Mechanistic insights into l-proline-catalyzed transamidation of carboxamide with benzylamine from density functional theory calculations

Abstract

The mechanism of the transamidation reaction between carboxamides and benzylamine catalysed by L-proline in toluene was investigated using density functional theory (DFT) at the M06/SMD/6-311+G(2d,p)//M06/6-31+G(d,p) level. The calculations reveal that the reaction proceeds through a stepwise mechanism, in which the L-proline acts as a Lewis base to activate acetamide. The hydrolysis step is predicted to be the rate-determining step (RDS) in the reaction with an energy barrier of 26.0 kcal mol⁻¹. The comparison of the catalytic effect between the acetamide with benzylamine in three different solvents including toluene, EtOH, and H₂O, suggests that toluene exhibits higher catalytic efficiency for the transamidation, and less polar solvents are favourable for the reaction, which is in good agreement with the experimental observations.