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

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.