Isotope effects nucleophilic reactions

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... 

TABLE 1. Isotope effects for reactions of alkyl halides with nucleophiles... 

A number of very interesting conclusions are arrived at in this study.86 (1) Reaction of hydroxide ion as a base on carbocation 77 to form epoxide (k 2[HO-]) is energetically more favorable than its reaction with 77 as a nucleophile to form diols. (2) The reaction pathway for formation of ketone 128 is completely separate from the stepwise mechanism for diol formation. (3) The observed kinetic deuterium isotope effect for reaction of 76-f>-d at pH 11 is 2.15 the kinetic deuterium isotope effect on the 1,2-hydrogen migration is estimated to be 4. Hydrogen migration must be occurring at the transition state for ketone formation. 

Secondary isotope effects at the position have been especially thoroughly studied in nucleophilic substitution reactions. When carbocations are involved as intermediates, substantial /9-isotope effects are observed. This is because the hyperconjugative stabliliza-... 

However, measurements of substituent effects supported the hypothesis that the aryl cation is a key intermediate in dediazoniations, provided that they were interpreted in an appropriate way (Zollinger, 1973a Ehrenson et al., 1973 Swain et al., 1975 a). We will first consider the activation energy and then discuss the influence of substituents, as well as additional data concerning the aryl cation as a metastable intermediate (kinetic isotope effects, influence of water acitivity in hydroxy-de-di-azoniations). Finally, the cases of dediazoniation in which the rate of reaction is first-order with regard to the concentration of the nucleophile will be critically evaluated. 

If one limits the consideration to only that limited number of reactions which clearly belong to the category of nucleophilic aromatic substitutions presently under discussion, only a few experimental observations are pertinent. Bunnett and Bernasconi30 and Hart and Bourns40 have studied the deuterium solvent isotope effect and its dependence on hydroxide ion concentration for the reaction of 2,4-dinitrophenyl phenyl ether with piperidine in dioxan-water. In both studies it was found that the solvent isotope effect decreased with increasing concentration of hydroxide ion, and Hart and Bourns were able to estimate that fc 1/ for conversion of intermediate to product was approximately 1.8. Also, Pietra and Vitali41 have reported that in the reaction of piperidine with cyclohexyl 2,4-dinitrophenyl ether in benzene, the reaction becomes 1.5 times slower on substitution of the N-deuteriated amine at the highest amine concentration studied. 

The observed normal isotope effect of 1.9 provides further evidence supporting the role of Asp55 as the general base. Namely, a normal isotope effect of 1.9 is most consistent with general base catalysis by an amino acid side chain, as inverse isotope effects are commonly observed when a zinc-bound water molecule, or hydroxide, is the attacking nucleophile. For example, the zinc-containing enzymes AMP deaminase [111], thermolysin [112], stromelysin [113], and a desuccinylase [114] are each believed to utilize a zinc-bound water as the nucleophile, and all of these reactions are characterized by an inverse deuterium isotope effect. This inverse isotope effect is thought to result from a dominant... 

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