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

To better understand electronic effects on the diastereoselectivity of nude ophilic additions to the carbonyl group, a series of 2-X-4-tert-butylcycloh exanones (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 much less than OCH3}. Th ese data cannot be explained by steric or chelation effects or by the theor ies of Felkin-Anh or Cieplak. Instead, an electrostatic argument is introdu ced: due to repulsion between the nucleophile and the X group, axial approa ch becomes energetically less favorable with an increase in the component o f 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. Fo r 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 f or these data regardless of adjustments. Ab initio calculated diastereosele ctivities were reasonably accurate for the nonpolar substituents but were p oor for the polar substituents.