Esters oxygen isotope exchange

Esters can be hydrolyzed nonenzymatically in acidic and alkahne solutions. In both cases, a tetrahedral intermediate is indicated on the basis of the measured rates of hydrolysis and the rates of oxygen isotope exchange. 

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). 

Another example is the absence of oxygen exchange with solvent in the hydrolysis of gluconolactone. Simple acyclic esters usually undergo isotopic exchange at a rate that is conqietitive with hydrolysis. This occurs through the tetrahedral addition intermediate. 

If the reaction is carried out in water enriched in the heavier oxygen isotope 180, (a) will lead to an alcohol which is 180 enriched and an acid which is not, while (b) will lead to an l80 enriched acid but a normal alcohol. Most simple esters are in fact found to yield an lsO enriched acid indicating that hydrolysis, under these conditions, proceeds via (b) acyl/oxygen fission (p. 238). It should of course be emphasised that these results are only valid provided that neither acid nor alcohol, once formed, can itself exchange its oxygen with water enriched in 180, as has indeed been shown to be the case. 

Probably the most widely cited evidence for the existence of a tetrahedral intermediate comes from isotopic exchange reactions. For example, in the reaction of a carboxylic acid derivative, such as an ester, the two OH groups in the tetrahedral intermediate are equivalent (examine the T.L in Scheme 10.22). If the reaction were performed in 0-labeled water, one of these OH groups would be isotopically labeled. Reversal of the nucleophilic addition step would exchange the 0 into the carbonyl oxygen 50% of the time. As the reaction proceeds... 

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... 

Bender104 found that when ethyl benzoate, labelled with excess, sO in the carbonyl group, is hydrolyzed at 99°C in isotopically normal aqueous 1 M acid, oxygen exchange between the unreacted ester and the solvent takes place, and the enrichment of the remaining ester decreases steadily as hydrolysis proceeds. This is precisely the result expected if hydrolysis involves a full intermediate and the addition elimination mechanism receives further support from the observation that hydrolysis and exchange proceed at similar rates, with a constant ratio, Arhyd/)tex of 5.2 for ethylbenzoate. The reaction can thus be written as... 

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