Understanding the Relative Acyl-Transfer Reactivity of Oxoesters and Thioesters:  Computational Analysis of Transition State Delocalization Effects

Abstract

Computational studies were performed in an effort to understand the relative reactivity of oxoesters and thioesters in nucleophilic acyl transfer reactions. Transition state models were developed for the reactions of methyl acetate and methyl thioacetate with hydroxide, ammonia, and methylcyanoacetate carbanion. Quantum mechanical calculations based on these models reproduced experimental observations that oxoesters and thioesters have similar reactivity toward hydroxide while thioesters are about 100-fold and at least 2000-fold more reactive than oxoesters toward amine and carbanion nucleophiles, respectively. NBO analysis was performed to elucidate the role of electron delocalization in reactant and transition state stabilization. These calculations indicate similar losses of delocalization energy for the oxoester and thioester in going from the reactants to the transition state in reaction with hydroxide while the loss of delocalization energy is significantly greater for the oxoester in reactions with the other nucleophiles. Bond rotational analysis of the transition states for the reactions with hydroxide and ammonia provide support for an important role of the p(X) --> sigma(C-Nu) interaction (X = O or S of the oxoester or thioester respectively, Nu = nucleophile) in governing the reactivity of oxoesters and thioesters in nucleophilic acyl substitution.

An Unprecedented Combination of Serine and Cysteine Nucleophiles in a Split Intein with an Atypical Split Site

“…Together, these observations raise the question if a Ser/Cysϩ1 combination is potentially incompatible with an efficiently splicing intein. The simple chemical explanation would be that a thioester is more energy-rich than an oxoester (22).…”

S-Phenyl 4-methoxybenzothioate

“…For background to and applications of thioesters, see : Agapiou & Krische (2003); Choi et al (2003); El-Azab & Abdel-Aziz (2012); Horst et al (2007); Howell et al (2006); Jew et al (2003); Liebeskind & Srogl (2000); McGarvey et al (1986); Ozaki et al (2003); Shah et al (2002); Yang & Drueckhammer (2001). For related structures and the synthesis of similar compounds, see: Barbero et al (2003).…”

“…Recently, the α-β-unsaturated thioester analogs have been successfully applied for asymmetric additions which allow the access to chiral intermediates for the synthesis of more complex compounds. Furthermore, they were used in natural product synthesis and also are acting as biologically relevant substances finding application for in vivo tumor suppression (Agapiou & Krische (2003); Barbero et al, 2003;Choi et al, 2003;Horst et al, 2007;Howell et al, 2006;Jew et al, 2003;Liebeskind & Srogl 2000;McGarvey et al, 1986;Ozaki et al, 2003;Shah et al, 2002;Yang & Drueckhammer, 2001). Owing to these applications of thioesters, the title compound (I) was synthesized.…”

Direct and Efficient Conversion of Tertiary Thioamides to S-2-Oxo Thioesters under Solvent-free Conditions

“…[10][11][12] Also, thioesters have distinct chemical properties compared to ordinary esters 13 and their enhanced reactivity has been employed successfully in a wide range of synthetic organic reactions.…”