Mechanisms of Acid-Catalyzed Proton Exchange in N-Methyl Amides

Article abstract of DOI:10.1021/ja00388a036

Kinetics of acid-catalyzed proton exchange in an extensive series of N-methyl amides, RCONHCH3, were followed by NMR line-shape analysis in aqueous solution.Electron-withdrawing substituents retard the reaction, but the only good correlation is between log k_H+ for substituted N-methyl acetamides and the pK_a of the corresponding RCOOH.The correlation shows a change in slope, from 0.43 for amides with electron-withdrawing substituents to ca. 1.84 for other amides.This change is taken as evidence for a changeover from the imidic acid mechanism to the N-protonation mechanism.In particular, it is concluded that peptides and proteins represent amides with electron-withdrawing substituents, so that the NH protons of their backbone exchange predominantly via the imidic acid.The difference in slopes and the changeover in mechanism, as well as the comparison between primary and secondary amides, are rationalized in terms of substituent effects and transition-state structures.