Hydrogen kinetic isotope effects

German ED, Kuznetsov AM (1981) Dependence of the hydrogen kinetic isotope effect on the reaction free energy. J Chem Soc, Faraday Trans 1 77 397—412... 

The pyridine-catalysed lead tetraacetate oxidation of benzyl alcohols shows a first-order dependence in Pb(OAc)4, pyridine and benzyl alcohol concentration. An even larger primary hydrogen kinetic isotope effect of 5.26 and a Hammett p value of —1.7 led Baneijee and Shanker187 to propose that benzaldehyde is formed by the two concurrent pathways shown in Schemes 40 and 41. Scheme 40 describes the hydride transfer mechanism consistent with the negative p value. In the slow step of the reaction, labilization of the Pb—O bond resulting from the coordination of pyridine occurs as the Ca—H bond is broken. The loss of Pb(OAc)2 completes the reaction with transfer of +OAc to an anion. 

These reactions proceed through symmetrical transition states [H H H] and with rate constants kn,HH and kH,DH, respectively. The ratio of rate constants, kH,HH/kH,DH> defines a primary hydrogen kinetic isotope effect. More precisely it should be regarded as a primary deuterium kinetic isotope effect because for hydrogen there is also the possibility of a tritium isotope effect. The term primary indicates that bonds at the site of isotopic substitution the isotopic atom are being made or broken in the course of reaction. Within the limits of TST such isotope effects are typically in the range of 4 to 8 (i.e. 4 < kH,HH/kH,DH < 8). 

Secondary hydrogen kinetic isotope effects are further classified as alpha, beta, etc. depending on the distance of the isotopically substituted atom from the bond(s) that is (are) being made or broken (a = 1 bond, 3 = 2 bonds, etc.). Consider the simple Sn2 reaction between hypochlorite anion and ethyl chloride ... 

This zinc metalloenzyme [EC 1.1.1.1 and EC 1.1.1.2] catalyzes the reversible oxidation of a broad spectrum of alcohol substrates and reduction of aldehyde substrates, usually with NAD+ as a coenzyme. The yeast and horse liver enzymes are probably the most extensively characterized oxidoreductases with respect to the reaction mechanism. Only one of two zinc ions is catalytically important, and the general mechanistic properties of the yeast and liver enzymes are similar, but not identical. Alcohol dehydrogenase can be regarded as a model enzyme system for the exploration of hydrogen kinetic isotope effects. 

Unusually large hydrogen kinetic isotope effects might, therefore, be better regarded in the first instance as diagnostic of a mechanism involving a transient intermediate, and the simplest case is illustrated in Scheme 9.18. Application of the steady-state assumption to the intermediate I yields the expressions shown for the pseudo-first-order rate constants for disappearance of the reactant R (kR) and formation of products PA and PB (kpA and kPB). The expressions for the kinetic isotope effects for formation of each product (superscripts L and H refer to light and heavy isotopes) are also shown. 

HEAVY ATOM AND REMOTE HYDROGEN KINETIC ISOTOPE EFFECTS IN GLYCOSYL TRANSFER... 

Figure 7.6. Multiple hydrogen kinetic isotope effects used to diagnose a concerted versus stepw/ise mechanisms.

A method for obtaining very precise multiple hydrogen kinetic isotope effects was developed in order to determine whether alanine racemase catalyzes a concerted or a stepwise process [21]. The method employs an equilibrium perturbation-type... 

Stern, M. J., Schneider, M. E., Vogel, P. C. (1971) Low-magnitude, pure-primary, hydrogen kinetic isotope effects, J. Chem. Phys. 55, 4286-4289. 

Figure 19.3. Models [60] used in calculations of hydrogen kinetic isotope effects with tunneling contributions.

The last three columns of Table 19.5 report results obtained with the micro-canonically optimized multidimensional tunneling approximation, which represents the currently most trusted method for including a tunneling contribution. These results predict that the hydrogen kinetic isotope effect for the hydrogen atom step in methylmalonyl-CoA reaction in the direction of succinyl formation is -100. 

Dybala-Defratyka, A., Paneth, P. (2001) Theoretical evaluation of the hydrogen kinetic isotope effect on the first step of the mefhylmalonyl-CoA mutase reaction, J. Inorg. Biochem. 86, 681-689. 

Recognition should be made of the fact that includes both a primary and a secondary kinetic isotope effect, but the latter is usually much smaller than the former and should not contribute greatly to the large difference in activation energies (for normal primary hydrogen kinetic isotope effects, the difference in activation energies is usually around 1 kcal/mol). 

Bell (14) has pointed out that a plot of hydrogen kinetic isotope effects for a variety of proton transfer reactions vs. the difference in pK between the two bases shows a central maiximum near fipK =0.0 and decreasing limbs for ApK <0 or > 0. An example of this is shown in figure 4 from Bell and Cox (14). 

Hydrogen kinetic isotope effects in cyclopropane-propene and related... 

Reaction coordinate diagram for intramolecular primary hydrogen kinetic isotope effect. (Adapted from reference 118b.)... 

The counterion was found to be a significant factor in the equilibrium, with the more highly substituted enolate increasingly favored as the cation varied from sodium or potassium to lithium. Beutelman, H. P. Xie, L. Saunders, W. H., Jr. /. Org. Chem. 1989,54,1703 determined that the primary hydrogen kinetic isotope effect for proton removal from alkyl ketones by strong bases such as lithium diisopropylamide in THF or DME was kn/ko = 2.3 to 5.9 at 0°C. The results suggested a very early transition state. The reactions appeared to depend on more than one base reacting with each ketone, however. See also Xie, L. Saunders, W. H., Jr. /. Am. Chem. Soc. 1991, 113, 3123. 

If equation 8.57 represents a one-step process, then a primary hydrogen kinetic isotope effect should be observed for the reaction. In most cases, however, Ich/ d is near unity for typical SgAr reactions such as lutration or bromination. Therefore, we surmise that the loss of the C—H bond... 

This type of elimination is known as an ElcbR (elimination, unimolecular, conjugate base, reversible) reaction, and a generalized reaction coordinate diagram is shown in Figure 10.14. Such reactions exhibit C s-H/D exchange and a 1° hydrogen kinetic isotope effect (ku/ko) of 1.0. An example of an ElcbR is shown in Figure 10.15. ... 

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