Thorpe-Ingold acceleration of oxirane formation is mostly a solvent effect

J Am Chem Soc. 2010 Jun 30;132(25):8766-73. doi: 10.1021/ja1023755.

Abstract

The Thorpe-Ingold hypothesis for the gem-dimethyl effect in the cyclization reactions of 2-chloroethoxide derivatives has been investigated computationally in the gas phase and in aqueous solution. Ab initio MP2/6-311+G(d,p) and CBS-Q calculations reveal little intrinsic difference in reactivity with increasing alpha-methylation for the series of reactants 1-3. However, inclusion of continuum hydration or of explicit hydration through mixed quantum and statistical mechanics (MC/FEP) simulations does reproduce the substantial, experimentally observed rate increases with increasing alpha-methylation. Analysis of the MC/FEP results provides clear evidence that the rate increases stem primarily from increased steric hindrance to hydration of the nucleophilic oxygen atom with increasing alpha-methylation. Thus, the gem-dimethyl acceleration of oxirane formation for 1-3 is found to be predominantly a solvent effect.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Chlorohydrins / chemistry
  • Cyclization
  • Ethylene Oxide / chemistry*
  • Hydrogen-Ion Concentration
  • Kinetics
  • Models, Molecular
  • Molecular Conformation
  • Monte Carlo Method
  • Quantum Theory
  • Solvents / chemistry*
  • Thermodynamics

Substances

  • Chlorohydrins
  • Solvents
  • Ethylene Oxide