Westheimer effect

The Westheimer effect and its implications form the main subject of this chapter, and no attempt is made to consider for example the more traditional application of primary isotope effects to the study of reaction mechanisms. However, a further point that is emphasized is that interpretations of isotope effects may be appreciated without resort to calculations, and before discussing kinetic effects some time is spent in considering, from a qualitative standpoint, the origins of hydrogen isotope effects and the isotopic properties of stable molecules and equilibria. In this preliminary review previous accounts of hydrogen isotope effects are extensively used [2-9] and among these... 

This implication of the Westheimer effect has the important corollary that variations in isotope effect may be used as an empirical guide to changes in transition-state structure. Coming at a time when the importance of the transition state to practical interpretations of reactivity had become widely appreciated, it is not surprising that Westheimer s paper stimulated an experimental search for examples of isotope maxima. Before attempting a more critical evaluation of the effect it is appropriate to consider the results of these investigations. 

Non-linear transition states. The operation of the Westheimer effect depends on the transition state being linear. If it is not, the balance of forces that leads to isotopic insensitivity for the real stretching vibration in a symmetrical transition state cannot occur. An obvious... 

Thus each of the factors (a), (b) and (c) suggests that the tunnelling contribution to /ch//cd will show the same qualitative variation as that from zero-point energy, with a maximum value for a symmetrical transition state. Provided that the correction is not large it will represent only a minor accentuation of the Westheimer effect. A number of calculations have modified Westheimer s model to include behaviour of this type [26, 85, 87]. Typical maximum values of coJ,(H) used have been 700/and 1000/cm for which at 25 C, Bell s tunnel... 

F. H. Westheimer, in Steric Effects in Organic Chemistry, M. S. Newman, ed., John Wiley Sons, New 3 rk, 1956, Chapter 12. 

The work of Melander and Carter (1964) on 2,2 -dibromo-4,4 -di-carboxybiphenyl-6,6 -d2 (1) has been referred to above in the introductory and theoretical sections, where it was pointed out that the availability of two detailed theoretical computations of the inversion barrier (Westheimer and Mayer, 1946, Westheimer, 1947 Hewlett, 1960) made this system especially attractive for the study of steric isotope efifects. Furthermore, in the preferred initial-state conformation the two bromines are probably in van der Waals contact (cf. Hampsoii and Weissberger, 1936 Bastiansen, 1950), and thus initial-state steric effects are unaffected by deuterium substitution in the 6 and 6 positions. The barrier calculations provided two different theoretical values for the non-bonded H Br distance in the transition state which, together with the corresponding H Br potential function, could be inserted in equation (10) to yield values for A AH. For... 

For reviews, see L. Melander, Isotope Effects on Reaction Rates, Ronald Press, New York, 1960 F.W. Westheimer, Chem. Rev., 61, 265 (1961) Streitwieser, A., Jr., Solvolytic Displacement Reactions, McGraw-Hill, New York, 1962 E. H. Halevi,Prog Phys. Org. Chem., 1, 109 (1963) C. J. Collins and N. S. Bowman, eis.. Isotope Effects in Chemical Reactions, Van Nostrand Reinhold Co., New York, 1970. 

Kemp and Waters found a primary kinetic isotope effect of 8.7 for oxidation of C-deuterated mandelic acid and noted a large difference in rate between the oxidations of mandelic acid k at 24.4 °C = 1.7 l.mole . sec ) and a-hydroxy-isobutyric acid ( 2 at 24.4 °C = 5.6 x 10 l.mole . sec ) — a difference not reproduced for the oxidation of these compounds by the one-equivalent reagent, manganic sulphate. The various data are fully in accord with a Westheimer-type mechanism, viz. 

Furthermore, reaction (27) of Westheimer s scheme seems to be rather arbitrary. If chromium(II) were really formed, the rate of oxidation of alcohol would certainly be influenced by oxygen. However, careful experiments show that there is no oxygen effect at all . 

None of the other reactions so far discussed involve interaction between a pair of charged species. This is but another instance of the electrostatic effect shown by Kirkwood and Westheimer to be responsible for the disparity between the first and second ionization constants of dibasic acids, for the effect of the carboxylate ion on the basicity of an a-amino acid, and for the difference in reactivity of ionic compounds compared with analogous nonionic species in acid- or base-catalyzed reactions. ... 

Oae found that for both base- and acid-catalyzed hydrolysis of phenyl benzenesul-fonate, there was no incorporation of 0 from solvent into the sulfonate ester after partial hydrolysis. This was interpreted as ruling out a stepwise mechanism, but in fact it could be stepwise with slow pseudorotation. In fact this nonexchange can be explained by Westheimer s rules for pseudorotation, assuming the same rules apply to pentacoordinate sulfur. For the acid-catalyzed reaction, the likely intermediate would be 8 for which pseudorotation would be disfavored because it would put a carbon at an apical position. Further protonation to the cationic intermediate is unlikely even in lOM HCl (the medium for Oae s experiments) because of the high acidity of this species a Branch and Calvin calculation (See Appendix), supplemented by allowance for the effect of the phenyl groups (taken as the difference in between sulfuric acid and benzenesulfonic acid ), leads to a pA, of -7 for the first pisTa of this cation about -2 for the second p/sTa. and about 3 for the third Thus, protonation by aqueous HCl to give the neutral intermediate is likely but further protonation to give cation 9 would be very unlikely. 

Clearly, if one takes a smaller value of D, one gets a higher value of IVj j, for a given distance Rufj. Kirkwood and Westheimer (1938), Westheimer and Kirkwood (1938), and Westiieimer and Shookhoff (1939) indeed argued that one should take a much smaller dielectric constant, since the intervening medium between the two protons more closely resembles a hydrocarbon liquid rather than water. In fact, for any dicarboxylic acid one can define an effective dielectric constant to fit the experimental value of W, by an equation of the form (4.8.13), with Dg being dependent on the proton-proton distance, the type and size of the acid and the solvent. 

Westheimer, F. Steric Effects in Organic Chemist.rv.f Ed./ Wiley, New York, 1956, Chapter 12,... 

A through-space electrostatic effect (field effect) due to the charge on X. This model was developed by Kirkwood and Westheimer who applied classical electrostatics to the problem. They showed that this model, the classical field effect (CFE), depended on the distance d between X and Y, the cosine of the angle 6 between d and the X—G bond, the effective dielectric constant and the bond moment of X. 

In 1962 too, Fridovich showed that the addition of sodium borohydride to a mixture of acetoacetate decarboxylase and acetoacetate inactivates the enzyme, whereas the addition of borohydride to a buffered solution of the enzyme alone has no effect on the rate at which it can promote the decarboxylation of acetoacetate (Fridovich and Westheimer, 1962) this work confirmed the ketimine mechanism that had previously been advanced for the decarboxylation. Subsequent work (beyond the scope of this review) showed that the reaction product, on hydrolysis, yielded e-isopropyllysine [8], formed by the reduction of the ketimine of acetone (11), and control experiments showed that this ketimine was actually an intermediate in the enzymic pathway, as had been postulated (Warren et al., 1966). 

The computation was improved by Westheimer and Kirkwood, who assumed a dielectric constant of 2.0 within the molecule. By approximating the molecule as an ellipsoid of revolution, they were able to make reasonably accurate calculations of electrostatic effects on pKa values.15 Thus, for malonic acid Westheimer and Shookhoff16 predicted r = 0.41 nm for malonic acid dianion. Recently more sophisticated calculations17 have been used to predict pKa values for the compounds in Table 7-1 and others.18... 

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