Proton Transfer to and from Carbon in Model Reactions

Proton Transfer to and from Carbon in Model Reactions 

Rate and Equilibrium Constants for Carbon Deprotonation in Water 

The most fundamental experimental determinations in model studies of proton transfer at weakly basic carbon are of the rate and equilibrium constants for carbon deprotonation to form an unstable carbanion (Eq. (1.1)). These parameters define the kinetic and thermodynamic barriers to proton transfer (Eq. (1.2) for Fig. 1.1). They are of interest to enzymologists because they specify the difficulty of the problem that must be solved in the evolution of proteins which catalyze proton transfer with second-order rate constants kcat/ m of 10 -10 s that are typically ob- 

Hydrogen-Transfer Reacldons. Edited by J. T. Hynes, J. P. Klinman, H.-H. limbadi, and R. L. Sdiowen Copyright 2007 WILEY-VCH Verlag GmbH Co. KGaA, Weinheim ISBN 978-3-527-30777-7 

Acidity constants for ionization of weak carbon acids in water caimot be determined by direct measurement when the strongly basic carbanion is too unstable to exist in detectable concentrations in this acidic solvent. Substituting dimethyl-sulfoxide (DMSO) for water causes a large decrease in the solvent acidity because, in contrast with water, the aprotic cosolvent DMSO does not provide hydrogenbonding stabilization of hydroxide ion, the conjugate base of water. This allows the determination of the pfC s of a wide range of weak carbon acids in mixed DMSO/water solvents by direct measurement of the relative concentrations of the carbon acid and the carbanion at chemical equilibrium [3, 4]. The pfC s determined for weak carbon acids in this mixed solvent can be used to estimate pfC s in water. 

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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. 

The preference for the amine-catalyzed aldol reaction to go through a TS having the features of 53a or 55a is now called the Houk-List model. This type of TS has three major characteristics (1) proton transfer from the carboxylic acid to the incipient alcohol concomitant with the formation of the C-C bond (TS D of Scheme 6.8) (2) the enamine is in the anti orientation and (3) the aldehyde substituent is anti to the enamine carbon. 

Although we have only discussed the partial-proton-transfer model for one of the B 12-dependent carbon-skeleton mutases [69], we can expect that there also exists a continuum between no protonation and full protonation of the substrate in the other reactions. Analogously, partial hydride removal from the substrate of glutamate mutase may serve to facilitate this rearrangement. 

Akinetic study was also performed in a variety of vesicular solutions (DDAB, DODAB, DODAC [NaOH] = 2.25mM, 25 °C). Interestingly, the vesicles possess stronger catalytic reaction environments than the micelles. The rate-determining proton transfer from carbon to the hydroxide ion was accelerated up to 850 fold in di- -dodecyldimethylam-monium bromide (DDAB) vesicles. This is evidence that the reaction sides are less aqueous than those in micelles, as anticipated. Application of the pseudophase model afforded the bimolecular rate constants in the vesicles (kves). For the different vesicles, ves is significantly higher (ca. 12 times for DODAB) than the second-order rate constant in water. This shows that the catalysis is due to both a medium effect and a concentration effect. It was assumed that there was a fast equilibrium for substrate binding to the inner and outer leaflets of the bilayer, in accord with the fact that no two-phase kinetics were found. 

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