N-Protonation vs O-Protonation in Strained Amides: Ab Initio Study

Protonation plays an important catalytic role in amide bond hydrolysis. Although the protonation site of an amide is still debatable, O-protonation is generally preferred to N-protonation in ordinary amides. However, N-protonation can be favored in strained molecular systems. To investigate this strain effect systematically, we studied formamide, strained N-formylazetidine, and highly strained N-formylaziridine using ab initio calculations. The electron correlation effect is found to be important in determining the protonation sites of strained amides, since it contributes to stabilize N-protonation somewhat more than O-protonation. Although O-protonation is highly favored in N-formylazetidine as well as in formamide, N-protonation is favored in N-formylaziridine in both aqueous and gas phases. In case of O-protonation, the geometries become planar even for highly strained amides. The presence of polar solvents contributes to stabilize N-protonation more than O-protonation. The planarity found in O-protonated strained amides and the nonplanarity in N-protonated strained amides would have an important bearing in enzymatic reactions as well as in asymmetric syntheses.