Isotope primary effects

See also isotope effect, primary isotope effect,... 

Supporting evidence against irreversible intermediate formation is found in some unpublished studies by H. G. Vilhuber (i5), E. Werstiuk (16), and V. Chuang (3) on the primary deuterium isotope effect. Primary isotope effects of 1.2 to 2.1 were determined for deuterated olefins 34-36,... 

In a number of different kinds of neighboring group processes, deuterium isotope effects have proven useful in providing information about the transition state of the rate-determining step. There are several kinds of isotope effects that can be studied they are solvent isotope effects, primary isotope effects, and secondary isotope effects. Of these types, primary and secondary isotope effects are of more general importance in the study of neighboring group effects. 

Alteration of either the equilibrium constant or the rate constant of a reaction if an atom in a reactant molecule is replaced by one of its isotopes, distinguished are kinetic isotope effect, equilibrium isotope effect, primary isotope effect, secondary isotope effect. 

Kinetic isotope effects primary and secondary deuterium kinetic isotope effects. Heavy atom isotope effects. Solvent isotope effects. SnI and Sn2 mechanisms. 

It has been found that the measured kinetic isotope effects (primary and secondary) are sometimes significantly higher than the expected values. Maximum isotope effects will be observed when there is practically no difference between the zero-point energies of isotopically labeled substrates in the reaction transition state (eq. 1.14.6). Then, as already pointed out, the difference between the energies of activation E - E. ... 

These are most often deuterium isotope effects, - A(D) meaning that both and (often called D) resonances are observed and subtracted to give the isotope effects. Primary isotope effects on chemical shifts can again be divided into intrinsic and equilibrium isotope effects. The intrinsic ones are observed in systems like... 

It is clear, then, that the measurement of primary kinetic isotope effects will not give a wholly unambiguous clue to mechanism in the absence of other evidence. Nevertheless, the absence of a kinetic isotope effect is most easily understood in terms of the /S 2 mechanism... 

A primary isotope effect /ch/ d of 6.4 (extrapolated for 35 C) is observed for the metalation and the methylation of 171b when the C-5 position is deuterated. This value is in excellent agreement with the primary isotope effect of 6.6 reported for the metalation of thiophene (392) and it confirms that the rate-determining step is the abstraction by the base of the acidic proton. 

A special type of substituent effect which has proved veiy valuable in the study of reaction mechanisms is the replacement of an atom by one of its isotopes. Isotopic substitution most often involves replacing protium by deuterium (or tritium) but is applicable to nuclei other than hydrogen. The quantitative differences are largest, however, for hydrogen, because its isotopes have the largest relative mass differences. Isotopic substitution usually has no effect on the qualitative chemical reactivity of the substrate, but often has an easily measured effect on the rate at which reaction occurs. Let us consider how this modification of the rate arises. Initially, the discussion will concern primary kinetic isotope effects, those in which a bond to the isotopically substituted atom is broken in the rate-determining step. We will use C—H bonds as the specific topic of discussion, but the same concepts apply for other elements. 

Fig. 4.9. DifiBoing zero-point energies ofprotium- and deuterium-substituted molecules as the cause of primary kinetic isotope effects.

Detailed analysis of isotope effects reveals that there are many other factors that can contribute to the overall effect in addition to the dominant change in bond vibrations. For that reason, it is not possible to quantitatively predict the magnitude of either primary or seconday isotope effects for a given reaction. Furthermore, there is not a sharp numerical division between primary and secondary effects, especially in the range between 1 and 2. 

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. 

For E2 eliminations in 2-phenylethyl systems with several different leaving groups, both the primary isotope effect and Hammett p values for the reactions are known. Deduce from these data the relationship between the location on the E2 transition state spectrum and the nature of the leaving group i.e., deduce which system has the most El-like transition state and which has the most Elcb-like. Explain your reasoning. 

Isotope effects are also useful in providing insight into other aspects of the mechanisms of individual electrophilic aromatic substitution reactions. In particular, because primary isotope effects are expected only when the breakdown of the c-complex to product is rate-determining, the observation of a substantial points to a rate-... 

Bromination has been shown not to exhibit a primary kinetic isotope effect in the case of benzene, bromobenzene, toluene, or methoxybenzene. There are several examples of substrates which do show significant isotope effects, including substituted anisoles, JV,iV-dimethylanilines, and 1,3,5-trialkylbenzenes. The observation of isotope effects in highly substituted systems seems to be the result of steric factors that can operate in two ways. There may be resistance to the bromine taking up a position coplanar with adjacent substituents in the aromatization step. This would favor return of the ff-complex to reactants. In addition, the steric bulk of several substituents may hinder solvent or other base from assisting in the proton removal. Either factor would allow deprotonation to become rate-controlling. 

Indicate mechanisms that would account for the formation of each product. Show how the isotopic substitution could cause a change in product composition. Does your mechanism predict that the isotopic substitution would give rise to a primary or secondary deuterium kinetic isotope effect Calculate the magnitude of the kinetic isotope effect from the data given. 

For a given hydrogen donor S—H, replacement by S—D leads to a decreased rate of reduction, relative to nonproductive decay to the ground state." This decreased rate is consistent with a primary isotope effect in the hydrogen abstraction step,... 

A kinetic isotope effect that is a result of the breaking of the bond to the isotopic atom is called a primary kinetic isotope effect. Equation (6-88) is, therefore, a very simple and approximate relationship for the maximum primary kinetic isotope effect in a reaction in which only bond cleavage occurs. Table 6-5 shows the results obtained when typical vibrational frequencies are used in Eq. (6-88). Evidently the maximum isotope effect is predicted to be very substantial. 

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