Formation and stability of organic zwitterions in aqueous solution: Enolates of the amino acid glycine and its derivatives

Second-order rate constants for carbon deprotonation of glycine zwitterion, N-protonated glycine methyl ester, betaine methyl ester, and betaine by deuterioxide ion in D2O have been determined by following deuterium exchange into these carbon acids in buffered solutions at 25 degrees C and I = 1.0 (KCl) by H-1 NMR spectroscopy. The data were used to calculate the following carbon acidities for glycine zwitterion and its derivatives in aqueous solution: +H3NCH2CO2-, pK(a) = 28.9 +/- 0.5; +H3NCH2CO2Me, pK(a) = 21.0 +/- 1.0; +Me3NCH2CO2Me, pK(a) = 18.0 +/- 1.0; +Me3NCH2CO2-, pK(a) = 27.3 +/- 1.2. The rate constants for deprotonation of glycine methyl ester by Bronsted base catalysts are correlated by beta = 0.92. Two important differences between structure-reactivity relationships for deprotonation of neutral alpha-carbonyl carbon acids and cationic esters are attributed to the presence of the positively charged ammonium substituent at the latter carbon acids: (1) The smaller negative deviation of log k(DO) from the Bronsted correlation for deprotonation of +H3NCH2CO2Me than for deprotonation of ethyl acetate is attributed to stabilization of the transition state for enolization by electrostatic interactions between DO- and the positively charged ammonium substituent. (2) The positive deviation of log k(HO) for deprotonation of cationic esters from the rate-equilibrium correlation for deprotonation of neutral alpha-carbonyl carbon acids is attributed to both transition-state stabilization by these same electrostatic interactions and movement of negative charge at the product enolate away from oxygen and onto the alpha-carbon. This maximizes the stabilizing interaction of this negative charge with the positively charged ammonium substituent and leads to a reduction in the Marcus intrinsic barrier to proton transfer, as a result, of the decreased resonance stabilization of the enolate. The implications of these results for enzymatic catalysis of racemization of amino acids is discussed.