KINETICS AND MECHANISM OF HYDROLYSIS OF AMIDALS - THEIR RELATIVE STABILITY COMPARED TO STRUCTURALLY RELATED ACETALS AND ACYLALS

The preparation, kinetics and mechanism of degradation of four amidals (1-4), formed from the reaction of benzamide, N-methylbenzamide, nico tinamide, and N-methylnicotinamide with 3,4-dihydro-2H-pyran, are repo rted. The hydrolyses of the N-methyl amidals 2 and 4 were found to fol low first-order kinetics. The degradation of amidal 2 Was studied in d etail and was catalyzed not only by specific acid catalysis, but also by a general acid catalysis; the second-order rate constant for the in volvement of H3PO4 was about 4 M(-1) h(-1). Amidal 3 was resistant to acid-catalyzed degradation in 0.05 M phosphate buffer at pH 3.0 and 37 degrees C, whereas the phenyl analogue, 1, under similar conditions, exhibited a t(1/2) value of 98.4 days. N-methylation of the carboxamid e moiety in both the phenyl and pyridyl amidals (i.e., 1 and 3, respec tively) had a marked accelerating effect on the rate of hydrolysis, an d this was attributed to the inductive effect of the N-methyl group wh ich stabilizes the proposed transition state in the degradation mechan ism. In acid media, amidals of 3,4-dihydro-2H-pyran were found to hydr olyze much more slowly than acetals and acylals of 3,4-dihydro-2H-pyra n due to the greater stability of the protonated amidal species to uni molecular 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 hydrolyt ic cleavage reaction. The results indicated that the amidals formed fr om carboxamides and 3,4-dihydro-2H-pyran undergo degradation to the pa rent carboxamide via an acid-catalyzed unimolecular mechanism.