DFT Study of Single and Double Proton Transfer Mechanisms in Schiff Base Formation from 3-Pyridinecarboxaldehyde and...

A comparative density functional theory (DFT) study was performed to elucidate the mechanistic details of Schiff base formation between 3-pyridinecarboxaldehyde and the three positional isomers of aminobenzoic acid (o-, m-, and p-). Both single proton transfer (SPT) and methanol-assisted double proton transfer (DPT) pathways were systematically investigated in the gas phase and within a polarizable continuum model (PCM) for methanol. All stationary points were optimized at the B3LYP/6-31G and 6-311++G(d,p) levels, and transition states were confirmed by vibrational frequency and intrinsic reaction coordinate (IRC) analyses. The results reveal that the DPT mechanism is consistently associated with significantly lower activation free energies compared to the direct SPT pathway, particularly in methanol, where solvent-mediated proton relay markedly stabilizes the transition states. The positional effect of the amino group influences both the electrostatic potential distribution and the activation barriers, with the para isomer exhibiting enhanced nucleophilicity and improved reaction efficiency. These findings provide detailed mechanistic insight into solvent-assisted proton transfer processes in Schiff base synthesis and highlight the cooperative role of hydrogen-bond networks in reducing energetic barriers.