An Examination of Hyperconjugative and Electrostatic Effects in the Hydride Reductions of 2-Substituted-4-tert-butylcyclohexanones

Abstract

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, CH(3), OCH(3), F, Cl, Br) were reacted with LiAlH(4). Reduction of ketones with equatorial substituents yields increasing amounts of axial alcohol in the series for X [H < CH(3) < Br < Cl < F << OCH(3)]. 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 < CH(3) < OCH(3) < 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.

Stereodivergent synthesis of jaspine B and its isomers using a carbohydrate-derived alkoxyallene as C3-building block

“…We assume that in both diastereomers the azido group occupies a pseudoaxial position shielding this face of the furanone ring and therefore steers the hydride attack to the other side. Similar observations have been reported for the reduction of carbonyl compounds bearing an electronegative group in α-position [37]. After palladium-catalyzed hydrogenolysis of α-azidotetrahydrofuranols rac - 9 and rac - 10 an inseparable mixture of racemic jaspine B ( rac - 1 ) and its C-2-epimer rac - 2 was obtained.…”

Understanding organofluorine chemistry. An introduction to the C–F bond

“…20. 55 During the reduction of 62 ax the nucleophile approaches anti rather than gauche to the fluorine with a large preference of 10 : 1. There has been some debate over competing frontier orbital hypotheses (e.g.…”

Felkin–Anh is not enough

“…A second explanation, mentioned above, is due to Cieplak . While this theory has been challenged it continues to find occasional use . Like the other models, Cieplak accepts the formation of Felkin's six staggered TSs.…”

“…The steric demands of the Grignard reagents obscure the relative importance of the electronic effects in this system. In other mechanistic studies, hydride additions to polar ketones such as 4‐ tert ‐butyl‐2‐X‐cyclohexanones and 2‐substituted dibenzocycloheptenones have been used to argue against the Cieplak mechanism, discussed below. There are numerous other examples where hydride additions are used to probe subtle electronic effects in sterically unbiased ketones .…”