Swain secondary

Here we will not discuss these problems and the intriguing observation that am and strong correlation which is, however, difficult to explain (reviews Charton, 1981 Cook et al., 1989 Hansch et al., 1991). These questions were intensively studied in the 1970s and 1980s, leading gradually to the development of field and resonance parameters denoted by F and R respectively (after an original proposal of Swain and Lupton, 1968), which can be considered as independent of each other. The secondary parameters R + and R reflect the potential for an additional mesomeric donor-acceptor interaction (as in 7.7, and the opposite type with a donor instead of NQ2 and the reaction site as acceptor). 

Important additional evidence for aryl cations as intermediates comes from primary nitrogen and secondary deuterium isotope effects, investigated by Loudon et al. (1973) and by Swain et al. (1975 b, 1975 c). The kinetic isotope effect kH/ki5 measured in the dediazoniation of C6H515N = N in 1% aqueous H2S04 at 25 °C is 1.038, close to the calculated value (1.040-1.045) expected for complete C-N bond cleavage in the transition state. It should be mentioned, however, that a partial or almost complete cleavage of the C — N bond, and therefore a nitrogen isotope effect, is also to be expected for an ANDN-like mechanism, but not for an AN + DN mechanism. 

The deuterium isotope effect for each hydrogen atom ortho to the diazonio group ( H/ D = 1.22, Swain et al., 1973b) is the largest secondary aromatic hydrogen isotope effect yet observed. It is comparable to those observed for a-deuterium in reactions involving carbocation formation from secondary aliphatic esters. Ob-... 

The secondary deuterium KIEs obtained by converting the secondary tritium KIEs found for the E2 reactions of several different 2-arylethyl substrates into secondary deuterium KIEs with the Swain-Schaad equation (Swain et al., 1958) are in Table 36. As discussed above, one would expect the secondary deuterium isotope effect to reflect the extent to which rehybridization of the /3-carbon from sp3 of the reactant to sp2 in the product has taken place in the transition state. According to this reasoning, the secondary tritium EIE should be a good estimate of the maximum secondary tritium KIE. Because these reactions were not reversible, the EIE could not be measured. However, one can estimate the EIE (the maximum expected secondary KIE) using Hartshorn and Shiner s (1972) fractionation factors. The predicted EIE (Kh/Kd) values were 1.117 at 40°C and 1.113 at 50°C. Seven of the reactions... 

Ah/At = 7.4 and A /Ax = 1.8 and isotopic activation energy differences that are within the experimental error of zero. The values of the two A-ratios correspond to a Swain-Schaad exponent of 3.4, not much different from the semiclassical expectation of 3.3. The a-secondary isotope effects are 1.19 (H/T), 1.13 (H/D), and 1.05 (D/T), which are exactly at the limiting semiclassical value of the equilibrium isotope effect. The secondary isotope effects generate a Swain-Schaad exponent of 3.5, again close to the semiclassical expectation. At the same time that the isotope effects are temperature-independent, the kinetic parameter shows... 

Thus the primary and secondary isotope eifects are all within the semiclassical limits and their relationship is in full accord with the semiclassical Swain-Schaad relationship. There is no indication from the magnitudes of the secondary isotope elfects in particular of any coupling between motion at the secondary center and the reaction-coordinate for hydride transfer. Thus the sole evidence taken to indicate tunneling is the rigorous temperature-independence of the primary isotope elfects. 

Bahnson et al. extended the series of mutations to include ones in which reductions occurred in the second-order rate constant / cat/ M by as much as a factor of 100. No substantial changes were observed in the primary isotope effects or their Swain-Schaad exponent. However, the precisely measured secondary isotope effects changed systematically as the rate constant decreased, such that the Swain-Schaad exponent decreased monotonically with decreasing fecat/ M from exponent of 8.5 for the L57F mutant (reactivity equivalent to the wild-type enzyme) to an exponent of 3.3 for the V203G mutant, slower by 100-fold. 

Fig. 6 Illustration from Chin and Klinman. Increased catalytic activity of horse-liver alcohol dehydrogenase in the oxidation of benzyl alcohol to benzaldehyde by NAD, measured by cat/ M (ordinate), correlates with the Swain-Schaad exponent for the -secondary isotope effect (abscissa), for which values above about four are indicators of tunneling. This is a direct test of the hypothesis that tunneling in the action of this enzyme contributes to catalysis. As the rate increases by over two orders of magnitude and then levels off, the anomalous Swain-Schaad exponents also increase and then level off. Reproduced from Ref. 28 with the permission of the American Chemical Society.

Swain, T. (1977). Secondary compounds as protective agents. Annual Review of Plant Physiology 28, 479-501. 

It is important to note that these equations are based on the Swain-Schaad relationship, which assumes that there is no tunnelling in any of the isotopic reactions (the KIEs are semiclassical) and that the relationship between the KIEs is determined only by the masses of the hydrogen, deuterium and tritium atoms. The secondary and kfyko KIEs calculated both with and... 

Swain, T., Tannins and lignins, in Herbivores Their Interactions with Secondary Plant Metabolites, Rosenthal, G. A. and Janzen, D. H., Eds., Academic Press, New York, 1979, chap. 19. 

Quantum dynamics effects for hydride transfer in enzyme catalysis have been analyzed by Alhambra et. al., 2000. This process is simulated using canonically variational transition-states for overbarrier dynamics and optimized multidimensional paths for tunneling. A system is divided into a primary zone (substrate-enzyme-coenzyme), which is embedded in a secondary zone (substrate-enzyme-coenzyme-solvent). The potential energy surface of the first zone is treated by quantum mechanical electronic structure methods, and protein, coenzyme, and solvent atoms by molecular mechanical force fields. The theory allows the calculation of Schaad-Swain exponents for primary (aprim) and secondary (asec) KIE... 

Finally the temperature dependence of the primary isotope effects was determined. Here the traditional expectations of Chart 3 were fully met the results translate into AH/AD = 1.1 0.1, aD — aH = 0.8 kcal/mol. Thus the amount of tunneling present, adequate to produce the observed exaltation of secondary isotope effects, violations of the Swain-Schaad relationship, and violations of the Rule of the Geometric Mean in the neighborhood of room temperature, does not lead to anomalies in either the ratio of isotopic pre-exponential factors nor the isotopic activation energy difference over the temperature range studied (approximately 0-40 °C). As will be seen later, the temperature dependence of isotope effects for reactions that include tunneling is in general a complex, unresolved issue. 

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