Analyzing the efficiency in intramolecular amide hydrolysis of Kirby’s N-alkylmaleamic acids – A computational approach

A mechanistic study using DFT calculation methods at B3LYP/6-31G (d,p), B3LYP/311+G (d,p) levels and hybrid GGA (MPW1k) on an intramolecular acid catalyzed hydrolysis of maleamic (4-amino-4-oxo-2-butenoic) acids (Kirby’s N-alkylmaleamic acids) 1–7 confirmed that the reaction proceeds in three steps: (1) proton transfer from the carboxylic group to the adjacent amino carbonyl carbon, (2) nucleophilic attack of the carboxylate anion onto the protonated carbonyl carbon; and (3) dissociation of the tetrahedral intermediate to provide products. Furthermore, the calculation results indicate that the rate-limiting step is dependent on the reaction medium. When the calculations were run in the gas phase the rate-limiting step was the nucleophilic attack of the carboxylate anion to form the tetrahedral intermediate, whereas when the calculations were conducted in the presence of a cluster of water the dissociation of the tetrahedral intermediate was the rate-limiting step. When the leaving group (CH3NH2) in 1–7 was replaced with a group having a low pKa value (such in 10) the rate-limiting step of the hydrolysis in water was the formation of the tetrahedral intermediate. In addition, the calculations demonstrate that the efficiency of the intramolecular acid-catalyzed hydrolysis by the carboxy group is remarkably sensitive to the pattern of substitution on the carbon–carbon double bond. The rate of hydrolysis was found to be linearly correlated with the strain energy of the tetrahedral intermediate or the product. Systems having strained tetrahedral intermediates or products experience low rates and vice versa.