Eschweiler-Clarke reaction

Also known as: Eschweiler-Clarke methylation or reductive alkylation

Schematic of the Eschweiler-Clarke reaction. Reagents: primary or secondary amine, formaldehyde, formic acid. Product: tertiary amine.

The Eschweiler-Clarke reaction is an organic reaction used to convert a primary or secondary amine to a tertiary amine using formaldehyde and formic acid. This is essentially an amine methylation process which begins with the reaction of the amine starting material with the protonated formaldehyde to provide an intermediate iminium ion. The iminium ion then reacts with the formic acid to give a methylated ammonium ion and release carbon dioxide gas which drives the process forward. Deprotonation of the ammonium ion affords the final methylated amine product. In the case of primary amine starting materials, these steps repeat twice to give the tertiary amine final product.[1][2]


Mechanism of the Eschweiler-Clarke reaction.


Eschweiler, W. Ber. Dtsch. Chem. Ges. 1905, 38, 880–882.
Clarke, H. T.; Gillespie, H. B.; Weisshaus, S. Z. J. Am. Chem. Soc. 1933, 55, 4571–4587.

Other Alkylation Reactions: