Solvent isotope effects inverse

The details of proton-transfer processes can also be probed by examination of solvent isotope effects, for example, by comparing the rates of a reaction in H2O versus D2O. The solvent isotope effect can be either normal or inverse, depending on the nature of the proton-transfer process in the reaction mechanism. D3O+ is a stronger acid than H3O+. As a result, reactants in D2O solution are somewhat more extensively protonated than in H2O at identical acid concentration. A reaction that involves a rapid equilibrium protonation will proceed faster in D2O than in H2O because of the higher concentration of the protonated reactant. On the other hand, if proton transfer is part of the rate-determining step, the reaction will be faster in H2O than in D2O because of the normal primary kinetic isotope effect of the type considered in Section 4.5. 

Values of kH olki3. o tend to fall in the range 0.5 to 6. The direction of the effect, whether normal or inverse, can often be accounted for by combining a model of the transition state with vibrational frequencies, although quantitative calculation is not reliable. Because of the difficulty in applying rigorous theory to the solvent isotope effect, a phenomenological approach has been developed. We define <[), to be the ratio of D to H in site 1 of a reactant relative to the ratio of D to H in a solvent site. That is. 

A similar analysis applies to CBS mutated tetrachlorohydroquinone dehalo-genase but normal rather than inverse solvent isotope effects are involved. This... 

An S Ar (nucleophilic substitution at aromatic carbon atom) mechanism has been proposed for these reactions. Both nonenzymatic and enzymatic reactions that proceed via this mechanism typically exhibit inverse solvent kinetic isotope effects. This observation is in agreement with the example above since the thiolate form of glutathione plays the role of the nucleophile role in dehalogenation reactions. Thus values of solvent kinetic isotope effects obtained for the C13S mutant, which catalyzes only the initial steps of these reactions, do not agree with this mechanism. Rather, the observed normal solvent isotope effect supports a mechanism in which step(s) that have either no solvent kinetic isotope effect at all, or an inverse effect, and which occur after the elimination step, are kinetically significant and diminish the observed solvent kinetic isotope effect. 

Williams and co-workers provided solvent isotope effect data that supported the mechanism of Scheme 4P The rearrangement of N-phenyl-hydroxylamine (pAl = 1.9) in aqueous H2SO4 exhibits an inverse solvent isotope effect at pH > 2 and a normal solvent isotope effect of 1.5 in the plateau region at pH < 1.0. This is expected for the mechanism of Scheme 4... 

Kinetic evidence for the involvement of a-hydroxydialkylnitrosamines (142) in the pH-independent solvolysis of the a-(acyloxy)dialkylnitrosamines (141) has been obtained.120 The aminolysis in benzene of 0-(2,4-dinitrophenyl)-/7,/ -disubstituted benzophenone oximes (143) with pyrrolidine and piperidine are third order in amine.121 Hir st s mechanism involving electrophilic catalysis operates and can explain the various effects observed. The bis(pentamethylphenyl)-A-isopropylketenimine (144) undergoes pre-equilibrium /V-protonation in aqueous acetonitrile followed by water attack. An inverse solvent isotope effect and the observation of the diol (145) confirm this.122... 

The pL (L = H or D) dependence of the solvent DIEs associated with progesterone 493 oxidation to 17a-hydroxyprogesterone 494 and 17-0-acetyltestosterone 495 and 17a-hydroxyprogesterone oxidation to androstenedione 496 has been determined in microcosms from pig testes580 (equation 290). The initial rate of oxidation of 493 to 494 has been associated with the pL-independent inverse solvent isotope effect (SIE) (fce/ D = 0.75 — 0.95 in 30% DOD) while the oxidation of 495 has been associated with the pL-independent positive SIE in 30% DOD (ku/ku of about 2), DOD inhibited the formation of 496 from 444 in noncompetitive in pL-dependent manner. Androgens are synthesized from progesterone in a two-step reaction involving the 17a-hydroxylation... 

The inverse kinetic solvent isotope effects, corresponding to the replacement of H20 by DjO, strongly supports the two-step mechanism (Reitz, 1937 MacTigue and Sime, 1967 Toullec and Dubois, 1974). For example, the isotope effect kH)0 /kDi0+ = 0.54 0.03 observed for acetone enolisation results from opposite effects on the pre-equilibrium C hId/ hIh = 0.37) and on the rate coefficient of the rate-limiting step (k o/k o = 1.45). 

The kinetic solvent isotope effects, h.o/ d,o> range between 2 and 4 in the case of compounds 2 (Noyce et al., 1965, 1967 Noyce and Schiavelli 1968b Noyce and De Bruin, 1968) and between 1-7 and 2 0 in the case of compounds 3 (Stamhuis and Drenth, 1963a Drenth and Hogeveen, 1960). The observed values accord with the idea of a rate-limiting proton transfer to the triple bond a small inverse isotope effect would have been observed in the case of specific acid catalysis (Noyce et al., 1967). 

Inverse solvent isotope effect and an aryl substituent at the electrophilic carbon atom gives the small Positive p value expected for S 2 with an anion. 

Isokinetic relationship, 261, 368 Isokinetic temperature, 368 Isolation technique, 26, 78 Isotope effects inverse, 299 kinetic, 292 primaiy, 293, 295 secondaiy, 298 solvent, 272, 300 Isotopic exchange, 300 Isotopic substitution, 6... 

In these reactions, retention can only be accommodated by formation of a phosphorane intermediate, followed by pseudorotation, before loss of the leaving group. Inversion could result either from a concerted reaction, or a stepwise process, if the phosphorane collapses before pseudorotation can occur. The stereochemical and LFER data indicate that both mechanisms occur. In a study of similar cyclic triesters (Fig. 12c and d) that combined LFER studies, stereochemical analysis, and solvent isotope effects, Rowell and Gorenstein found a trend in / g values as a function of attacking nucleophile.61 These, and the stereochemical data, are strong evidence for a mechanistic continuum from concerted to stepwise reactions of six-membered cyclic phosphate triesters.61... 

Acyl-transfer of j8-lactam and acyclic substrates to active site Ser of the f-lactamase of Enterobacter cloacae P99 occurs with a unique mechanism for nucleophilic activation in which the phenolate of Tyr , stabilized in free enzyme by interaction with both the hydroxyl of Ser and by ionic interaction with protonated Ly , acts as general-base [25]. The unusual hydrogen bonding system which exists in free enzyme is thought to manifest as a ground state fractionation factor that is less than unity and account for the inverse solvent isotope effects around 0.7 that have been observed on kc/Km [25-27]. 

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