Ritter Reaction

The Ritter Reaction is the acid-induced nucleophilic addition of a nitrile to a carbenium ion to deliver a N-alkyl amide.

General features:
1. The reaction is used for the preparation of acyclic amides and heterocycles such as lactams.
2. Alcohols that are easily ionized (secondary, tertiary, and benzylic alcohols) give the best results.
3. The nitrile substrate may not contain acid-sensitive functional groups that would be destroyed under the strongly acidic reaction conditions employed. Despite this, a wide range of aliphatic and aromatic nitriles will undergo the reaction.

Reaction mechanism:
1. The hydroxyl group is protonated.
2. The C–O bond is heterolytically cleaved to generate a carbanion.
3. This cation is attacked by the nitrogen of the nitrile to form a nitrilium ion.
4. The nitrilium ion reacts with the conjugate base of the acid to give an imidate.
5. Final hydrolysis produces the amide.

Seminal publications:
1. John J. Ritter and P. Paul Minieri, J. Am. Chem. Soc. 1948, 70, 12, 4045–4048. https://doi.org/10.1021/ja01192a022
2. John J. Ritter and Joseph Kalish, J. Am. Chem. Soc. 1948, 70, 12, 4048–4050. https://doi.org/10.1021/ja01192a023

Additional references:
NROChemistry: https://nrochemistry.com/ritter-react...