The kinetics and mechanism of acid catalysed hydrolysis of lactams

Abstract

This paper is dedicated to Prof. Raymond U . Lemieux on the occasion of his 60th birthday PETER WAN, TOMASZ A. KEITH YATES. Can. J. Chem. 58,2423 (1980). The acid-catalysed hydrolysis of lactams of ring size 4-7, and of N-ethylacetamide, has been studied at various temperatures in 0-70% aqueous sulfuric acids. The kinetics have been analysed by means of the r-hydration parameter treatment and the transition-state activity coefficient (TSAC) approach. Except for the (3-lactam, all substrates show a strongpos~tiverate dependence on water activity, indicating a tetrahedral intermediate type of mechanism (A82), similar to that found for simple (acyclic) amide hydrolyses; only the (3-lactam shows a negative rate -water activity dependence, which is interpreted in terms of a unimolecular (Aal) mechanism, involving rate-determining acylium ion formation. Similarly, all substrates except the (3-lactam show a pronounced destabilization of the transition-state as ac~dity is increased, typical of oxonium Ion specles. The behaviour of the (3-lactam resembles that of methyl mesitoate hydrolys~s. Basicity constants for lactams of ring size 4-9 show a definite dependence on ring s u e , with the 6-lactam being unusually basic. Both rate and pK dependence on ring size are discussed In terms of ring strain and steric effects. The activat~on parameters, particularly AS*, are fully consistent with the conclus~ons drawn concerning transitionstate hydration.

The hydrolyses of benzamides, methylbenzimidatium ions, and lactams in aqueous sulfuric acid. The excess acidity method in the determination of reaction mechanisms

“…By far the best combination of mechanisms, for compounds 2-6 and 9-12, was found to be an A-2 reaction with 3 H 2 0 in the dilute acid region and another A-2 process, this time using only one H 2 0 , in the more concentrated region, as suggested by the r-plots and in full agreement with the previous proposal for lactam hydrolysis (33). These mechanisms also fitted the experimental data well for benzamide, 1, except in the highly concentrated acid region; it was found that inclusion of a third mechanism, involving one bisulfate ion, produced an excellent fit in this case.…”

“…Data for 9-10, and 11 in the 5-60% and 65-97°C ranges were taken from Wan el al. (33), as were data for 8 between 5% and 46% H,S04 at 33'C and for 12 between 5% and 6Wo at 25°C. The hydrolysis reaction products are detailed in the references cited.…”

“…The AH* of 3 is low compared to 1 and 2, probably because the nonplanarity of 3 (5) enhances the carbon electrophilicity by reducing positive charge delocalization into the phenyl ring. Ring size effects in the lactams have been discussed elsewhere (33).…”

“…the activity coefficients f,,+ and f+ for the protonated amide and for the hydrolysis transition state exactly cancel (6), and if the nucleophile is water, a plot of the left hand side (LHS) against log water activity will be linear with slope r , where r is the number of water molecules involved in the hydroly sis (29). In this case r-plots are curved (25,33,34); for the amides and lactams (excluding 8) they vary from about slope 3 in dilute acid to about slope 1 in more concentrated solutions, and deviate still more in strong acid. Either the molarity-based water activities used in this work (7,8) or the molefraction-based ones used before (25) give essentially the same result.…”

“…1, N-methylbenzamide, 2, and N,Ndimethylbenzamide, 3 (23,25,34), with the corresponding methylbenzimidatium ions used as O-protonated models, 4, 5, and 6 (12); methyl-2,6-dimethylbenzimidatium ion 7 (32), used as a check for S,2 displacement at the 0-methyl group in these ions; and the 4-, 5-, 6-, and 7-membered ring lactams 8, 9, 10, and 11, with the open-chain compound N-ethylacetamide, 12 (33 (8). AS* is easily obtained via AG* = AH* -€)AS*.…”