Kinetic isotope effect hydrogen isotopes

Stable isotope fractionation was predicted and calculated by Urey and coworkers as early as 1932. Bigeleisen (1961) dealt with the statistical mechanics of isotope effects. Hydrogen isotope fractionation is mainly connected with the processes in the hydrosphere, but its equilibrium and kinetic effects were also studied for water of crystallization, ore-forming fluids, as represented by liquid inclusions, and biological cycles. 

Figure 6.12 Free energy correlation (shown schematically) for the H and D zero-point vibrations for a degenerate stepwise double hydrogen transfer reaction according to Eq. (6.31), where secondary kinetic isotope effects and isotopic fractionation between the initial and the intermediate state were neglected. Adapted from Ref [18c],...

This reduction almost certainly proceeds via the activation of the aldehyde carbonyl both by bond polarization in the ground-state and by stabilization of bonding interactions in the transition state. Although deuterium isotope labeling experiments show that hydrogen transfer is direct, comparison of kinetic isotope effects with isotope discrimination studies (23) suggest that the transition state of this reaction may not be a simple transfer of hydride ion (see Section IV—2). 

Melander first sought for a kinetic isotope effect in aromatic nitration he nitrated tritiobenzene, and several other compounds, in mixed acid and found the tritium to be replaced at the same rate as protium (table 6.1). Whilst the result shows only that the hydrogen is not appreciably loosened in the transition state of the rate-determining step, it is most easily understood in terms of the S 2 mechanism with... 

The azo coupling reaction proceeds by the electrophilic aromatic substitution mechanism. In the case of 4-chlorobenzenediazonium compound with l-naphthol-4-sulfonic acid [84-87-7] the reaction is not base-catalyzed, but that with l-naphthol-3-sulfonic acid and 2-naphthol-8-sulfonic acid [92-40-0] is moderately and strongly base-catalyzed, respectively. The different rates of reaction agree with kinetic studies of hydrogen isotope effects in coupling components. The magnitude of the isotope effect increases with increased steric hindrance at the coupler reaction site. The addition of bases, even if pH is not changed, can affect the reaction rate. In polar aprotic media, reaction rate is different with alkyl-ammonium ions. Cationic, anionic, and nonionic surfactants can also influence the reaction rate (27). 

Kinetic isotope effects are an important factor in the biology of deuterium. Isotopic fractionation of hydrogen and deuterium in plants occurs in photosynthesis. The lighter isotope is preferentially incorporated from water into carbohydrates and tipids formed by photosynthesis. Hydrogen isotopic fractionation has thus become a valuable tool in the elucidation of plant biosynthetic pathways (42,43). 

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. 

When one of the ortho hydrogens is replaced by deuterium, the rate drops from 1.53 X 10 " s to 1.38 X lO s. What is the kinetic isotope effect The product from such a reaction contains 60% of the original deuterium. Give a mechanism for this reaction that is consistent with both the kinetic isotope effect and the deuterium retention data. 

Table 6-5. Calculated Hydrogen/Deuterium Primary Kinetic Isotope Effects" ...

The kinetic isotope effect kD kT for hydrogen exchange of ferrocene in both trifluoroacetic acid-acetic acid and trifluoroacetic acid-dichloromethane has been measured558. In the former medium (1 1 molar ratio at 25 °C) kD kT was 1.2—1.3, which was less than that obtained for the 2 position of thiophene (D) = 1,200 xlO-7, ki(T) = 660xl0-7, kD kT = 1.9. It is also lower than that obtained for pentamethylbenzene fcx(D) = 3,300 x 10-7, Art(T) =... 

It is clear from the results that there is no kinetic isotope effect when deuterium is substituted for hydrogen in various positions in hydrazobenzene and 1,1 -hydrazonaphthalene. This means that the final removal of hydrogen ions from the aromatic rings (which is assisted either by the solvent or anionic base) in a positively charged intermediate or in a concerted process, is not rate-determining (cf. most electrophilic aromatic substitution reactions47). The product distribution... 

Calculated primary kinetic isotope effects for hydrogen/deuterium at 298 K... 

Kinetic isotope effect. Calculate the kie for R-H/R-T and R-D/R-T, taking for a carbon-hydrogen bond a stretching frequency of 2900 cm 1. 

Transition state theory has been useful in providing a rationale for the so-called kinetic isotope effect. The kinetic isotope effect is used by enzy-mologists to probe various aspects of mechanism. Importantly, measured kinetic isotope effects have also been used to monitor if non-classical behaviour is a feature of enzyme-catalysed hydrogen transfer reactions. The kinetic isotope effect arises because of the differential reactivity of, for example, a C-H (protium), a C-D (deuterium) and a C-T (tritium) bond. 

The only (to the best of our knowledge) theoretical treatment of hydrogen transfer by tunnelling to explicitly recognise the role of protein dynamics, and relate this in turn to the observed kinetic isotope effect, was described by Bruno and Bialek. This approach has been termed vibration-ally enhanced ground state tunnelling theory. A key feature of this theory... 

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