Primary deuterium

Song and Beak found intramolecular and intermolecular hydrogen-deuterium kinetic isotope effects of 1.1 0.2 and 1.2 0.1, respectively, for the tin tetrachloride catalysed ene reaction. Since significant intramolecular and intermolecular primary deuterium kinetic isotope effects of between two and three have been found for other concerted ene addition reactions161, the tin-catalysed reaction must proceed by the stepwise pathway with the k rate determining step (equation 107). 

Because solvent viscosity experiments indicated that the rate-determining step in the PLCBc reaction was likely to be a chemical one, deuterium isotope effects were measured to probe whether proton transfer might be occurring in this step. Toward this end, the kinetic parameters for the PLCBc catalyzed hydrolysis of the soluble substrate C6PC were determined in D20, and a normal primary deuterium isotope effect of 1.9 on kcat/Km was observed for the reaction [34]. A primary isotope effect of magnitude of 1.9 is commonly seen in enzymatic reactions in which proton transfer is rate-limiting, although effects of up to 4.0 have been recorded [107-110]. 

A primary isotope effect results when the breaking of a carbon-hydrogen versus a carbon-deuterium bond is the rate-limiting step in the reaction. It is expressed simply as the ratio of rate constants, i wlky,. The full expression of k /kn measures the intrinsic primary deuterium isotope for the reaction under consideration, and its magnitude is a measure of the symmetry of the transition state, e.g., -C- H- 0-Fe+3 the more symmetrical the transition state, the larger the primary isotope effect. The theoretical maximum for a primary deuterium isotope effect at 37°C is 9. The less symmetrical the transition state, the more product-like or the more substrate-like the smaller the intrinsic isotope effect will be. 

Because of their dependence on mass, KIEs have been used in two ways to detect tunnelling. One is that primary deuterium KIEs are larger than predicted on the basis of zero-point energy alone when tunnelling makes a significant contribution to the KIE. For example, primary deuterium KIEs larger than 25 have been reported (Lewis and Funderburk, 1967 Wilson et al., 1973) for proton transfer reactions where tunnelling is important. 

Because unexpectedly large primary deuterium KIEs are observed in reactions where tunnelling is important, and unexpectedly large secondary deuterium KIEs have been observed in some hydron transfers in elimination and enzyme-catalysed hydride transfer reactions, Saunders (vide infra) wondered whether very large secondary deuterium KIEs were also indicative of tunnelling. 

Table 35 Calculated secondary a- and primary deuterium KIEs for the model hydride transfer reaction (45).°...

More experimental data where the secondary KIE was larger than the EIE were subsequently published by Subramanian and Saunders (1984). The 2-arylethyl system was employed in these studies because other relevant data, such as the primary deuterium KIE, were available for this reaction. Special techniques were developed to determine the primary and the secondary tritium KIEs for this system. Three isotopically distinct elimination reactions (49-51) are possible for a 2-arylethyl derivative tracer labelled with tritium at the 2-position. 

The results of these calculations have implications on the applicability of the rule of the geometric mean, which indicates that the KIE for a doubly labelled species should be the product of the KIEs for the corresponding singly labelled substrates. For instance, the KIE for the doubly labelled [17] should be the product of the secondary deuterium KIE, ]/ ]> associated with the nontransferring hydrogen and the primary deuterium KIE, / , produced by the transferring hydrogen (equation 58)). 

An alternative to evaluating the KIE and the rate constants from the above equations is to apply nonlinear least-squares fitting to the complete kinetic set of a and t values. This latter procedure has the advantage that errors in the reaction model, e.g. an incorrect mechanism, or extraneous data points are more easily discovered. This method was applied by Bergson et al. (1977) and Matsson (1985) in the determination of both the primary deuterium and secondary a-deuterium KIEs in the 1-methylindene rearrangement to 3-methylindene (reaction (67)). For example, a secondary /3-deuterium KIE of 1.103 0.001 was determined very accurately in toluene at 20°C using this method (Bergson et al., 1977). 

Another polarimetric method for the accurate determination of KIEs bears a strong resemblance to the isotopic quasi-racemate method, described above. In this method, Bach and co-workers (1991) utilized what they called isotopically engendered chirality to determine the primary deuterium KIE for an elimination reaction. In theory, the method can be used for any reaction where a substrate with a plane of symmetry yields, under normal conditions, a racemic mixture. For instance, if the plane of symmetry in the unlabelled... 

Deuterium nmr spectroscopy has been utilized for the last decade to determine large (primary deuterium) KIEs in reactions with isotopes present at the natural abundance level (Pascal et al., 1984,1986 Zhang, 1988). A great advantage of this approach is that labelled materials do not have to be synthesized. Neither is there any need for selective degradation procedures, which are often necessary to produce the molecules of low mass, e.g. C02, acceptable for isotope ratio mass spectrometry. Moreover, the KIEs for several positions can be determined from one sample. However, until quite recently the relatively low precision of the nmr integrations that are used for the quantitative assessment of the amount of deuterium at specific molecular sites has limited the applicability of this technique for determining small (secondary deuterium) KIEs. 

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). 

A label (L = D or T) can be introduced in the transferable position (left subscript of the rate constant) or in the non-transferable position (right subscript of the rate-constant) Then A hh/ dh hd/ dd primary deuterium isotope effects, while hh/ hd dh/ dd secondary deuterium isotope effects. In the general case, we can relate each of the two effects by ... 

The hydroxo complex [D] is assumed to rearrange to the cr-bonded compound [A] since only a secolidary isotope effect is observed with C2D4, and if the n complex went directly to acetaldehyde Henry claims that the hydride shift involved would have produced a primary deuterium effect. Although the hydroxo complex [D] would have been expected to be traris, it was suggested that kinetically significant amounts of the cis isomer are present. 

Pyrazolines have been used as models of intramolecular dyotropy (87T5981, 93JCS(P2)l2li). By combining primary deuterium kinetic isotope effects and X-ray crystallography, polycyclic systems, like (426), were shown to undergo a double proton transfer to (427). 

In 1895, Emil Ficher proposed an enediol intermediate for this isomerization. As would be expected, the enzyme-catalyzed isomerization of glucose-6-phosphate in 2H20 is accompanied by incorporation of deuterium into the product fructose 6-phosphate at C-l. In the reverse reaction 2H-containing fructose 6-phosphate was found to react at only 45% of the rate of the 1H-containing compound. Thus, the primary deuterium isotope effect expected for a rate-limiting cleavage of the C-H bond was observed (see Chapter 12, Section B,3). 

Acyl complex XVI was prepared from 3-perdeuteriophenyl-3,3-dideu-teriopropionyl chloride (XV), and its rate of decarbonylation (Reaction 9) along with that of the undeuteriated complex was measured at 80 °C. The rate constants (KH = 3.34 X 10 5, Kv = 4.75 X 10"6) show a primary deuterium isotope effect of 7.04. These results are also consistent with... 

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