca. 1.5

Atom efficiency = 120/138 = 87% Byproduct: H2O

Etheor = ca. 0.1(0)

CHROMIUM(VI): THE ORGANIC CHEMISTS FAVOURITE OXIDANT

1856 :

Attempted synthesis of quinine (W.H.Perkin)

K2Cr2O7 C20H24N2O2 + H2O

2 C10H13N + 3 O

allyltoluidine

quinine

HO MeO N quinine

Led to the serendipitous synthesis of the first synthetic dyestuff mauveine (aniline purple)

CHROMIUM(VI): THE ORGANIC CHEMISTS FAVOURITE OXIDANT

2000 : Julia Roberts in Erin Brokovich Its hexavalent chromium, highly toxic, highly carcinogenic. Gets into your DNA, so you pass the trouble along to your kids.

ATOM EFFICIENT PROCESSES

Hydrogenation:

O Ar + H2

catalyst

H Ar

OH

100% atom efficient

Carbonylation:

H Ar

OH

CO

catalyst Ar O Ar 87% atom efficient (Ar = C6H5) + H2O CO2H 100% atom efficient

Oxidation:

H Ar

OH

+ 1/2 O2

catalyst

The Environmental Impact EQ

EQ
E(kg waste) Q (Unfriendliness ) e.g. NaCl=1 ( arbitrary)

Cr salts= 1000?

Solid Acid Catalysts

ZEOLITE-CATALYZED FRIEDEL-CRAFTS ACYLATION

O + CH3COCl MeO AlCl3 solvent MeO O + (CH3CO)2O MeO H-beta MeO + CH3CO2H + HCl

Homogeneous AlCl 3 >1 equivalent Solvent (recycle) Hydrolysis of products 85-95% yield 4.5 kg aqueous effluent per kg 12 unit operations

Heterogeneous H-beta, catalytic & regenerable No solvent No water necessary >95% yield /higher purity 0.035 kg aqueous effluent per kg 3 unit operations

S. Ratton, Chem. Today (Chim. Oggi), March/April, 1998, 33

SALT-FREE ESTERIFICATION OF AMINO ACIDS

CONVENTIONAL: NH3 R O ZEOLITE-CATALYZED: NH3 R O O
+ +

HCl (1 eq.) R

NH3 Cl

OH O

MeOH/HCl (cat.) R

NH3 Cl OMe + H2O O

MeOH, H-USY, 100 C R

NH2 OMe + H2O O

R = PhCH2 (aspartame intermediate); S/C = 20 (w/w), 83% yield (TON = 180) Naphtha cracking catalyst (H-USY) Opt. Active amino acids (partially) racemized
M.Wegman, J.M.Elzinga, E.Neeleman, F.van Rantwijk and R.A.Sheldon, Green Chem., 3,61,2001

Catalytic Oxidations

TS-1 CATALYZED OXIDATIONS WITH H2O2

Hydrophobic molecular sieve (5.6 x 5.3) / HI (Xoctane / XH2O) TS-1=3.4 ; Ti / SiO2=0.1

NOH

O O

Enichem

NH3

TS - 1 + 30% H2O2 PhOH

OH + OH

OH OH

R2CHOH R2C O

B.Notari, Stud. Surf. Sci. Catal., 37 , 431 (1988)

Cyclohexanone Oxime Manufacturing Process

Current Process
O

Ammoximation Process
NOH O NOH

(NH4)2SO4

Oximation NH3 H2 dil H2SO4 O2 O2 NO NH3 Air

(NH3OH)2SO4

Oximation H2O2 NH3 H2

Sumitomo Process:Combined Ammoximation and Vapor Phase Beckmann Rearrangement

O NOH

+ NH3 + H2O2

TS-1

+ 2H2O NH O High Silica MFI

By-product: H2O Green Chemical Process

Personal communication, H.Ichihashi,Sumitomo

Comparison between the Current and New Processes

Overall reaction of a typical current process
O

+ 0.5(NH3OH)2SO4 + 1.5H2SO4 + 4NH3

NH

+ 2(NH4)SO4 + H2O

Atom Economy = 29% E-factor = 2.5

Overall reaction of the new process

O

+ NH3 + H2O2 Atom Economy = 75%

NH

+ 2H2O

E-factor = 0.32
H.Ichihashi

Homogeneous Catalysts

PALLADIUM-CATALYZED CARBONYLATION: BHC IBUPROFEN PROCESS

H2 Pd /C

OH

OH

CO Pd II /Ph3P Ibuprofen 3500 tpa

CO2H

99% conv. 96% sel. TOF = 375 h-1

100% atom efficiency Cumbersome catalyst recovery /product contamination

V. Elango et al, US Patent 4981995 (1991) to Hoechst Celanese

Asymmetric Catalysis

PASTEURS CHIRAL FORCE

THE ESSENTIAL PRODUCTS OF LIFE ARE ASYMMETRIC AND POSSESS SUCH ASYMMETRY THAT THEY ARE NOT SUPERIMPOSABLE ON THEIR IMAGES?THIS ESTABLISHES PERHAPS THE ONLY WELLMARKED LINE OF DEMARCATION THAT CAN AT PRESENT BE DRAWN BETWEEN THE CHEMISTRY OF DEAD MATTER AND THE CHEMISTRY OF LIVING MATTER
Louis Pasteur, 1822-1895

HISTORICAL DEVELOPMENT 1848 First separation of a racemate (Pasteur)

1853 First separation of a racemate by diastereomer crystallization (Pasteur)

1858 First racemate separation by fermentationPenicillium glaucum (Pasteur)

J.H.van t Hoff: Father of Stereochemistry

First Nobel Prize in Chemistry,1901 Title of paper written at the age of 22: Proposal for the extension of the structural formulae now in use in chemistry into space,together with a related note on the relationship between the optical active power and the chemical constitution of organic compounds J.H.van t Hoff,Arch.Neerl.Sci.Exacts Nat., 9,445-454,1874

THE WRONG ISOMER HAS UNDESIRABLE SIDE-EFFECTS

O N NH O O teratogen NH (S) Ketamine (R) Cl anaesthetic CO2H O O Cl hallucinogen HO2C O (S) Thalidomide (R) O HN O O sedative HN N O

HS

(S) Penicillamine (R)

SH NH2 mutagen

NH2 antiarthritic OH H N (S,S)-Ethambutol (R,R) N H HO

N H blindness

H N HO

OH tuberculostatic

MILESTONES IN ASYMMETRIC CATALYSIS

1939 1956 1963 1966 1968 1970 1971 1980 1984 1988 1991 2001 Cinchonine-modified Pt (Lipkin and Stewart) Pd modified with silk fibroin (Akabori, Izumi) Raney Ni/tartrate (Izumi) Asymmetric cyclopropanation catalyzed by a chiral Schiff's base complex, 10% ee (Nozaki, Noyori) Asymmetric hydrogenation with a rhodium-chiral phosphine complex, 15% ee (Knowles and Sabacky; Horner) Monsanto L-Dopa process DIOP ligand (Kagan) Asymmetric epoxidation, Ti/TBHP/tartrate (Sharpless) Takasago l-menthol process, Rh-Binap (Otsuka, Akutagawa, Noyori) Asymmetric dihydroxylation of olefins, OsO4/quinine (Sharpless) Jacobsen-Katsuki epoxidation Nobel prize in Chemistry for Knowles,Noyori and Sharpless

MONSANTO L-DOPA PROCESS

COOH NHAc AcO OMe Catalyst = [ Rh(COD)L*2] BF4 COD = 1,5-cyclooctadiene L* = chiral phosphine C 6H5 H3CO P CH 3 H3CO C 6H11 P CH 3 H3CO C6H5 C 6H5 OCH3
+ -

H2 chiral catalyst AcO OMe

COOH H NHAc

C6H5 P CH 3 C3H7 PMPP 28% ee

P CH H C P 2 2

PAMP 60% ee

CAMP 85% ee

DIPAMP 95% ee

W.S.Knowles, Acc. Chem. Res., 16, 106-122 (1983); J. Chem. Educ., 63, 222-225 (1986)

TAKASAGO l-MENTHOL SYNTHESIS

NEt2
Rh (( S) BINAP) 2 ClO4

Et2NH

NEt2

Myrcene
+

99% ee

H3O

ZnBr2 CHO OH

H2 Raney Ni

OH (-)-Menthol

Citronellal
Ph2 P

Ph2 Rh
+

THF solvent, 80 oC substrate: catalyst ratio = 8000 turnover number = 300,000

P Ph2

P ClO4 P Ph2
-

S.Akutegawa, in Chirality in Industry, pp.313-323; S.Akutegawa and K.Tani, in Catalytic Asymmetric Synthesis, I.Ojima Ed., VCH, Berlin, 1993, pp.41-61; S.Otsuka and K.Tani, Synthesis, 665 (1991)

ASYMMETRIC HYDROGENATION OF AN IMINE

N H2 (80 bar)
I OCH3 Ir -xyliphos HOAc / I o 50 C/ 4hr

H N OCH3 (S ) > 80% opt.yield H3CO

P Fe PPh 2 xyliphos
S/C=750,000 TOF (initial)=1.8 x106h-1 (1 mio turnovers in 6 hrs)
2

N O Cl (S)-metolachlor (mixture of two atropisomers)

R.R.Bader and H.U.Blaser, 4th Int.Symp.Het.Catalysis & Fine Chemicals, Basel, 1996

HIGHLY EFFICIENT ASYMMETRIC HYDROGENATION OF KETONES

O + Ar R H2

Ru catalyst

OH Ar R ee 80-98% e.g. Ar=Ph; R=CH3 S/C = 2,400,000 o 30 C/45 bar/48 h 100% yield; 80%ee TOF =228000 h-1 at 30% conv.

(1-45 bar) t-BuOK (0.45m%) i-PrOH; 24-30 o C

Ar2 P P Ar2 Cl Ru Cl N H2

H2 N

(S)-BINAP (Ar = Ph)

(S,S)-DPEN

Rate 100x faster with preformed complex R.Noyori et al., Angew. Chem. Int. Ed., 37, 1703-1707, 1998

Homogeneous vs Heterogeneous Catalysis

Homogeneous Advantages - Mild reaction conditions - High activity & selectivity - Efficient heat transfer Disadvantages and / or -Product contamination -Not readily adapted to a continuous process selectivity - Cumbersome separation & recycling of catalyst Heterogeneous - Facile separation of catalyst and products - Continuous processing - Heat transfer problems - Low activity

Homogeneous liquid / liquid biphasic catalysis

THE QUESTION OF SOLVENTS THE PROBLEM:

Toxicity / emissions of volatile solvents (e.g. chlorinated hydrocarbons) Aqueous contamination by non-volatile, polar solvents

Solvents contribute ca.85% of non-aqueous mass in processes. Current recovery efficiencies typically 50-80% (Alan Curzons,GSK)

Restrictions on Solvent Use in the Pharma Industry

Driving force: exposure of the user to residual solvents Solvents that should never be used: benzene, tetrachlorocarbon, 1,2-dichloroethane, 1,1-dichloroethane, Solvents that can be used if unavoidable (residues in the product subject to regulations): hexane, toluene, dichloromethane, dioxane, pyridine, methanol, ............. Preferred solvents: water, scCO2, heptane, tert-butyl methyl ether, ethyl acetate, tert-butyl alcohol, ethanol, ............. FDA, Q3C - Tables and List (www.fda.gov/cder/guidance/index.htm)

What are Green Solvents? Low toxicity Easy recyclability (no disposal) Further desirable characteristics: -Easy removal from the product -Low reactivity

New Sertraline process (Pfizers Antidepressant) is Greener

NC H3 H2 P d/CaCO3 + H2 O Cl Cl EtO H

NH CH3

NH CH3

CH3NH2 E tO H Cl Cl

D-Mandelic acid E tO H Cl Cl Ethylacetate Cl HCl Cl

Three step process Introduction of EtOH as solvent Replacement of Pd/C with Pd/CaCO 3 - higher yields Elimination of titanium chloride, toluene, THF, CH2Cl2, and hexane Reduction of solvents from 60,000 to 6,000 gal/ton Elimination of 440 tons of titanium dioxide, 150 tons of 35% HCl, and 100 tons of 50% NaOH

NH CH3

HC l Cl Cl Sertraline HCl

A Green Process for Sildenafil (ViagraTM)

P.J.Dunn,S.Galvin and K.Hettenbach,Green Chem. 6,43(2004)

Comparison of E factors Industry segment Oil refining Bulk chemicals Sildenafil citrate Fine chemicals Pharmaceuticals Prodn(tons) 106108 104106 3040 102104 10103 E-factor < 0.1 <15 6 5>50 25>100

THE QUESTION OF SOLVENTS

The Solution
Solvent-free (catalytic )processes (the best solvent is no solvent) Aqueous biphasic catalysis Fluorous biphasic cataysis Supercritical carbon dioxide Ambient temperature ionic liquids
Catalyst in separate phase (recyclable)

Water as a reaction medium

Economically & Environmentally attractive - Inexpensive and abundantly available - Non-inflammable and non-toxic - Odourless and colourless Highly polar reaction medium - Novel reactivity of organometallic complexes - Facile product separation/catalyst recycling - Reduced product contamination
G. Papadogianakis, R.A. Sheldon, New J. Chem., 20 (1996) 175-184 G. Papadogianakis and R.A. Sheldon, Catalysis, 13 (1997) 114-193

Rhodium Catalyzed Hydroformylation;Union Carbide Process

100 - 300 psi CO/H 2, 100o C, P:Rh = 1000 O H2 R CH2CH2C H normal H P Rh C O P = P 3 P Advantages High catalytic activity Good n/i selectivity Disadvantages Separation of the catalyst from Cn-aldehydes (n>8) is difficult iso + R( H3 C ) HC H O

CH CH 2 + CO +

Sodium salt of tri-msulfonatotriphenylphosphine (tppts)

SO3Na P 3
NaO3S

- Solubility in water: 1100 g / L

SO3Na

E.G. Kuntz, 1974

SO3Na

The Ruhrchemie/Rhne Poulenc hydroformylation process

> 400.000 tpa Organic Aqueous
H2 L L Rh CO L L O Rh CO H CHO L L Rh CO H CHO + CO + H2

L=P SO3Na 3
CO

L L

Rh

CO

B. Cornils and E. Wiebus, Chemtech, 1995, 25, 33

Pause

Hydroformylation in a Reversed Biphasic System

H3C O H2, CO O Rh catalyst (hydrophilic) Normal biphasic
H3C O

H N

H2, CO Rh catalyst (lipophilic)

H N O

organic layer water layer

Reversed biphasic H3C CH3

Hydroformylation in the organic phase is efficient, but ca. 20 slower than in water (using the tppts ligand) The xantphos ligand induces a high (15) n/iso ratio No leaching of the catalyst into the aqueous phase (5 recycle without loss of activity) Ph2P

O PPh2

Ligand: xantphos

G. Verspui et al., Chem. Commun. 1363 (2000)

A One-Pot Synthesis of Melatonin

NH2 Ac2O - AcOH H N O CH3 Rh/xantphos toluene-H2O, 10 bar H2/CO, 90 C O H N O H N H3CO CH3

NH2

H N H3CO NHAc

H+ - NH3 H3CO

H N

N H NAc

melatonin, 44% yield (not optimised) G. Verspui et al., Chem. Commun. 1363 (2000)
melatn.ppt/FvR

17

O-, 31P- and 35Cl NMR study of the redox reaction between PdCl 2, tppts and H2O
+ tppts + H2{17O} 8 days [Pd(tppts)3] + 17O=tppts + 2 HCl

Pd(II)Cl2 + 3 tppts

H2O

+ L Pd (II) + Cl L Cl L + CO (2 bar) + H2O 5 minutes

SO3Na 3

[Pd(tppts)3] + CO2 + 2 HCl (100% yield)

L= tppts = P

G. Papadogianakis, J.A. Peters, L. Maat and R.A. Sheldon, Chem. Commun., 1995, 1105 G. Papadogianakis, L. Maat and R.A. Sheldon, Inorg. Synth., 32 (1998) 25-29

Biphasic carbonylation of 1-(4-isobutylphenyl)ethanol

COOH OH Pd / tppts / H CO IBPE Ibuprofen

+

COOH + 3-IPPA

conversion: 83% selectivity to ibuprofen: 82% Low activity (TOF = 2.3 h-1)

R.A. Sheldon, L. Maat, G. Papadogianakis, US Patent 5,536,874 (1996) to Hoechst Celanese Corp. G. Papadogianakis, L. Maat and R.A. Sheldon, J. Chem. Tech. Biotechnol., 70 (1997) 83-91.

Green, Catalytic Alcohol Oxidations

NaO 3S

N Pd(OAc) 2 N

NaO 3S

air

Pd -bathophenanthroline (L)
Air as oxidant

2+

OH R R

Pd2+ L

water

No organic solvent Catalyst recycling via phase separation

G.J. ten Brink, I.W.C.E. Arends and R.A. Sheldon, Science 287 (2000) 1636-9.

Fluorous Biphasic Catalysis

The Principle of Fluorous Phase Catalysis

gas phase hydrocarbon phase gas phase hydrocarbon phase H2O gas phase hydrocarbon phase fluorous phase

(Ph3P)3(CO)RhH

(tppts)3(CO)RhH

((CnF2n-1)P)3(CO)RhH perfluoroalkane, perfluoroether, etc

Fluorous pony tail fixes the catalyst into the fluorous phase Fluorous phases dissolve higher olefins better than water No Rh is carried over into the hydrocarbon phase
I.T. Horvath, J. Rabai, Science, 72 , 266 (1994)
FPC-1.ppt/FvR

Evolution of Rhodium Hydroformylation Catalysts

R C HC 2H + C O 2 H + R O h ( C 3]3 O ) [ P R H R C 2H C 2H C H R ( C H H C 3) C O H

PPh3
Gas Phase

P(C6 H4SO 3Na )3

Gas Phase

P [(C H

F 2 )5 C F 3 ]3 2)(C
Gas Phase

Hydrocarbon Phase

Hydrocarbon Phase Aqueous Phase

Hydrocarbon Phase Fluorous Phase

H R h ( C {P O) Ph 3 }3

HRh(CO ) [P(C 4H6SO 3Na) 3] 3

H R h (C O ){P [( C H

F 2)5C F 3)3}3 2) 2(C

Limitations
Separation of catalysts from C n>8 aldehydes and heavy side-products Solubility of higher olefins Side reactions with water Cost of ligands/solvents Persistence of fluorocarbons

Supercritical CO2

What is a Supercritical Fluid?

Critical Point Vapour
Supercritical Region

Tc Temperature

Liquid

Solid Pressure Pc

Supercritical CO2 as a Reaction Medium

Tc 31.0 C, pc 73.8 bar, dc 0.477 kg L-1 Low viscosity (more like a gas than like a liquid); hence, fast mass transfer Cheap and abundantly available Easy to remove (N.B. no net production of CO2) Non-toxic,non-inflammable,inert

Continuous Supercritical Chemistry

Simple Safe Efficient Selective Versatile Clean

Reactants

scCO2

Catalyst Product CO2

H2 and scCO2 Completely Miscible

H2 Liquid

T < Tc

T > Tc

Continuous Supercritical Hydrogenation Large number of reactions

high conversion high selectivity
Substrate

H2

scFluid

Small reactors:
high throughput good safety

Reactor + Catalyst

Environmentally Clean: reduced waste

on-line IR

Product(s)

Fluid

Continuous Hydroformylation of 1-Octene in scCO2

H3C CO, H2 L2(CO)RhH, [BMIm][PF6], 100 C, ~ 30 bar H3C H3C

H O CH3

H Ph2P

Rh O N

CO PPh2

CHO

n/iso 35 - 50 No loss of activity over several days Turnover frequency, compared with toluene: -4 faster than immobilised catalyst -0.5 the rate of the homogeneous catalyst

OO

Rhodium complex catalyst, chemically anchored to a silica surface to prevent leaching

Ionic Liquids

grnslv-7.ppt/FvR

CATALYSIS IN IONIC LIQUIDS

CA TI ONS R1 R3 N R2 R 3 R3 R1 P R2 R3 N R R1 N N R2 AN I O NS BF4-, PF6-, SbF6-, NO 3CF3SO 3-, (CF3SO3)2N -, ArSO 3-, CF3CO 2-, CH3CO 2-, Al2Cl7 -

Liquid at room temperature/no vapor pressure Liquid range of 300 oC (c.f. H2O, 100 oC ) Designer solvents, e.g. bmim BF4 hydrophilic, bmim PF6 hydrophobic

Reactions: hydrogenation,hydroformylation,Heck reactions, dimerization/oligomerization of olefins, etc, and biocatalysis in ILS

R.A.Sheldon,Chem.Comm.,2001,2399-2407

Friedel-Crafts Acylation in Ionic Liquid

X + CH3COCl emim Cl /AlCl3 (1:2) X O

R MeO Me Cl

Temp (oC) -10 20 20

Time (h) 0.25 1 24

Yield (%) 99 98 97

CH3COCl

emim Cl /AlCl3 (1:2) 0 /1h O traseolide 99% yield

o

K.R.Seddon et al,Chem.Comm. 2097(1998)

Asymmetric Hydrogenation in Ionic Liquids

OH MeO O + H2 Ru(S)-BINAP bmim BF4 / i-PrOH MeO O (S)-naproxen, 80% ee OH (3)

OH O

+ H2

Ru(OAc)2(R)-tolBINAP bmim PF6 / H2O 25 o / 5 bar

OH O 100% conversion 99% ee

(4)

OH O

+ H2

Ru(OAc)2 tolBINAP bmim PF6 / MeOH 25 o / 100 bar O

OH

(5)

(S)-ibuprofen, 85% ee

Palladium Catalysed Heck Arylation in Ionic Liquid Medium

I

COOCH3

COOCH3 (Ph3P)2Pd(OAc)2, Et3N, [BMIm][PF6] 1 h, 100 C yield 95 - 99%

+ (Et3)NH+I-

Ph3P Ph3P

Pd

OAc OAc

catalyst (4 mol%) organic layer (product) Workup: Add cyclohexane and water Separate the triphasic mixture Recycle IL layer with catalyst ionic liquid layer (cat) water layer (salt)

A.J. Carmichael et al., Org. Lett. 1, 997 (1999)

Using Homogeneous Catalysts Efficiently

Biphasic homogeneous catalysis integrates reaction and products and catalyst separation into a single operation Other possible solutions: -Supported liquid phase catalysis -Thermoregulated biphasic catalysis

Supported Liquid Phase Catalysis

supported liquid (working) phase homogeneous catalyst
micropore

solid carrier

extractive phase

solid carrier

Combines advantages of homogeneous and heterogeneous catalysis Only a small amount of working phase is present in the reactor Particularly suited with ionic liquids as the working phase

Thermoregulated Biphasic Catalysis

Ph P Ph

H3C
n

RhCl

Mw = 2400
The polyethylene ligand is soluble in hydrocarbons at 90 - 110 C Quantitative precipitation at 25 C Demonstrated in olefin hydrogenation in xylene medium - Activity is comparable with that of (Ph3P)3RhCl - Catalyst 18 recycled without loss
D.E. Bergbreiter et al. J. Am. Chem. Soc. 109, 174 (1987)

Thermoregulated Biphasic Catalysis:

Inverse Temperature Dependence

O Ph2P Ph2P EO N O PO O CH3 EO O

O N PPh2 PPh2

Mw = 1100 - 4400

The ligand and its Rh complex are soluble in water at 0 C At 40 - 50 C the complex separates and reaction stops Ligand dehydration is the driving force Demonstrated in simple hydrogenation
D.E. Bergbreiter et al. J. Am. Chem. Soc. 115, 9295 (1993)

Biocatalysis

Why Biocatalysis?
Mild conditions: ambient temperature and pressure and physiological pH Fewer steps ( avoids protection/deprotection steps) Largely avoids toxic/hazardous reagents & solvents High chemo-,regio- and stereoselectivities

ENZYMATIC VS CHEMICAL PROCESS FOR 6-APA

N H O 1. Me3SiCl 2. PCl5 / PhNMe2/ CH2Cl2 N Cl N O N O CO2H 37 oC pen acylase H2O S N O CO2H 6-APA S

penicillin G -40 oC S

1. n-BuOH, -40 oC H2N 2. H2O, 0 oC

CO2SiMe3

Key improvements: enhanced enzyme production and immobilization Process Chemical Enzymatic Reagents Me3SiCl (0.6) Pen acylase (1-2) (kg/ kg 6-APA) PCl5 (1.2) PhNMe2 (1.6) NH3 (0.09) n-BuOH (8.4 ltr), NH 3 (0.2) Solvent (ltr/kg 6-APA) CH2Cl2 (8.4) H2O (2)

BIOCATALYTIC PRODUCTION OF ACRYLAMIDE: MITSUBISHI

NHase O NH2

CN

+ H2O

conv. > 99.99% sel. 100,000 tons per annum and increasing Simpler than chemical process (Cu catalyst) Immobilized whole cells of Rh.rhodocrous J1 Mild conditions (5oC); no polymerization inhibitor needed >400 gl-1 h-1; higher product quality
A.Liese, K. Seelbach and C. Wandrey, Industrial Biotransformations, Wiley-VCH, 2000

> 99.99%

BIOCATALYTIC HYDROLYSIS OF NITRILES DuPont

NC CN + H2O O NHase 5 C
O

NC

NH2

herbicide intermediate 97% conv. / 96% sel.

Immobilized whole cells of P. chlororaphis B23 Catalyst consumption 0.006 kg/kg product Higher conv./sel. than chemical process (MnO2 cat. /130 oC)
R.Dicosimo et al, Bioorg. Med Chem. 1999, 7, 2239
O

Lonza
N

CN + H2O

NHase Rh.rhodocrous J1 N

NH2

100% yield/ 1465 g l-1/3000 M. Petersen and A. Kiener, Green Chem., 1999,tpa 4, 99

Enzymes in Ionic Liquids

Two phase
IL H2O
E E E E E E

Single phase

E E

E E E

Whole Dissolved cells

Isolated enzyme (dissolved in aqueous phase)

Suspension (immob. enzyme or whole cells)

Potential Benefits of Enzymes in Ionic Liquids Higher activity compared with organic solvents Higher (enantio)selectivity Higher operational stability Highly polar substrates (e.g. carbohydrates) Product separation/catalyst recycling

Organic Solvents vs Ionic Liquids

O O + OH CAL 40 C O O + OH

Reaction conditions: 40 mM ethyl butanoate, 200 mM . butan-1-ol, 25 mg Novozym 435 in 1 ml solvent at 40C

R.Madeira Lau,F.van Rantwijk,K.R.Seddon and R.A.Sheldon,Org.Lett.,2, 4189-91 (2000)

In situ product removal with scCO2

OH CH3 H3C O O (S) (R) OH CH3 O O CH3 CH3

C. antarctica lipase [BMIm][Tf2N]/scCO2

The ionic liquid containing the biocatalyst was recycled 4 times without loss of activity [1]. Demonstrated in a continuous mode [1] and with a supported liquidphase biocatalyst [2]
IL= N + N R (
3SC 2) -

N O F Bu R=Et,

1. M.T. Reetz et al., Chem. Commun. 992 (2002) 2. P. Lozano et al., Chem. Commun. 692 (2002)

SWEETN GREEN: SUGAR-BASED SURFACTANTS

Sucrose fatty acid esters: from canned coffee to cosmetics
OH HO HO O HO OH sucrose O OH C11H23CO2Et O HO HO O O2CR O OH + OH RCO2 OH HO HO O O OH O OH

HO

C.antarctica lipase OH t-BuOH, 82 oC HO 7 days

O OH

HO OH

HO

1:1 35% yield (V.effective emulsifier)

3 x Green (renewable raw material,biocatalytic process, biodegradable product) Current chemical process (Mitsubishi Kagaku) yields complex mixture, mono-, di-, etc How to increase the rate? Use an ionic liquid medium?
M.Woudenberg-van Oosterom, F.van Rantwijk and R.A.Sheldon, Biotechnol. Bioeng., 49, 328 (1996)

Solubility of Sucrose in Ionic Liquids

Ionic liquid [bmim][dca] [hmim][dca] [omim][dca] [moemim][dca] [moemim][Tf2N] [moemim][BF4] [moemim][PF6] [moemim][Tf] Solubility (g/L) 195 167 151 220 0.13 0.4 0.7 2.1

Preliminary expts showed that the Nov 435-catalyzed acylation of sucrose with dodecanoic acid proceeded smoothly in [bmim][dca] dca = (CN)2N Q.Liu,M.Janssen,submitted

Process Integration

A NEW SALT-FREE CAPROLACTAM PROCESS :RHODIA

Du Pont Ni catalyst CN

+ 2 HCN CN

NC

Rhodia

NC

+ H2

catalyst

NC

NH2

NC

NH2 + H2O

Al2O3 300 C
o

O + NH3 NH caprolactam > 99% conv. > 99.5% sel.

overall:

+ 2 HCN + H2O + H2 caprolactam + NH3

The next generation? Biomass fermentation

Caprolactam

PROCESS INTEGRATION: LONZA NICOTINAMIDE PROCESS

H2 CN CN by-product of Nylon 6,6 manuf. [ Pd ] - 3H2 N [ Ni ] H2N NH2 zeolite - NH3

N H O

O2 / NH3 oxide cat. gas phase N

CN

H2O N vitamin B3

NH2

whole cells Rh. rhodocrous

Overall: C6H8N2 + 3/2 O2 + H2 C6H6N2O + 2 H2O

J. Heveling, Chimia, 50, 114 (1996)

CATALYTIC VANILLIN SYNTHESIS: RHODIA PROCESS

OH H2O2 solid catalyst OH aq. H2CO H - MOR CH2OH 4 steps, all employing a heterogeneous catalyst
Overall: C6H6O + H2O2 + CH3OH + H2CO + 1/2 O2 C6H8O3 + 3 H2O
S.Ratton, Chem. Today, March / April, 1998, p.33

OH OH CH3OH La phosphate gas phase 250o C

OH OCH3

OH OCH3 O2 noble metal catalyst CHO OCH3

Conclusion: the Take-Home Message

Catalytic processes can be redesigned for eliminating or decreasing the use of hazardous organic solvents Downstream processing must be an integral part of the process design

The resulting procedures are not just greener, but often also better and cheaper

Fine Chemical Processes of the Future

Generic processes Fewer steps/minimum waste Inherently safe More catalysis Continuous operation Process intensification(mini-reactors) 100% yield/100% ee concept (e.g.DKR) Process integration Catalytic cascade processes

Integration of Chemo- and Biocatalysis:Cascade Catalysis

Chemoenzymatic syntheses,e.g. dynamic kinetic resolutions. 100% yield/100% ee concept (the ultimate in efficiency One-pot,multi-enzyme cascades (the ultimate emulating Nature) Compartmentalization for compatibility (c.f. the living cell)

CHEMOENZYMATIC DKR OF SEC-ALCOHOLS

OH Nov 435 + OAc Ru cat (0.5m%) K2CO3, PhCH3, 70 C, 20h
o

OAc +

reduced pressure

Catalyst Backvall catalyst + PhCOCH3 (25m%) [RuCl2 (p-cymene)]2 + PhC(CH3)(NH2)CONH2 (1m%) + K2CO3 (> 2eq.)

Yield % 97 82

ee (%) 99 99
O Ph H2 N N H2 Ru Cl

G. Verzijl, J.G. de Vries and Q.B.Broxterman, PCT WO 01/90396 A1 (2001) to DSM

Synthesis of a dehydro sugar

O O O HO O O H H H

3 s t e p s ,1 p o t w a t e r ,p H 7
M

OH

O H
e

O O Me OH

HO

D-galactose oxidase

O2, catalase water, pH 7

H2, Pd/C water, pH 7

O

O H O H O H O HO O H O M e

0.1 eq L-proline C, 5h water, pH 7

HO

O O O H M e

Schoevaart R., Kieboom T.Tetrahedron

Letters 2002, 43, 33993400

Cascade Catalysis:One Pot/Four Enzymes

OH HO OPO3
2-

Glycerolphosphate oxidase HO H2O2 1/2 O2 Catalase H2O

O OPO3 DHAP
2-

OH FruA butanal OH

O OPO3
2-

L-glycerolphosphate (50%)

pH 7.5

PO4

3-

pH 4
Phytase pyrophosphate PO4
3-

Phytase OH HO glycerol

OH OH

O OH

R.A. Sheldon et al. J. Org. Chem. 2000, 65, 6940

glycerol 95% 55%

OH 5-deoxy-5-ethyl-D-xylulose (57%)

Merci beaucoup

Fin

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