Proton Transfers to and from Carbon

OTHER EXAMPLES OF KINETIC ISOTOPE EFFECTS. The power of kinetic isotope effects in enzymol-ogy is well illustrated in the work of Rose ° and Knowles deahng with hydrogen effects in proton transfer to and from carbon. Abstraction of a proton from a tetrahedral carbon is a fundamental step in many enzyme-catalyzed reactions. Intramolecular proton transfer as well as partial loss (wash-out) migrating protons have provided important clues in mechanistic investigations. Enol and enediolate formation constitute several... 

The interest in proton transfer to and from carbon arises partly because this process occurs as an elementary step in the mechanisms of a number of important reactions. Acid and base catalysed reactions often occur through intermediate carbonium ions or carbanions which are produced by reactions (1) and (2). A knowledge of the acid—base properties of carbonium ions or carbanions may also help in understanding reactions in which these species are present as reactive intermediates, even when they are generated by processes other than proton transfer. Kinetic studies of simple reactions such as proton transfer are also important in the development of theories of kinetics. Since both rates and equilibrium constants can often be measured for (1) and (2) these reactions have been useful in the investigation of correlations between rate coefficients and equilibrium constants (linear free energy relations). 

Proton transfer reactions to and from carbon have also provided data to test theories of kinetic isotope effects. The large difference in mass between hydrogen and deuterium means that large kinetic effects are observed with these isotopes and proton transfer to and from carbon is therefore a suitable reaction for measuring these effects. 

Various aspects of proton transfer to and from carbon have been reviewed previously. Bell s classic work [1] covers the whole field of proton transfers and discusses in detail the mechanisms of acid and base catalysed reactions. The structure and stabilization of carbanions has been described [2] and a general review of the ionization of carbon acids has been published [3], The role of proton transfers in the mechanisms of chemical and biological reactions has also been described [4]. 

Proton transfers to and from carbon have been observed which vary in rate from those reactions occurring in less than one microsecond to those which take several years to reach completion, thus covering almost the whole range of experimentally accessible rates for reactions in solution. A wide range of techniques has therefore been applied to the problem of following proton transfers to and from carbon. A selection of the methods used most often in recent years is described here. The measurements are not limited to conditions under which the carbon acid is appreciably... 

Studies of proton transfer to and from carbon involving direct measurement of reactions like (1) and (2) are less common than studies of an overall reaction in which proton transfer is one step. It is this latter type of study to which we now turn. 

In recent years the overall picture of proton transfer to and from carbon has changed considerably, partly because new results have been obtained and partly because new theories have been developed to explain these results. In this section kinetic data for proton transfer to and from carbon will be presented and in Sect. 5 a relatively new theory which is helpful in explaining the data will be described. 

Discussion of results for proton transfer to and from carbon 5.1 MECHANISM OF PROTON TRANSFER TO AND FROM CARBON... 

Kinetic isotope effects in proton transfer to and from carbon... 

It is clear from the experimental results that the magnitude of the primary isotope effect in proton transfer to and from carbon provides a useful guide to transition state structure. It is also clear that reactions which apparently proceed through a rate-limiting proton transfer to or from carbon may not always show large primary isotope effects. Small isotope effects will be observed when the transition state is strongly product-like or reactant-like (Sect. 4.3). 

The use of solvent isotope effects in studies of reaction mechanism and the theoretical interpretation of the kinetic effect of replacing H2 O by D20 have been thoroughly described [122, 123, 204, 211], Results for reactions involving proton transfer to and from carbon [122, 123, 204] have played a major role in the development of the fractionation factor theory for explaining solvent isotope effects, but other reactions [211(b), 211(c)], for example, nucleophilic substitution at saturated carbon, have also been well studied. In this section it will be shown how detailed information about a proton transfer transition state can be obtained by studying the solvent isotope effect for a reaction with known mechanism. Reactions with the A—SE2 mechanism will be discussed since this probably represents the most widely studied example of the application of solvent isotope effects in proton transfer to and from carbon [42, 47, 122,123, 204, 211(a), 212],... 

As a general introduction, the first chapter deals with homogeneous catalysis of organic reactions, mainly acid—base catalysis, but also with nucleophilic catalysis and catalysis by metal ions. In Chapter 2, proton transfer to and from carbon is discussed and in Chapter 3 proton transfer to and from other atoms, mainly oxygen and nitrogen. 

Proton Transfer to and from Carbon in Model Reactions... 

There is only a small barrier for thermoneutral proton transfer between electronegative oxygen or nitrogen acids and bases [31]. These reactions proceed by encounter-controlled formation of a hydrogen-bonded complex between the acid and base (ka, Scheme 1.6), proton transfer across this complex (kp, Scheme 1.6), followed by diffusional separation to products (k a, Scheme 1.6) [31]. Much larger Marcus intrinsic barriers are observed for proton transfer to and from carbon [67]. There are at least two causes for this difference in intrinsic barriers for proton transfer between electronegative atoms and proton transfer at carbon. 

Studies on proton transfer to and from carbon in model reactions have shown that the activation barrier to most enzyme-catalyzed reactions is composed mainly of the thermodynamic barrier to proton transfer (Fig. 1.1), so that in most cases this barrier for proton transfer at the enzyme active site will need to be reduced in order to observe efficient catalysis. A smaller part of the activation barrier to deprotonation of a-carbonyl carbon is due to the intrinsic difficulty of this reaction to form a resonance stabilized enolate. There is evidence that part of the intrinsic barrier to proton transfer at a-carbonyl carbon reflects the intrinsic instability of negative charge at the transition state of mixed sp -sp -hybridization at carbon [79]. Small buffer and metal ion catalysts do not cause a large reduction in this intrinsic reaction barrier. 

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