Diminished isotope effects

Interestingly, in a comparison of the CD3 and CHj carbenes, an unusual temperature dependence of the kinetic isotope effect was observed. In contrast to typical reactions, the ratio of rates of H versus D shift, k /ko, actually increased as temperature was raised. In fact, k was measured to be larger than k at 248 K. It was suggested that these results required a normal temperature dependence of the isotope effect for the classical component of the reaction, but an unusual diminished isotope effect for the QMT reaction. 

The determination of the intrinsic isotope effect is based on the Swain-Schaad relationship (Eq. (17.2)). For diminished isotope effects, a fixed relationship between deuterium and tritium is maintained,... 

Stabilization of a carbocation intermediate by benzylic conjugation, as in the 1-phenylethyl system shown in entry 8, leads to substitution with diminished stereosped-ficity. A thorough analysis of stereochemical, kinetic, and isotope effect data on solvolysis reactions of 1-phenylethyl chloride has been carried out. The system has been analyzed in terms of the fate of the intimate ion-pair and solvent-separated ion-pair intermediates. From this analysis, it has been estimated that for every 100 molecules of 1-phenylethyl chloride that undergo ionization to an intimate ion pair (in trifluoroethanol), 80 return to starting material of retained configuration, 7 return to inverted starting material, and 13 go on to the solvent-separated ion pair. 

The values of kH/kD for the uncatalysed and catalysed reactions were 4.36 and 4.47 respectively, yet the isotope effect is not necessarily diminished on reducing the concentration of iodide ion to zero and by the arguments elaborated above (p. 95) this implies that molecular iodine is not the iodinating species and that this species is formed in some pre-equilibrium, the function of the base being to form the species and not to remove the proton. This argument assumes, as does the previous discussion of the effect of iodide ion concentration on isotope effects, that a minute concentration of I- is insufficient to compete effectively with the reaction involving proton loss. 

The principal goal of most studies of kinetic isotope effects on enzymatic reactions is to deduce intrinsic rate constants, which, in turn, can be correlated with the geometric features, that is the structure, of the corresponding transition states. Formal kinetics provides several options for reaching this goal. For example, as we have seen above, changes in concentration can diminish the commitment to the point where the KIE experimental value corresponds directly to the intrinsic kinetic... 

If the isotope sensitive step is reversible the equations get more complicated and cannot be solved explicitly for the intrinsic isotope effects (unless Cf = 0, or the equilibrium isotope effect is unity). The last two equations in Equation 11.48 demonstrate that a normal deuterium kinetic isotope effect diminishes the apparent commitment if both isotopes are present. Thus 13(V/K) is smaller than 13(V/K)d when both isotope effects are related to the same step. 

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. 

In the case of oxalic acid dihydrate the isotope effect has diminished by 7 per cent on lowering the temperature from 293°K to 90°K. At room temperature a certain proportion of the hydrogen or deuterium atoms are excited to the first energy level more than 99 per cent of these are promoted in the temperature range of 90°K to 300°K, so that at 90°K thermal effects will have almost completely disappeared and the isotope effect at 0°K should be substantially the same as at 90°K. The expansion in oxalic acid dihydrate must, therefore, be a Kero point energy phenomenon. The reversal of the expansion to a contraction in ice will be discussed later. 

As outlined above, the process of substitution by the nitronium ion is satisfactorily described by an SE2 mechanism in which k2 E > k v In certain circumstances the process could be changed so that this condition did not hold, and the step in which the proton is lost could become kinetically important. One such circumstance is that in which the hydrogen atom being replaced is situated between bulky substituents steric hindrance would then make it difficult for the nitro group to move from its position in the intermediate complex to that between the bulky substituents k2 would be diminished, and a kinetic isotope effect might appear. It is for this reason that 1,3,5-tri-f-butylbenzene and its derivatives are interesting (table 6.1) whilst the hydrocarbon undergoes... 

The second isotope effect, 8R, requires the proton and deuteron to be accurately located. The distance between the equilibrium positions of the potential energy well of double minima, symmetrical hydrogen bonds, which Ichikawa calls RH/H, is defined as RH/H = R0 0 - 2POH. This distance can be calculated from neutron-diffraction data and it decreases as Rq. 0 diminishes. Early work suggested a smooth transition over the whole range down to 245 pm, although with an inflection point at ca. 260 pm (Ichikawa, 1978a). 

Isotope effects are useful in determining chemical mechanisms. In an oxidative decarboxylation where a hydride ion is removed from one carbon and CO2 is lost from another, one can tell whether the reaction is concerted or stepwise by the effect of deuteration on the isotope effect in the CO2 (21). In a concerted mechanism, deuteration makes the chemical step more rate limiting, and one will see a larger isotope effect, or the same one if commitments were small to start with. In a stepwise mechanism, however, deuteration of the substrate makes the decarboxylation step less rate limiting and thus diminishes the size of the observed isotope effect. 

In the absence of an equihbrium isotope effect, that is, if JEeq = 1, the general expression for diminished V/K isotope effect becomes a simpler function of the diminished intrinsic effect ... 

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