Isotopes ester hydrolysis

In an extension of the work described m the preceding section Bender showed that basic ester hydrolysis was not concerted and like acid hydrolysis took place by way of a tetrahedral intermediate The nature of the experiment was the same and the results were similar to those observed m the acid catalyzed reaction Ethyl benzoate enriched m 0 at the carbonyl oxygen was subjected to hydrolysis m base and samples were isolated before saponification was complete The recovered ethyl benzoate was found to have lost a por tion of Its isotopic label consistent with the formation of a tetrahedral intermediate... 

This variation from the ester hydrolysis mechanism also reflects the poorer leaving ability of amide ions as compared to alkoxide ions. The evidence for the involvement of the dianion comes from kinetic studies and from solvent isotope effects, which suggest that a rate-limiting proton transfer is involved. The reaction is also higher than first-order in hydroxide ion under these circumstances, which is consistent with the dianion mechanism. 

We said in Section 21.6 that mechanistic studies on ester hydrolysis have been carried out using ethyl propanoate labeled with lsO in the etherlike oxygen. Assume that Odabeled acetic acid is your only source of isotopic oxygen, and then propose a synthesis of the labeled ethyl propanoate. 

This is the same mechanism as that given above for esters, in equation (42). The difference between esters and amides is apparent from a comparison of the two tetrahedral intermediates [5] and [17], The former contains three oxygens, any of which can be protonated, resulting in much lsO exchange being observed when the reaction takes place in 180-enriched water,275,276 but [17] contains a much more basic nitrogen, which will be protonated preferentially and lead to much less 180 exchange, as observed.274 277,278 Also, ammonium ion formation makes the overall reaction irreversible, unlike ester hydrolysis. The calculated solvent isotope effect for the Scheme 15 process is 1.00,280 exactly in accord with experimental observation.278,279... 

Enzyme action, discovery of the mechanisms of, 1947-1963, 21, 1 Equilibrating systems, isotope effects on nmr spectra of, 23, 63 Equilibrium constants, N.M.R. measurements of, as a function of temperature, 3,187 Ester hydrolysis, general base and nucleophilic catalysis, 5, 237 Exchange reactions, hydrogen isotope, of organic compounds in liquid ammonia, 1, 156... 

This is the general mechanism for acid catalyzed oxygen isotope exchange of carboxylic acids and esters, esterification, ester hydrolysis, and amide hydrolysis (see Vol. 10). 

The neutral or uncatalyzed hydrolysis of carboxylic acid derivatives has two very interesting characteristics (1) large negative entropies of activation, and (2) fairly substantial solvent isotope effects. Hydrolysis of carboxylic ester derivatives then must be quite different at the molecular level from hydrolysis of saturated carbon derivatives which... 

Because transition states may have lifetimes of only several nanoseconds, in most cases, it is impossible to observe them directly. However, there are numerous lines of evidence for the existence of a tetrahedral-like transition state for non-enzymatic ester hydrolysis a) substitution at a carbonyl group (as is the case of the hydrolysis of esters) most often proceeds by a tetrahedral mechanism, a second-order addition-elimination (for a review of this mechanism, see (23)) b) the kinetics are pseudo-first order either in the substrate or in the nucleophile, as predicted by the mechanism c) for the 180 labeled esters, the 180 isotope is detectable in both products (in a "normal" Sjj2 reaction all the 180 isotopes should remain in the acid functionality)(24) d) in a few cases tetrahedral intermediates have been isolated or detected spectrally (25). 

The most important species in the mechanism for ester hydrolysis is the tetrahedral intermediate. Evidence in support of the existence of the tetrahedral intermediate was developed by Professor Myron Bender on the basis of isotopic labeling experiments he carried out at the University of Chicago. Bender prepared ethyl benzoate, labeled with the mass-18 isotope of oxygen at the carbonyl oxygen, then subjected it to acid-catalyzed hydrolysis in ordinary (unlabeled) water. He found that ethyl benzoate, recovered from the reaction before hydrolysis was complete, had lost a portion of its isotopic label. This observation is consistent only with the reversible formation of a tetrahedral intermediate under the reaction conditions ... 

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