CY2002D : ORGANIC CHEMISTRY

Module-3, Lecture-1

Dr. Janardhan Banothu

Assistant Professor
Department of Chemistry, NITC
Room No: 210C
Phone no: +91-8111938615
Email: [email protected]

Book References:
• R. T. Morrison and R. N. Boyd. Organic Chemistry. New Jersey : Prentice Hall, 1992
• J. March. Advanced Organic Chemistry: Reactions, Mechanisms and Structure. New York: Wiley, 2006.
 Module 3: (17 hours)
Part-1
• Functionalization of alkenes: hydroboration, dihydroxylation, epoxidation and oxidative
cleavage.
• Oxidation: oxidation of hydrocarbons, alcohols and ketones.
• Reduction: catalytic hydrogenation, reduction by dissolving metals and reduction by hydride
transfer reagents.

Part-2:
• Methods of polymerization: Radical chain polymerization, Step polymerization:
polycondensation, polyaddition, ring opening-lactams, lactones , Electrochemical
polymerization, Group transfer polymerization,
• Ion chain polymerization: cationic and anionic and emulsion polymerization.
• Molecular weight determination of polymers.
• Polymer reactions: hydrolysis, acidolysis, aminolysis, hydrogenation and cyclization.
• Cross linking: sulphur and peroxides.
• Stereochemistry of polymers
 Alkenes: Nomenclature

CH3-CH2-CH=CH2 CH3-CH=CH2-CH3 CH3-CH=CH-CH2-CH2-CH3

1-Butene 2-Butene 2-Hexene
(But-1-ene) (But-2-ene) (Hex-2-ene)

CH3-CH2-CH2-CH2 -C-CH2-CH2-CH3

=
CH2
2-Propyl-1-hexene
 Alkenes: Nomenclature

If the same number for the alkene functional group suffix is obtained in
both directions, the correct name is the name that contains the lowest
substituent number.

2,5-Dimethyl-4-octene / 4,7-dimethyl-4-octene
--------------------------------- 2-Bromo-4-methyl-3-hexene -------------------------------------------
/ 5-bromo-3-methyl-3-hexene
Vinyl group and Allyl group.

H2C=CH- H2C=CHCH2-
Vinyl group Allyl group

H2C=CH-Cl H2C=CH-CH2-Br
Vinyl chloride Allyl bromide

5
The isomers of alkenes

Four isomeric alkenes of molecular formula C4H8:

structural isomers geometrical isomers

6
 Carbon-carbon -bond of alkenes can be reduced easily to the corresponding saturated
C-C bond.

Other -bonds such as C=O and CN are not easily reduced by catalytic hydrogenation.

The C=C bonds of aryl rings are not easily reduced.

O O

O
H2, PtO2
O
H2, PtO2 ethanol
ethanol
O
O
H2, Pd/C
H2, Pd/C C5H11 OH CH3(CH2)16CO2H
C 5H11 OH CH3(CH2)16CO2H
Linoleic Acid (unsaturated fatty acid) Steric Acid (saturated fatty acid) Linoleic Acid (unsaturated fatty acid) Steric Acid (saturated fatty acid)
O O
O
O
OCH3 H2, Pd/C
OCH3 OCH3 H2, Pd/C
ethanol OCH3
ethanol

H2, Pd/C C
C
N N
ethanol H2, Pd/C
C C
N N
ethanol

O O

H2, PtO2

O O ethanol
H2, PtO2

ethanol O
O H2, Pd/C
C5H11 OH CH3(CH2)16CO2H
H2 , Pd/C
C5H11 OH CH3(CH2)16CO2H
Linoleic Acid (unsaturated fatty acid) Steric Acid (saturated fatty acid)
Linoleic Acid (unsaturated fatty acid) Steric Acid (saturated fatty acid)
O
O O
OCH3 H2, Pd/C O
OCH3
ethanol OCH3 H2, Pd/C
OCH3
ethanol
H2, Pd/C C
C
N N
ethanol

H2, Pd/C C
C
N N

2-cyclohexylideneacetonitrile
ethanol
 Hydrogenation of Alkenes:
Addition of H2 to the π-bond of alkenes to afford an alkane.
The reaction must be catalyzed by metals such as Pd, Pt, Rh, and Ni.
H H H H
Pd/C
C C
C C + H H
H H H°heat of hydrogenation = -136 KJ/mol
EtOH
H H H H

C-C π-bond H-H C-H

= 243 KJ/mol = 435 KJ/mol = 2 x -410 KJ/mol = -142 KJ/mol

The catalyst is not soluble in the reaction media, thus this process is referred
to as a heterogeneous catalysis.
The catalyst assists in breaking the -bond of the alkene and the H-H -bond.
The reaction takes places on the surface of the catalyst. Thus, the rate of the
reaction is proportional to the surface area of the catalyst.
The isomers of alkenes
Heats of Hydrogenation
relative stability of isomeric alkenes

H H H CH3
H2 , Pd H2 , Pd
CH3 CH2 CH2 CH3
H3 C CH3 H3 C H

cis-2-butene trans-2-butene

H°hydrogenation: -119 KJ/mol -115 KJ/mol

# The greater release of heat, the less stable the reactant.

# trans isomer is 4 KJ/mol more stable than the cis isomer
 Heats of Hydrogenation of Some Alkenes
Alkene H° (KJ/mol)
H2C=CH2 136

H H
monosubstituted
125 - 126
H3C H

H H
117 - 119
H3C CH3

H CH3
disubstituted 114 - 115
H3C H

H3C H
116 - 117
H3C H

H3C H • C-C bond between a sp3 carbon and a sp2 carbon is slightly stronger than
trisubstituted 112 a C-C bond between two sp3 carbons. 
H3C CH3
• Increasing the number alkyl substituents of a double bond also
H3C CH3
increases the number of sp3-sp2 C-C bonds making the alkene more
tetrasubstituted 110 stable.
H3C CH3
Heats of combustion
Relative stability of isomeric alkenes

H H H CH3

H3C CH3 H3C H

cis-2-butene trans-2-butene

H°combustion: - 2710 KJ/mol - 2707 KJ/mol

# The greater release of heat, the less stable the reactant.

# trans isomer is 3 KJ/mol more stable than the cis isomer

Hydrogenation on metal surface

at the beginning of adsorption physisorbed condition chemisorbed condition

Physisorption of hydrogen Chemisorption of hydrogen

on nickel surface on nickel surface

L-1
Stereochemistry of Alkene Hydrogenation
Mechanism:

H H
H2C CH2 H H H2C CH2

H2C CH2
H2

HH
H H
H H C C
C H H H
H H
C H
Module-3, Lecture-2
Stereochemistry of Alkene Hydrogenation
Mechanism:

The addition of H2 across the -bond is syn,

i.e., from the same face of the double bond

H CH3
CH3 H2, Pd/C CH3 H

EtOH CH3
CH3 CH3
H H

syn addition
of H2 Not observed
Electrophilic Addition

C-C -bond: H°= 368 KJ/mol

C-C -bond: H°= 243 KJ/mol
-bond of an alkene can act as a nucleophile!!

Electrophile can be: X2, HX etc.

 Stereochemistry of Alkene Bromination
Mechanism:
The addition of Br2 across the -bond is anti,
i.e., from the opposite face of the double bond

In this reaction alkene interacts with LUMO of bromine (i.e. empty σ* orbital)to form a
three membered cyclic bromonium ion intermediate.
The bromide anion attacks the cyclic bromonium ion resulting in generation of product 1,2-
dibromide
Bromination of cis 2-butene
Br Me
+
Me Br
Me
Br + Br
Br-Br Me
Me H
Me
H H
H

H H

Me
Me H
Br H Br
Br H
Br
Br H
Me
H
Me
Br Me
Br Me Me
H Br Me
H
Br
H Br H
Me
H H Br
Me
H Br Me Me
Bromination of trans 2-butene
Br H
+
H Br
H
Br + Br
Br-Br Me
Me Me
Me
Me Me
H

H H

Me
Br
H Br H
H H
Br Br
Br H
Me Me
Me Me
Br Me
H Me
H Br H Br
Br
H H Br

Me H Br
Me Me
Me Me
H Br
Explain the observation

HO
CH3 CH3
Br2, H2O
+ HBr
Br
H
Conversion of Alkenes to Vicinal Halohydrins

X2, H2O X
+ HX
OH

anti
stereochemistry

Mechanism involves a halonium ion intermediate

22
Unsymmterical alkenes: Halohydrin formation is governed by
carbocation stability

 CH3

Br 
+


more + charge on the more substituted carbon

H2O adds in the second step

H2O adds to the carbon that has the most + charge

23
Electrophilic Addition of Hydrogen Halides to Alkenes

H H Br H
C C + H-Br C C
H H
H H H H
nucleophile electrophile

Bonds broken Bonds formed

C=C -bond 243 KJ/mol H3C-H2C–H -410 KJ/mol
H–Br 366 KJ/mol H3C-H2C–Br -283 KJ/mol

calc. H° = -84 KJ/mol

expt. H°= -84 KJ/mol
Regioselectivity of Hydrogen Halide Addition:
Markovnikov's Rule

H
H-Br Br H H Br
C H +
R C R C C H R C C H H
H-Br Br H H Br
H H H H H C H +
R C R C C H R C C H
none of this
H H H H H
R none of this
H-Br Br H H Br
C H + R
R C R C C H R C C H

x
H-Br Br H H Br
C H +
H R H R H R C R C C H R C C H
none of this H R H R H
R none of this
Br H H Br R
C H H-Br + Br H H Br
R C R C C R R C C R C H H-Br
R C R C C R + R C C R
R R H R H
R R H R H
none of this
none of this
R R
Br H H Br Br H H Br
C H H-Br + C H H-Br
H C R C C R R C C R' H C R C C R + R C C R'
R' H H H H R' H H H H
Both products observed Both products observed

For the electrophilic addition of HX across a C=C bond, the H (of HX) will add to the carbon
of the double bond with the most H’s (the least substitutent carbon) and the X will add to
the carbon of the double bond that has the most alkyl groups.
Reactivity of HX correlates with acidity

Slowest HF << HCl < HBr < HI fastest

Mechanism: Electrophilic addition of HX to alkenes
Explain the observation

H
Cl H
H H
H3C C H H-Cl H3C C H
+ H3C C H
C C C C
C C
H3 C H3C H
H H H H H3 C H
Cl H

~ 50% ~ 50%
expected product
Module-3, Lecture-3
Regioselectivity of Hydrogen Halide Addition in presence of peroxide:
Anti Markovnikov's Rule

H H H
H-Br Br H H Br H-Br Br H H Br H-Br Br H H Br
C H + C H + C H +
R C R C C H R C C H R C R C C H R C C H R C R C C H R C C H
H H H H H H H H H H H H H H H
none of this none of this none of this
R R R
Br H H Br Br H H Br Br H H Br

x
C H H-Br C H H-Br C H H-Br
R C R C C H + R C C H R C R C C H + R C C H R C R C C H + R C C H
H R H R H H R H R H H R H R H
none of this none of this none of this
R R R
Br H H Br Br H H Br Br H H Br
C H H-Br C H H-Br C H H-Br
R C R C C R + R C C R R C R C C R + R C C R R C R C C R + R C C R
R R H R H R R H R H R R H R H

H2O2
none of this none of this none of this
R R R
Br H H Br Br H H Br Br H H Br
C H H-Br C H H-Br C H H-Br
H C R C C R + R C C R' H C R C C R + R C C R' H C R C C R + R C C R'
R' H H H H R' H H H H R' H H H H
Both products observed Both products observed Both products observed

For the electrophilic addition of HX across a C=C bond, the H (of HX) will add to the carbon
of the double bond with the most H’s (the least substitutent carbon) and the X will add to
the carbon of the double bond that has the most alkyl groups.
Addition of Radicals

Markovnikov addition

Anti Markovnikov addition

Heterolysis & Homolysis
Heterolytic bond cleavage or heterolysis

H Br H+ + Br

H Br H+ + Br
Homolytic bond cleavage or homolysis
H Br H + Br

H Br H + Br

Homolysis produces radicals, which are very reactive species

Radical chain reactions
Radical chain reactions
Radical chain reactions
The regiochemistry of free radical addition of H-Br to alkenes
reflects the stability of the radical intermediate.

H H R
R C• R C• R C•
H R R
Primary (1°) < Secondary (2°) < Tertiary (3°)

36
Acid-Catalyzed Hydration of Alkenes

C C + H—OH H C C OH

acid catalyzed hydration reaction in 50% H2SO4-50% H2O

Follows Markovnikov's Rule

H3C H CH3
50% H2SO4
C C CH3 C CH2CH3
50% H2O
H3C CH3 OH
(90%)
Step (1) Protonation of double bond

H3C H
+
C CH2 + H O:
H3C H
slow
H3C H
+
C CH3 + :O :

H3C H
Step (2) Capture of carbocation by water

H3C H
+
C CH3 + :O :

H3C H
fast

CH3 H
+
CH3 C O:

CH3 H
Step (3) Deprotonation of oxonium ion

CH3 H H
CH3 C O: + :O :
+
CH3 H H
fast
CH3 H
.. +
CH3 C O: + H O:

CH3 H H
Principle of microscopic reversibility

H3C CH3
H+
C CH2 + H2O CH3 C CH3
H3C OH

In an equilibrium process, the same intermediates and transition states

are encountered in the forward direction and the reverse, but in the
opposite order
Hydroboration reaction

C C + H—BH2 H C C BH2

Hydroboration can be viewed as the addition of borane (BH3) to the

double bond
Hydroboration Step

C C + H—BH2 H C C BH2

Hydroboration reagents:
1. Borane-tetrahydrofuran complex (H3B-THF)
H
Diborane (B2H6) normally used in an
H2B BH2 ether-like solvent called "diglyme
2. O
O
O

(bis(2-methoxyethyl) ether)"
H
 Addition of borane (BH3) or alkyl boranes to alkenes (or alkynes) is called hydroboration.

4 BF3 + 3 NaBH4 2 B2H6 + 3 NaBF4

 Borane exists as a dimer, but solutions containing an electron donor, such as an ether,
amine or sulfide, allow adduct formation.
 The complexes BH3·THF and the borane–dimethyl sulfide (BH3·SMe2) are commercially
available and provide a convenient source of borane.
 BH3·SMe2 complex is more stable than BH3·THF and has the additional advantage that it
is soluble in a variety of organic solvents, such as diethyl ether and hexane.
45
 The most important synthetic application of borane is for the preparation of alkyl boranes
by addition to alkenes, a process known as hydroboration.
 In nearly all cases the addition proceeds rapidly at room temperature, and only the most
hindered alkenes do not react.
 Hydroboration occurs by a concerted process and takes place through a four membered
cyclic transition state.

 The reaction is stereospecific, with syn addition of the boron and

hydrogen atoms.
 The reaction can also be stereoselective, with hydroboration taking
place preferentially on the less hindered side of the double bond.

4-Membered cyclic TS

46
Oxidation Step

H2O2, NaOH
H C C BH2 H C C OH

Organoborane formed in the hydroboration step can be oxidized into

alcohol by hydrogen peroxide
Hydroboration-Oxidation of Alkenes:
Anti-Markovnikov addition of H-OH/ syn addition of H-OH

CH3 1) B2H6, THF H

2) H2O2, NaOH, H2O CH3

H
HO

48
Mechanism of Hydroboration
syn addition of the H2B–H bond to the same face of the -bond in an anti-
Markovnikov sense
 Hydroboration of mono- and disubstituted alkenes with borane gives rise typically to a
trialkylborane product. However, trisubstituted alkenes normally give a dialkylborane and
tetrasubstituted alkenes form only the monoalkylboranes.
 The extent of hydroboration may also be controlled by the stoichiometry of alkene and
borane.
CH3 CH3
H3C CH3
B
CH3 H CH3

2-Methyl-2-butene Disiamylborane
(Trisubstituted alkene) (di-s-isoamyl group, dialkylborane)

H3C CH3
BH2
H3C CH3

2,3-Dimethyl-2-butene Thexylborane
(Tetrasubstituted alkene) (t-hexyl group, monoalkylborane)
50
 9-BBN
1,5-Cyclooctadien (9-Borabicyclo[3.3.1]nonane)

 Disiamylborane, Thexylborane and 9-BBN (partially alkylated boranes) may themselves

be used to hydroborate less-hindered alkenes.
 Addition of borane to an unsymmetrical alkene could, of course, give rise to two different
products by addition of boron at either end of the double bond.
 Typically, the less-hindered end of the alkene double bond is also the more electron rich
and therefore interacts better with the electron-deficient boron atom. However, the
selectivity is diminished with increasing electronegativity of the substituent.
Module-3, Lecture-4
 Reactivity with
Borane

 With 1,2-disubstituted alkenes, however, there is little discrimination in reactions with

borane itself.
 In addition, the region-selectivity in the hydroboration of terminal alkenes, although high,
is not complete.
 Further, there is little difference in the rate of reaction of borane with differently substituted
double bonds, so that it is rarely possible to achieve selective hydroboration of one double
bond in the presence of others.
 These difficulties can be overcome by hydroboration with substituted boranes such as
disiamylborane, thexylborane or 9-BBN. These reagents are less reactive and more
selective than borane.

For example,
BH
2 B2H6 B
B B +
(Disiamylborane) 3 3
H H
1-Hexene H
99% 94% 6%
9-BBN

B
H
99.9%

54
 (C5H11)2BH B2H6
B B +
(Disiamylborane) H 3 B
H H
4-Methyl-2-pentene
97% 57% 43%
9-BBN

B
H

99.8%

Important:
• Terminal alkenes react more rapidly than internal alkenes.
• Z-alkenes react more rapidly than E-alkenes.

55
 Hydroboration of dienes with borane itself usually leads to the formation of polymers.
 The monoalkylborane, thexylborane can promote the hydroboration of dienes to give
cyclic or bicyclic organoboranes.

For example,

(Thexylborane)
1,5-Hexadiene Boracycloheptane

 Thexylborane has been used to make trialkylboranes containing three different alkyl
groups by stepwise addition to two different alkenes.

Less reactive
alkene – Otherwise
two alkenes can
attacks at the same
time
56
 H OH
Generally, B2H6 C H2O, H+
OH H3C CH2
H3C H2O2 / NaOH H3C CH3
1-Propanol 1-Propene 2-Propanol
(Anti-Markovnikov's product) (Markovnikov's product)

Mechanism of hydroboration:

H H
+ B H B
B B
H
1-Propene H H
Mono-alkyl borane Di-alkyl borane Tri-alkyl borane
 Mechanism of Oxidation:

R R
B
H H R O H R H2O R
O OH O R
R B O _ OH R B O R B O
O (aq. NaOH) O
H _ H O R R R H
2 Hydroperoxide
anion OH

R B OH + R OH
R
This proceed further Alcohol
Some example: H
B2H6 H2O2
BH OH
Diglyme 2
aq. NaOH
(2-Methoxyethyl ether) 2

B2H6 or BH3 BH Na2Cr2O7 O

H2SO4
2

+ BH3 COOH
B 3
Propane

In the presence of
Acetic acid
59
 syn addition
Symmetrical alkyne
Reactive
isolation is tedious

H
OH
B
H
B2H6 or BH3 H2O2
aq. NaOH

-Pinene cis Myrtanol

(Monoterpene)

60
 PCC
(Pyridinium chlorochromate)

61
 Hydration of Alkenes / Addition of Water
 Alkenes react with water in the presence of strongly acidic medium to form an alcohol.
 Hydration of an alkene is reverse of the dehydration of an alcohol.
R2 R3 H OH
H+
+ H2O R2 R3
R1 R4 R1 R4
Markovnikov orientation
Forward Reaction Hydration of alkene
Backward Reaction Dehydration of alcohol

 For dehydration of alcohols, a concentrated dehydrating acid such as H2SO4 or H3PO4 is

used to drive the equilibrium to favor the alkene.
 Hydration of an alkene on the other hand is accomplished by adding excess water to drive
the equilibrium towards the alcohol.
62
 Mechanism: Acid catalysed dehydration of alcohols
H2O

H+
H
R2 R3 H H H O H H OH
H2O H2O
+ H O H R2 R3 R2 R3
Protonation _ H O+ R2 R3
R1 R4 R1 R4 Nucleophilic 3
R1 R4 R1 R4
attack Deprotonation
Carbocation
(on more substituted carbon)

 The mechanism is similar as addition of hydrogen halide.

 Hydration is regioselective; it follows Markovnikov rule giving a product in which the new
hydrogen has added to the less substituted end of the double bond.

63
Some Examples:
H2O, H+ OH

1-Propene 2-Propanol

H2O, H+
HO

2-Methyl-2-butene 2-Methyl-2-butanol

H3O+ OH

1-Methyl-1-cyclohexene 1-Methylcyclohexanol
64
 50% H2SO4
HO

3,3-Dimethyl-1-butene 2,3-Dimethyl-2-butanol
Rearrangement:
From less stable carbocation to more stable carbocation
(Wagner Meerwein Rearrangement)
 Hydration of Alkenes by Oxymercuration - Demercuration

 Many alkenes do not easily undergo hydration in aqueous acid. Some alkenes are nearly
insoluble in aqueous acid, and other undergo side reactions such as rearrangement,
polymerization or charing under strongly acidic conditions.
 In some cases, the overall equilibrium favors the formation of alkenes rather than alcohol.
No amount of catalysis can cause a reaction if the energetics are unfavorable.
 Oxymercuration – Demercuration is another method for converting alkenes to alcohols with
Markovnikov’s orientation.
 This method works with many alkenes, that do not easily undergo direct hydration, and it
take place under mild reaction conditions. No free carbocation is formed, so there is no
opportunities for rearrangement and polymerization.

66
General reaction:

Mechanism:

Oxymercuration: Addition of Hg and oxygen

Act as nucleophile

_ AcOH

Cyclic mercurinium ion Organomercurail alcohol

Demercuration: Removal of Hg

4 + NaBH4 + 4 NaOH + NaB(OH)4 + 4 Hg + 4 NaOAc

Na tetrahydroxyborate

Some Examples:

OAc
Hg(OAc)2 Hg H2O Hg(OAc) Hg(OAc)
NaBH4
H2O - AcOH
HO OH HO
Cyclic mercurinium ion 2-Propanol
H2O attacks the most substituted carbon atom
(more +ve charge)
 Hg(OAc)2 Hg(OAc) H2O Hg(OAc)
NaBH4
- AcOH OH OH OH
3,3-Dimethyl-1-butene Markovnikov's product 3,3-Dimethyl-2-butanol

Note: No rearranged product as like acid catalyzed reaction

Advantageous:
 This method is most commonly used in the laboratory.
 This method gives better yields than the direct acid catalyzed reactions.
 It avoids the possibility of rearrangement and it does not involve harsh reaction conditions.

Disadvantageous:
 Organomercurial compounds are highly toxic, they must be used with great care and must
be disposed properly.
69
 Alkoxymercuration - Demercuration
 Conversion of alkenes to ethers.
 When mercuration takes place in an alcohol solvent, the alcohol serve as a nucleophile to
attack the mercurinium ion. The resulting product containing an alkoxy group.

R OH NaBH4
+ Hg(OAc)2 H
OR Hg(OAc) OR

Mechanism:
It attacks at more substituted end of the double bond

Hg(OAc)2 NaBH4
R OH
RO H
Hg - AcOH RO Hg(OAc)
R O Hg(OAc)
OAc H
Cyclic mercurinium ion Organomercurial ether
70
 Solvent attacks on the mercurinium ion at the more substituted end of the double bond
(where there is a more positive charge), giving Markovnikov’s orientation product.

Some Examples:
OAc
Hg H3C OCH3 H3C OCH3
Hg(OAC)2 H3C OH Hg(OAc) NaBH4 H
H H H

1-Methyl- Mercurinium ion 1-Methoxy-

1-cyclopentene 1-methylcyclopentane

Hg(OAC)2 NaBH4
EtOH EtO Hg(OAc) EtO H
2-Methyl-2-butene 2-Ethoxy-2-methylbutane

71
Module-3, Lecture-5
 Epoxidation of Alkenes (IUPAC name: Oxiranes)
 Epoxidation: Conversion of olefin into oxiranes using oxidizing agents is called epoxidation.
R2 R3 R2 R3
Oxidizing agent
R1 R4
R1 R4 O
Epoxide

Nomenclature: Alkane / Cycloalkane

H H 3 H H 4 H H H3C CH3
H H H3C H H3C CH3 H3C CH3 O
2 2 1 3 O 2 1
O1 O O
1,2-Epoxy ethane 1,2-Epoxy propane 2,3-Epoxy butane 2,3-Dimethyl 2,3-epoxy butane 1,2-Epoxy cyclohexane

CH3 CH3 H3C

O O
O
CH3
1-Methyl 1,2-epoxy cyclohexane 1,2-Dimethyl 1,2-epoxy cyclohexane 3-Methyl 1,2-epoxy cyclopentane
Types of Reagents:
a. Per acids / Peroxy acids
b. Hydrogen peroxide / OH-
c. Alkyl hydroperoxides / Metal complexes
d. Dioxiranes
e. Hypohalo acids (HOX)
f. Iodine catalysed epoxidations
 a. Per acids / Peroxy acids (RCO3H)
Preparation:
O O
Heating
+ H2O2 O
R OH R O H

R = H / Alkyl / Alkoxide

 Due to the easy liberation of nascent oxygen, peroxides used for epoxidation of olefins.
O O O O
O O O O
H O H H3C O H F3C O H Ph O H

Per formic acid / Per acetic acid / Per trifluoroacetic acid / Per benzoic acid /
Peroxy formic acid Peroxy acetic acid Peroxy trifluoroacetic acid Peroxy benzoic acid
(PFA) (PAA) (PTFAA) (PBA)

O O O
O O O
O H O H O H
O Mg+2

Cl NO2 O
2
m-Chloro per benzoic acid m-Nitro per benzoic acid Magnesium mono perphthalic acid
(m-CPBA) (m-NPBA) (MMPTA)
Use of m-CPBA:
 m-CPBA is used widely used in the laboratory
 Stable
 Low cost
 Easily soluble in most of the organic solvents.

Solvents:
 Halogenated solvents: DCM, Chloroform
 Aromatic hydrocarbons: Benzene, toluene and Xylene
 Ethers: Diethyl ether and THF
 Alcohols: Methanol and Ethanol
 Acid: Acetic acid
 Water

Temperature: ─ 10 oC to Room temperature

General Reaction:
O O O O
NaHCO3
+ O + H
R R O H R O R ONa
R
Nucleophile Electrophile Epoxide Water soluble

Mechanism:

Transition state
Stereochemistry of the epoxidation: Syn addition of oxygen

Groups that are trans on the alkene will end up trans on the epoxide product.

Groups that are cis on the alkene will end up cis on the epoxide product.
Reactivity of olefins in epoxidation:
H H H H H3C H H3C H H3C CH3

H H H3C H H3C H H3C CH3 H3C CH3

 Electron rich olefins are good nucleophiles, thus faster in epoxidation.

 Steric crowding can be neglected.

Reactivity order:
H H H H H3C H H3C H H3C H H3C CH3

H H H3C H H3C H H CH3 H3C CH3 H3C CH3

Reactivity with respective to per acid:
 At carbonyl of per acid presence of electron withdrawing group increases the
reactivity
 Trifluro peracetic acid (TFPAA) – Highly reactive per acid in epoxidation due to the
presence of strong electron withdrawing group at carbonyl.
 Although TFPAA less commonly used in laboratory due to:
o Highly expensive
o Highly unstable (difficult to store)
o By-product, trifluro acetic acid opens the epoxide. To prevent the opening of
epoxide, basic buffer or simple bases can be used in combination with TFPAA.

Regioselectivity in epoxidations with peracids:

 If the compound contain multiple double bonds, selective epoxidation takes place at
highly alkylated double bond.
 In a chemical reaction, if structural isomers produced in unequal ratio is regioselective.
Examples:
PhCO3H m-CPBA
O + O O
DCM DCM

Major
Major Minor

PhCO3H PhCO3H
O O
DCM CH3Cl

Major Major

Conjugated (weak nuclophiles

PhCO3H
CH3Cl O m-CPBA
DCM
O
Stereoselectivity in epoxidation:
 In a chemical reaction, if stereoisomers produced in unequal amount is called
stereoselective reactions.
 In epoxidations, stereoselectivity controlled by Steric crowding near the double bond
and Chelation or H-bonding.

i. At olefin if no steric crowding at top and bottom faces, epoxidation is equally probable
in both faces, resulting product is in equal amount / equal ratio. Thus, no
stereoselectivity in epoxidation.
Front face attack
O
O
O 50 %
H O R Stereoisomers in equal ratio
Not a stereoselective reaction

Back face attack

O

50 %
ii. Near to unsaturation if there is a alkyl substituent, at double bond one of the face
suffers from steric crowding at the time of epoxidation approaching reagent preferably
deliver oxygen at sterically less crowded face. In the resulting product stereoisomers are in
unequal ration, thus stereoselective epoxidation.
R R R
m-CPBA
DCM +
O O
Major Minor
(Anti product) (Syn product)

Examples:
Sterically croded face CH3 CH3
CH3 CH3 CH3
m-CPBA
m-CPBA DCM
O + O
DCM O
Major
Major Minor
Chelation / H-bonding:
 At allylic position, if there is a chelating group (OH, NH2) epoxidation preferably takes
place at the same side of chelating group.
 Steric crowing supressed by chelation between group at allylic position and
approaching reagent.
 Group at allylic position develops hydrogen bonding with reagent and holds specially
at one face of olefin of unsaturation.
 Cyclic systems are best examples for chelating effect.
OH
OH OH
m-CPBA
O + O
DCM
Hydrogen bonding
Major Minor R H OH
OH O O
O Front approach O
O O
O O
H H
Major
Examples:
OH OH NH2 NH2
m-CPBA m-CPBA
O O
C6H6 DCM

CH3 CH3
m-CPBA

OH DCM OH
O
Limitations:
1. Peracids are inefficient in epoxidation of conjugated olefins
O m-CPBA O
O
R DCM
R
5-10 % yield

2. In some of the α, β unsaturated olefins, Baeyer-Villiger oxidation is side reaction or

competitive reaction.
O m-CPBA O
O O O
+
R DCM
R R
Low yield Baeyer-Villiger
oxidation product

3. Peracids also in efficient in epoxidation of terminal alkenes because of low nucleophilicity.

Epoxidation: diastereoselectivity
Relative Rates of Epoxidation

Ethylene H2C=CH2 1
Propene CH3CH=CH2 22
2-methylpropene (CH3)2C=CH2 484
2-methyl-2-butene (CH3)2C=CHCH3 6526
Examples:
 b. Hydrogen peroxide / OH-
 H2O2/OH- is a alternative to peracids.
 It is mainly useful for the oxidation of conjugated olefins such as e.g. α,β-unsaturated
carbonyl compounds, α,β-unsaturated nitriles and α,β-unsaturated nitro compounds.
R H2O2/OH- O
R
O
O
High % of yield

NC CN H2O2/OH- NC CN
NC CN
NC CN O

H2O2/OH- H3C NO2

H3C NO2
O
Mechanism:
H HO-
O O O O
H H

R
R
O O
R
O O
O O - OH-
O
O H
H

Examples:
O O O O
H2O2/NaOH Me H2O2/NaOH Me
O
O
H H
Module-3, Lecture-6
Oxidation of alkenes into 1,2-diols
a. Opening of epoxides in acidic/basic medium (H +/OH-)
b. Prevost and Woodward hydroxylation (RCOOAg/I2)
c. Osmium tetroxide (OSO4)
d. Potassium permanganate (KMnO4)
a. Opening of epoxides in acidic/basic medium (H +/OH-)
In acidic medium:

Mechanism:
In basic medium:

• Alkenes → Epoxides → Anti 1,2-diol (Anti glycols)

OH
m-CPBA OH- H+ OH
O O
HO
Anti 1,2-diol

50 %

m-CPBA OH OH
OH-
O +
H+ OH OH
50 %
 b(i). Prevost Hydroxylation (Dry hydroxylation/Anti hydroxylation)
• Alkenes → Anti 1,2-diol (Anti glycols).
• The reaction was discovered by the French chemist Charles Prévost.
Reagents: O
+
I2, C6H6
R O Ag
R = Alkyl / Aryl
Most widely used: CH3COOAg, PhCOOAg
O
O
R O Ag+ O R OH
OH-
I2 R O HO
O Anti 1,2-diol

O O R

R O Ag+ O OH
OH-
I2 O OH

O R
Mechanism:

Neighbouring group
participation (NGP) 
 Me Me
CH3COOAg/I2 H OH HO H
+
Me Me OH- HO H H OH
cis alkene Me Me
Racemic mixture

Me Me
CH3COOAg/I2 H OH
Me OH- H OH
trans alkene Me
Meso compound
 b(ii). Woodward Hydroxylation (Wet hydroxylation/Syn hydroxylation)
• Alkenes → Syn 1,2-diol (Syn glycols).
• The reaction was discovered by American Organic Chemist Robert Burns Woodward.
Reagents: O
I2, aq. AcOH
R O Ag+
R = Alkyl / Aryl
Most widely used: CH3COOAg
Mechanism:

Neighbouring group
participation (NGP) 
 O

R O Ag+ OH OH
+
I2, aq. AcOH
OH OH

Meso compound (Both are same)

• Near to olefin if there is a substitution, Woodward hydroxylation preferably takes place at

sterically more crowded side of the olefin.
O O
Me Me Me
Me HO
H3C O Ag+ OH H3C O Ag+

I2, aq. AcOH/OH- I2, aq. AcOH/OH- HO

OH H
H
Major
• In a molecule if there is a conjugated and isolated olefins. Woodwards hydroxylation takes
place at isolated double bond.

O OH
Me Me
Ph O Ag+
OH
-
I2, aq. AcOH/OH
O O
 c. Osmium tetroxide (OSO4) – Syn hydroxylation
• OsO4 is formed slowly when osmium powder reacts with O2 at ambient temperature.
Reaction of bulk solid requires heating to 400 °C.
• Alkenes → cis 1,2-diol.
• OsO4 is expensive and highly toxic. Thus, it can be used in catalytic amount OsO4 in the
presence of co-oxidant
• Potassium chlorate (KClO3) / hydrogen peroxide / N-methylmorpholine N-oxide (NMO) /
K3Fe(CN)6 in water can be used as a co-oxidant.
• Lewis bases such as tertiary amines and pyridines increase the rate of dihydroxylation. The
ligand-acceleration arises via the formation of adduct OsO4L, which adds more rapidly to
the alkene.
OSO4 HO OH
R1 R2 H2O R1 R2
Mechanism:
Cis addition

Osmate ester

VIII
Dihydroxylation : diastereoselectivity
Examples:
CHO Cat. OSO4, Et2O, Py CHO
KClO3
HO OH

COOH
COOH Cat. OSO4, Et2O, Py H OH
KClO3 H OH
COOH
COOH
cis alkene Meso compound

COOH COOH
HOOC Cat. OSO4, Et2O, Py H OH HO H
+
KClO3 HO H H OH
COOH
COOH COOH
trans alkene Racemic mixture
 OH OH
Cat. OSO4, NMO OH

Py, Et2O
OH

Me Me
Cat. OSO4, NMO OH
OH
Py, Et2O

EtOOC EtOOC OH
Cat. OSO4, NMO
OH
Py, Et2O
EtOOC EtOOC
 d. Potassium permanganate (KMnO4) – Syn hydroxylation
• Cheaper solid
• Insoluble in organic solvents, but soluble in water.

Application: Alkenes → Syn 1,2-diol.

Solvents: Water, aq. Benzene, aq. Acetone, aq. Alcohols, aq. Acetic acid, aq. Ether

Limitations:
o Insoluble in organic solvents.
o Useful for organic compounds which are soluble in water. e.g. unsaturated carboxylic
acid, unsaturated sulfonic acids and Oleic acid etc.
o Oxidation product depends on nature of reaction condition. In neutral and acidic
medium over oxidation product produces. In basic medium usually products are 1,2-
diols, over oxidation product almost negligible.
Mechanism: Cold KMnO4/OH-

R R OH
KMnO4/OH-

R R OH

O H
R O R O O OH-
R O O O- H+
R OH O
+ Mn Mn Mn +
R O O Mn
O R O R O O R OH
O O
Mn-O bond cleavage Syn 1,2-diol
• Similar to OsO4, selective hydroxylation takes place at sterically less crowded olefins in the
presence of alkaline KMnO4.
• cis alkene + Syn addition → Meso compound
• trans alkene + Syn addition → Racemic mixture
Me Me Me
-
H KMnO4/OH H H OH
Me Me OH
Aq. Benzene H OH
H HO H
Me
Meso compound

H Me Me
-
Me KMnO4/OH H OH HO H
Me +
Aq. Benzene HO H H OH
H
Me Me
Racemic mixture
• If the reaction carried out using hot concentrated acidified potassium manganate(VII)
solution; R
R2 R3 +
hot KMnO4/H R2 3
O + O
R1 R4 R1 R4

Overoxidized product (via 1,2-diol)

R2 R3 hot KMnO4/H+ R2 R3
O + O
H R4 HO R4

Overoxidized product (via 1,2-diol)

H R3 hot KMnO4/H+ R3
CO2 + H2O + O
H R4 R4
 ++
Ozonolysis of Alkenes O _
O O -
 Oxidative cleavage of an alkene to carbonyl compounds (aldehydes and ketones). Both
- and - bonds are breaking during the ozonolysis of alkenes.
 Unsaturated bonds of alkenes, alkynes and azo compounds are cleaved with ozone.
 Alkenes and alkynes multiple carbon–carbon bond has been replaced by a carbonyl
group while azo compounds form nitrosamines.
 The outcome of the reaction depends on the type of multiple bond being oxidized and
the work-up conditions.
 Useful for the determination of position of double bond in a molecule.
Mechanism:
 Mechanism proposed by Rudolf Criegee (German organic chemist) in 1953.
 Mechanism proceed through a Criegee intermediate or Criegee zwitterion.

Carbonyl oxide
(Criegee zwitterion)
Mechanism: Oxidative workup
Mechanism: Oxidation of aldehyde to acids with H2O2
Mechanism: Reductive workup
Overall reaction mechanism:
Examples:
1) O3
2) Zn
O + O

1) O3
2) Zn H
H + O C
H
O

1) O3
2) Zn O

H
O
Ozonolysis of alkynes:
 The exact mechanism is not completely known.
Examples:
Oxidative cleavage of alkenes
Oxidative cleavage: Ozonolysis

O3, CH2Cl2 O
R1 R3 -78 °C O O O O R1 R3
R1 R3 Zn
-or- O + O
R2 R4 R1 R3 R2 R4
O (H3C)2S R2 R4
R2 R4
molozonide ozonide + ZnO or (H3C)SO
 Module-3, Lecture-7
Oxidation of Alcohols to carbonyls
Oxidation: Addition of oxygen or removal of hydrogen in a chemical reaction.

1. Chromium-based Reagents
a. H2CrO4: Chromic acid

b. CrO3 + Aq. H2SO4 + Acetone ─ Jones Oxidation

c. CrO3 + Pyridine ─ Saretts Oxidation

d. CrO3 + Pyridine + DCM ─ Collins Oxidation

e. PDC: Pyridinium Dichromate
f. PCC: Pyridinium Chlorochromate
 a. H2CrO4 (Chromic acid)
 CrO3 + H2O/H3O+ O
HO Cr OH
 Na2Cr2O7/K2Cr2O7 + H2SO4 Unstable must be generated in situ.
O
 NaCrO4/KCrO4 + H2SO4
 CrO3 is a strong oxidizing agent that appears in the form of deep-red hygroscopic
crystals.
Applications:
i. 1o alcohols ─ Acids (Over oxidized product)

ii. 2o alcohols ─ Ketones

iii. Aldehydes ─ Acids

Mechanism:
H2CrO4 H+ + HCrO4-

O O H HO O
+
H O R H HO O
Cr OH H
HO Cr OH HO Cr OH R O Cr OH
OH R O
O O H O H
H
H
(Activated Chromic acid) (Chromate ester)

H2O
(or) - H2O
O
HO Cr OH CrO2 + H2O Conjugate base of the acid (HCrO4-)
Unstable
O O
H + HO Cr OH
R
(Aldehyde) (Chromous acid)
Not the final product
Oxidation to carboxylic acids
O
H HO Cr OH H
O O H H H O O HO O
H+ H2O O H2O O H
O O Cr OH
R H R H H H R O
R H R H OH
H
(Activated aldehyde) gemdiol

Conjugate base of H
O O HO O
O the acid (HCrO4-) /
HO Cr OH + R OH Cr OH
R O
H2O H O H
(Unstable (Acid)
H
Chromous acid) (Chromate ester)
Limitations:
1. Primary alcohols always leads to carboxylic acids. Therefore it is not suitable for
them.

2. If alcohols having other oxidisable groups, those also get oxidized.

For example.
R O R
H2CrO4
HO
OH O

2. Acid labile groups get opened in this oxidation process.

For example.
OH O

H2CrO4
O
O
O
Hexahydronaphthalene-
1,6(2H,7H)-dione
Examples: Me OH O O
H2CrO4
Me Me
OH
Me
Vicinal diol

Axial O
OH
OH Cr O
O
H2CrO4 O Fast
H
H - H2O
cis - CrO2
Chromate ester
Stirically crowded

H
H2CrO4 O Slow
OH O Cr OH - H2O O
trans O - CrO2
Chromate ester
Stirically free
b. Jones Oxidation (CrO3 + Aq. H2SO4 + Acetone):
 Chromium trioxide is a strong oxidizing agent, and its use in organic
synthesis had to overcome two problems:
 Its lack of solubility in most organic solvents.
 Its tendency to explode in the presence of organic matter.
 In 1946, Jones discovered that 2o alcohols could be efficiently
oxidized to ketones by pouring a solution of chromium trioxide in
diluted sulfuric acid over a solution of the alcohol in acetone.
 This procedure, which has proved to be quite safe, allows a Sir Ewart Ray Herbert Jones
sufficient contact of the alcohol with chromium oxide derivatives for (Organic Chemist, UK)

a reaction to take place.

 The action of sulfuric acid on chromium trioxide results in a number
of equilibria, in which the major specie is chromic acid. Thus, Jones
conditions are often referred as ‘‘chromic acid’’ in acetone.
 Jones oxidation is carried out under very convenient experimental conditions with
no need to employ a dry environment or an inert atmosphere.
 Note: Safe method for the oxidation of alcohols.

Applications:
i. 1o alcohols ─ Acids
Useful yields of aldehydes can be obtained when the proportion of hydrate in
equilibrium with the aldehyde is low. It rarely succeeds in the transformation of
primary alcohols into aldehydes due to its tendency to cause over-oxidation to
carboxylic acids.
ii. 2o alcohols ─ Ketones
Mechanism:
Chromous acid

Alcohol Chromate ester

Advantages and Limitations:
1. Over oxidation product (acid) can be minimized in the case of 1 o alcohols using 1:1
ratio of CrO3 . aq. H2SO4 and alcohol (or) using less than 1 eq. of CrO 3 . aq. H2SO4
comparing with alcohols.
2. Unsaturated groups will not be effected.
3. Using limited quantity of sulfuric acid helps to avoid removal of acid sensitive
functional groups. On the other hand, this causes a decrease in the oxidizing
power of Jones reagent.
Note:
 The solution of the alcohol in acetone can be kept either over an ice-water bath or
at room temperature during all the reaction. For reactions on a multigram scale,
cooling on an ice-water bath is particularly recommended.
 During the oxidation of very sensitive substrates, it may be advisable to perform
the entire oxidation at a temperature as low as – 20 oC.
Examples:

Ethyl 3-hydroxypent-4-enoate
c. Sarett’s Oxidation (CrO3 + Pyridine / CrO3 . 2 Py):

 When CrO3 is added over pyridine, the complex CrO3.2Py is formed.

 This complex is soluble in most of the organic solvents.
 The complex, CrO3.2Py is highly hygroscopic and can explode during its
preparation or in contact with organic matter.
 To use it in the oxidation of alcohols with the greater safety and experimental
simplicity, in 1953 Sarett reported by adding CrO3 to excess of pyridine results in
the formation of a solution of the complex so-called Sarett reagent.
 This reagent is efficient for the transformation of alcohols into aldehydes and
ketones.
Applications
i. 1o alcohols ─ Aldehydes
ii. 2o alcohols ─ Ketones

Advantages:
i. No over oxidation products
ii. No effect on unsaturated double/triple bonds
iii. Acid labile groups unaffected

Limitations:
i. After oxidation, isolation of the product (carbonyl compound) in pure form from
the pyridine solvent is difficult (Copper sulphate can be used to remove pyridine).
ii. The reagent is little expensive
Mechanism:
O
CrO3 . 2Py
R OH R H
Example:
HO HO
+
1. H , CH3CHO
2. CrO3 . 2Py
HO OH HO H O
3. H3O+

Protection H3O+
CH3CHO - CH3CHO
- H2O Deprotection

H3C H3C O
O
H CrO3 . 2Py H

O OH O H O
d. Collins Oxidation (CrO3 . Pyridine + DCM):
 In 1968, Collins was used pre-formed CrO3.2Py dissolved in DCM for the oxidation
of alcohols, which became known as Collins oxidation.
 This method—although suffering from the inconvenience of handling highly
hygroscopic CrO3.2Py—possesses the advantage over Saretts reagent of avoiding
the use of pyridine as solvent.
 In 1970, Ratcliffe and Rodehorst described the in situ preparation of the complex
CrO3.2Py by adding one equivalent of CrO3 over a solution of two equivalents of
pyridine in DCM.
 This variant of the Collins protocol, as it avoids the dangerous isolation and
handling of the very hygroscopic complex CrO 3.2Py, is nowadays greatly preferred.
 Very often, Celite is added to the Collins solution during the oxidation of alcohols
in order to prevent loss of product in chromium precipitates.
Note:
 As CrO3 is hygroscopic, care must be taken to avoid contamination with
atmospheric moisture. Water must be avoided from the reaction mixture, for
instance, with a CaCl2 tube or with a blanket of an inert gas.
 The complete synthetic operations till the work-up can be made at room
temperature or at 0 oC. Low temperature is particularly advisable on multigram
reactions, at least during the initial mixing operations, in which greater exotherms
are expected.
 It takes normally between 2 min and overnight.
 A quick quenching of the oxidation can be done by addition of aqueous Na 2SO3.

Mechanism: Is same as Sarret’s oxidation.

Applications
i. 1o alcohols ─ Aldehydes
ii. 2o alcohols ─ Ketones

Advantages:
i. After oxidation removal of DCM is easy. Therefore, carbonyl compounds in pure
form can be obtained.
ii. No over oxidation products.
iii. No effect on unsaturated double/triple bonds.
iv. Acid labile groups unaffected.
Examples:

Tr: Trityl(Triphenyl methyl)

e. PDC: Pyridinium Dichromate (PDC in DCM or DMF: Corey-Schmidt reagent)
 The slow addition of pyridine on a concentrated aqueous solution of CrO 3 leads to
the formation of pyridinium dichromate (PDC).
 This can be precipitated by the addition of 4 volumes of acetone per volume of
water and cooling at -20 oC as orange crystals.
 An explosion can occur during the preparation of PDC. This can be avoided by
 i) Chromium trioxide must be completely dissolved in the concentrated
aqueous solution.
 The temperature must be kept bellow 25 oC during mixing of the reagents.

 The use of PDC for the oxidation of alcohols was first described by Coates and
Corrigan in 1969. Nevertheless, full attention of the synthetic community for this
useful reagent was achieved by the publication of E.J. Corey and Schmidt in 1979.
 PDC exists in the form of stable bright-orange crystals that remain unaltered by
manipulation in the open air. Its lack of hydrophylicity and almost neutral
properties facilitate its handling and allows the selective oxidation of alcohols in
the presence of very sensitive functional groups.
 Although the presence of pyridinium cations makes PDC slightly acidic, very acid
sensitive functionalities are able to withstand the action of PDC.
 Sodium acetate can be added as a buffer for a completely acid-free oxidation.
 Normally, the oxidation of alcohols to aldehydes or ketones is carried out using a
suspension of PDC in DCM at room temperature. Other organic solvents, such as
EtOAc, MeCN, benzene or CHCl3, are occasionally used.
 Sometimes, oxidations with PDC can be slow. However, the following chemicals
can be added in order to achieve a synthetically useful acceleration.
 Molecular sieves (MS)
 An organic acid
 Acetic anhydride (in sugar and nucleoside chemistry)
Applications
i. 1o alcohols ─ Aldehydes
ii. 2o alcohols ─ Ketones

Advantages:
i. No over oxidation products.
ii. No effect on unsaturated double/triple bonds.
iii. Acid labile groups unaffected.
iv. Easy to handle in laboratory.
v. In expensive and readily available/purchased.
vi. Excellent reagent for the oxidation of allylic and benzylic alcohols.
Mechanism:
f. PCC: Pyridinium Chlorochromate (Corey-Suggs reagent)

 Addition of one equivalent of CrO3 to 1.1 equivalents of HCl (6N) leads to a

homogenous solution containing chlorochromic acid (ClCrO 3H). Slow addition of
one equivalent of pyridine to this solution at 0 oC, leads to the formation of
pyridinium chlorochromate (PCC) that separates as yellow-orange crystals.
 PCC was first prepared in 1899. But, its use in the oxidation of alcohols was
started as late as in 1975, following a landmark publication by E.J. Corey and
Suggs. Hence, the name Corey-Suggs reagent, often employed to refer PCC.
 Corey and Suggs described that most alcohols are oxidized in good yields to
aldehydes and ketones using a suspension of PCC in DCM at room temperature.
 They also described the addition of NaOAc to the reaction mixture, in order to
moderate the slightly acidic character of PCC.
 PCC is a stable solid of very moderate hydrophylicity that can be bought and
stored for long periods without apparent decomposition.
Mechanism:
Examples:
 Module-3, Lecture-8
Functionalization of alkenes

Swern Oxidation

Dr. Daniel Swern

(American chemist)
DMSO Mediated Oxidations
a. DMSO + DCC (dicyclohexylcarbodiimide) + Weak acid (pyridinium
trifluoroacetate/H3PO4/Cl2CHCOOH) – Pfitzner–Moffatt Oxidation
b. DMSO + Ac2O – Albright–Goldman Oxidation
c. DMSO + P2O5 – Albright–Onodera Oxidation
d. DMSO + SO3.Py – Parikh–Doering Oxidation
e. DMSO + Trifluoroacetic anhydride (TFAA) – Omura–Sharma–Swern
Oxidation (TFAA-Mediated Moffatt Oxidation)
f. DMSO + (COCl)2 + Triethylamine – Swern oxidation
 Swern oxidation
(DMSO + (COCl)2 + Triethylamine)

• According to Swern, oxalyl chloride is the most effective activator of DMSO. Probably
they has tried the highest number of DMSO activators (e.g. Ac2O, P2O5, SO3.Py,
Trifluoroacetic anhydride) for the oxidation of alcohols.

• It offers the advantage of quite consistent good yields in many substrates, with an
operation performed under very low temperature and mild conditions.

• Thus, Swern oxidation has become the default oxidation method whenever activated
DMSO is desired.
Applications:
 1o alcohol → aldehyde
 2o alcohol → Ketone
Mechanism:

Sulfonium species chlorodimethylsulfonium chloride

• DMSO and oxalyl chloride react in an explosive manner at room temperature.

• As soon as, a drop of a solution of DMSO in DCM contacts a solution of oxalyl chloride in
DCM at -60 oC, an almost instantaneous reaction takes place, resulting in the formation of
chlorodimethylsulfonium chloride.
• The primary product (sulfonium species) decomposes very quickly even at -140 oC
• The activated DMSO molecule (chlorodimethylsulfonium chloride) remains stable bellow -
20 oC.
• Chlorodimethylsulfonium chloride decomposes above -20 oC to chloromethyl methyl
sulfide via the reactive species H2C=S(+)-Me.
Activated DMSO Activated alcohol - 60 oC to room temperature
(Alkoxy dimethylsulfonium chloride)
Overall mechanism:
Advantages:
 Removal of byproduct is simple (CO2, CO, dimethyl sulfide - boiling point 37 oC).
 Very high yield of the product.
 No over oxidation
 Unsaturated double and triple bonds unaffected.
 Acid labile groups unaffected.

Limitations:
 Reactions have to be preformed at a very low temperature approximately -60 oC.
 At higher temperature the activated DMSO decomposes.
 At higher temperature the reaction is explosive.

Solvents: DCM is almost exclusively used as the solvent. THF can be used rarely.
Examples:
Modified Swern Reagent:
 The standard Swern oxidation employing DMSO results in the formation of dimethyl
sulfide, which is a toxic volatile liquid (b.p. 38 oC) with an unpleasant smell.
 This can be avoided by using other sulfoxides that generate sulfides lacking volatility
such as;

O O O
S S
OH

Dodecyl methyl sulfoxide 6-(Methylsulfinyl)hexanoic acid

 Sulfoxides containing perfluorated alkyl chains

 Sulfoxides bound to polymers such as polystyrene or poly(ethylene)glycol
Importance of these variants:
• These are not only avoid the generation of an unpleasant odour, but also facilitate the
work-up.
• For example,
o 6-(Methylsulfinyl)hexanoic acid generates a sulfide that is easily separated by
chromatography.
o Fluorated sulfoxides produce sulfides that can be extracted with a fluorous solvent.
o Polymer-based sulfoxides generate sulfide-containing polymers that can be filtered.
• All these expensive sulfoxides can be regenerated by oxidation of the resulting sulfides
using H2O2.
Reduction Reactions
Reduction: Addition of hydrogen or removal of oxygen from a substrate.
1. Hydride ion transfer reductions

3 types
Reductions 2. Electron transfer reductions

3. Concerted reductions

1. Hydride ion transfer reductions:

H-

Reducing agent A B A B
H+
A B
H H H

H-

H H
LiAlH4 H+
C O C O C OH
 H-

Reducing agent A A B
+ B H+
A B +
H H H
H-

R H H
LiAlH4 H+
H C X H C R + X H C R + HX
R R R

2. Electron transfer reductions:

e- e-
M H+ M H+ A B
A B A B A B A B
H H
H H
3. Concerted reductions:
a. Diimide reductions (N2H2):
N2H2 A A
A A
H H

A A A A
A A
H H H + N N
H
H H
N N N N

b. Catalytic hydrogenation: H2
H2C CH2 H3C CH3
Ni/Pt/Pd

H2C CH2

H H
 1. Hydride ion Transfer Reducing agents
(a)Lithium aluminium hydride (LiAlH4)
 White crystalline substance.
 Unstable.
 Reacts violently with water. Therefore, the reaction must and should carry out under
anhydrous/inert conditions.
H2O
LiAlH4 LiOH + Al(OH)3 + 2 H2

Preparation:
LiH + AlCl3 LiAlH4

Solvents: Dry ethers, Et2O, THF

Applications:
o Highly reactive, versatile and a strong reducing agent due to the weaker Al-H bond,
which capable of liberating H-.
o It reduces wide range of functional groups.
O O OH
LiAlH4
O No selectivity OH
butane-1,3-diol

Less reactive

O O OH O
NaBH4/MeOH
More reactive
O Selective O
ethyl 3-hydroxybutanoate

O O O
HO OH O O LiAlH4 H+ O
O O
O O
H+ OH Deprotection OH
Protection
4-hydroxybutan-2-one
 Almost all organic functions reduced by LAH.
Applications:
o Carbonyl (-C=O)
o Halo compounds (R-X) LAH
o Acid (-COOH) Hydrocarbons
o Alkyl sulfonates (R-SO3R1)
o Ester (-COOR) LAH
Alcohols
o Acid halide (-COX)
LAH
o Cyclic ester o Propargyl alcohols/ethers trans olefins
o Epoxides
o Amides (-CONR2)
o Simple isolated olefins, alkynes and ethers would
o Nitrile (-CN) not reduced by LAH. However, the double or
o Imine (-CH=NR) LAH triple bonds in conjugation with the polar
Amines multiple bonds can be reduced.
o Azide (-CH2-N3)
o Oxime (-C=N-OH)
o Nitro (-CH2-NO2)
 O (i) 1 eq. LAH, Dry ether OH
Mechanism: With carbonyl compounds 4 eq. 4 eq.
R R R R
(ii) H3O+
H

H Al H
O H O
H Li O Li H H Li
R R Al R R
+ O Al H
Very fast R R
H R
R H Fast
Aluminium hydride
R

R O O H H
Li Li O Li
O Al O R R O Al +
O Al O R R
R R Slow R R R
R H R R H R R H

O
Very slow
R R
R

R O
Li
H3O+ OH
O Al O 4 eq. + Al(OH)3
R R R R
R O R

R R
 Alkoxy groups exerts – I effect on Aluminium. With increasing in no. of alkoxy groups, – I
effect become stronger on Aluminium hydride as a result the reactivity decreases as the
alkoxy groups increases.
 Reactivity order: LiAlH4 > LiAl(OR)H3 > LiAl(OR)2H2 > LiAl(OR)3H > LiAl(OR)4

Mechanism: With Esters

H

H Al H
O H
H Li O Li H H Li
R OR Al
+ O Al H
R OR
H R
OR H

H3O+ O Al + R O Li
R OH R
- Al(OH)3 H
H H
Mechanism: With Acid Mechanism: With Acid chloride
Mechanism: With cyclic ester

Mechanism: With amide

Mechanism: With Nitrile
H

H Al H
H
H
H Li N Li H H Li H3O+
R N Li
Al N Al
+ N Al H R NH2
R H R - Al(OH)3
H R H
H H
H H

Mechanism: With Azide

Stereochemical Aspects:
o In opening of epoxides and reduction of halo compounds - SN2 addition and Inversion
of configuration can be observed.

LiAlH4 H
Me LiAlH4 Me
H Cl H H H3O+
Ph SN2 addition Ph O HO
Inversion of configuration
 Me Me
LiAlH4
O OH
H3O+

Regioselectively attack at less crowded position

 In confirmationally rigid molecules, opening of epoxides by attacking in axial direction.

OH
O OH
O
LiAlH4
H3O+

O
LiAlH4 OH

H3O+
O OH
 Module-3, Lecture-9
Functionalization of alkenes
Reduction of rigid cyclohexanone derivatives:
Axial approach
O
O OH
LiAlH4
OH +
H3O+

Equitorial approach via axial approach via equitorial approach

(Major) (Minor)

• Axial and equatorial approaches are free form steric crowding in the above examples.
Thus selectivity is controlled by the stability of the product.
Axial approach
Me Me Me
O OH
Me LiAlH4 Me
Me
+ OH +
H3O
Me Me Me
Equitorial approach
via axial approach via equitorial approach
(Minor) (Major)
 Me Me
LiAlH4

O H3O+ HO
H H
Major compound
Favoured approach

• In the case of aromatic α,β-unsaturated aldehydes, product depends on the reaction

conditions.
LiAlH4, Et2O LiAlH4, Et2O
CHO Ph OH
Ph OH Ph 35 oC
0-5 oC
Cinnamaldehyde

• In amides, if “N” is a part of heterocyclic ring. In LAH reduction products are aldehyde and
amines. But, cyclic amide converts to amines.
LiAlH4
O O
LiAlH4, Et2O
N NH + HN N O N
NH
H
 Cl LiAlH4
Br

LiAlH4
Cl I Cl H

Regioselective reaction

O
O H
S LiAlH4
O

LiAlH4
O
OH
 O O O O HO OH
LiAlH4 LiAlH4
OH-
O

O
O O HO HO S LiAlH4
LiAlH4 O
O Me
-
OH

O OH
LiAlH4
O
Chelating effect OH
How to quench LiAlH4:

Fieser method:
For a reaction containing x grams of LAH
1. Cool the reaction mixture to 0 °C (or lower depending on the scale/equivalents of
LAH)
2. Slowly (drop wise) add x mL of water
3. Add x mL of 15% aqueous sodium hydroxide (or potassium hydroxide).
4. Add 3x mL of water
5. Warm the reaction mixture to room temperature and stir for 30 min
6. Filter and wash the solid with ether 2 - 3 times
7. Collect the filtrate and evaporate the solvent using rotary evaporator.
 1. Hydride ion Transfer Reducing agents
(b) Sodium Borohydride (NaBH4)
 White crystalline Solid.
 In aqueous medium stable, therefore water can also be used as a solvent
 Solvents:
H + Water and alcohols like MeOH, EtOH,
H Isopropanol
Li+ and tertary butanol etc.
Na
H B H H Al H
Less polar bond H More polar bond
H
(Electron negitivity difference is low) (Electron negitivity difference is high)

 Therefore, LiAlH4 releases H- rapidly. Whereas NaBH4 releases H- slowly. Means the
reactivity
OH of NaBH4 lesser than LiAlH
O O4. OH O
LiAlH4 NaBH4/MeOH
OH O O
Selective
No selectivity
butane-1,3-diol ethyl 3-hydroxybutanoate

Chemoselective reaction with NaBH4

Applications:
o Carbonyl (-C=O) Alcohols
o Ester (generally not reactive but in Alcohols
the presence of additives like Iodine)
o Imine Amine
o Iminium salts Amine

 In a molecule, if aldehyde and ketones are present at lower temperature (-78 oC) NaBH4
selectively reduces aldehyde but not ketone.
Me NaBH4 Me CHO LAH (or) Me
OH OH
O -78 Co
O NaBH4, r.t. OH
 In the case of aromatic α,β-unsaturated carbonyl compounds, even at higher temperature
NaBH4 reduces only carbonyl functions into alcohols. Unsaturation unaffected.
LAH CHO LAH
Ph OH Ph Ph OH
0-5 oC 35 oC
NaBH4, r.t.

Ph OH

Mechanism: O OH
1 eq. NaBH4
4 eq. 4 eq. +
R R H3BO3
R R
Boric acid
 H

H B H
O H O
H Na O Na H H Na
R R B R R
+ O B H
Very slow R R
H R
Borane R H Slow

R O O H
H
Li Na O Na
O B O R R O B +
O B O R R
R R Fast R R R
R H R R H R R H

Very fast

R O
Na
H3O+ OH
O B O 4 eq. + H3BO3
R R R R
R O R

R R
 Alkoxy groups exerts + Mesomeric effect (+M.E) on Boron. With increasing in no. of alkoxy
groups, +M.E effect become stronger on boron hydride as a result the reactivity increases
as the alkoxy groups increases.
 Reactivity of alkoxy NaBH4 in reduction reverse to LiAlH4
 Reactivity order:
o LiAlH4 > LiAl(OR)H3 > LiAl(OR)2H2 > LiAl(OR)3H > LiAl(OR)4
o NaB(OR)4 > NaB(OR)3H > NaB(OR)2H2 > NaB(OR)H3 > NaBH4

 Reason
R for difference in
R reactivity order:
R O - I.E R O + M.E

H Al H H B H

H H
 O B O Al

2p 2p 2p 3p
Less energy gap More energy gap
Strong overlap Poor overlap

 Empty orbital of Boron and occupied orbitals of oxygen energetically closer which allows
strong overlapping. Transfer of electron cloud from oxygen to Boron + M effect. Hence
increases the reactivity.
 Empty orbital of Aluminium and occupied orbitals of oxygen are belongs to the different
shells. Therefore poor overlapping, weak in strength of + M effect. In preference to +M
effect, alkoxy oxygen exerts –I effect which decreases the reactivity of Alkoxy aluminium
hydrides.
Less electrophilic
O O
H O R

R R R R
More electrophilic  Alcohols little enhances rate of NaBH4
H- reductions by establishing H-bond with
NaBH4 H-
carbonyl oxygen.
Stereochemical aspects of NaBH4:
o Same as LiAlH4, NaBH4 also attacks at sterically less crowded side of the carbonyl
Axial approach
function.
O OH
NaBH4
OH +
H3O+

Equitorial approach via axial approach via equitorial approach

(Major) (Minor)

OH Br NaBH4
O NaBH4 N Br
N
H
N
N
Major
Luche’s Reduction: NaBH4 + CeCl3 . 6H2O (cerium(III) chloride hexahydrate)
 NaBH4 in combination with Ce(III) salts selectively reduces less reactive carbonyl
groups in carbonyl compounds.
 Ketones are less reactive than aldehydes
 Conjugated carbonyl are less reactive than isolated carbonyls.
Less reactive Less reactive
O OH O O OH O
H NaBH4 H NaBH4
R R
CeCl3 . 6H2O CeCl3 . 6H2O
O O

Keto carbonyl oxygen is good nucleophile

than aldehyde carbonyl oxygen. Therefore,
the keto carbonyl oxygen preferentially Ce(III)
O O
coordinate with Ce ion. Similarly in the H Ce(III) H
case of conjugated carbonyl also.
O O
 With keto carbonyl oxygen makes carbonyl carbon more electron deficient than
competitive more reactive carbonyl carbon.
 Approaching nucleophile selectively attacks more electron deficient carbonyl carbon. As
the results selective reduction of less reactive carbonyl by leaving behind more reactive
carbonyls.
Examples:
H
O OH H
NaBH4 HO
NaBH4 O
O
O CeCl3 . 6H2O
Me CeCl3 . 6H2O Me

O O

O OH
NaBH4
CeCl3 . 6H2O
 (c) Sodium Cyano Borohydride (NaBH₃CN)
H H
Na+ Na+
H B H H B CN

H H

 Cyano electron withdrawing group stabilizes borohydride.

 Compare to NaBH4, NaBH₃CN is less reactive and more selective in reduction.
 Reactivity of NaBH₃CN depends on pH of the reaction medium (neutral/acidic/basic).
Functions:
i. Under neutral conditions (pH ≈ 7), selectively displaces Halo and Tosyloxy groups. Any
other functional groups like carbonyl, epoxy etc. are unaffected.
Cl
NaBH3CN
R CHO R CHO
Neutral
ii. At pH ≈ 2-3, reduces carbonyl into alcohols.
iii. At pH ≈ 5-6, reduces imines into amines.
iv. In acidic medium, tosyl hydrazones of acylic and cyclic carbonyl compounds reduces into
hydrocarbons.
v. In acidic medium, opens epoxide into alcohols – Opens at sterically more crowded
position.
NaBH3CN
Applications: Carbonyl compounds Alcohol
pH 2-3
NaBH3CN
Halo/Tosyloxy Displacement Hydrocarbons
pH 7
NaBH3CN
Imine/Iminium salts Amine
pH 6
NaBH3CN
Tosyl hydrazones Hydrocarbons
Acidic
NaBH3CN
Epoxy Alcohols
Acidic
Examples: OTs
NaBH3CN
CHO CHO
HMPA (Neutral)
Hexamethylphosphoramide (HMPA)
Me Me
R NaBH3CN
N NaBH3CN R O
HN THF, BF3 . Et2O OH
Ph H HCl gas
pH 6 Ph H Because of presence of Lewis acid opening of
epoxide at more crowded side

(a) Ts-NH-NH2, H+
CHO
( )8 ( )8
(b) NaBH3CN

 Whenever carbonyl function is in conjugation with α,β-unsaturation, isomerization of

unsaturation takes place.
O
(a) Ts-NH-NH2, H+

(b) NaBH3CN
Mechanism for isomerization:
HN Ts HN Ts NH
O
N H N N
+
Ts-NH-NH2, H NaBH3CN
(or)
H
N N

H
N
N Ts
O NaBH3CN O NaBH3CN
Br
Ph HMPA, THF Ph H3O+
2. Electron Transfer Reducing agents
Metal/Acid (or) Metal/Base
Metals
d-block – Fe, Sn etc.
I group: Li, Na, K
II group: Ca, Mg
 Metal-Base Medium Reactions
Metals: I group - Li, Na, K; II group: Ca, Mg
Bases: Liq. NH3 (or) R-NH2
Solvents: Dry ethers: Et2O, THF, Dioxane
 Electron released in liq. Ammonia is called as solvated electrons.
Applications:
i. Conjugated olefins → Isolated olefins
ii. Aromatic hydrocarbons → Unconjugated olefins (or) 1,4-dihydro products
iii. Simple carbonyl compounds → Alcohols
iv. α,β-unsaturated carbonyl compounds → Saturated alcohols (or) Saturated carbonyl
compounds (or) Unsaturated alochols
v. Alkynes → Trans Olefins
 i. Reduction of Conjugated olefins → Isolated olefins
Li/liq. NH3
e.g. H2C C C CH2 H3C C C CH3
H H Aq. NH4Cl H H
buta-1,3-diene (proton source) but-2-ene

Mechanism:
e-
M H
H2C C C CH2 H2C C C CH2 H2C C C CH2
H H H H H

- H+
e
H+ M
H3C C C CH3 H2C C C CH3 H2C C C CH3
H H H H H H
 ii. Reduction of Aromatic hydrocarbons: Birch Reduction
Metal / liq. NH3 / R-NH2
Aromatic hydrocarbon 1,4-Dihydro olefins
Alcohol (Partial reduction)
Metal: Li, Na, K

Mechanism:
Regioselectivity: Substitution effect

Mechanism: Aromatic hydrocarbon containing electron donating group

Mechanism: Aromatic hydrocarbon containing electron withdrawing group.
HO O HO O HO O O O O O O O

Na/liq. NH3 Na
- H+

H+

O O O O
R R
R
H+ R-X

Examples:
OMe OMe Me Me
M/liq. NH3 Me M/liq. NH3 Me

Alcohol Alcohol
 COOH COOH
Me M/liq. NH3 Me

Alcohol

MeO OMe MeO OMe O O

M/liq. NH3 H3O+

Alcohol

OMe OMe H
O O O
Na / liq. NH3 H3O+ H Isomerization
EtOH
 Li / liq. NH3
EtOH

Li / liq. NH3
+
EtOH

Na / liq. NH3 Na / liq. NH3

COOH EtOH COOH
N EtOH N O O
H

Na / liq. NH3
Me EtOH Me
O O