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 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. T...

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Veröffentlicht in:Journal of the American Chemical Society 2011-03, Vol.133 (9), p.3173-3183
Hauptverfasser: Crugeiras, Juan, Rios, Ana, Riveiros, Enrique, Richard, John P
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creator Crugeiras, Juan
Rios, Ana
Riveiros, Enrique
Richard, John P
description 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.
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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. 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Am. Chem. Soc</addtitle><description>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. 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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. 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subjects Acetone - chemistry
Aldehydes - chemistry
Benzaldehydes - chemistry
Catalysis
Glycine - chemistry
Imines - chemistry
Protons
Pyridoxal - analogs & derivatives
Pyridoxal - chemistry
title Substituent Effects on Electrophilic Catalysis by the Carbonyl Group: Anatomy of the Rate Acceleration for PLP-Catalyzed Deprotonation of Glycine
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