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...

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Bibliographic Details
Published in:Journal of physical organic chemistry 2023-10, Vol.36 (10)
Main Authors: Rodrigues Silva, Daniela, Zeoly, Lucas A., Vermeeren, Pascal, Cormanich, Rodrigo A., Hamlin, Trevor A., Fonseca Guerra, Célia, Freitas, Matheus P.
Format: Article
Language:English
Subjects:
Borohydrides
Carbonyl groups
Carbonyls
Cyclohexanone
Density functional theory
Hydrides
Hydrogen bonds
Reduction
Sodium
Solvation
Solvent effect
Stereoselectivity
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Summary: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 NaBH 4 . 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.
ISSN:0894-3230
1099-1395
DOI:10.1002/poc.4556