Kinetic isotope effects, elucidating reaction

Secondary a-deuterium kinetic isotope effects (KIEs) have been widely used to determine the mechanism of SN reactions and to elucidate the structure of their transition states (Shiner, 1970a Westaway, 1987a). Some of the significant studies illustrating these principles are presented in this section. 

If the overall reaction rate is controlled by step three (k3) (i.e. if that is the rate limiting step), then the observed isotope effect is close to the intrinsic value. On the other hand, if the rate of chemical conversion (step three) is about the same or faster than processes described by ks and k2, partitioning factors will be large, and the observed isotope effects will be smaller or much smaller than the intrinsic isotope effect. The usual goal of isotope studies on enzymatic reactions is to unravel the kinetic scheme and deduce the intrinsic kinetic isotope effect in order to elucidate the nature of the transition state corresponding to the chemical conversion at the active site of an enzyme. Methods of achieving this goal will be discussed later in this chapter. 

The kinetic isotope effect, a change of rate that occurs upon isotopic substitution, is a widely used tool for elucidating reaction mechanism.48 The most common isotopic substitution is D for H, although isotope effects for heavier atoms have been measured. Our discussion will be in terms of hydrogen isotope effects the same principles apply to other atoms. 

Early work by Thode et al. (1949) established that there are large variations in the isotopic composition of sulfur compounds in nature. Since then sulfur isotope abundance data have been frequently used to elucidate many terrestrial processes including the genesis of sulfide ore bodies. The mechanisms of isotopic fractionation (alteration of relative isotopic abundances) can be broadly categorised under exchange processes or the kinetic isotope effects discussed on pp. 324ff. Isotopic exchange may be represented by the reaction ... 

Kresze and coworkers have found about a three order of magnitude rate increase in imino ene reactions when an N-tosyl group is replaced with an N-perfluoroalkanesulfonyl moiety [87]. Thus, with the glyoxylate ester-derived imine and the one from chloral 255 as the enophiles, reactions with acyclic olefins are very rapid and occur at room temperature [Eq. (60)]. In these ene reactions one stereoisomeric homoallylic amine 256 was typically generated, although the stereochemistry was not elucidated. However, in one reported case a 1 1 mixture of diastereomers was obtained. Mechanistic studies based upon kinetic isotope effects seem to indicate that this reaction may in fact be a two-step process rather than a concerted one [87b]. 

In the last ten years the exploration of the kinetics and the mechanism of these reactions has become very fruitful, owing to the continuous effort of research workers in different countries all over the world, who made use of all the modern tools now available in catalytic research. Especially the simultaneous application of different measuring techniques, for instance the infrared study of adsorbed reaction intermediates combined with the study of kinetics and kinetic isotope effects, appeared to be very elucidating. 

The photochemical aspects of carbonyl photochemistry remain important subjects of research. Wagner and Thomas have used CIDNP to elucidate radical formation from a,a,a-trifluoroacetophenone. Irradiation of benzophenone and its derivatives in the presence of molecules with abstractable hydrogen atoms can give rise to intensely fluorescent compounds. This effect may interfere with the observation of nanosecond-domain kinetics.Quantum yields and kinetic isotope effects in nanosecond flash studies of the reduction of benzophenone by aliphatic amines have been measured by Inbar et Rate constant data are given in Tables 13 and 14. Winnik and Maharaj have studied the reaction of benzophenone with n-alkanes through hexane to hexatriacontane is 3.9 0.2kcal for all chain lengths.The effects of substituents on the benzophenone on these reactions have also been examined. The reactions of phenylacetophenone when used as polymerization initiator have been reviewed by Merlin and Fouassier. ... 

Studies of kinetic-isotope effects have also provided valuable information about the mechanisms of reactions, and have been very helpful in elucidating biological mechanisms. Unfortunately, thje theory is somewhat complicated, and there are a few pitfalls. Only a very general and brief outline can be given here. For further details, with special reference to biological mechanisms, the reader is referred to the book by Laidler and Bunting listed in Selected Reading at the end of this chapter. 

A. Differentiation between S 2- and S -Mechanisms Kinetic isotope effects had a fundamental importance, however, for the elucidation of the substitution proper. Melander (1950) showed that a series of benzene derivatives containing tritium were nitrated and brominated at the same rate as the corresponding ordinary protium compound. This is the most important and elegant experimental support for the Sjj2- or two-stage mechanism (reactions 1-2, the... 

Kinetic isotope effect studies. Kinetic isotope effect (KIE) measurements are a powerful approach for the elucidation of reaction mechanism and the quantification of rate constants. This gives insight into molecular mechanisms and increases one s understanding of molecular interaction. The KIE is dependent on the mass difference between the isotopes and the largest practical value for a carbon KIE ratio is obtained using (Axelsson et al. 1990 Matsson et al. 

Isotopes can be used in another way to measure the energy barrier heights for various steps in the catalytic mechanism as noted above for the reaction catalyzed by dihydrofolate reductase. For example, if a proton transfer is involved in the rate-limiting step, then substitution of that proton with one of the heavier isotopes of hydrogen (deuterium or tritium) will cause the step to proceed more slowly. These so-called kinetic isotope effect experiments in combination with steady-state rate measurements in the case of TIM allowed the elucidation of the rate constants for partitioning of the cw-enediol intermediate and construction of a detailed kinetic scheme as shown above for dihydrofolate reductase. 

The rate of certain chemical reactions can be significantly changed if one atom in a reactant molecule is replaced by an isotope of the same element. Changes in reaction rates which are brought about by isotopic substitution are called kinetic isotope effects. These effects are very important because they are used to elucidate the reaction mechanism. 

The investigation of isotope effects in chemical kinetics has come to play an important role in the study of reaction mechanisms. Doubly labeled hydrogen chloride is useful in the elucidation of isotope effects in isotopic exchange reaction studies. 

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