Computational insights into the spontaneity of epoxide formation from halohydrins and other mechanistic details of Williamson’s ether synthesis

The reaction mechanism of several Williamson‟s ether syntheses have been studied using density functional theory with triple-ζ basis sets. These computations show that the synthesis of geometrically-strained epoxide from deprotonated halohydrins is due to the combined effects of favourable solvation of the products, higher bond enthalpy of C-O bonds vs. C-Cl bonds and increased vibrational entropy of the epoxide vs. the original halohydrin. Examination of the pathways leading to the formation of larger cyclic ethers revealed that the experimentally-observed preference for the formation of five-atom rings over six-atom-rings is due to the preference of the intervening methylene groups for staggered conformations, which entails that the alkyl carbon in the reactant state leading to the six-atom cyclic ether is initially not properly aligned with the attacking alkoxide. Study of the competing elimination reactions further shows that during the synthesis of five-atom cyclic ethers the competing elimination reaction is strongly disfavoured due to steric effects. The temperature dependence of both reactions favours elimination over SN2 as temperature rises, though only when the alkoxide and the halogen moieties are not part of the same carbon chain.