Ab initio molecular orbital study on the mechanism of amide hydrolysis dependent on leaving groups.

The alkaline hydrolysis of amides, N-methyl acetamide 1, acetanilide 2, and N-acetyl imidazole 3, was investigated by use of ab initio molecular orbital calculations. A detailed analysis was performed for two possible mechanisms, Path 1 and 2. Path 1, similar to ester hydrolysis, releases CH,COOH and RNH whereas Path 2 contains the RNH group that extracts the H atom from the OH fragment in the tetrahedral intermediate. In this mechanism, carboxylate ion and an amine directly form. It was ascertained that Path 2 is a better route to decompose the TD intermediate than Path 1 for 1 and 2 in the gas phase. The stability of the leaving group RNH determines which route, Path 1 or 2, is preferred in the gas phase. The solvent effect was estimated for the two mechanisms by using the SCRF calculations of the IPCM model. (C) 1997 Elsevier Science Ltd.