Mechanism of Hydrolysis of N-(1-Aminoalkyl) Amides

Article abstract of DOI:10.1021/ja00405a036

Many of the title compounds (structure 1) are remarkably stable to hydrolysis and can be isolated and characterized.The pH-rate profile for hydrolysis of the title compounds involves plateaus in the acid and base region, with the rate of hydrolysis in the basic region somewhat faster.The compounds hydrolyze to amides, aldehydes, and ammonia; the intermediacy of an imine in the basic region is demonstrated by its trapping with added CN^-.An optically active derivative of 1 hydrolyzes and loses optical activity at about the same rate in both the acidic and basic regions of pH.The reaction is characterized in basic solution by highly positive activation entropies, and alkylation of the amino nitrogen increases the rate significantly.The hydrolysis reaction shows no detectable buffer catalysis at any pH studied.The hydrolysis reaction is very sensitive to the amide leaving group; electron-withdrawing substituents on the amide portion of 1 substantially increase the rate of hydrolysis.The mechanism of hydrolysis in basic solution seems to be best described as a unimolecular solvolysis with an amide anion as a leaving group (Scheme I).In acidic solution the most likely mechanism of hydrolysis (Scheme II) appears to involve the expulsion of an amide enol (imidic acid).The implications of these findings are discussed for situation in which compounds of type 1 have found utility.