Hydrogen isotope effects

The occurrence of a hydrogen isotope effect in an electrophilic substitution will certainly render nugatory any attempt to relate the reactivity of the electrophile with the effects of substituents. Such a situation occurs in mercuration in which the large isotope effect = 6) has been attributed to the weakness of the carbon-mercury bond relative to the carbon-hydrogen bond. The following scheme has been formulated for the reaction, and the occurrence of the isotope effect indicates that the magnitudes of A j and are comparable ... 

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). 

Wawzonek et al. first investigated the mechanism of the cyclization of A-haloamines and correctly proposed the free radical chain reaction pathway that was substantiated by experimental data. "" Subsequently, Corey and Hertler examined the stereochemistry, hydrogen isotope effect, initiation, catalysis, intermediates, and selectivity of hydrogen transfer. Their results pointed conclusively to a free radical chain mechanism involving intramolecular hydrogen transfer as one of the propagation steps. Accordingly, the... 

The idea that hydrogen bonding, as a special ortho effect of the substrate, may be involved in the transition state of the reactions with amines was first proposed by Chapman et al. Attempting to test this hypothesis, Hawthorne investigated the hydrogen-isotope effect in the reaction of o- and p-chloronitrobenzene with... 

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 first unequivocal evidence for the AE + DE mechanism came in three papers by Zollinger (1955 a-c) dealing with general base catalysis and primary kinetic hydrogen isotope effects in azo coupling reactions of various types. Three classes of reactions were identified i) reactions with no isotope effects (ArH/A D - 1.0) and no general base catalysis, ii) others with large isotope effects (k /k — 6.5) and (practically) linear base catalysis, and iii) intermediate cases with isotope effects of around 3.0 and less-than-linear base catalysis. 

Table 12-3. Kinetic hydrogen isotope effects found in azo coupling reactions of 4-chlorobenzene-diazonium ion with naphtholsulfonic acids (Zollinger, 1955 a Ernst et al., 1958).

An attractive feature of a mechanism of this type would be its ability to explain the observed ring-hydrogen isotope effect. A difficulty is the absence of the ortho isomer product, although conceivably as yet unidentified products derived from the (unstable) ortho isomer may be formed. An intermediate analogous to 71-complex has been suggested94 during the diazotisation of aniline at high acidities, viz. 

Aromatic substitution, a quantitative treatment of directive effects in, 1, 35 Aromatic substitution reactions, hydrogen isotope effects in, 2, 163 Aromatic systems, planar and non-planar, 1, 203 Aryl halides and related compounds, photochemistry of, 20, 191 Arynes, mechanisms of formation and reactions at high temperatures, 6, I A-Se2 reactions, developments in the study of, 6,63... 

Hydrogen isotope effects in aromatic substitution reactions, 2, 163... 

Substitution reactions, aromatic, hydrogen isotope effects in, 2, 163 Substitution reactions, bimolecular, in protic and dipolar aprotic solvents, 5,173 Sulphur, organic oxyacids of, and their anhydrides, mechanisms and reactivity in reactions of, 17, 65... 

Analysis of deacylation by histidinyl-functionalized micelles suggests that the histidinyl group can act both nucleophilically, generating an acylated histidine intermediate, and as a general base. These conclusions are consistent with the kinetic solvent hydrogen isotope effect (Murakami et al., 1981). 

The AC values for muonium hydrogen isotope effects are listed in Table 2.1. The AAC value obtained for LiH, H2 isotopic exchange involving Mu-H is 92 cm-1,... 

The BO approximation, which assumes the potential surface on which molecular systems rotate and vibrate is independent of isotopic substitution, was discussed in Chapter 2. In the adiabatic regime, this approximation is the cornerstone of most of isotope chemistry. While there are BO corrections to the values of isotopic exchange equilibria to be expected from the adiabatic correction (Section 2.4), these effects are expected to be quite small except for hydrogen isotope effects. 

The R s refer to isotope ratios, D/H, 13C/12C, 180/160, etc. By convention R is the ratio of heavy to light isotope. The factor of 1000 converts to per mil (%o) units. In the case of hydrogen isotope effects (Rd - Rstd)/Rstd is sometimes multiplied by 100 instead of 1000 and reported in per cent (%) rather than per mil, but in this text we use per mil notation almost exclusively. 

Table 10.1 Temperature dependence of some hydrogen isotope effects (After D. G. Truhlar and coworkers) ...

For historic and practical reasons hydrogen isotope effects are usually considered separately from heavy-atom isotope effects (i.e. 160/180, 160/170, etc.). The historic reason stems from the fact that prior to the mid-sixties analysis using the complete equation to describe isotope effects via computer calculations was impossible in most laboratories and it was necessary to employ various approximations. For H/D isotope effects the basic equation KIE = MMI x EXC x ZPE (see Equations 4.146 and 4.147) was often drastically simplified (with varying success) to KIE ZPE because of the dominant role of the zero point energy term. However that simplification is not possible when the relative contributions from MMI (mass moment of inertia) and EXC (excitation) become important, as they are for heavy atom isotope effects. This is because the isotope sensitive vibrational frequency differences are smaller for heavy atom than for H/D substitution. Presently... 

Not only primary but also secondary hydrogen isotope effects can be indicative of tunneling. The most frequently employed criteria of tunneling are the temperature dependence of kinetic isotope effects and the isotopic ratio of the pre-exponential factors in Arrhenius plots, but the pre-exponential criterion has been shown to be invalid for small secondary isotope effects. 

Northrop, D. B. Determining the Absolute Magnitude of Hydrogen Isotope Effects in W.W. Cleland, W. W., O Leary, M., Northrop, D. B. (Eds.) Isotope Effects on Enzyme-Catalyzed Reactions, University Park Press, Baltimore, MD, 1976, pp. 122-152. 

Chart 3. Traditionally expected features of hydrogen isotope effects ... 

Welsh, K.M., Creighton, D.J. and Khnman, J.P. (1980). Transition-state structure in the yeast alcohol dehydrogenase reaction the magnitude of solvent and alpha-secondary hydrogen isotope effects. Biochemistry 19, 2005-2016... 

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