Theoretical study of base-catalyzed amide hydrolysis: Gas- and aqueous-phase hydrolysis of formamide

Base-catalyzed hydrolysis of formamide in the gas phase and in aqueous solu tion has been studied using a combination of quantum chemical and statistic al mechanical methods. A three-step procedure has been applied which compri ses the determination of a gas-phase reaction path by high-level ab initio calculations, the calibration of empirical solute-solvent potentials, and c lassical Monte Carlo simulations of the solute immersed in a bath of solven t molecules. These simulations yield the solvent effect as a potential of m ean force along the predetermined reaction coordinate. Each of the three co nsecutive steps of base-catalyzed hydrolysis has been analyzed in detail: t he formation of a tetrahedral intermediate, its conformational isomerizatio n, and the subsequent breakdown to products. The reaction is very exothermi c in the gas phase and involves only moderate barriers for the latter two s teps. Aqueous solvent, however, induces a significant barrier toward format ion of the intermediate. On the other hand, it also facilitates conformatio nal isomerization and produces a more product-like transition state for the breakdown step. Solvent effects, as expressed by differences in free energ y of solvation, are found to reflect variations in the solute's charge dist ribution and are readily explained by the analysis of hydrogen bond pattern s. The calculated free energy profile is in satisfactory agreement with ava ilable experimental data for the solution-phase reaction.