An examination of hyperconjugative and electrostatic effects in the hydride reductions of 2-substituted-4-tert-butylcyclohexanones

Article abstract of DOI:10.1021/jo0011787

To better understand electronic effects on the diastereoselectivity of nucleophilic additions to the carbonyl group, a series of 2-X-4-tert-butylcyclohexanones (X = H, CH₃, OCH₃, F, Cl, Br) were reacted with LiAlH₄. Reduction of ketones with equatorial substituents yields increasing amounts of axial alcohol in the series for X {H < CH₃ < Br < Cl < F ? OCH₃}. These data cannot be explained by steric or chelation ·effects or by the theories of Felkin-Anh or Cieplak. Instead, an electrostatic argument is introduced: due to repulsion between the nucleophile and the X group, axial approach becomes energetically less favorable with an increase in the component of the dipole moment anti to the hydride approach trajectory. The ab initio calculated diastereoselectivities were close to the experimental values but did not reproduce the relative selectivity ordering among substituents. For reduction of ketones with axial substituents, increasing amounts of axial alcohol are seen in the series for X {Cl < Br < CH₃ < OCH₃ < H < F}. After some minor adjustments are made, this ordering is consistent with both the electrostatic model and Felkin-Anh theory. Cieplak theory cannot account for these data regardless of adjustments. Ab initio calculated diastereoselectivities were reasonably accurate for the nonpolar substituents but were poor for the polar substituents.