Water-promoted hydrolysis of a highly twisted amide: rate acceleration caused by the twist of the amide bond

The water-promoted hydrolysis of a highly twisted amide is studied using density functional theory in conjunction with a continuum dielectric method to introduce bulk solvent effects. The aim of these studies is to reveal how the twisting of the C-N bond affects the neutral hydrolysis of amides. To do so, both concerted and stepwise mechanisms are studied and the results compared to the ones from the hydrolysis of an undistorted amide used as reference. In addition, an extra explicit water molecule that assists in the required proton-transfer processes is taken into account. Our results predict important rate accelerations of the neutral hydrolysis of amides when the C-N bond is highly twisted, the corresponding barrier relaxation depending on the specific reaction pathway and transition state involved. Moreover, our calculations strongly suggest a change in reaction mechanism with degree of amide bond twist, and clearly point to a concerted mechanism at neutral pH for the hydrolysis of highly twisted amides. In addition, the twisting of the amide bond also provokes a higher dependence on an auxiliary water molecule for the concerted mechanism, due to the orthogonality of the lone pair of the nitrogen and the carbonyl pi orbital. There is a direct implication of these findings for biological catalytic mechanism of peptide cleavage reactions that undergoes ground-state destabilization of the peptide.