PART III NAMED REACTIONS 1 Organic Chemistry 2nd Semester

ARNDT-EISTERT REACTION
Introduction:
Arndt-Eistert reaction is a homologation reaction in which a carboxylic acid is
activated, then, homologated with diazomethane, finally followed by the Wolff-
Rearrangement of the intermediate diazoketone in the presence of a nucleophile and
metal catalyst to produce next higher homologue of carboxylic acid or carboxylic
acid derivative.
The Ardnt-Eistert synthesis is a series of chemical reactions designed to convert a
carboxylic acid to a higher carboxylic homologue. In other words, the homologation
process is used to add an additional carbon atom (methylene unit) onto a carboxylic
acid.
The reaction was reported by German chemists Fritz Arndt and Bernd Eistert in
1935.
Type of Reaction:
 It is a homologation reaction.
 It is a Wolff rearrangement reaction (carbene rearrangement).
Starting Materials:
Carboxylic acid, thionyl chloride, diazomethane and nucleophile such as water,
alcohol, amine or ammonia.

Carboxylic acid

Thionyl chloride

Diazomethane or
PART III NAMED REACTIONS 2 Organic Chemistry 2nd Semester

Nuceophile or

Reaction Conditions:
 Thionyl chloride is required for the activation of starting carboxylic acid.
 Excess amount of dizomethane is used for the conversion of activated carboxylic
acid (acid chloride) to α-diazoketone and to scavenge HCl produced.
 Mild heating or UV light are used for conversion of α-diazoketone to ketene.
 A metal catalyst such as silver oxide (Ag2O) is required for the reaction.
 A nucleophile is required for the conversion of ketene produced during Wolff
rearrangement to final product. Water, alcohols, amines or ammonia may be used
as nucleophile.
 Ether is used as solvent.
Reaction Products:
Next higher homologue of the starting carboxylic acid is obtained when water is
used as nucleophile.
When alcohol is used as a nucleophile, then ester product is obtained. Whereas
amines or ammonia nucleophiles result in amide formation.

Carboxylic acid homologue

Ester derivative of homologue

Amide derivative of homologue

PART III NAMED REACTIONS 3 Organic Chemistry 2nd Semester

General Reaction:
Reaction completes in three phases.

Where,
R = Alkyl or Aryl group.

Reaction Mechanism
Reaction completes in three phases. The mechanism of reaction involves following
steps.

Phase-I: Activation of Carboxylic Acid

Thionyl chloride converts carboxylic acid to acid chloride which is a more reactive
derivative of carboxylic acid (activated carboxylic acid). Several steps are involved
in the mechanism.
PART III NAMED REACTIONS 4 Organic Chemistry 2nd Semester

Phase-II: Formation of α-Diazoketone

Activated carboxylic acid is homologated by diazomethane resulting in formation of
α-diazoketone in following steps.

HCl produced during this process decomposes diazomethane to methyl chloride.

Phase-III: Product Formation

Wolff rearrangement of α-diazoketone leads to ketene formation upon heating,
exposure to UV light or by using Ag2O catalyst. Finally, carboxylic acid homologue
is produced from ketene by its hydrolysis.
PART III NAMED REACTIONS 5 Organic Chemistry 2nd Semester

Examples:
 Homologation of acetic acid

 Homologation of benzoic acid

 Homologation of Amino acid

 Homologation of o-nitro benzoic acid

PART III NAMED REACTIONS 6 Organic Chemistry 2nd Semester

 Homologation of Pivalic acid

 Homologation of cyclohexenylacetic acid

 Homologation of heterocyclic carboxylic acid

Importance/Uses:
 Preparation of Carboxylic Acid Homologues:
Arndt-Eistert reaction is used for homologation of carboxylic acids.
PART III NAMED REACTIONS 7 Organic Chemistry 2nd Semester

 Preparation of Amides and Esters:

This reaction can also be used for preparation of homologated acid derivatives such
as amides and esters.

 Preparation of β-Amino Acids from α-Amino Acids:

This reaction is widely used nowadays for the synthesis of β-amino acids from α-
amino acids. The amino group must be protected by a suitable protecting group
during the reaction such as Boc.

 Pharmaceutical Applications:
This reaction is employed in the synthesis of papaverine (a vasodilator) and
mescaline (causes euphoria).
PART III NAMED REACTIONS 8 Organic Chemistry 2nd Semester

Drawbacks/Limitations:
 Diazomethane is toxic and potentially violently explosive thus limiting its safe
use.
 HCl produced may retard the reaction by reacting with diazoketone to form
chloromethyl ketone and N2. However, this may be avoided by using excess
amounts of diazomethane.