Oxidation of the Side Chain

Alkyl and unsaturated side chains of aromatic rings can be

oxidized to the carboxylic acid using hot KMnO4

 Oxidations of Alkenes: Syn 1,2-Dihydroxylation

Either OsO4 or KMnO4 will give 1,2 diols (glycols)

Mechanism for Syn Hydroxylation of Alkenes

Cyclic intermediates result from reaction of the oxidized metals
The initial syn addition of the oxygens is preserved when the
oxygen-metal bonds are cleaved and the products are syn diols

 Oxidative Cleavage of Alkenes

Reaction of an alkene with hot KMnO4 results in cleavage of
the double bond and formation of highly oxidized carbons
Unsubstituted carbons become CO2, monosubstituted carbons become
carboxylates and disubstituted carbons become ketones

This be used as a chemical test for alkenes in which the purple

color of the KMnO4 disappears and forms brown MnO2 residue
if alkene (or alkyne) is present

 Solved Problem
An unknown alkene with formula C7H12 yields only the
following product on oxidation with hot KMnO4

Answer: Since no carbons are missing in the product, the

alkene must be part of a ring in the original molecule

 Ozonolysis of Alkenes
Cleavage of alkenes with ozone and workup with zinc in acetic
acid leads to less highly oxidized carbons than products from
cleavage with hot KMnO4
Unsubstituted carbons are oxidized to formaldehyde, monosubstituted
carbons are oxidized to aldehydes and disubstituted carbons are
oxidized to ketones

 Ozone adds across the double bond to form the initial

ozonide which rearranges to a highly unstable ozonide
The ozonides react with zinc and acetic acid to effect the cleavage

 Oxidative Cleavage of Alkynes

Reaction of alkynes with ozone or basic potassium
permanganate both lead to formation of carboxylic
acids

 Oxidation-Reduction Reactions in Organic Chemistry

Reduction: increasing the hydrogen content or decreasing the
oxygen content of an organic molecule
A general symbol for reduction is [H]

Oxidation: increasing the oxygen content or decreasing the hydrogen

content of an organic molecule
A general symbol for oxidation is [O]
Oxidation can also be defined as a reaction that increases the content of any
element more electronegative than carbon

 Alcohols by Reduction of Carbonyl Compounds

A variety of carbonyl compounds can be reduced to alcohols

Carboxylic acids can be reduced to primary alcohols

These are difficult reductions and require the use of powerful reducing
agents such as lithium aluminum hydride (LiAlH4 also abbreviated LAH)

 Esters are also reduced to primary alcohols

LAH or high pressure hydrogenation can accomplish this transformation

Aldehydes and ketones are reduced to 1o and 2o alcohols

respectively
Aldehydes and ketones are reduced relatively easily; the mild reducing agent
sodium borohydride (NaBH4) is typically used
LAH and hydrogenation with a metal catalyst can also be used

 The key step in the reduction is reaction of hydride with the carbonyl
carbon

Carboxylic acids and esters are considerably less reactive to

reduction than aldehydes and ketones and require the use of LAH

Lithium aluminium hydride is very reactive with water and must be

used in an anhydrous solvent such as ether
Sodium borohydride is considerably less reactive and can be used in
solvents such as water or an alcohol

 Oxidation of Alcohols
Oxidation of Primary Alcohols to Aldehydes
A primary alcohol can be oxidized to an aldehyde or a carboxylic acid
The oxidation is difficult to stop at the aldehyde stage and usually proceeds to
the carboxylic acid

A reagent which stops the oxidation at the aldehyde stage is

pyridinium chlorochromate (PCC)
PCC is made from chromium trioxide under acidic conditions
It is used in organic solvents such as methylene chloride (CH2Cl2)

 Oxidation of Primary Alcohols to Carboxylic Acids

Potassium permanganate (KMnO4) is a typical reagent used for
oxidation of a primary alcohol to a carboxylic acid
The reaction is generally carried out in aqueous solution; a brown precipitate
of MnO2 indicates that oxidation has taken place

Oxidation of Secondary Alcohols to Ketones

Oxidation of a secondary alcohol stops at the ketone
Many oxidizing agents can be used, including chromic acid (H2CrO4)
and Jones reagent (CrO3 in acetone)

 Mechanism of Chromate Oxidation

Step 1: A chromate ester is formed from the alcohol hydroxyl
Step 2: An elimination reaction occurs by removal of a hydrogen
atom from the alcohol carbon and departure of the chromium group
with a pair of electrons.

 Aldehydes form hydrates in water

An aldehyde hydrate can react to form a chromate ester which can
subsequently undergo elimination to produce a carboxylic acid

Pyridinium chlorochromate reactions are run in anhydrous

methylene chloride and the aldehyde cannot form a hydrate
The oxidation of a primary alcohol therefore stops at the aldehyde stage

Tertiary alcohols can form the chromate ester but cannot eliminate
because they have no hydrogen on the alcohol carbon
Tertiary alcohols are therefore not oxidized by chromium based reagents

 A Chemical Test for Primary and Secondary Alcohols

Chromium oxide in acid has a clear orange color which changes
to greenish opaque if an oxidizable alcohol is present

 Synthesis of Aldehydes
Aldehydes by Oxidation of 1o Alcohols
Primary alcohols are oxidized to aldehydes by PCC

Aldehydes by Reduction of Acyl Chlorides,

Esters and Nitriles
Reduction of carboxylic acid to aldehyde is
impossible to stop at the aldehyde stage
Aldehydes are much more easily reduced than carboxylic
acids

 Reduction to an aldehyde can be accomplished by using a

more reactive carboxylic acid derivatives such as an acyl
chloride, ester or nitrile and a less reactive hydride source
The use of a sterically hindered and therefore less reactive aluminum
hydride reagent is important

Acid chlorides react with lithium tri-tert-butoxyaluminum

hydride at low temperature to give aldehydes

 Hydride is transferred to the carbonyl carbon

As the carbonyl re-forms, the chloride (which is a good
leaving group) leaves

 Reduction of an ester to an aldehyde can be

accomplished at low temperature using DIBAL-H
As the carbonyl re-forms, an alkoxide leaving group
departs

 Oxidation of Aldehydes and Ketones

Aldehydes are generally much more easily oxidized than
ketones

The Baeyer-Villiger Oxidation of Aldehydes and Ketones

The Baeyer-Villeger reaction results in insertion of an oxygen
atom adjacent to a ketone or aldehyde carbonyl
Oxidation of a ketone yields an ester
A peroxyacid such as m-chloroperbenzoic (MCPBA) acid is used

 The migratory aptitude of a group attached to a carbonyl is

H > phenyl > 3o alkyl > 2o alkyl > 1o alkyl > methyl

 Chemical Analysis of Aldehydes and Ketones

Tollens Test (Silver Mirror Test)
Aldehydes and ketones can be distinguished from each other
on the basis of the Tollens test
The presence of an aldehyde results in formation of a silver mirror (by
oxidation of the aldehyde and reduction of the silver cation)
a-Hydroxyketones also give a positive Tollens test

 Synthetic Applications of Friedel-Crafts Acylations:

The Clemmensen Reduction
Primary alkyl halides often yield rearranged products in FriedelCrafts alkylation which is a major limitation of this reaction
Unbranched alkylbenzenes can be obtained in good yield by
acylation followed by Clemmensen reduction
Clemmensen reduction reduces phenyl ketones to the methylene (CH2) group

 This method can be used to add a ring to an

aromatic ring starting with a cyclic anhydride
Note that the Clemmensen reagents do not reduce the
carboxylic acid

 Preparation of Aromatic Amines by Reduction of Nitro

Compounds
Aromatic amines can be synthesized by reduction of the
corresponding nitro compound

One molar equivalent of hydrogen sulfide in alcoholic ammonia can

be used to reduce one nitro group in the presence of another

 Preparation of Primary, Secondary and Tertiary Amines

through Reductive Amination
Aldehydes and ketones react with ammonia, primary or secondary
amines to yield imines or iminium ions
The imines and iminium ions can then be reduced to new primary, secondary or
tertiary amines, respectively

 The reduction can be accomplished using catalytic

hydrogenation or a hydride reducing reagent
NaBH3CN and LiBH3CN are especially effective in
reductive aminations

 Preparation of Primary, Secondary, or Tertiary Amines

through Reduction of Nitriles, Oximes, and Amides
Reduction of nitriles or oximes yield primary amines
Reduction of amides can yield primary, secondary or tertiary
amines

 Reduction can be accomplished by using catalytic

hydrogenation or LiAlH4

Monoalkylation of an amine can be achieved by acylation of

the amine and then reduction of the resulting amide