Isotope effects relative

The occurrence of a hydrogen isotope effect in an electrophilic substitution will certainly render nugatory any attempt to relate the reactivity of the electrophile with the effects of substituents. Such a situation occurs in mercuration in which the large isotope effect = 6) has been attributed to the weakness of the carbon-mercury bond relative to the carbon-hydrogen bond. The following scheme has been formulated for the reaction, and the occurrence of the isotope effect indicates that the magnitudes of A j and are comparable ... 

By protodetritiation of the thiazolium salt (152) and of 2 tritiothiamine (153) Kemp and O Brien (432) measured a kinetic isotope effect, of 2.7 for (152). They evaluated the rate of protonation of the corresponding yiides and found that the enzyme-mediated reaction of thiamine with pyruvate is at least 10 times faster than the maximum rate possible with 152. The scale of this rate ratio establishes the presence within the enzyme of a higher concentration of thiamine ylide than can be realized in water. Thus a major role of the enzyme might be to change the relative thermodynamic stabilities of thiamine and its ylide (432). 

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. 

In analyzing the behavior of these types of tetrahedral intermediates, it should be kept in mind that proton-transfer reactions are usually fast relative to other steps. This circumstance permits the possibility that a minor species in equilibrium with the major species may be the major intermediate. Detailed studies of kinetics, solvent isotope effects, and the nature of catalysis are the best tools for investigating the various possibilities. 

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,... 

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 small isotope effect has been observed in nitration of benzene by nitronium borofluoride in tetramethylene sulphone at 30 °C (kH/kD = 0.86) and this has been attributed to a secondary effect of the change in hybridisation from sp2 to sp3 of the ring carbon during the course of the reaction109. However, naphthalene gives an isotope effect of 1.15 under the same conditions, and anthracene a value of 2.6115. It does not seem at all clear why these relatively unhindered and normally more reactive molecules should give rise to an isotope effect when benzene does not. 

Kinetic isotope effects have not been observed in the reaction of 1-naphthol-4-sulphonic-2-acid with 2-methoxydiazobenzene127, imidazole-2,4,5-d3 with 4-diazobenzene sulphonic acid128, or indole-3- / with 4-nitrodiazobenzene12S, nor has base catalysis been observed in those cases where it has been measured in each of these reactions one or both of the reagents is relatively reactive. 

A kinetic isotope effect, kH/kD = 1.4, has been observed in the bromination of 3-bromo-l,2,4,5-tetramethylbenzene and its 6-deuterated isomer by bromine in nitromethane at 30 °C, and this has been attributed to steric hindrance to the electrophile causing kLx to become significant relative to k 2 (see p. 8)268. A more extensive subsequent investigation304 of the isotope effects obtained for reaction in acetic acid and in nitromethane (in parentheses) revealed the following values mesitylene, 1.1 pentamethylbenzene 1.2 3-methoxy-1,2,4,5-tetramethyl-benzene 1.5 5-t-butyl-1,2,3-trimethylbenzene 1.6 (2.7) 3-bromo-1,2,4,5-tetra-methylbenzene 1.4 and for 1,3,5-tri-f-butylbenzene in acetic acid-dioxan, with silver ion catalyst, kH/kD = 3.6. All of these isotope effects are obtained with hindered compounds, and the larger the steric hindrance, the greater the isotope... 

Baechler and coworkers204, have also studied the kinetics of the thermal isomerization of allylic sulfoxides and suggested a dissociative free radical mechanism. This process, depicted in equation 58, would account for the positive activation entropy, dramatic rate acceleration upon substitution at the a-allylic position, and relative insensitivity to changes in solvent polarity. Such a homolytic dissociative recombination process is also compatible with a similar study by Kwart and Benko204b employing heavy-atom kinetic isotope effects. 

The isotope effects of reactions of HD + ions with He, Ne, Ar, and Kr over an energy range from 3 to 20 e.v. are discussed. The results are interpreted in terms of a stripping model for ion-molecule reactions. The technique of wave vector analysis, which has been successful in nuclear stripping reactions, is used. The method is primarily classical, but it incorporates the vibrational and rotational properties of molecule-ions which may be important. Preliminary calculations indicate that this model is relatively insensitive to the vibrational factors of the molecule-ion but depends strongly on rotational parameters. 

Solvolytic experiments specifically designed to test Bartell s theory were carried out by Karabatsos et al. (1967), who were primarily interested in an assessment of the relative contributions of hyperconjugation and non-bonded interactions to secondary kinetic isotope effects. Model calculations of the (steric) isotope effect in the reaction 2- 3 were performed, as well as that in the solvolyses of acetyl chloride... 

Both sets of results may also be discussed in terms of inductive differences between hydrogen and deuterium (see Halevi, 1963). Brown et al. (1966) jDoint out that both the inductive and steric explanations qualitatively predict isotope effects in the same direction, but that an inductive effect would be expected to operate from the 3 and 4 positions nearly as effectively as from the 2 position . Furthermore, there is no observable isotope effect on the heat of reaction of 2,6-(dimethyl-de)-pyridine with the relatively small molecule diborane A AH = —20 18 cal mol ), but a significant effect is obtained with the larger molecule boron trifluoride AAH = 230 + 150 cal mol ). 

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