Hydrolysis nucleophile isotope effect

In a review of nucleophile isotope effects in chemistry, the hydrolysis of formates was discussed.10 The effect of dioxane on the acid-catalysed hydrolysis of ethyl formate was studied by carrying out the reaction in 0-80% (v/v) dioxane at different temperatures ranging from 20 to 40 °C. It was proposed that up to 1.5 mol of water are associated with the activated complex.11 Kinetic studies of the alkaline hydrolysis of ethyl decanoate12 in DMF-H2O solutions and of ethyl isovalerate13 in aqueous acetone were reported. 

In a review of nucleophile isotope effects, results of studies of the hydrolysis of esters and amides by carboxypeptidase were discussed.10... 

The small solvent isotope effect shows clearly that a proton transfer is not part of the rate-determining step of the hydrolysis. Christensen (1966, 1967) favors an SN2-type mechanism (164) for the hydrolysis, with nucleophilic attack of water on a sulfonyl group synchronous with the departure of ArSO. The alternative formulation (165), however, where a pentacovalent inter-... 

The haloalkane dehalogenase DhlA mechanism takes place in two consecutive Sn2 steps. In the first, the carboxylate moiety of the aspartate Aspl24, acting as a nucleophile on the carbon atom of DCE, displaces chloride anion which leads to formation of the enzyme-substrate intermediate (Equation 11.86). That intermediate is hydrolyzed by water in the subsequent step. The experimentally determined chlorine kinetic isotope effect for 1-chlorobutane, the slow substrate, is k(35Cl)/k(37Cl) = 1.0066 0.0004 and should correspond to the intrinsic isotope effect for the dehalogenation step. While the reported experimental value for DCE hydrolysis is smaller, it becomes practically the same when corrected for the intramolecular chlorine kinetic isotope effect (a consequence of the two identical chlorine labels in DCE). 

The experimental evidence that these reactions do, in fact, represent general base catalysis, rather than nucleophilic catalysis of hydrolysis, is very strong. The solvent deuterium isotope effect of 2-3 (Table 39) is consistent with the breaking of a bond to hydrogen in the rate-determining step of the reaction ... 

For acid-catalyzed hydrolysis of methyl glucosides53 the kinetic isotope effect observed for the oxygen of the leaving group was /c,6()//c18() = 1.024-1.026. Observation of similar effects for enzymes supports the participation of an acidic group of the protein (Glu 35 of lysozyme) in catalysis but does not eliminate the possibility of concerted involvement of a nucleophilic group, e.g., Asp 52 in lysozyme.81 82... 

A review (91 references) on electrophilic and nucleophilic reactions of trivalent phosphorus acid derivatives, reactions of two-coordinate phosphorus compounds, and miscellaneous reactions has appeared.228 Earlier in this review we looked at the heavy-atom isotope effects on reactions of Co(III)-bound /vnitrophenyl phosphate,186 the uranyl ion hydrolysis of /vnitrophcnyl phosphodiesters (218)-(220),190 and the Th(IV) hydrolysis of these.191... 

If hopes were dupes, fears may be liars (Clough, 1855)2 and we now see if we can reconcile the data. Firstly it seems to us that the solvent isotope effect must underestimate the degree of nucleophilic participation. We start by concluding that for the hydrolysis of methyl compounds there is no contribution from 0S2. The evidence for this may be summarized as follows ... 

D. G. Oakenfull, T. Riley, V. Gold, J. Chem. Soc., Chem. Comm. 385 (1966). Nucleophilic and General Base Catalysis by Acetate Ion in Hydrolysis of Aryl Acetates Substituent Effects, Solvent Isotope Effects, and Entropies of Activation. 

It is possible that conjugated enamines such as enaminones hydrolyze by the mechanism shown in Scheme 2, a variation of Scheme 1 in which nucleophilic hydration occurs on an O-protonated enamine rather than on the C-protonated (iminium) ion. This mechanism has been proposed for the acidic hydrolysis of compounds 36 and 37. This mechanism cannot be considered established, however, as the experiments that would rule out C-protonation were not done. It is highly pertinent that hydrolyses of other conjugated enamines, 10,11, 25, 26,39 and 40, all obey the expectations of Scheme 1, equation 15, namely they exhibit general-acid catalysis and (for 25, 26, 39 and 40) primary kinetic solvent isotope effects. 

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