Metal Ion Effects in Intramolecular Reactions. Effects of Divalent Metal Ions on Intramolecular Acetamido Group Participation in Ester Hydrolysis

Article abstract of DOI:10.1021/ja00232a031

The hydrolysis reactions of a series of esters of α-acetamidocinnamic acid proceed with formation of an oxazolinone intermediate.In 50percent dioxane-H2O (v/v) at 50 deg C, an oxazolinone can be observed spectrophotometrically in the OH- catalyzed cyclization reactions of the α-acetamido-substituted esters with leaving groups of pK_a 12.4 or less.In comparison with the OH- catalyzed hydrolysis of the corresponding cinnamate esters, the rate enhancement due to the presence of the acetamido group is a factor of 200 with the trifluoroethyl ester and increases to 2x1E6 with the p-nitrophenyl ester.The plot of log k_OH vs ?, the Hammett substituent constant, is linear and has a slope (ρ) of 2.7 (1.8 when ?^- is employed) for the cyclization reactions of the phenolic esters, but the ρ value is only 1.4 for the OH- catalyzed hydrolysis of the corresponding cinnamates.The slope of log k_OH vs the pK_a of the leaving group for the cyclization of the α-acetamidocinnamic acid derivatives, β_lg, is -0.9.Thus, there must be considerable C-O bond breaking in the critical transition state for oxazolinone formation.In H2O as the solvent, 6-carboxy-2-pyridylmethyl α-(N-acetylamino)cinnamate and the corresponding 2-pyridylmethyl derivative cyclize rapidly to the oxazolinone with K_OH (5xE4)-fold larger than that for hydrolysis of 2-pyridylmethyl cinnamate, even though the leaving group is an aliphatic alcohol.There is significant metal ion catalysis in the cyclization reactions with Cu2+, Ni2+, Co2+ or Zn2+.The binding of the metal ions to the 6-carboxy-substituted derivative is very strong, and saturation occurs at metal ion concentrations less than 0.01 M.A saturating concentration of Cu2+ (0.001 M) enhances the rate of cyclization by a factor of 5x1E4.Thus, the total rate enhancement provided by bifunctional catalysis (Cu2+ and the neighboring acetamido group) is 1E9-fold.Metal ion binding to 2-pyridylmethyl α-(N-acetylamino)cinnamate is weak, but nevertheless, the second-order rate constants k_OH are similar to those of the 6-carboxy-substituted ester at equal metal ion concentrations.The metal ions must exert their catalytic effect by stabilizing the leaving group alcohol in the transition state.This appears to be a general mechanism for metal ion catalysis of reactions in which C-O bond breaking is the rate-determining step.