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

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 k_B = 4.8 × 10^-8 M^-1 s^-1 for deprotonation of acetamide by quinuclidine (pK_BH = 11.5) and k_BH = 2-5 × 109 M^-1 s^-1 for the encounter-limited reverse protonation of the enolate by protonated quinuclidine give pK_a^c = 28.4 for ionization of acetamide as a carbon acid. The limiting value of k_HOH = 1 × 10¹¹ s^-1 for protonation of the enolate of acetate anion by solvent water and k_HO = 3.5 × 10^-9 M^-1 s^-1 for deprotonation of acetate anion by HO^- give pK_a^c ≈ 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 k_HO against carbon acid pK_a for deprotonation of a wide range of neutral α-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 α-SEt, α-OMe, α-NH₂, and (αO^- substituents. The α-NH₂ and α-OMe groups show similar stabilizing interactions with the carbonyl group, while the interaction of α-O^- is only 3.4 kcal/mol more stabilizing than for α-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.