Carboxylic Acid Participation in Amide Hydrolysis. Evidence That Separation of a Nonbonded Complex Can Be Rate Determining

Article abstract of DOI:10.1021/ja00374a032

Maleamic acids derived from aliphatic amines of a wide range of basicity (compounds 1-8) undergo hydrolysis in solutions of acidity between 1E-4 M and 1 M hydrogen ion concentration by a mechanism involving participation of the carboxyl group at the adjacent amide.Kinetic analysis of the reaction (50 deg C) reveals that the identity of the rate-determining step (or steps) is a function of both the basicity of the leaving group and the acidity of the solution.At pH 4, the rate-determining step is O to N proton transfer to form a zwitterionic intermediate for compounds with weakly basic leaving groups.For compounds with more basic leaving groups, conversion of the zwitterionic intermediate to products is rate determining.In more acidic solutions, where proton transfer is facilitated, diffusion apart from the complex formed from C-N bond breakage of the zwitterionic intermediate is rate determining for compounds with the most basic leaving groups.C-N bond breakage is rate determining for compounds with the least basic leaving groups.This suggests that at pH 4 the breakdown of the zwitterion may also involve rate-determining diffusion.It is concluded that other facile elimination reactions may involve rate-determining diffusion and that changes in the rate-determining step can serve as an indicator of its occurrence and as a means of calibration of rate constants.It is also suggested that since pepsin may catalyze peptide hydrolysis by a carboxyl-participation mechanism, the occurrence of sequential covalent intermediates may exist to permit diffusion of the noncovalently held products.