On the role of water in amide hydrolysis

The mechanism of the water-assisted amide hydrolysis of N-methylacetamide has been elucidated by Car-Parrinello simulation and related to prior investigations of the acid- and the base-catalyzed pathways. Each process was investigated in aqueous solution, and the water molecules were found to play a crucial role in the amide hydrolysis, with several reaction steps involving proton-transfer events in which the water molecules serve as donors or acceptors. This calls for a quantum treatment of all electronic degrees of freedom, including those of the solvent molecules. A detailed analysis of the mechanisms of the amide hydrolysis pathways obtained from our simulations is given.