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 °C and I = 1.0 (KCl) by ¹H 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 β = 0.92. Two important differences between structure-reactivity relationships for deprotonation of neutral α-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 α-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 α-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.