Substituent Effects on Electrophilic Catalysis by the Carbonyl Group: Anatomy of the Rate Acceleration for PLP-Catalyzed Deprotonation of Glycine

First-order rate constants, determined by H-1 NMR, are reported for deuterium exchange between solvent D2O and the alpha-amino carbon of glycine in the presence of increasing concentrations of carbonyl compounds (acetone, benzaldehyde, and salicylaldehyde) and at different pD and buffer concentrations. These rate data were combined with H-1 NMR data that define the position of the equilibrium for formation of imines/iminium ions from addition of glycine to the respective carbonyl compounds, to give second-order rate constants k(DO) for deprotonation of alpha-imino carbon by DO-. The assumption that these second-order rate constants lie on linear structure-reactivity correlations between log k(OL) and pK(a) was made in estimating the following pK(a)'s for deprotonation of alpha-imino carbon: pK(a) = 22, glycine-acetone iminium ion; pKa = 27, glycine-benzaldehyde imine; pK(a) approximate to 23, glycine-benzaldehyde iminium ion; and, pK(a) = 25, glycine-salicylaldehyde iminium ion. The much lower pK(a) of 17 [Toth, K; Richard, J. P.J. Am. Chem. Soc. 2007,129,3013-3021] for carbon deprotonation of the adduct between 5'-deoxypyridoxal (DPL) and glycine shows that the strongly electron-withdrawing pyridinium ion is unique in driving the extended delocalization of negative charge from the alpha-iminium to the alpha-pyridinium carbon. This favors carbanion protonation at the alpha-pyridinium carbon, and catalysis of the 1,3-aza-allylic isomerization reaction that is a step in enzyme-catalyzed transamination reactions. An analysis of the effect of incremental changes in structure on the activity of benzaldehyde in catalysis of deprotonation of glycine shows the carbonyl group electrophile, the 2-O- ring substituent and the cation pyridinium nitrogen of DPL each make a significant contribution to the catalytic activity of this cofactor analogue. The extraordinary activity of DPL in catalysis of deprotonation of a-amino carbon results from the summation of these three smaller effects.