Solvent effects on the sodium borohydride reduction of 2-halocyclohexanones

We have investigated the stereoselectivity and reactivity of the sodium borohydride reduction of 2-X-cyclohexanones (X=H, Cl, Br) using a combined approach of competitive experiments and density functional theory calculations. Our results show that the hydride addition proceeds via a late transition state in which the C-H bond is nearly formed, consistent with the mild reducing power of NaBH4. The reaction barrier decreases from the 2-halocyclohexanones to the unsubstituted cyclohexanone, in line with relative reactivities observed in the competitive experiments. Furthermore, we provide a protocol to solve the longstanding issue of properly modelling the axial-equatorial facial selectivity of hydride addition to the carbonyl group substituted with a vicinal polar group. The inclusion of implicit solvation in combination with an explicit solvent molecule is crucial to reproduce the stereoselective formation of the cis product observed experimentally.

Automated summary

We investigated the stereoselectivity and reactivity of sodium borohydride reduction of 2-X-cyclohexanones (X=H, Cl, Br) using a combined approach of competitive experiments and density functional theory calculations. The results showed that the hydride addition proceeded via a late transition state and the reaction barrier decreased as the halogen substitution decreased, in line with relative reactivities observed in the competitive experiments. Moreover, including implicit solvation in combination with an explicit solvent molecule was crucial to accurately reproduce the experimentally observed stereoselective formation of the cis product.