Formation and stability of enolates of acetamide and acetate anion: an eigen plot for proton transfer at α-carbonyl carbon

Abstract

Second-order rate constants were determined in D2O for deprotonation of acetamide, N,N-dimethylacetamide, and acetate anion by deuterioxide ion and for deprotonation of acetamide by quinuclidine. The values of kB = 4.8 × 10-8 M-1 s-1 for deprotonation of acetamide by quinuclidine (pKBH = 11.5) and kBH = 2-5 × 109 M-1 s-1 for the encounter-limited reverse protonation of the enolate by protonated quinuclidine give pKaC = 28.4 for ionization of acetamide as a carbon acid. The limiting value of kHOH = 1 × 1011 s-1 for protonation of the enolate of acetate anion by solvent water and kHO = 3.5 × 10-9 M-1 s-1 for deprotonation of acetate anion by HO- give pKaC 33.5 for acetate anion. The change in the rate-limiting step from chemical proton transfer to solvent reorganization results in a downward break in the slope of the plot of log kHO against carbon acid pKa for deprotonation of a wide range of neutral -carbonyl carbon acids by hydroxide ion, from -0.40 to -1.0. Good estimates are reported for the stabilization of the carbonyl group relative to the enol tautomer by electron donation from -SEt, -OMe, -NH2, and -O- substituents. The -NH2 and -OMe groups show similar stabilizing interactions with the carbonyl group, while the interaction of -O- is only 3.4 kcal/mol more stabilizing than for -OH. We propose that destabilization of the enolate intermediates of enzymatic reactions results in an increasing recruitment of metal ions by the enzyme to provide electrophilic catalysis of enolate formation.