On the Mechanism of Base-catalyzed Hydrogen Isotope Exchange in Cyclic Ketones

Abstract

The kinetics of H → D exchange in norcamphor (1) and of D → H exchange in norcamphor-3,3-d2 (6) have been determined. The rate ratio kexo/kendo drops from 661 in H → D exchange to 72 for D → H exchange. These data imply the presence of a dual mechanism for endo exchange and emphasize the importance of isotope effects in dictating exchange selectivity.

Towards a complete account of the mechanism of hydrogen isotope exchange of diastereotopic protons of carbon acids. II. Acid- and base-catalyzed enolization of bicyclo[2.2.1]heptan-2-ones. Evidence for exchange by inversion

“…[6] as the expression for the rate constant for slow H -D exchange.' 'The ratio of 7.2 is somewhat smaller than the ratio of 9.1 reported in our preliminary communication (10). The difference arises from the fact that the ratios were obtained in a slightly different manner.…”

“…A research program was initiated at that time to detail the mechanistic intricacies of hydrogen isotope exchange (enolization) of bicyclic ketones and determine the effect of groups located remote (P or y) from an a enolizable site. A number of papers documenting our work have been published (9)(10)(11)(12)(13)(14)(15)(16). We noted, most importantly, from a study of the stereoselectivity of H -+ D and D -+ H exchange of l a and its 3,3-dideuteriated analog l b , that the k , , , , /k ,.,,, /,, (k,,,,/k , , , , ) ratio decreased from 660 for exchange of l a in deuteriated medium to 72 for exchange of l b in nondeuteriated medium.…”

“…We noted, most importantly, from a study of the stereoselectivity of H -+ D and D -+ H exchange of l a and its 3,3-dideuteriated analog l b , that the k , , , , /k ,.,,, /,, (k,,,,/k , , , , ) ratio decreased from 660 for exchange of l a in deuteriated medium to 72 for exchange of l b in nondeuteriated medium. We pub- (10) of an analysis that established that the difference was due to involvement of an inversion pathway for exchange of the endo (slow) proton (deuteron) at C-3. In this paper we give a complete account of our work on bicycloheptanones l a , l b , l c , and Id, develop equations including primary, secondary, and solvent KlEs (kinetic isotope effects) which relate the observed selectivity to the intrinsic selectivity S, and interpret the difference between (ker,,/kn ,(,,, )H-D and (k ,,,,, /k ,.,,, on the basis of a significant contribution of an inversion pathway to exchange of the slow proton (deuteron) of a diastereotopic pair.…”

Unequal primary kinetic isotope effects in the base-catalysed H–D exchange of diastereotopic protons

“…A special type of internal return has already been proposed independently by two groups. Work by Lamaty (13) and by Banerjee and Werstiuk (14) has clearly established a much greater selectivity in the deuteration of a chiral ketone than in the dedeuteration of the same a,a-dideuterated chiral ketone. Their results and those for ketones 1 and 2 are summarized in Table 3.…”

Base-catalyzed enolization of 2,5-norbornanediones. Evidence for homoenolic assistance

“…As a continuation of our studies (1)(2)(3)(4) designed to detail the i~tricacies of acid-and base-catalyzed enolization, and hydrogen isotope exchange of ketones, we have studied the base-catalyzed hydrogen isotope exchange of 2,5-norbornanedione (2), 3,3-dimethyl-2,5-norbornanedione (3), and 1,3,3-trimethyl-2,5-norbornanedione (4). Specifically, we were interested in establishing whether or not a carbonyl group situated 1,3 from an enolizable site enhances the rate of enolization through ho~noenolic delocalization (5-10) of the developing negative charge.…”