Question

2-Phenylindole is prepared from the reaction of acetophenone and phenylhydrazine, a method known as the Fischer indole synthesis. Propose a mechanism for this reaction. (Hint: the reactive intermediate is the enamine tautomer of the phenylhydrazone.)

Short answer

Mechanism of Fischer indole synthesis

Step-by-step solution

Hydrazines

Hydrazines are also called diamines and contain two nitrogen atoms connected by a single bond. The chemical formula for a hydrazine is N₂H₄. Hydrazine is a strong base and is highly unstable.

Hydrazine is an inorganic compound and the hydrogen atoms of hydrazine can be replaced with phenyl groups to obtain phenyl hydrazine used in organic synthesis. Phenyl hydrazines react with carbonyl compounds like aldehydes and ketones to form a –C=N bond removing water. The product is called as a hydrazone.

Fischer indole synthesis

Indole is a compound that contains a benzene ring fused to a pyrrole ring at two carbons. The final product of Fischer indole synthesis is indole.

Fischer indole synthesis occurs between a carbonyl compound and a phenylhydrazine. The hydrazone thus formed undergoes an intramolecular cyclization to form the indole.

Mechanism of the given reaction

The first step is the condensation reaction between the ketone and the phenylhydrazine, forming a hydrazone. An intramolecular rearrangement takes place in the hydrazone so that the aromaticity of the benzene ring is lost.

To restore the aromaticity, beta elimination is carried out to form substituted aniline. Another intramolecular rearrangement causes the formation of a five-membered ring. The deprotonation of the amine group stabilizes the compound.

A proton abstraction and subsequent rearrangement cause the removal of the amine group in beta elimination, forming indole.

Mechanism of Fischer indole synthesis