Enolization intrinsic barriers

Alternatively one can make use of No Barrier Theory (NBT), which allows calculation of the free energy of activation for such reactions with no need for an empirical intrinsic barrier. This approach treats a real chemical reaction as a result of several simple processes for each of which the energy would be a quadratic function of a suitable reaction coordinate. This allows interpolation of the reaction hypersurface a search for the lowest saddle point gives the free energy of activation. This method has been applied to enolate formation, ketene hydration, carbonyl hydration, decarboxylation, and the addition of water to carbocations. ... 

From this we can conclude that two pKa values can be as much as eight units apart and AG will still be less than 50 kj / mol, low enough to permit rapid enzymatic reactions. However, for transfer of a proton from a C-H bond to a catalytic group, for example, to form an enolate ion for an aldol condensation (Chapter 13), the intrinsic barrier is known to be about 50 kj / mol.141 In this case, to allow rapid enzymatic reaction either the thermodynamic barrier must be very low, as a result of closely matching pKa values, or the enzyme must lower the intrinsic barrier. It may do both. 

In cases where there is strong solvation of the carbanion, as for example hydrogen bonding solvation of enolate or nitronate ions in hydroxylic solvents, the intrinsic barrier is increased further because the transition state cannot benefit significantly from this solvation. This is the reason why AG for the deprotonation of nitroalkanes in water is particularly high, i.e., much higher than in dipolar aprotic solvents, see, e.g., entry 11 versus 15 and entry 13 versus 16 in Table 1. These solvation effects will be discussed in more detail below. 

Solvation can have a large effect on intrinsic barriers or intrinsic rate constants, especially hydrogen bonding solvation of nitronate or enolate ions in hydroxylic solvents. Table 4 reports intrinsic rate constants in water and aqueous DMSO for a number of representative examples.19,20,23 25,40,54 56 Entries 1-4 which refer to nitroalkanes show large increases in ogka when... 

The Marcus intrinsic barriers for deprotonation of carbon acids to form enolates that are stabilized by resonance delocalization of negative charge from carbon to oxygen are larger than for deprotonation of carbon acids to form carbanions where the charge is localized mainly at carbon. 

It has been proposed that part or all of the intrinsic barrier for deprotonation of a-carbonyl carbon is associated with the requirement for solvation of the negatively charged oxygen of the enolate anion [80]. However, the observation of small intrinsic barriers for deprotonation of oxygen acids by electronegative bases to form solvated anions [31] suggests that the requirement for a similar solvation of enolate anions should not make a large contribution to the intrinsic barrier for deprotonation of a-carbonyl 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. 

Wirz has reviewed his work with Kresge on the generation of unstable tautomers by flash photolysis, and the subsequent kinetics of conversion to the stable tautomer. The enols of ketones and aldehydes, of carboxylic acids and esters, of ketenes, and the keto tautomers of phenols are described. The ratios of forward and reverse rate constants yield tautomeric constants over 30 orders of magnitude. A Marcus treatment yields an intrinsic barrier of 57 2kJmol for oxygen-to-carbon proton transfer. Possible evidence for protonation of n,7r -excited triplet ketones is presented. 

A quantitative understanding of how enzymes catalyze rapid proton abstraction from weakly acidic carbon acids is necessarily achieved by dissecting the effect of active site structure on the values of AG°, the thermodynamic barrier, and AG int, the intrinsic kinetic barrier for formation of the enolate anion intermediate. The structural strategies by which AG° for formation of the enolate anion is reduced sufficiently such that these can be kinetically competent are now understood. In divalent metal ion-independent reactions, e.g., TIM, KSI, and ECH, the intermediate is stabilized by enhanced hydrogen bonding interactions with weakly acidic hydrogen bond donors in divalent metal-dependent reactions, e.g., MR and enolase, the intermediate is stabilized primarily by enhanced electrostatic interactions with... 

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