Theoretical Study of the Mechanisms of Acid-Catalyzed Amide Hydrolysis in Aqueous Solution

Acid-catalyzed amide hydrolysis is elucidated by means of Car−Parrinello molecular dynamics simulation. The reaction is investigated in aqueous solution. Therein all molecules, including those of the solvent, are treated quantum mechanically. In our simulations N-methylacetamide is taken as a model to describe the amide group of a peptide. The first step in acid-catalyzed amide hydrolysis is the protonation of the carbonyl oxygen atom of the amide group. The rate-determining step is the nucleophilic attack of a water molecule to the carbon atom of the amide group. During this process one proton is transferred to the water phase. In the following, the nitrogen atom of the intermediate is protonated. Finally, the C−N bond is broken, yielding carboxylic acid and methylamine.