OXIDATIONS

Marino Petrini
Advanced Organic Chemistry
Chemistry and Advanced Chemical
Methodologies

OXIDATION OF ALCOHOLS TO ALDEHYDES,

KETONES AND CARBOXYLIC ACIDS

CHROMIUM (VI)
Conditions:

CrO3 : H2O, Ac2O, Pyridine, t-BuOH, H2SO4/H2O, Acetone, CH2Cl2/H2O (Phase Transfer
Catalysis), HMPA.

K2Cr2O7 : AcOH, H2SO4/H2O.

General Mechanism:
 The aldehyde is usually more reactive than the starting alcohol.

O O OH OH O
R C + H+ + Cr R C O Cr OH
H O O H O

H2O

O
Secondary alcohols can be converted into ketones R C + HCrO3-
without any particular trouble. OH

The Jones reagent (CrO3 – H2SO4) shows no selectivity and oxidized primary alcohols
into carboxylic acids.

Pyridinium chlorochromate (PCC) is a stable solid, easily prepared:

Primary alcohols are oxidized into aldehydes in dichloromethane.

O PCC O
O OH CH2Cl 2 O H
O

PCC
OH CH2Cl2 H
O O
O
 Pyridinium dichromate (PDC) is neutral: NH Cr2O7=
2

The oxidative strenght can be suitably tuned upon the solvent employed.
In DMF, PDC is very soluble so that primary alcohols are oxidised into carboxylic acids.
(exception: allylic primary alcohols afford less reactive a,b-unsaturated aldehydes even in DMF).
In CH2Cl2 PDC is less soluble and this results in the selective conversion of primary alcohols
into aldehydes.

PDC O

OH DMF, 25°C H

O
PDC OH
OH
DMF, 25°C

PDC
OH H
O O
CH2Cl 2 O

MANGANESE
KMnO4 is the most employed Mn-based reagent.
It can be used under different pH conditions.:

2MnO4- + 5R2CHOH + 6H+ ® 5R2C=O + 2Mn++ + 8H2O

2MnO4- + 3R2CHOH ® 3R2C=O + 2MnO2¯ + 2H2O + 2OH-

Is poorly selective:

OH KMnO4 O

CO2Et NaH2PO4 CO2Et

MgSO4-H2O

O O
H KMnO4 OH
O O
H2O, 70°C
O O
Activated manganese dioxide (MnO2) is more selective:

OH O
OH MnO 2 OH
Acetone
MeO 25°C MeO
OMe OMe

O
MnO2
OH H
C6H6

Drawbacks with MnO2 usage:

1. Useful only for allylic and benzylic alcohols.

2. High reaction times (days)

3. High excess of MnO2 required.

RUTHENIUM
Ruthenium oxide RuO4 is more active than OsO4, thus is less selective.

Perrhutenate anion RuO4- is less reactive than RuO4 but its alkaline salts are poorly soluble
in organic solvents.

Using alkylammonium cations as counterions it is possible to increase the oxidant solubility

as in tetrapropylammonium perruthenate (TPAP):

RuO4 + Pr4N+OH- Pr4NRuO4 TPAP

TPAP is: non volatile, stable to air, soluble in a large variety of organic solvents.

can be used in catalytic amount (5-10%) in the presence of cooxidants such as

N-methylmorpholine-N-oxide (NMO) which is used to reoxidize the reduced
ruthenium species
 TPAP selectively oxidizes primary alcohols into aldehydes:

O
OH 5% TPAP
O H
NMO O 70%
O Si CH2Cl 2 r.t. O Si

5% TPAP
OH H 94%
Br NMO Br
CH2Cl2 r.t. O

TPAP can be also used in the oxidation of alcohols when the substate contains stereolabile
chiral centers or is particularly sensitive to acid or basic conditions:

Other tolerated functional groups are: ethers, epoxides, acetals.

DIMETHYLSULFOXIDE
DMSO alone without any activation is able to oxidize only at high temperature.
It act selectively toward primary alcohols which can be converted to aldehydes
but it must be activated using electrophilic reagents.

Mechanism

The reaction conditions strongly depend from the nature of the activating reagent
 Dicyclohexylcarbodiimide (DCC)

H+ H+

O S
N C N + O S N C RCH2OH
HN

O O
H H
N C N + RCH2 O S R C H

Reaction is carried out at room temperature, DCC also works as the base
in the decomposition step of alkoxysulfonium ion intermediate.

O
O OMe O OMe
HO DMSO / DCC H

O O H3PO 4 r.t. O O

Oxallyl chloride. (SWERN REACTION):

Reactions are performed at -60°C.
Chemical yields are usually satisfactory.
Reaction between DMSO and (COCl)2 is strongly exothermic.

O
1. DMSO / (COCl)2
OH CH2Cl 2, -78 °C H
2. Et3N
N O N O
H H
O O

O 1. DMSO / (COCl)2 O
CH2Cl2, -55 °C
O O O
2. Et3N
OH H
 HYPERVALENT IODINE REAGENTS
Are pentacoordinate iodine (V) reagents also called periodinanes.
The most important reagents are iodoxybenzoic acid (IBX) and is acetylated derivative
named Dess-Martin periodinane (DMP) which can be prepared as follows :

Iodoxybenzoic acid (IBX)

Relatively strong acid (pKa=2.40), is poorly soluble in most organic solvents.
Used for the selective conversion of primary alcohols to aldehydes:

Oxidation with IBX can be carried out in the presence of free amino groups provided
that these are temporarily convetred into ammonium salts ( e.g using TFA)

Dess-Martin Periodinane (DMP)

Rather expensive reagent, is strongly preferred over IBX for its superior selectivity
and mildness. Similarly to TPAP is used for selective conversion of primary alcohols to
aldehydes in the presence of labile stereocenters or other sensitive functional groups.

Mechanism
 DOUBLE BOND OXIDATIONS
MANGANESE
KMnO4 under controlled basic conditions affords diols:
H
R H NaOH R O O R OMnO2 R OH
+ MnO4 - H2O
Mn O
R H O O H H OH-
R R OH R OH
H

This reaction is SYN-stereospecific:

R H OH OH
Z
H H
R H R R

H R OH OH
E H R
R H R H

Double C=N bond oxidations: the NEF REACTION

Is a largely employed procedure to convert NITROALKANES into CARBONYLS

Primary nitroalkanes can be alternatively converted into aldehydes or carboxylic acids,

depending upon the reaction conditions:
 SHARPLESS ASYMMETRIC EPOXIDATION
The epoxidation is an enantioselective process carried out on primary allylic alcohols.
It allows formation of epoxyalcohols in enantioenchired form with high enantiomeric excess.

Enantiomeric excess: ee = % [R] - % [S]

OXIDANT:
t-BuOOH: stable, oxidizes C=C but not alcohols.
Must be used anhydrous in toluene o CH2Cl2.

CATALYTIC SYSTEM:

The main feature of this process is that is possible anticipate the stereochemical outcome of
the formed apoxyalcohol on the basis of the nature of chiral catalyst (tartrate) used.
 Nature of the catalytic system and mechanism:

Tartrates: the most emplyed one is diethyl tartrate,

diisopropyl- and t-butyl tartrate are seldom used.

Typical reaction conditions: low temperature (-20°C), dry conditions (otherwise low ee).

Ti(i-PrO)4 - t-BuOOH OH
95%
OH H ee
(+)DET, CH2Cl2 O
-20°C, 77%

Ti(i-PrO)4 - t-BuOOH O 93%

OH (-)DET, CH2Cl2 ee
HO H
-20°C

O
H OH
Ti(i-PrO)4 - t-BuOOH
R OH H
(-)DET, CH2Cl 2
-20°C R
 KINETIC Resolution of secondary allylic alcohols

Secondary allylic alcohols may be kinetically resolved, thanks to the different rate by
which every single enantiomer reacts in the epoxidation reaction.

Mandatory condition: KR - KS ³ 100

For the kinetic resolution diisopropyl tartrate (DIPT) is mostly used.

It is worth to observe that often the fast process also shows an excellent
diastereoselectivity while the slow one is è poorly diastereoselective.
This concept is referred to as double stereodifferentiation.
In other words in the fast reaction there is a matching between the stereochemical
attributes of the catalyst and one enantioner of the substrate.
The other enantiomer mismatch with the catalyst and this results in al slow reaction
and a poor diastereoselection.

OH
OH TIPS - t -BuOOH OH
+
(-)DIPT O H
94% ee
 REACTION WITH OZONE
Ozone is a molecule containing three oxygen atoms, and is partially stabilized by different
resonance structures

O O O O
O O O O O O O O

It is produced starting from molecular O2 subjected to a high voltage electric discharge

Ozone is used to carry out a complete cleavage of C=C bonds, resulting in the molecular
fragmentation and formation of a couple of carbonyl appendages.

Mechanism:

Water alone is seldom used to decompose ozonides. Intermediate hydroperoxides

may cause overoxidation of the resulting carbonyls if these are aldehydes.
For practical reasons decomposition of the ozonide is carried out both under
reductive or oxidative conditions

1. O3
REDUCTIVE: H
N 2. Na2SO3 N
O

Other reducing agents: H2, Zn / AcOH, NaBH4, Ph3P

O
1. O 3 H
2. Ph3P H

OXIDATIVE:
 HYDROBORATION - OXIDATION
H H H
Pure borane is a gas and exists B B
in dimeric form B2H6 H H H

It forms Lewis acid-base adducts R2O BH3 R3N BH3 R2S BH3

R R
Borane releases all three hydrogen atoms BH3
3 R B
leading to trialkylboranes:
R
With polysubstituted alkenes the stoichiometry is different:

MECHANISM –SYN stereospecific addition:

Obtained trialkylboranes can be oxidized to the corresponding alcohols.

The R migration in the oxidation step occurs with retention of configuration:

 Ph 1. B2H6 Ph
Oxidation can be forced to
carbonyl derivatives
2. K2Cr2O7 O

Chemoselectivity in hydroboration can be obtained using sterically demanding boranes

OAc 1. BH OAc
2
2. PCC O

Enantioselective reactions can be made using optically active dialkylboranes:

Z disubstituted alkenes ® ee 75¸90%

Ph (IPC)2BH Ph
OH
OX

ee 100%

E disubstituted alkenes ® ee 5¸30%

(IPC)2BH OH
Me
Me Me ee 82%
Me
Ph OX
Ph
Z Anti
 BAEYER-VILLIGER OXIDATION

Allows the oxidative conversion of a ketone into an ester by reaction with a peracid.

Peracids can be prepared as follows:

m-chloroperoxybenzoic acid (MCPBA)

Peracids are generally weaker than their corresponding carboxylic acids because of the lack of
stabilization of the conjugate base

O O
H C OH pKa = 3.6 H C O OH pKa = 7.1

They also are more volatile since they exist in monomeric form:

O H O O H
H3C C C CH3 H3C C
O H O O O

Mechanism involves a migration (transposition) of a R group to the oxygen:

 Migratory aptitude:

Migration is stereospecific and occurs with retention of the configuration

of the migrating group

O mCPBA
CHCl 3 O
CH3 CH3
H 0°C H
O