Concerted or Stepwise Mechanisms for Acyl Transfer Reactions of p-Nitrophenyl Acetate? Transition State Structures from Isotope Effects

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Journal of the American Chemical Society

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Isotope effects have been measured for the acyl transfer reactions of p-nitrophenyl acetate (PNPA) with the oxyanion nucleophiles hydroxide, phenolate, and the anion of hexafluoroisopropyl alcohol; with the sulfur anions of mercaptoethanol and methyl 3-mercaptopropionate; and with the nitrogen nucleophile methoxyethylamine. The kinetic isotope effects measured were the oxygen-18 isotope effects in the carbonyl oxygen, 18kcarbonyl, and in the phenolic oxygen atom of the leaving group, 18klg; the ��-deuterium isotope effect in the acetyl group, Dk, and the nitrogen-15 isotope effect in the leaving group, 15k. The equilibrium phenolic oxygen-18 (18Keq = 1.0277 ± 0.0007) and nitrogen-15 (15Keq = 1.0016 ± 0.0006) isotope effects for the equilibrium between p-nitrophenolate anion and PNPA were also determined. The 15k and 18klg kinetic isotope effects for the hydroxide reaction with PNPA are smaller than for the other oxyanion nucleophiles, suggesting an earlier transition state. For the other oxyanion nucleophiles 15k was about 1.0010, versus near unity for the sulfur nucleophiles; 18kcarbonyl for oxyanions ranged from 1.0039 to 1.0058; versus from 1.0117 to 1.0119 for thiolates. Values for 18klg were between 1.0182 and 1.0210 for oxyanions, and 1.0172 and 1.0219 for thiolates. The Dk effects were between 0.9481 and 0.9617 for oxyanions, and 0.9765 and 0.9780 for thiolates. The transition state structures implied by these data are consistent with studies by others using phenolate nucleophiles which concluded that the acyl transfer process is concerted, with no intermediate. The isotope effect data indicate that the transition state for the reaction with phenolate is not substantively different from that with an aliphatic oxyanion nucleophile of similar pKa. The reactions with thiolate nucleophiles have a considerably different transition state structure, characterized by greater loss of the carbonyl ��-bond and the maintenance of more positive charge on the carbonyl carbon atom. The degree of transition state bond cleavage to the leaving group is similar for oxyanion and thiolate nucleophiles. Acyl transfer to the nitrogen nucleophile methoxyethylamine gave 15k = 1.0011, 18klg = 1.0330, 18kcarbonyl = 1.0064, and Dk = 0.9682. These data require that bond fission to the leaving group is well advanced in the rate-limiting step.

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