Download Oxidation

OXIDATION
1
OXIDATION
The term oxidation can be defined in different ways:



Addition of oxygen to a molecule
Removal of hydrogen molecule from a given molecule
Loss of electrons
Addition of Oxygen i.e.
[O]
C
C
C
C
O
An alkene
An epoxide
or oxirane
Removal of Hydrogen from a Molecule
OH
C
C
O
-H2
H
CH
C
R
R
Removal of Electron or Loss of Electrons
O
O
.
-e
Phenoxide anion
o
Zn
Phenoxide radical
2
Zn
2
Calculating Oxidation State of a Particular Carbon
Here a question arises how we calculate the oxidation of a carbon bonded with other
atoms?
For calculating the oxidation state of carbon, we have to consider following two key
things.
1
2
Carbon is often more electronegative (2.5) than some of the other atom which
it bonds such as hydrogen has electronegativity 2.2. So in this case what we
have to do?
Unlike metal-metal bond, carbon bonds are found all over the organic
chemistry then how can we calculate the oxidation state.
There is a simple rule for knowing the oxidation states of an atom in a molecule or
over all oxidation state of a reaction.
If the number of H atoms bonded to a C decreases, and/or if the number of bonds to
more electronegative atoms increases, the Carbon in question will be oxidized (i.e. it
will be in a higher oxidation state).
How we assign the oxidation state of carbon?
1. Examine the groups attached to a carbon atom.
2. Give the carbon a -1 oxidation number if the each atom attached to less
electronegative atom than the carbon in question?
3. Give the carbon a +1 oxidation number if to carbon is attached to more
electronegative atom than the carbon in question?
4. Give 0 to each other carbon atom attached to the particular carbon.
5. Give 0 to undefined (R) group attached to particular carbon atom.
6. = Double bond will stand for two single bonds
3
7. ≡ Triple bond will stand for three single bonds
8. Each carbon in a molecule can be labeled with its oxidation state and sum of
these oxidation states in a molecule may be compared to the sum in any
reaction weather oxidation state increased or decreased.
9. Addition of a species containing XY to a double will not change the overall
oxidation state of reaction (sum of the individual carbon states will be remain
same). Such as: HBr, HOH, HNO2, HCl, etc
10. Addition of a species Y-Y’ will definitely change the oxidation state of the
reaction. Therefore, addition of Y-Y’ (eg. Br-Br) to a double bond is an
Oxidation, however, elimination of Y-Y’ from a single bond is reduction.
Now let us examine the molecules containing a single carbon
Overall oxidation number is -4
4
Why oxidation state is -4? Because carbon is attached with four hydrogen atoms
which are less electronegative than carbon
Overall oxidation number is -2
Why it is -2? Because oxygen replaced one hydrogen atom and more electronegative
than carbon.
Overall oxidation number is 0
Why oxidation state is 0? Because two oxygen replaced two hydrogen atoms and
oxygen is more electronegative than carbon.
Overall oxidation number is +2
Why oxidation state is +2? It is due to the fact that three oxygen replaced three
hydrogen atoms
5
Overall oxidation number is +4
Why oxidation state is +4? Because four oxygens replaced four hydrogen atoms
Overall oxidation number is +4
Why oxidation state is +4? Because four oxygen atoms replaced four hydrogen
atoms
Consider molecules with more than one carbon
6
Oxidation number of C = 0
-1
H
-1
H
H
+1
-1
O
-1
-1
H
C
C
C
C
H
OH H
+1
O +1
C
C
C
+1
-1
+1
H2O
H
-1
-1H
-H2O
-1 H
-1 H
6 X (-1) = -6
2 X (+1) = +2
TOTAL = -4
C
H -1 H
H
-1
7 X (-1) = -7
3 X (+1) = +3
TOTAL = -4
-1
H
+1
Br
-1
C
-1
-1
H
H
C
+1
-1H
C
O
-1
H
-1
H
H2O
+1
Br
C
-1
H
+1
OH
C
-1
C
H
H -1
+1
5 X (-1) = -5
3 X (+1) = +3
TOTAL = -2
-1H +1OH
5 X (-1) = -5
3 X (+1) = +3
TOTAL = -2
7
-1
H
-1
H
C
-1H
+1
S
+1
-1H
C
-1 -1
H
H
C
C
-1
H
C
+1 +1 +1
C
N
H -1 H -1
9 X -1 = -9
5 X +1 = +5
TOTAL = -4
OXIDATION STATE:
-4
-3
-2
-1
0
+1
+2
+3
+4
Molecules
CH4
RCH3
CH3-OH, R2CH2
RCH2OH
CH2O, R2CHOH
RCHO, R3COH
HCO2H, R2CO
RCOOH
CO2, CO4
Generally no oxidation state change in the total organic molecule is observed in reaction
like Hydrolysis or comparable reactions with alcohols (alcoholysis) or amines
(aminolysis) with addition or elimination of HX, HOH, and HOR or with
tautomerization but oxidation occurs when oxygen added to the molecule.
8
Are These Oxidations or Not???????????
9
10
Oxidation of Alkenes
Oxidation of alkenes may take place at the double bond or at the adjacent allylic
position.
Oxidation at Double Bond
X
H
H
Alkynes
OH
Halohydrins, Amino hydroxy
O
O
Dioxetanes
HO
OH
H
H
H
H
HO
Anti or Trans diol
OH
Cis diol
H
Cleavage of Doble Bond
Carbonyl and Caboxylic Acid
H
H
O
H
Epoxide
11
Epoxidation
Some oxidation reactions of alkenes give cyclic ethers in which both carbons of a
double bond become bonded to the same oxygen atom. These products are called
epoxides or oxiranes. An important method for preparing epoxides is by reaction
with peracids, RCO3H. The oxygen-oxygen bond of such peroxide derivatives is not
only weak (35 kcal/mole), but in this case is polarized so that the acyloxy group is
negative and the hydroxyl group is positive.
Epoxides or oxiranes are the important intermediates in synthetic organic
chemistry. The facile epoxide ring opening is extensive useful in C-C bond
formations and diol preparation etc.
Epoxidation of alkenes are usually carried out by using peroxy acids.
1. Peracid Reactivity
Reactivity Increases
R
CH3
C6H5
m-ClC6H5
p-NO2C6H5
o-CO2C6H5-
CF3
pKa
4.8
4.2
3.9
3.4
2.9
0
The lower the pKa, greater the reactivity.
12
13
The reaction involves the nucleophilic attack on the O-O bond by the π-electron of
the double bond.
Therefore
Epoxidation takes place more rapidly and preferentially at electron rich double
bonds.
The reaction-rate increase when the substituents on alkenes are electron releasing.
This is the basis of regioselectivity in epoxidation.
Tetra subs. > Tri subs. > Di subs. > Mono subs. > Unsubs.
Similarly, electron withdrawing groups on alkenes decreases the rate of reaction.
O
F
Cis-alkenes give Cis Epoxides
Trans-alkenes give Trans Epoxides
Concerted reaction at one of the double bonds through cyclic intermediate is the
basis of stereocontrol.
When two faces of the π-bond are unequally shielded, the two expected
stereoisomers will not form to the same extent.
14
The reaction has relatively low steric requirements and even hindered alkenes can
be epoxidized easily.
Stereochemistry of olefins is maintained: Diasterespecific
Reaction rate is insensitive to solvent polarity implying concerted mechanism
without intermediacy of ionic intermediate
Less hindered face of olefin is epoxide
If,
R=H
20 min, 25 °C
99%
1%
R = CH3
24 h, 25 °C
< 10%
90%
Epoxidation of an alkene containing one or more chiral centers gives two
diastereomeric epoxides, depending on the face from which the reagent approaches
the π-bond. This chiral induction is cause of diastereoselectivity in epoxidation.
15
Epoxidation with Organic Peroxy Carboxylic Acid
Electron-withdrawing groups on peroxy acids increase the reaction rate.
MCPBA is most commonly used reagent in epoxidation.
It is fairly stable, solid, and soluble in many organic solvents, such as CH2Cl2,
CHCl3.
Caution: It is SHOCK SENSATIVE
Subsequent work-up depend upon the stability of resulting epoxide.
Mechanism:
When epoxide react with water in the presence of catalytic amount of acid or base
ring opening takes place to afford vicinal diol and it is a well known fact that the
epoxide ring opening always takes place in trans manner so we will get an anti diol
product in the result of epoxide ring opening e.g.
16
H 3C
HO
H
C
H
1) m-CPBA
C
H3C
H 3C
1) m-CPBA
C
CH3
2) H, H2O
C
H
CH3
OH
meso 2,3-butane diol
HO
H
C
C
CH32) H, H2O
Trans 2-butene
H
H
H
H3C
H
C
C
OH
H
CH3
+ H 3C
OH
HO
C
C
H
CH3
Cis 2-butene
(2R,3R)-2,3 butane diol
(2S,3S)-2,3 butane diol
SALIENT FEATURES OF EPOXIDATION
The reactivity of alkene depends on the degree of substitution.
1. Monosubstituted terminal alkenes are least reactive.
17
Substituted versus Terminal Alkene
2. Deactivated double bonds are less reactive.
Deactivated
Deactivated
O
C
MCPBA, CH2Cl2
OCH3
O
F
20 oC
C
OCH3
O
F
70%
3. The oxygen transfer is stereospecifically syn the stereochemistry of the starting
alkenes is retained in the product. e.g.
D
H
C
C
m-CPBA
H
D
Trans alkene
H
H
m-CPBA
C C
O
D
C
H
H
D
Trans Oxirane
O
H
C
D
D
D
Cis alkene
C
C
H
D
Cis Oxirane
4. Conjugation of alkene double bond with other unsaturated groups such as CN,
NO2, COR, COOR, SO2 etc reduce the rate of epoxidation because of the
delocalization of π electrons.
O
OH
CH3COOOH
18
It requires strong reagents e.g. MCPBA, triflouro per acetic acid at higher
temperature
5. If one or more chiral centers present in substrate the epoxidation will be
diastereoselective.
SiMe2Ph
SiMe2Ph
O
o
MCPBA, CH2Cl2, 20 C
+
SiMe2Ph
O
Anti face
67%
33%
Peroxy attack takes place majorly from the anti face to the bulky silyl group.
6. In general, for linear chain and flexible cyclic molecule, it is very difficult to
predict the stereochemical out come of the reaction.
MCPBA, CH2Cl2, 20 oC
RO
OAc
O
O
+
RO
RO
OAc
47%
OAc
53%
19
6. With conformationally rigid cyclic alkenes the epoxidation generally takes place
from the less hindered side of the double bond in stereoselective fashion.
Less hindered face
H
O
o
MCPBA, CH2Cl2, 20 C
+
O
H
H
H
H
More hindered face
H
94%
6%
20
Equatorial
H
H
Less hindered
H
H3C
H
H
H
H
H
H3C
CH3
H3C
O
Axial methyl
More hindered
+
O
H
H
87%
CH3
13%
Less hindered
H3C
H3C
H3C
CH3
CH3
H3C
CH3
CH3
CH3
Pseudoaxial
CH3
CH3
O
MCPBA, CH2Cl2
24 h, r.t.
H3C
CH3
H3C
CH3
93%
Axial methyl
More hindered
CH3
O
+
H3C
CH3
H 3C
CH3
7%
21
7. Folded molecules are epoxidized selectively from the less hindered side.
More hindered
O
O
O
O
o
O
MCPBA, 3 h, 5 C
O
O
O
95%
Less hindered
H
H
o
O
OBn MCPBA, 3 h, 5 C
H
H
OBn
OBn
H
PhSiO
PhSiO
H
OBn
72%
8. Unhindered exomethylenic cyclohexene undergo preferential axial epoxidation
More hindered
CH3
Ph
Ph
CH3
Ph
CH2
O
MCPBA
CH3
86%
Less hindered
22
9. Stereoselectivity is even more pronounced in polar solvents, since in polar solvents
the effective steric bulk of the peroxy acid in the transition state become somewhat
greater make attack from hindered side even more difficult.
More hindered
CH3
H
CH2
CH3
H
C11H23COOOH
H3C
O
+
H3C
H3C
CH3
H
O
H3C
H3C
H3C
Less hindered
(C2H5)O
65%
CH2Cl2
83%
35%
17%
10. The polar substituent at allylic and homoallylic positions influence the direction
of the attack.
OH
OH
Cis to OH
C6H5COOOH, C6H6, 0 oC
O
Association of reactant with hydroxyl group of the substrate through hydrogen
bonding cause preferential attack from that side.
In contrast if no hydrogen bonding occurs than it attacks from less hindered side.
23
OCOCH3
OH
OCOCH3
o
C6H5COOOH, C6H6, 0 C
O
Normal Product
No hydrogen bonding i.e. attack from less
hindered side
Mechanism of directive effect:
C6H5
C
H
O
O
C6H5COOOH
CMe3
H
C6H6
O
H
O
O
H
H
CMe3
CMe3
H
HO
+
H
H
H
O
CMe3
H
HO
H
H
O
H
H
96%
4%
H
O
O
O
O
O
H
R
+
C
O
R
24
The effect is also observed in open chain compounds.
CH3
CH3
CH2OH
C6H5H2CO
CH2Cl2, 0 oC
C6H5H2CO
CH2OH
MCPBA
O
Coordination of MCPBA with ethereal and hydroxyl oxygen direct the attack from
that side.
11. In acyclic alkenes the directive effect of polar allylic substituents is based on the
stability of transition state.
HO
HO
HO
MCPBA
R3
R
1
o
CH2Cl2, 0 C
O
R3
R1
+
R2
R
O
R1
R2
2
Erythro
Threo
OH
H
R2
H
R3
H
R3
R3
R2
H
R1
Rotamer for threo
R1
OH
Rotamer for Erythro
Less stable due R1, R3 interaction
When R1 and R2 are alkyl more threo will be stable
Trisubstituted or Cis - disubstituted
Trans - disubstituted or monosubstituted
Threo
Erythro
12. In cyclohexene system pseudoequatorial hydroxyl is more effective than the
pseudoaxial hydroxyl in directing epoxidation.
25
Homoallylic group can also direct the attack. Homoallylic axial hydroxyl can direct
the attack, but homoallylic equatorial cannot.
Pseudo equatorial (Effective)
O
OH
OH
MCPBA, THF, 48 h
N
r. t.
N
OH
OH
Homoallylic
equatorial
and cannot direct
69%
Pseudo axial (not effective)
Homoallylic
axial (Effective)
OH
OH
HO
HO
O
MCPBA
75%
OAc
OAc
HO
HO
CO2CH3
CO2CH3
MCPBA, CH2Cl2
0 oC, 1 h
O
91%
26
CH3
CH3
OH
OH
MCPBA, CHCl3
o
Ph
0 C, 1 h
Ph
O
97%
Trans
CH3
OH
Directive effect of hydroxyl is not
large enough to overcome the steric interference
Ph
Less hindered
13. Besides hydroxyl, carbamates, ethers and ketones also direct the epoxidation.
O
O
CH3
O
CH3
N
O
N
CH3
CH3
o
MCPBA, CH2Cl2, 0 C
O
97%
Hydrogen bonding between MCPBA and the carbonyl is the basic reaction of
directive effect.
27
OSiBuMe2
OSiBuMe2
CF3COOOH, CH2Cl2, -40 oC
O
Bu
Bu
OSiBuMe2
+
O
Bu
7%
93%
Directive effect is due to hydrogen bonding between hydroxyl of peroxy and allylic
ether.
Electrolysis and microorganism such as Corynebactrium equii have also been used
for epoxidation.
Epoxidation with Metal Complexes
H
+
H
H
Alkene
H
O
H
C
R
H
+
O
O
O
H
H
Per oxy carboxylic acid
O
H
C
R
H
O
Epoxide
Mechanism
O R
O
H O
O + RCOOH
Epoxide
or Oxirane

Per acids are not only way for epoxidations

t-BuOOH with V+5 or Mo+6 species are also used for epoxidation.
28

t-BuOOH with Mo+6 species are excellent for epoxidation of isolated double
bonds.

t-BuOOH with V+5 species are excellent for epoxidation of allylic alcohol and
Terminal alkenes.
t-BuOOH
V+5
O
Terminal alkene Difficult to epoxidize with peroxyacid
V(acac)2
OH
O
t-BuOOH
OH +
O
7%
93%
m-MCPBA
OH
O
OH +
OH
O
65%
35%
Effect of polar substituents
 Controls the stereochemistry of resulting epoxide.
 Allylic
 Homollylic
 Bishomoallylic
 or even remote position
29
OH
OH
V(acac)2
t-BuOOH
OH
O
83%
OH
Mo(Co)6
t-BuOOH
O
 Precise cause of reaction in not very clear
 Very fast
 High stereoselectivity
 Formation of intermediates
 Minimum steric interactions
R1
L
R2
L
O
V
R3
O
O
t-Bu
R4
30
SHARPLESS EPOXIDATION

Epoxidation of allylic alcohol

t-BuOOH

Ti(iPrO)4

Natural L-(+)-diethyl Tartarate

Unnatural D-(-)-diethyl Tartarate

High optical purity

Diseterofacial stereoselectivity

Sharpless epoxidation
L(+)-Diethyl Tartarate
O
Ti (iPrO),t-BuOOH
90%
R
OH
Prochiral
allylic alcohol
R
OH
D(-)-Diethyl Tartarate
O
Ti (iPrO),t-BuOOH
R
OH
90%
The discovery of epoxidation.
K. B. Sharpless, Chem. Brit. 38. 1986 and references therein.
31
Advantages
High asymmetric induction
Absolute configuration of product is predictable
(+) or (-)- Tartarate ensure one or other epoxide in over 90% optical purity.
R2
:
:
D(-)-Diethyl tartarate
(Unnatural)
:O:
TOP :O: Delivery
R1
R2
R1
Ti(iPrO)4, t-BuOOH
O
o
OH
R3
CH2Cl2, -20 C
OH
R3
:
:
:O:
L(+)-Diethyl tartarate
(Natural)
BOTTOM :O: Delivery
Top or Bottom [O] delivery depends on the isomers of tartarate used and depends
on pre-existing chirality of substrate. In a recemic Titanium complex reacts with
only one enantiomer.
32
Slow Top attack due to
bulky R group
:
D(-)-Diethyl tartarate
(Unnatural)
:O:
Ti(iPrO)4, t-BuOOH
O
OH
OH
:
:O:
R
Fast bottom attack due to
bulky R group
R
Ti(iPrO)4 ,t-BuOOH
L(+)-Diethyl tartarate
(Natural)
O
OH
R
:
D(-)-Diethyl tartarate
(Unnatural)
:O:
Ti(iPrO)4, t-BuOOH
H
H
Fast top attack due to
bulky R group
O
OH
R
OH
:
R
:O:
Ti(iPrO)4, t-BuOOH
L(+)-Diethyl tartarate
(Natural)
Slow bottom attack due
to bulky R group
O
OH
R
Diseterefacial stereo selectivity
K. B. Sharpless, J. Am. Chem. Soc, 1981, 103, 6237.
33
Loading of complex
[Ti(DET) (OR)2] + 2ROH
Ti(OR)4 + Diethyl tatarate
TBHP
ROH
ROH
[Ti (OR) (TBHP) (DET)]
Allylic alcohol
[Ti (OR) (Allylic alcohol) (DET)]
ROH
TBHP
ROH
Allylic alcohol
[Ti (TBHP) (Allylic alcohol) (DET)]
"Loaded Complex"
[Ti (OR) (epoxy alcohol) (tatarate)]

Rapid ligand exchange of Ti(O-i-Pr)4 with DET.

The resulting complex further ligand exchange with the alcohol and then
THP.

The exact structure of the active catalyst is difficult to determine due to rapid
exchange but it is likely to have dimeric structure.

The hydroperoxide and the allylic alcohol accopy the axial coordination sit
on the titanium and this account for the enantionfacial selectivity.

Oxygen transfer from TBHP to allylic alcohol to give a complex [Ti(OBu)
(epoxy alcohol) (Tatarate)] This is a slow step.

Both Ti(OR)4 and Ti(Tartarate) (OR)2 are active epoxidizing catalyst. Ti
(Tartarate)2 is catalytically inactive

Excess of Ti(OR)4 and its contribution in epoxidation will results in loss of
enantioselectivity because it is achiral.

Excess of Ti(Tartarate)2 causes a decrease in reaction rate.
34

10-20% mol% excess of tartarates over titanium results in the formation of
Ti (tatarate) (OR)2 which gives high enantioselectivity and acceptable rate of
reaction.

Since the reactions involve a nucleophilic attack on peroxy oxygen in the
reactions the electron rich alkene reacts faster than electron deficient
alkenes. For example in case of substituted cinnamyl alcohols, an
electron-withdrawing (p-nitro) group decreases the reaction rate while
electron donating (p-methoxy) increase the rate of reactions.
H
OH
H
NO2
OH
OMe
Slow reacting p-nitro cinnamyl alcohol Fast reacting p-methoxy cinnamyl alcohol
Highly subtituted double bond epoxidize prefereably than less substituted
OH
OH
O
(CH2)10
(CH2)10
Highly substituted double bond
35
36
E
O
Ti
O
(1)
E
O
(2)
A reaction path way invoking orbital controlled approach of C-C bond to the
peroxide oxygen O(1) in the direction of axis of O(1)-O(2) in the complex has been
suggested by Sharpless
K. B. Sharpless et. al. Pure and Appl.Chem., (1983) 55, 589.
37
Epoxidation of homoallylic alcohol with other reagents

Homoallylic alcohol

Transfer of stereochemistry by phosphate and

Cyclic iodophosphate formation

Treatment of cyclic iodophosphate with ethoxide
OP(OR)3, I2,
o
CH3CN, NaOEt, 25 C
OH
O
OH
Mechanism:
O
P
RO
OH
I
I
O
OR
O
OR
P
RO
OR
O
RO
P
I
-RI
O
O
I
O
O
R
I
O
P
OR
OR
O
O
P
O
+
O
OR
OR
OH
O
P
RO
OR
RO
OR
38
Carbonyl Group Assisted Asymmetric Epoxidation
Oxidative cyclization or Iodolactonization
I2, CH3CN, 0 oC
HO
O
HO
O
O
Mechanism:
HO
O
I
I
O
I
OH
O
O
O
I
O
+
I
Na2CO3
O
H3CO
o
CH3OH, 25 C
O
Iodolactone (10:1)
What will be the mechanism of last step?
39
Epoxide formation by the action of base on bromohydrins
It is very useful method for epoxidation of terminal double bond.
OH
O
B
NBS, H2O
DME
Br
Mechanism:
O
Br N
OH2
+ H2O
Br
O
OH
B
O
Br
40
Base Catalyzed Ring Opening of Epoxides:
OCH3 CH3
H3C
CH3
H
O
NaOMe
MeOH
CH3
H3C
C
C
CH3
H
OH
Mechanism:
H3C
H3C
H3C
Y
H3C
O
CH3
H
Y
CH3
H3C
O
CH3
H
Transition state
CH3
H3C
O
H
Y
Y
CH3
OH
H
CH3
-Substituted alcohol
Alkoxide Ion
Acid Catalyzed Ring Opening of Epoxide
H 3C
H
O
CH3
H2SO4
CH3
MeOH
H3C
H
OCH3
C
C
OH
CH3
CH3
Mechanism:
H
H 3C
H
CH3
O
CH3
H
O
Fast
Me
H 3C
CH3
H
CH3
O
H
O
Me
H
CH3
Slow
H 3C
HO
H 3C
O
CH3
Fast
H 3C
H 3C
O
H
MeOH
HO
CH3
CH3
41
Reaction of KMnO4
An aqoues solution of KMnO4 reacts with olefins to add hydroxy function to double
bond in a cis manner provided the reaction mixture is alkaline. If the reaction
mixture is kept neutrals either by continuous addition of acid or by adding
magnesium sulfate the permagnate oxidation results in cleavage or in the formation
of α-hydroxy ketone.
H
H
C
HO2C(H2C)7
C
(CH2)7CO2H
HO
KMnO4
H
NaOH (excess)
H 2O
OH
C
C
HO2C(H2C)7
H
(CH2)7CO2H
81%
KMnO4, H2O
CH3(CH2)7C
(CH2)7CO2H
O 75%
OH
KMnO4 NaOH
o
H2O, t-BuOH, O C
HO
H
H
40%
CHO
KMnO4 MnSO4
H2O, AcOH, -15 O
o
54-66%
CHO
42
Oxidation of Double Bond BY KMnO4
There are two ways
Gives vicinal diols
R
CH
CH
R
(Olefin)
R
KMnO4
HC
HC
OH
OH
R
(Cis diol)
Mechanism of KMnO4
43
Oxidation of Double Bond with OsO4






Cis vicinal diol
Mechanism is very simple
Expensive and highly toxic reagent
Better yield than KMnO4
Strained and unhindered olefins react rapidly
Catalytic amount of OsO4 with less expensive oxidant works well.
CH3
CH3
OH
OsO4
OH
CH3
CH3
70%
R
R
H
H
C
OsO4
C
OH
C
H 2O 2
C
OH
+
H
OsO4
H
R
R
Mechanism:
R
R
R
O
CH
CH
O
O
HC
R
R
H2O
Os
Os
O
HC
O
R
O
O
O
HC
OOsO2
HC
OH
HC
OH
HC
OH
R
R
44
Oxidation with Prévost’s Reagent
Prévost’s Reagent (I2/CCl4 +AgOAc) or (I2/CCl4 +AgOBz)
AcO
OH
H
H
O
H2
+
I2/CCl4
anh
ydr
ous
con
dit
io n
OAc
H
H
AcO
Reaction of alkene with Prévost’s reagent in a solution of iodine in CCl4 together
with one aqueous solution of silver acetate or silver benzoate under anhydrous
condition (Prévost’s conditions) the oxidant directly yields the diacetyl derivative of
the trans-glycol. While in the presence of water the monoester of the cis-glycol is
obtained (Wood wards conditions)
The value of this reagent is due to its specificity and to the mildness of the reaction
conditions, free iodine, under these conditions used, hardly affects other sensitive
groups present in the molecule.
Reaction proceeds through the formation of iodonium ion.
45
Mechanism:
O
O
C
O
AgO
I
I
C
+
CH3
AgI
I
CH3
Iodonium Ion
CH3
CH3
CH3
O
C
C
O
O
O
O
O
Ag
I
OCOCH3
H 2O
H 3C
OH OCOCH3
Monoacetyl Cis diol
Wood wards Method
O
OH
O
OCOCH3
H
C
C
H
OCOCH3
Diacetyl Trans diol
Prevost Method
46
OZONOLYSIS
The most general and mildest method of oxdatively cleavage of alkene to carbonyl
compounds is Ozonolysis
Alkene is treated with Ozone (O3) at low temperature in solvents like methanol,
ethyl acetate and dichloromethane.
The first insoluble intermediate ozonide forms which is reduced to the two carbonyl
products by different treatment like cat. hydrogenation, Zn/HOAc or by reaction
with dimethyl sulfide.
O O
O3
Reduction
O+
O
O
Ozonide
H3C
H
C2H5
O3, CH2Cl2
O
O
+
H
CH3 Zn/HOAc
CH3
CH3 O CH Cl
3,
2 2
O
H
Zn/HOAc
O
CH3CH
2
O3, CH3OH
(CH3)2S
CH3O
O
+
H
H
47
STEP 1:
+
O
O
O
O
O
O
O
O
O
Molozonide
STEP 2:
O
(CH3)2S
O
O
O
C
O
C
O
O
+ (CH3)2S=O
Zn/HOAc
O
+
ZnO
+
H 2O
O
H2/Pt
Ozonoide
Treatment of the ozonoide with NaBH4 leads to alcohols. In this way, a double bond
can be oxidatively cleaved to produce two alcohols.
CH3(CH2)2CH CHCH2CH2CH3
1. O3, CH2Cl2
2. NaBH4,/CH3OH
2CH3CH2CH2CH2OH
O
O
CH3CH=CH3(CH2)7
C
OCH3
1. O3, CH2Cl2
2. NaBH4,/CH3OH
C2H5OH + HOCH2(CH2)
48
C
OCH3
Photosensitized oxidation of alkenes

Iradiation of alkenes and conjugated dienes in the presence of oxygen

Hydroperiodes

Alkene to allylic alcohols

Sensitized Organic dyes (fluorescence derivatives, methyl blue, propylene
Reduced to alcohol
derivatives

No reaction if lack of allylic hydrogen

= = = = = = = = = sensitizer

= = = = = = = = = O2

= = = = = = = = = light
H
H
C
H
C
OOH
O2
C
Sensitizer
H
C
H
C
C
H Reduction
H
OH
C
H
C
C
H
H
an allylic hydrogen
The position of double bond changes from α, β to β, γ.
49
Reaction mechanism:
Generally proceed by a concerted mechanism
C
C
C
H
O
O
C
H
C
O
Red
C
O
C
CH2 OH
An allylic alcohol
an allylic hydro peroxide
H3C
CH3
H3C O
O CH3
H3C
H3C O
CH3
O CH2
H
H3C
H3C
CH3
O
O
CH2
H3C
H3C OOH
CH3
CH2
H
50
Allylic Oxidation of Alkenes by SeO2

SeO2 is a useful reagent for allylic oxidation of alkenes.

Products include allylic alcohols, allylic esters, enals depending upon
the nature of substrate and reaction conditions.
R
H
H
CH3
R
H
H
CHO
H
H
R
CH2OH
Basic mechanism consists of three steps:
i) An eletrophilic ene reaction with SeO2
Ene reaction: Certain electrophilic double bonds undergo an addition
reaction with alkenes in which an allylic hydrogen is transferred to
electrophile.
O
R
O
Se
O
R
R
O
H
H
O
Se
O
H
H
H
Se
H
Allylic Selenic Acid
51
ii) A sigmatrpic rearrangement that restore the original location of double
bond because in the first step the position of double bond has been disposed.
OH
OH
Se
R
R
O
R
Se
OH
Se
O
O
H
H
H
Finally hydrolytic breakdown of resulting selenium ether
OH
R
R
Se
H2O/H
+
O
OH
H
H
Normally an excess amount of this reagent is used due to which resulting alcohols
are further oxidized to aldehydes,
R
R
SeO2
O
OH
H
H
Therefore, a modification is carried out in order to avoid further oxidation.
i) Reaction was carried out in acetic acid as solvent
R
OH
Se
R
AcOH
+ Se(OH)2
O
H
OAc
H
Allylic acetate ester can be hydrolyzed to required allylic alcohol.
ii) Use of catalytic SeO2 along with co-oxidant t-BuOOH which regenerate the
catalyst repeatedly and product will be allylic alcohol.
52
Stereoselectivity of the Reaction
i) In trisubstituted alkenes, oxidation occurs at more substituted end of the double
bond.
H3C
CH2CH3
H3C
H
Oxidizable site
ii) The oxidized product will be E-allylic alcohol
H3C
CH2CH3
HOH2C
H
The observed stereochemistry can be explained by considering the five membered
cyclic transition state for sigmatropic rearrangement.
H
OH
Se
C2H5
C2H5
HO
O
O
H3C
C2H5
Se
H
HOH2C
H3C
CH3
Transition state for E-allylic alcohol
C2H5
H
HO
O
Se
HOH2C
H3C
C2H5
H
CH3
Transition state for Z-allylic alcohol
53
Wacker Oxidation
Salient Features:
1. Offers a direct conversion of alkenes to carbonyl compounds.
2. Atmospheric O2 is used in presence of PdCl2 and CuCl2 as catalysts known as
Wacker-Smidt process. PdCl2 is used in catalytic amounts while CuCl2 is
stoichiometric co-oxidant.
3. Oxidation reaction is carried out in water in the presence of HCl.
4. Terminal alkenes react at much faster rate than internal or 1,1-disubstituted
alkenes.
5. α,β-unsaturated ketones and esters are oxidized regioselectively to
corresponding β-keto compounds using catalytic amounts of Na2PdCl4 and
H2O2 as co-oxidant.
The catalytic cycle can also be described as follows:
[PdCl4]2 − + C2H4 + H2O → CH3CHO + Pd + 2 HCl + 2 Cl−
Pd + 2 CuCl2 + 2 Cl − → [PdCl4]2− + 2 CuCl
2 CuCl + ½ O2 + 2 HCl → 2 CuCl2 + H2O
Wacker Oxidation
54
Mechanism
55
Oxidation of Alcohols

Several methods
→ Chemical → Catalytic → Microbial etc → Produces →, Aldehydes → Ketone
→ Acids

Primary alcohols

Secondary alcohols → Ketones

Tertiary alcohols
→ Aldehydes or carboxylic acid
→ Cleavage of C-C bond
Oxidation of Alcohols by chromium
Primary Alcohols ……………………. Aldehydes, Carboxylic Acids
Secondary Alcohols …………………... Ketones
Tertiary Alcohols ……………………….. Cleavage of C-C bond
Alcohol Oxidation must focus
 The relative strength of the reagent
 The condition under which is used
 Structure variation of the alcohols
Oxidizing properties of Chromium with respect to media
 Chromium (VI) in acidic media
 Chromium (VI) with heterocyclic nitrogen bases
56
O
O
HO
Cr
-
O-
O
O
Cr
O
Cr
O
O
O
-
+ H 2O
O
J. Am. Chem. Soc., 1958, 80, 2072
J. Am. Chem. Soc., 1960, 82, 290
General Mechanism of Alcohols Oxidation with Chromium
CH3
O
H
H
C
CH3
OH
HO
Cr
OH
CH3
+
H
-H2O
O
C
O
Cr
OH
CH3
O
Chromate ester
O
O
+
Cr
HO
O
OH
Cr(VI)
H 3C
CH3
Cr(IV)
J. Am. Chem. Soc., 1959, 81, 2116
57
Salient Feature:
In cyclohexanol axial OH generally oxidized rapidly than equatorial
O
O Cr OH
OH
O
Less stable
due to 1,3-diaxial interaction
Axial
O
OH
O
Cr OH
O

Conformation can be determined

Primary → aldehyde → carboxylic acid

Continuous distillation of aldehyde

Not suitable for alcohols containing acid sensitive group

Different solvent combinations

Na2Cr2O7/H2O4/H2O

CrO3/HOAc/H2O

CrO3/H2SO4/H2O/Acetone (Jones Reagent)

CrO3/H2O/HCl/Oxalic acid

CrO3/DMF

CrO3/HMPA
CrO3/DMSO/H2SO4
Aqoues / Non aqoues, Heterogeneous, Phase Transfer and Solid Support conditions
can also be used.
58
Jones Oxidation
Most widely used method of oxidation using
Chromic acid/sulfuric acid in aqueous acetone
Protect the substrate from over oxidation
Multiple bonds are not attacked by Jones reagent
O
OH
J. R.
NHTs
NHTs
H3C
98%
H3C
CH3
CH3
O
OH
J. R.
CH3
CH3
84%
Bu
J. R.
O
Bu
O
OH
82%
1. J. Org. Chem., 1976, 41, 177.
2. J. Org. Chem., 1971, 36, 387.
3. Can. J. Chem., 1976, 54, 3113.
59
Chromium (VI) with Heterocyclic Nitrogen Bases
i)
Chromium (VI) oxide forms complex with several nitrogen heterocyclic
compounds which show oxidizing properties.
ii)
They are milder more selective oxidants than acid based reagent systems.
iii)
Acid sensitive group are tolerated.
iv)
Preparation of aldehyde is generally easier.
Chromium Pyridine Complexes
a) Chromium trioxide pyridine complex (Sartt’s reagent)
O
+
N
Cr O
-
O
b) Dipyridine chromium (VI) oxide (Collin’s Reagent)
O-
OCr
N
N
O
c) Pyridiium Chlorochromate (Corey’ Reagent)
N
-
ClCrO3
+
H
2
d) Pyridinium dichromate
-
N
+
Cr2O7
H
60
Reactions
OH
O
O
H
PCC
3 eq. CH2Cl2, 1 h, r.t.
O
O O
Can. J. Chem., 1987, 65, 195.
MeO
OMe
MeO
PCC
OH 1.4 eq. CH2Cl2, 2 h, r.t.
NaOAc
H
OMe
O
J. Am. Chem. Soc., 1980, 102, 1983
Assignment for students having 1/2 solid marks (Propose Mechanisms)
Chromium Pyridine Complexes
a) Chromium trioxide pyridine complex (Sartt’s reagent)
O
+
N
Cr O
-
O
b) Dipyridine chromium (VI) oxide (Collin’s Reagent)
O-
OCr
N
N
O
c) Pyridiium Chlorochromate (Corey’ Reagent)
ClCrO3N
+
H
2
d) Pyridinium dichromate
-
Cr2O7
N
+
H
61
Oxidation of Alcohol by Silver Carbonate

Ag2CO3 on Celite

Fatizon Reagent

Solid Support

Mild Conditions

No Acid

No Base

Very Selective

Other functionalities are unaffected

No work-up only filtration.
H
H
C
HO
H
H
O
H
(a)
(b)
H
C
O
+
OAg
AgO
OAg
AgO
H
C
C
C
O
O
AgO-
OAg
C
O
(c)
C
+ 2Ag + CO2 + H2O
O
Point to Remember for Ag2CO3-Celite mechanism:

Initial step is reversible adsorption of alcohol on the surface of oxidant

Formation of covalent bond b/w O of OH and Ag+

Second Ag+ will convert into Ag by heterolytic cleavage of C-H bond and
electron transfer and generation H+

CO3-2 pickup H+ and converted to carbonic acid which decomposes to
CO2 and H2O
62
H
.
63
Ref: A. Mckillop et.al. Synthesis, 401(1979)
F.J. Kakis et.al. J. Org. Chem. 523, 3, 39 (1974)
M.Fatizon et.al. Tetrahedron Lett., 4445 (1972)
Salient Feature
Reaction takes place at interface of solid and solution used inert solvent like
benzene ith excess of reagent.
O selective i.e. alcohols of different type are oxidized at different rate.
Benzylic or allylic > secondary > primary
Activated alcohols (such as benzylic and allylic alcohols) oxidized faster than
saturated alcohols
O
HO
1oalcohol
AgCO3 /Celite
Benzene
HO
HO
OH
o
2 alcohol
O
allylic alcohol
1oalcohol
O
OH
HO
OH
2 alcohol
70%
allylic oxidation
AgCO3 /Celite
o
O
HO
Benzene
HO
o
OH
48%
1 alcohol
Primary alcohols are oxidized more slowly than secondary
Highly hindered OH group are unaffected i.e. selectively based on steric
crowding.
64
CH3
OH
CH3
O
H 3C
H3C
AgCO3 /Celite
Benzene
H 3C
H 3C
CH3 OH
CH3 OH
Diols behaves differently generally only one OH group is oxidized
O
O
H
CH2OH
CH2OH
O
Ag2CO3-Celite
C6H6, Reflux
O
H
O
O
H
Lctone
H
One of the OH groups being converted to carboxylic acid and predominantly
lactone formation takes place.
Other diols (Pir, Sec, e.t.c) give hydroxy ketones.
OH
OH
Ag2CO3-Celite
C6H6, Reflux
O
OH
50%
This is an excellent reagent for oxidizing allylic, secondry under essentially
neutral conditions.
65
Oxidation of Alcohols Manganese Species

KMnO4 and MnO2

KMnO4 is relatively vigorous oxidant than MnO2

MnO2 is mild and more selective

KMnO4 oxidation of primary alcohol to carboxylic acids is a synthetically
useful reaction.
RCH2 OH
KMnO4
RCHO
RCOOH
O
HO
RCH CH3
RCH CH3

Usually carried out in the presence of alkali hydroxide

Also performed in buffer

Two phase system containing an aqueous KMnO4 solution and an
immiscible solvent such as C6H6, ether can also be used.
CH3 (CH2)6 CH2OH
Ag KMnO4/ C6H6
+
CH3 (CH2)6 COOH
BuN Br, RT

Solid Support KMnO4 in toluene provides a simple and milder
procedure.
(CH2)11
CHOH
KMnO4/Alumina
(CH2)11
C O
66
Mechanism:
-
(CH2)11CHOH + OH
(CH2)11CHO + H2O
O
O
O
H3C C H +
O Mn O
H O Mn O +
O
O
CH3

O
H3C
CH3
MnO4 abstract the α-hydroxy from alkoxide ion either as an atom (or an
electron transfer) or as hydride H ion (two electron transfer) But Hydride
shift is more reliable.

Permanganate ion is reduced from from Mn(VII) to Mn(V)
MnO2 Oxidation

Useful oxidizing agent for allylic and benzylic alcohols.

Mild and selective than KMnO4
MnO2/CH2Cl2
o
20 C
OH
H
O

Neutral solvents are used i.e. benzene, pet. ether, CHCl3

Simple stirring of alcohol in solvent with MnO2 for some hours

Used specially prepared MnO2

MnSO4 with KMnO4in alkaline solution produced very active
MnO2

This is not clear that actual oxidizing agent is MnO2 or some other
manganese species adsorbed on the surface of MnO2

C=C bonds and C
HC C C
H
C remain unaffected by this reagent
C CH2OH
H
MnO2
O
HC C C
H
C CH
H
67

Acid or base sensitive subatrate can easily be oxidized by this
reagent
OH
EtOC
C C
H
C CHCH3
H
O
MnO2
EtOC
C C
C CHCH3
H
Dimethyl Sulfoxide
O
H 3C
S
Red
H 3C
CH3
Dimathyl sulfoxide

S
CH3
Dimethyl sulfide
The development of mild oxidant based on dimethyl sulfoxide for the
efficient conversion of alcohols to their corresponding carbonyl compounds
was a major breakthrough in synthetic organic chemistry.

Wide spread applications

Alcohols to corresponding carbonyl compounds

Tosylate to = = = = = = = = = = = = = =

Halides to = = = = = = = = = = = = = =

Epoxide to α-hydroxy ketones
H
R'
Alcohol
(CH3)2S=O + Activation
R
C
Base
Tosylate RCH2OTs + (CH3)2SO
Halide
RR'CO + (CH3)2S
RCHO + (CH3)2S
H
R'
R
OH
C
+
X
(CH3)2SO
RR'CO + (CH3)2S
68
R
R
Epoxide HC
OH
CH +
R
(CH3)2SO
C
H
O
C
R + (CH3)2S
O
Arylic tosylate and halide can also convert into their corresponding carbonyl
compounds.
The commonly accepted gross mechanism
H
H3C
S O
+ R2
H3C
C
R1
H3C
X
S
O
C
-
H
H3C
R1
X
R1
H3C
R2
S +
H3C
C
R2
O
Alkoxy dimethylsulfonium ion
(A key intermediate in all type of DMSO
based reagents)
R1 = Ar, R2 = H, X = Br
R1 = Ar, R2 = H, X = OTs
R1 = Alkyl, R2 = H, X = OTs or halide
H3C
H3C
S O
+E
H3C
S OE + R2
H 3C
O
E
H3C
H
H3C
S
C
R1
H3C
OH
R1
S
O
C
R2
+
HOE
H 3C
H
Alkoxy dimethylsulfonium ion
(A key intermediate in all type of DMSO
based reagents)
E = C6H11N=C=N=C6H11 (DCC)
E = (COCl)2 (Oxalyl Chloride)
E = Anhydride
69
Decomposition of Alkoxydimethyl sulfonium ion
R1
H3C
S
O
H2C
H
C
..
B
R1
H3C
S
R2
O
C
H2C
H
R1
H3C
R2
S + O
R2
H3C
H
Alkoxy dimethylsulfonium ion
(A key intermediate in all type of DMSO
based reagents)
H
H
R
R
+ (CH3)2SO
OH
H
C
C
R
H
O
S
R2
O
R2
OH
O
C
C
H
R
S
H
CH2
B
CH3
CH2
CH3
R2
OH
O
C
C + (CH3)2S
H
R
C
H
In final step formation of a ylid which undergoes intermolecular hydrogen transfer
with formation of DMS and a carbonyl compound.
Ref: C.R. Johnson et.al. J. Org. Chem. 32, 1926, (1976)
Various variant of DMSO-based oxidants are available
In some cases formation of thio ether are also reported through following
mechanism.
70
H3C
H3C
S O + E
S
H3C
O
E
H 3C
-H
H3C
S
+ HOE
R1R2CHOH
H 2C
Methylene Sulfonium Ion
H
R1
C
OCH2
S
CH3
R2
Thioether
Different combination of DMSO with activators or electrophoiles
1. DMSO-N,N’-Dicyclohexylcarbodiimide (DCC) (Commonly known as
Pfitzer-Moffatt Reagent)
2. DMSO-(COCl)2 (Swern Reagent)
3. DMSO-(CH3CO)2O
4. DMSO- (CF3CO)2O
5. DMSO-SO3
6. DMSO-P2O5
7. DMSO-Cl2
SWERN OXIDATION
This is one of the best methods of oxidation. In this oxidation oxalyl chloride is used
as activator.
By reaction of DMSO and oxalyl chloride followed by treatment of the resulting
alkoxy sulfonium salt with a base, usually triethylamine, a wide variety of alcohols
has been converted into corresponding carbonyl compounds in high yields.
71
O
DMSO, (COCl)2
OH
H
CH2Cl2, Et3N
OHC
HOH2C
DMSO, (COCl)2
O
O
O
O
O
O
O
O
CH2Cl2, Et3N
O
O
High yield, mild conditions, by-product easily separable
Mechanism:
H3C
H 3C
o
S
O
+ (COCl)2
CH2Cl2, -60 C
S
H3C
O
C
C
Cl
Cl
H3C
RCHOHR'
S
S
Cl
R
S
O
O
H3C
H3C
H3C
R
H 3C
H 3C
H2C
O
O
C
H
C
H
R'
base
R
R'
C
O + H3C
S
CH3
R'
Oxidation via alkoxy sulfonium salts
A number of methods for oxidation primary and secondary alcohols to aldehyde
and ketone by the action of base on the derived alkoxy sulfonium salts differ from
72
each other mainly in the way in which the alkoxy sulfonium salt is obtained from the
alcohol.
One of the earliest procedure involved reaction of alcohol with dimethylsulfoxide
and dicyclohexyl carbodiimide (DCC) in the presence of proton source.
R1
C6H11N=C=N-C6H11
CH OH
o
(CH3)2SO, H3PO4, 75 C
R2
R1
O
R2
Mechanism:
C6H11N=C=N-C6H11
C6H11NH-C=N-C6H11
+
O
H
H 3C
R1CHOHR2
S
S
H 3C
O
CH3
H3C
H 3C
R1
O
S
Base
C
H 3C
+
H
R2
H
O
H 3C
S
H 2C
R1
R1
R2
R2
C
H
O + (CH3)2S
(C6H11NH)2CO
dicyclohexyl urea
The oxidation with DMSO, DCC also known as Pfitzner-Moffat oxidation.
A disadvantage of this route is that the product to be separated from the
dicyclohexyl urea formed in the reaction.
73
Oppenauer Oxidation

Primary and secondary alcohols to ketone

Aluminium alkoxide + carbonyl compound

Reverse of Meerwein-Pondroff-Verley Reduction

Useful in the field of steroids.

Al(i-PrO)3, (Al(t-BuO)2, Al(PhO)3

Carbonyl
compounds
include
butanone,
benzoquinone,
benzophenone,
flournone.

Flourenone is advantageous due to considerably short time and temperature of
reaction

α-hydrogen containing carbonyl compounds under alkaline conditions undergo
self condensation

Use of inert solvent suppresses self condensation.

Benzene-acetone and toluene-cyclohexane are commonly used solvents, however,
toluene-cyclohexane reduces the time of reactions.

Use of flourenone as hydride ion acceptor often reduces the temperature up to
room temperature.


Use of 1-methyl-4-piperidone as the hydride acceptor allow the easy removal of
excess oxidant and corresponding alcohol at the end of reaction by only washing
with aqueous acid.
74
Mechanism:

Exchange of alkoxide

Hydride transfer from alkoxide to carbonyl

Pseudocyclic intermediate formation
OH
R1
O +
H3C C
R2
CH3
Al(OR')3
R2
H
O
CH3
O
O
CH3 +
HOR'
Al(OR')2
H
H3C
CH3
O +
R1
H3C
Al
R'O
O + H3C C
R2
H
R1
H
R1
C
R2
O
Al(OR')2
OR'
Lead tetraacetate Oxidation

Crystalline solid

Decomposes at 140 °C

Used in Acetic acid or Benzene for Oxidation

Widely used for Oxidative cleavage of 1,2-diols, α-hydroxyl ketones, 1,2diketones and α-hydroxy acids

Oxidation carried out usually at or near room temperature

At elevated temperature the oxidative power dropped considerably

Acetic acid is usual solvent for Oxidation

Other solvents including Benzene, CH2Cl2, CHCl3, trichloroethane,
1,4-dioxane, ethylacetate, cyclohexane, nitrobenzene and CH3CN are also
used.

The mechanism aspects of 1,2 diols cleavage with lead tetraacetate are as
follows
75

The preferred mechanism for lead tetraacetate cleavage of a diols involves a
cyclic transition state.

An alternate cyclic mechanism involves coordination of one hydroxy group to
lead atom followed by interamolecular proton transfer
R2CH
OH
R2CH OH
Pb(OAc)4
2R2CO + Pb (OAc)2
CH3CO2H
Mechanism:
R
R2CH
OH
+ Pb (OAc)4
R2CH
R
C
O
R
C
OH
Pb (OAc)3
+ HOAc
OH
R
(R)2
O
Pb(OAc)2
C
2RC
O
O
+ Pb(OAc)2 + CH3CO2H
C
(R)2
O
O
C
CH3
H

In trans diols which cannot rapidly generate a cyclic transition state. The
intermediate (b) breaks down with a proton transfer to a base.
R
H
B:

R
C
O
O
C
H
R2
Pb (OAc)2
2R2CO + Pb(OAc)2
OAc
(b)
The oxidation of cyclohexan-1,2-diol is acid catalyzed
76

A strong acid e.g. H2SO4 is a better catalyst.

Acid could catalyze the reaction in various ways.

It could protonate lead tetraacetate and increases the rate of co-ordination to
the diol or it could catalyze the ring closure or its direct decomposition to
product.
Pb(OAc)4
+
H
+
Pb(OAc)3
+
OAc
H
R2
C
R2
OH
+
R2
C
OH
R2
C
C
O
C
H
OH
Pb(OAc)3
+
Pb(OAc)3O AcH
R2
O
R2
C
O
R2
C
OH
Pb(OAc)2
Pb(OAc)2
R2
C
O
O+
H
Ac
2R2CO
α-Hydroxy Acid

Lead tetraacetate also cleaves α-hydroxy acids

Various mechanisms are proposed for this cleavage.

One involves co-ordination of hydroxy group to lead atom, followed by the
loss of carbon dioxide

Secondly co-ordination of both hydroxyl and carboxyl to the lead followed by
the decomposition of cyclic intermediate.
77
H
R
H
C
OH + Pb(OAc)4
CO2H
R
O
C
O
Pb(OAc)2
OAc
C
O H
RCHO + Pb(OAc)2 + HOAc + CO2
H
R2
C
O
O C O
Pb(OAc)2
RCHO + CO2 + Pb(OAc)2
78
Periodate reagents

Solutions of periodic acid KIO4, NaIO4 in aq. or aq. organic media

Co-solvents used methanol, ethanol, t-butanol, 1,4-dioxane, THF, DMF and
acetic acid.

Co-solvents used less than 50% of the reaction media.

Primary use is the cleavage of 1,2-diols, 1-amino-2-hydroxy compounds, αhydroxy ketones, 1,2-diketones.

Useful method for water soluble poly-functional compounds such as
carbohydrates and certain amino acids.

For water-insoluble compounds Pb(OAc)4 is preferable.
I
I
O
O
+
HO
+
K or Na
Periodic salt
H
(CH3)7
C
H
C
OH
O
CH3 +
I
R
O
OH
OH
Periodic acid
O
H 3C
O
O
O
O
H
H
C
C
CH3
O
OH
O
O
I
O
O
OH OH
Periodic acid
O
H
RCHO + H CC
3
O +
I
O
R
O
H
H
C
C
O
CH3
O
I
O
O
O
79
Oxidation of Aldehydes
O
H2CrO4
R
C
RCOOH
H
Mechanism
OH
O
HCrO4
R
C
H
+ H
R
RCOOH + HCrO3
C
H
O
CrO3H
KMnO4 Oxidation
O
KMnO4
C6H5
C
C6H5COOH
H
H3O
Mechanism
O
C6H5
C
H
H2O +
+ H3O
C6H5
CH MnO4
OH
H
C6H5
C
O
MnO3
C6H5CO2H + MnO3
OH
Oxidation of Ketones
Chromic Acid:
Cleavage of C-C bond
O
H2CrO4
HO2C(CH2)4CO2H
80
O
OH
O
H
H2CrO4
O
CrO3H
H
OH
O
+
O
O
O
HO
Cr
HO
CrO2
O
O
OH
HO2C(CH2)4CO2H
Lead Tetraacetate
O
CH3CH2 C
OCOCH3
CH2CH3
H3C
C
H
C
CH2
CH3
C
CH
CH3
O
OCOCH3
+
O
OCOCH3
H3C
C
H
Mechanism
81
H3C
H
O
C
H
C
OAc
CH2CH3 +
H3C
Pb(OAc)3
H
O
Pb(OAc)2
C
C
CH2CH3
OAc
OCOCH3
OCOCH3
H3C
C
H
C
CH2
CH3
+
H3C
C
H
O
31%
C
CH
CH3
O
OCOCH3
7%
In sterically hindered enols, the acetoxylation procedure is accompanied by a
rearrangement.
CH3
Pb(OAc)4
O
CH3
CH3
CH3
(AcO)2Pb
Attack by
OAc
O
O
CH3
CH3
OAc
OAc
CH3
Rearrangement
CH3 Shift
-H
+
O
CH3
+
O
H
CH3
CH3
82
Bayer-Villiger Oxidation of Ketone

Peroxy acids are used as Oxidants.

Ketones to Ester or Lactones.

Organic peroxy acids i.e, MCPA, Per acetic acid, trifluoroacetic acid give
better results.

Mild Conditions.

Applicable to open chain, cyclic and aromatic ketones.

Used to prepare medium and large ring lactones which are difficult to
prepare.

With unsaturated ketone mixture of products results through competing
attack at C—C double bond

A new reagent bis(trimethylsilyl)peroxide Me3SiOOSiMe3 eliminate this
difficulty, it behaves as masked H2O2 and in the presence of cat.
Trifluoromethylmetane sulfonate. It does not affect the double bond.

Reaction takes place trough a concerted intermolecular process.

Migration of a group from carbon to electron deficient oxygen.

In the presence of strong acid, ketone protonated and addition of peroxy
acid to ketone.
O
O
O
MCPBA
Mechanism
83
O
OH
O
H
+ C2H5
C
..
OH
O
O
..
OH
O
O
O
C
O
C2H5
Oxidation of Ethers
 Interesting reaction of RuO4.
 Oxidation of aliphatic ethers to esters or lactones in case of cyclic ethers.
RuO4
O
O
O
 It is used under mild conditions.
 Reaction stops after first oxidation.
 Esters or lactones cannot oxidize with RuO4.
 So attempt prepare succinic anhydride by this way were failed.
RuO4
O
RuO4
O
O
O
O
O
84
 A mechanistic study proposed that a hydride from α-position of ether shift to
RuO4, then HRuO-4 attacks on the carbonium ion, whish is generated on the
α-position of the ether and oxidation takes place.
Mechanism of RuO4 Oxidation
O
HO
O
H
O
H
Ru
+
+
H
O
Ru
+
O
O
O
O
O
OH
O
+ H2RuO3
Ru
O
H
O
O
_
O
O
The formation of 2,5-hexadione by oxidation of 2,5-dimethyl tetrahydrofuran can
also be explained by hydride transfer mechanism.
85
HO
O
H3C
H
CH3
+
H
O
H 3C
CH3
Ru
O CH3
Ru
+
+
H
O
H3C
O
O
O
-
O
H 3C
H
H
O
O
-
O
O
Ru
Ru
O
O
O
OH
O
OH
+ H2RuO3
O
O
86
O
Oxidation of Amines
Primary amines
These are very sensitive to oxidation and generally darken on exposure to air,
through auto-oxidation at the surface, to give mixture of complex products.
Synthetically useful methods have therefore to be highly selective. The most
successful reagents are hydrogen peroxide and per acids.
Hydrogen peroxide
Hydrogen peroxide converts primary aliphatic amines into aldoxime.
n-C3H7CH2NH2
R CH2NH2 +
O
OH -H2O
H2O2
n C3H7CH
NOH
An Aldoxime
RCH2NH H2O2
RCH2N(OH)2
-H2O
RCH
NOH
H
OH
Oxidation of aromatic amines resulted in formation of nitroso compounds.
Perdisulphuric acid HO3S-O-O-SO3H is used as an oxidant.
NH2
NO
NO2
NO2
HO3S-O-O-SO3H
o- Nitrosonitro benzene
87
Nef Reaction
Primary and secondary nitroalkanes play an important role in organic synthesis
because of their ready transformation into carbonyl compounds.
R
CH
R'
RC
R'
O
NO2
Reaction of nitro compounds with base, α-proton is abstracted leads to the
formation of resonance stabilized nitronate anions which than hydrolyzed and give
a carbonyl compounds.
O
' "
R R CH
:B
+
N
O
O
' "
RR C
N
O
-
OH
OH
R'R"C
' "
O
-
O
O
' "
N+
RR C
H+
N+
RR C
N+
OH
H+
..
H2O
R
C
H
O
R"
OH
R'
C
N
HO
OH
Reference

Hawthorne, J.Am.Chem.Soc. 1957, 79, pp.2510.

Thicde, Ibid. 1952, 74, pp.2615.

Folliard, Tetrahedron, 1971, 27, pp.323.
88
R"
Oxidation of azobenzene to azoxybenzene
Azo compounds may be oxidized to azoxy compounds by per acids.
Ar
N
Ar CH3COOOH
N
Ar
N
N
Ar
O
Ar
N
..
N
Ar
Ar
N
N
Ar
OH
O
CH3C
O
OH
Ar
N
N
Ar
O
Oxidation of Isocyanides to Isocyanates
Isocyanides have been oxidized to Isocyanates with HgO and with O3 as well as
halogen and DMSO. Mechanism involves formation of R-N=CCl2 which hydrolyzed
to Isocyanates.
R
N
Cl2
C
R
O
C
N
Me2SO, H2O
Mechanism
R
C-
+
N
Cl
+
R
Cl
CCl
N
Cl
Cl
Cl
R
C
N
Cl
Cl
R
N
HOH
C
O
R
N
C
O
H
89
Trifluoroperacetic acid
A more powerful oxidant than hydrogen peroxide converts primary amines directly
into nitro compounds. The yield with aromatic amines are generally high e.g onitroaniline is oxidized in refluxing CH2Cl2 to o-dinitro benzene in 92% yield.
NH2
NO2
NO2
NO2
CF3CO3H
With aliphatic amines, however, yields are low. Other oxidants have been used with
moderate success e.g. n-hexylamine is oxidized in 33 % yield to the nitro compounds
by peracetic acid.
Secondary amines
Oxidation of secondary amines with H2O2 gives hydroxylamine.
R2NH
H2O2
R2N
OH + H2O
Tertiary amines
Tertiary amines with H2O2 give their N-oxide hydrates, by nucleophilic
displacement as in primary amines. The N-oxides is obtained by warming the
hydrate in vacuo.
R3N
H2O2
R3N
OH + OH
Heat
R3N
O
Aromatic amines behave similarly e.g. pyridine.
90
The Beckmann Rearrangement
The rearrangement of oxime to amide under the influence of acid, Lewis acid is
termed as the Beckmann Rearrangement.
 Commonly H2SO4, PCl5 in Et2O, poly phosphoric acid, aryl sulfonic halides,
HCl in HOAc and Ac2O.
 HCl in HOAc and Ac2O is useful if the starting oxime is insoluble in other
medium.
1
2
R CR
2
H+
R C NHR
O
N
OH
Mechanism
1
2
R CR
1
2
R CR
H+
-H2O
2 +
R C
NR
H 2O
1
2
R C
NR
1
N
N
OH
+OH2
+OH2
-H
2
R C
2
+
NR
1
1
R C NHR
O
H
O
91
The Schmidt Reaction
The acid catalyzed reaction of hydrazoic acid with carboxylic acid to give amines
with ketones to give amide and aldehydes to give nitriles are all known as Schmidt
reaction. The mechanism of reaction with ketone has similarities with Beckmann
rearrangement.
Ketone
O
R"
C
H+
R'
R"
C
+O
N+
N
-H2O
R"
C
R'
HN
N
C
R'
O
H
R"
HN3
N
-
H
N-N2
R'
R"
+
N
'
C R
R"
..
H 2O
N
CR'
OH2
-H
R"
H
O
R
R"
CR'
N
O
O
C
OH
HN3
R
-H2O
OH2
N
_
N
H
+
CR'
O
H
N+
N
+
O
C
+
R
N
N
-H2O
R
N
C
H
R
C
O
H
R
O
H
N
C
O
N
C
O
..
H-O-H
-H
H
RNH2 + CO2
92
N-
Oxidation of Primary Amine
(C6H5)3C-NH2
Pb(OAc)4
C6H6, heat
(C6H5)2-C=N-C6H5
Mechanism
H
..
Pb(OAc)4
(C6H5)3C-NH2
(C6H5)2C-N
(C6H5)3C-N-Pb(OAc)2
C6H5
O
(C6H5)2-C=N-C6H5
CH3-C=O
Oxidation of Alkyl Halides
C7H15CH2I + (CH3)3N-O
Mechanism
CHCl3
heat
C7H15CHO
H
C7H15CH2-I + (CH3)3N-O
C7H15C
O
N(CH3)3
H
C7H15CHO
Aldehyde
93
Oxidation of Sulfur Containing Compounds
Oxidation of Thiols:
2RSH
H2O2
RSSR
Thiols are easily oxidized to disulfides. Many reagents are used to convert them into
disulfides. Oxygen in the air oxidizes thiols on standing, if a small amount of base is
present.
RSH +Base
H2O2
RS
+ BH
RS + O2
RS + O2
RS + O2-2
RS + O2
2RS
RSSHR
-2
O2 + BH
OH + B + O2
J. Org. Chem. 1963, 28, 1311.
Oxidation of thioethers to sulfoxides and sulfones.
O
R-S-R
R-S-R + H-O-OH
H2O2
R-S-R
R-S-R
O
Sulfoxide
O
Sulfone
O
..
R-S-R + H-O-O-H
R-S-R + H2O
R-S-R + OH
H
O
O
O
R-S-R
R-S-R
O
O-OH
O
Tetrahedron Lett. 1963, 1479.
Ibid, 1966, 1127.
Ibid, 1980,3213,
J. Chem. Soc, Perkin Tran 2, 1978, 603
J. Chem. Soc, Chem. Commun. 1983, 1203.
94