Solvent isotope substitution

Finally, the canon of knowledge presented in this text and the preceding references has been developed over a long period of time from difficult, detailed experimental investigations of the effects of concentration, solvent, isotopic substitution, substrate structure, and other variables on the rates and yields of reactions. In fact, writing a reasonable mechanism from one s own knowledge is a piece of cake compared with the work required to verify it experimentally. The experimental methods used to determine reaction mechanisms are discussed in... 

Liquid-liquid demixing in solutions of polymers in low molar mass solvents is not a rare phenomenon. Dembcing depends on concentration, temperature, pressure, molar mass and molar mass distribution function of the polymer, chain branching and end groups of the polymer, the chemical nature of the solvent, isotope substitution in solvents or polymers, chemical composition of copolymers and its distributions, and other variables. Phase diagrams of polymer solutions can therefore show a quite complicated behavior when they have to be considered in detail (see Ref la). 

The second-order rate constants for hydration and the kinetic solvent isotope effect for hydration of several 2-substituted 1,3-butadienes ate given below. Discuss the information these data provide about the hydration mechanism. 

The log rate versus acid strength curve for the latter compound is of the exact form expected for reactions of the free base, whilst that of the former compound is intermediate between this form and that obtained for the nitration of aniline and phenyltrimethylammonium ion, i.e. compounds which react as positive species. That these compounds react mainly or entirely via the free base is also indicated by the comparison of the rate coefficients in Table 8 with those in Table 5, from which it can be seen that the nitro substituent here only deactivates weakly, whilst the chloro substitutent appears to activate. In addition, both compounds show a solvent isotope effect (Table 9), the rate coefficients being lower for the deuterium-containing media, as expected since the free base concentration will be lower in these. 

If one limits the consideration to only that limited number of reactions which clearly belong to the category of nucleophilic aromatic substitutions presently under discussion, only a few experimental observations are pertinent. Bunnett and Bernasconi30 and Hart and Bourns40 have studied the deuterium solvent isotope effect and its dependence on hydroxide ion concentration for the reaction of 2,4-dinitrophenyl phenyl ether with piperidine in dioxan-water. In both studies it was found that the solvent isotope effect decreased with increasing concentration of hydroxide ion, and Hart and Bourns were able to estimate that fc 1/ for conversion of intermediate to product was approximately 1.8. Also, Pietra and Vitali41 have reported that in the reaction of piperidine with cyclohexyl 2,4-dinitrophenyl ether in benzene, the reaction becomes 1.5 times slower on substitution of the N-deuteriated amine at the highest amine concentration studied. 

Secondly, it has been found that the benzidine rearrangement is subject to a solvent isotope effect d2o/ h2o > 1- If a proton is transferred from the solvent to the substrate in a rate-determining step the substitution of protium by deuterium will lead to a retardation in the rate of reaction (primary isotope effect) whereas if a proton is transferred in a fast equilibrium step preceeding the rate-determining step as in... 

White et al.1A have obtained similar kinetic results for the acid-catalysed rearrangement of N-nitro-N-methylaniline, i.e. a first-order dependence on the nitroamine with a linear H0 plot of slope 1.19 for phosphoric acid, and a deuterium solvent isotope effect of about three, although the results have only been presented in preliminary form. Further, an excellent Hammett a+ correlation was claimed for thirteen para substituted nitroamines which gave a p value of —3.9. Since it is expected that the rate coefficients would correlate with a (rather than different basicities of the amines, the a+ correlation implies that the amino nitrogen is electron-deficient in the transition state,... 

Chemical kinetics is the study of the rates of chemical reactions. Its practice entails the measurement of concentrations as a function of time. These measurements are extended to other variables, such as the concentrations of additional species, pH, temperature, pressure, isotopic substitution, solvent, salt concentration, and so on. 

The route from kinetic data to reaction mechanism entails several steps. The first step is to convert the concentration-time measurements to a differential rate equation that gives the rate as a function of one or more concentrations. Chapters 2 through 4 have dealt with this aspect of the problem. Once the concentration dependences are defined, one interprets the rate law to reveal the family of reactions that constitute the reaction scheme. This is the subject of this chapter. Finally, one seeks a chemical interpretation of the steps in the scheme, to understand each contributing step in as much detail as possible. The effects of the solvent and other constituents (Chapter 9) the effects of substituents, isotopic substitution, and others (Chapter 10) and the effects of pressure and temperature (Chapter 7) all aid in the resolution. 

It is reasonable to expect that isotopic substitution on solvent molecules will affect both equilibrium and rate constants. This is especially true for reactions in aqueous media, many of which are acid or base catalyzed and therefore sensitive to pH or pD. Furthermore H/D aqueous solvent isotope effects often display significant nonlinearity when plotted against isotope fraction of the solvent. The analysis of this effect can yield mechanistic information. The study of aqueous solvent isotope effects is particularly important in enzyme chemistry because enzyme reactions universally occur in aqueous media and are generally pH sensitive. 

As a practical matter of cost, studies on solvent isotope effects are usually limited to D/H substituted solvents, although recently a few lsO solvent effects have been measured. Interpretation of enzymatic solvent isotope effects is even more complicated than it is when the isotopic probe is incorporated in the substrate(s). This is because enzyme proteins have many exchangeable protons and, also, this is frequently true for reactants (substrates). Thus the observed isotope effect is the collective result of many different isotopic substitutions, each of which may influence... 

An S Ar (nucleophilic substitution at aromatic carbon atom) mechanism has been proposed for these reactions. Both nonenzymatic and enzymatic reactions that proceed via this mechanism typically exhibit inverse solvent kinetic isotope effects. This observation is in agreement with the example above since the thiolate form of glutathione plays the role of the nucleophile role in dehalogenation reactions. Thus values of solvent kinetic isotope effects obtained for the C13S mutant, which catalyzes only the initial steps of these reactions, do not agree with this mechanism. Rather, the observed normal solvent isotope effect supports a mechanism in which step(s) that have either no solvent kinetic isotope effect at all, or an inverse effect, and which occur after the elimination step, are kinetically significant and diminish the observed solvent kinetic isotope effect. 

The title indicates the scope of the text. The term isotope effects is used rather than applications of isotopes to indicate clearly that it deals with differences in the properties of isotopically substituted molecules, for example differences in the chemical and physical properties of water and the heavy waters (H2O, HDO, D2O, HTO, etc.). Thus H20, HDO and D2O have different thermodynamic properties. Also reactions in solvent mixtures of light and heavy water proceed at different rates than they do in pure H2O. On the other hand, the differences are not large and consequently, to the extent the difference in properties can be ignored, HDO or HTO can be used as tracers for H2O. An important point, however, is that this book does not deal with isotopes as tracers in spite of the widespread importance of tracer studies, particularly in the bio and medical sciences. Also the title specifically does not mention physics which would necessarily have been included if the term Physical Sciences had been used. Thus the text does not deal with differences in the nuclear properties of isotopic atoms. Such differences are in the realm of nuclear physics and will not be discussed. 

The only kinetic isotope effects so far reported for these reactions are those given by Pocker (1960), without experimental detail. He reports closely similar values for the rates of solvent-catalysed hydration of the species CHg. CHO, CD3. CHO, CH3. CDO and CD3. CDO in water at 0° C the replacement of CH3 by OD3 increases the velocity by about 7%. The same effect is reported for solutions in deuterium oxide at 0° C, presumably super-cooled. A comparison was also made of rates of hydration in HjO and DgO at 0°C, giving the following values for k(H.z0)lk(T>20) in presence of different catalysts H+/D+, 1 -3 AcOH/AcOD, 2 5 AcO , 2-3 H2O/D2O, 3-6. Almost exactly the same ratios were obtained by measuring rates of dehydration at 25° C in dioxan containing 10% of H2O or D2O and various catalysts. The presence of a considerable solvent isotope effect is consistent with the mechanism given in Section IV,B, and it would not be expected that substitution of deuterium on carbon would have an appreciable effect on the rate. 

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