Kinetics and mechanism of hydrolysis of amidals: Their relative stability compared to structurally related acetals and acylals

Abstract

The preparation, kinetics and mechanism of degradation of four amidals (1–4), formed from the reaction of benzamide, N-methylbenzamide, nicotinamide, and N-methylnicotinamide with 3,4-dihydro-2H-pyran, are reported. The hydrolyses of the N-methyl amidals 2 and 4 were found to follow first-order kinetics. The degradation of amidal 2 was studied in detail and was catalyzed not only by specific acid catalysis, but also by a general acid catalysis; the second-order rate constant for the involvement of H 3PO 4 was about 4 M −1h −1. Amidal 3 was resistant to acid-catalyzed degradation in 0.05 M phosphate buffer at pH 3.0 and 37° C, whereas the phenyl analogue, 1, under similar conditions, exhibited a t 1 2 value of 98.4 days. N-methylation of the carboxamide moiety in both the phenyl and pyridyl amidals (i.e., 1 and 3, respectively) had a marked accelerating effect on the rate of hydrolysis, and this was attributed to the inductive effect of the N-methyl group which stabilizes the proposed transition state in the degradation mechanism. In acid media, amidals of 3,4-dihydro-2H-pyran were found to hydrolyze much more slowly than acetals and acylals of 3,4-dihydro-2H-pyran due to the greater stability of the protonated amidal species to unimolecular C-N bond cleavage. Substitution of an N-nicotinoyl group in place of the N-benzoyl moiety in the N-methyl-3,4-tetrahydro-2H-pyran amidal 2 resulted in a much slower rate in the acid-catalyzed hydrolytic cleavage reaction. The results indicated that the amidals formed from carboxamides and 3,4-dihydro-2H-pyran undergo degradation to the parent carboxamide via an acid-catalyzed unimolecular mechanism.