DFT Studies on Schiff Base Formation of Vitamin B6 Analogues. Reaction between a Pyridoxamine-Analogue and Carbonyl Compounds

A comprehensive theoretical study based on density functional theory calculations (B3LYP and M06−2X functionals) of the formation of Schiff bases of pyridoxamine analogues with two different aldehydes was conducted. The reaction mechanism was found to involve two steps, namely: (1) formation of a carbinolamine and (2) dehydration of the carbinolamine to give the final imine. Also, consistent with available experimental evidence, the carbinolamine dehydration was the rate-determining step of the process determined by means of M06−2X functional. Using an appropriate solvation method and reactant conformation ensures that all proton transfers involved will be intramolecular, which substantially reduces energy barriers and facilitates reaction in all cases. The formation of a Schiff base between pyridoxal 5-phosphate (PLP) and an amine or amino acid requires the contribution of an external water molecule in order to facilitate proton transfers. On the other hand, the formation of a Schiff base between pyridoxamine 5-phosphate (PMP) and a carbonyl compound requires no external aid since the spatial arrangement of the functional groups in PMP ensures that all proton transfers will be intramolecular.