The mechanism of alkaline hydrolysis of amides: a comparative computational and experimental study of the hydrolysis of N-methylacetamide, N-methylbenzamide, and acetanilide

Theoretical computations and experimental kinetic measurements were applied in studying the mechanistic pathways for the alkaline hydrolysis of three secondary amides: N-methylbenzamide, N-methylacetamide, and acetanilide. Electronic structure methods at the HF/6-31+G(d,p) and B3LYP/6-31+G(d,p) levels of theory are employed. The energies of the stationary points along the reaction coordinate were further refined via single point computations at the MP2/6-31+G(d,p) and MP2/6-311++G(2d,2p) levels of theory. The role of water in the reaction mechanisms is examined. The theoretical results show that in the cases of N-methylbenzamide and N-methylacetamide the process is catalyzed by an ancillary water molecule. The influence of water is further assessed by predicting its role as bulk solvent. The alkaline hydrolysis process in aqueous solution is characterized by two distinct free energy barriers: the formation of a tetrahedral adduct and its breaking to products. The results show that the rate-determining stage of the process is associated with the second transition state. The entropy terms evaluated from theoretical computations referring to gas-phase processes are significantly overestimated. The activation barriers for the alkaline hydrolysis of N-methylbenzamide and acetanilide were experimentally determined. Quite satisfactory agreement between experimental values and computed activation enthalpies was obtained. Copyright (C) 2008 John Wiley & Sons, Ltd.