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

Abstract

First-order rate constants, determined by ¹H NMR, are reported for deuterium exchange between solvent D₂O and the α-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 ¹H 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 α-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 α-imino carbon: pK_a = 22, glycine−acetone iminium ion; pK_a = 27, glycine−benzaldehyde imine; pK_a ≈ 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 α-iminium to the α-pyridinium carbon. This favors carbanion protonation at the α-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 α-amino carbon results from the summation of these three smaller effects.