Intramolecular OH⋅⋅⋅Fluorine Hydrogen Bonding in Saturated, Acyclic Fluorohydrins: The γ-Fluoropropanol Motif.
Fluorination is commonly exercised in compound property optimization. However, the influence of fluorination on hydrogen-bond (HB) properties of adjacent functional groups, as well as the HB-accepting capacity of fluorine itself, is still not completely understood. Although the formation of OH⋅⋅⋅F intramolecular HBs (IMHBs) has been established for conformationally restricted fluorohydrins, such interaction in flexible compounds remained questionable. Herein is demonstrated for the first time-and in contrast to earlier reports-the occurrence of OH⋅⋅⋅F IMHBs in acyclic saturated γ-fluorohydrins, even for the parent 3-fluoropropan-1-ol. The relative stereochemistry is shown to have a crucial influence on the corresponding (h1) JOH⋅⋅⋅F values, as illustrated by syn- and anti-4-fluoropentan-2-ol (6.6 and 1.9 Hz). The magnitude of OH⋅⋅⋅F IMHBs and their strong dependence on the overall molecular conformational profile, fluorination motif, and alkyl substitution level, is rationalized by quantum chemical calculations. For a given alkyl chain, the "rule of shielding" applies to OH⋅⋅⋅F IMHB energies. Surprisingly, the predicted OH⋅⋅⋅F IMHB energies are only moderately weaker than these of the corresponding OH⋅⋅⋅OMe. These results provide new insights of the impact of fluorination of aliphatic alcohols, with attractive perspectives for rational drug design.
Department of Chemistry, University of Southampton, Highfield, Southampton SO17 1BJ (UK), Fax: (+44) 23-8059-6805. bruno.linclau@soton.ac.uk.
Bruno
B
Linclau
Department of Chemistry, University of Southampton, Highfield, Southampton SO17 1BJ (UK), Fax: (+44) 23-8059-6805.
Florent
F
Peron
CEISAM UMR CNRS 6230, Faculté des Sciences et des Techniques, Université de Nantes, 2, rue de la Houssinière - BP 92208, 44322 NANTES Cedex 3 (France), Fax: (+3) 2-51-12-54-02.
Elena
E
Bogdan
Department of Chemistry, University of Southampton, Highfield, Southampton SO17 1BJ (UK), Fax: (+44) 23-8059-6805.
Neil
N
Wells
Department of Chemistry, University of Southampton, Highfield, Southampton SO17 1BJ (UK), Fax: (+44) 23-8059-6805.
Zhong
Z
Wang
Department of Chemistry, University of Southampton, Highfield, Southampton SO17 1BJ (UK), Fax: (+44) 23-8059-6805.
Guillaume
G
Compain
Department of Chemistry, University of Southampton, Highfield, Southampton SO17 1BJ (UK), Fax: (+44) 23-8059-6805.
Clement Q
CQ
Fontenelle
CEISAM UMR CNRS 6230, Faculté des Sciences et des Techniques, Université de Nantes, 2, rue de la Houssinière - BP 92208, 44322 NANTES Cedex 3 (France), Fax: (+3) 2-51-12-54-02.
Nicolas
N
Galland
CEISAM UMR CNRS 6230, Faculté des Sciences et des Techniques, Université de Nantes, 2, rue de la Houssinière - BP 92208, 44322 NANTES Cedex 3 (France), Fax: (+3) 2-51-12-54-02.
Jean-Yves
JY
Le Questel
CEISAM UMR CNRS 6230, Faculté des Sciences et des Techniques, Université de Nantes, 2, rue de la Houssinière - BP 92208, 44322 NANTES Cedex 3 (France), Fax: (+3) 2-51-12-54-02. jerome.graton@univ-nantes.fr.
Jérôme
J
Graton
NMR spectroscopy; fluorination; hydrogen bonds; intramolecular interactions; quantum calculations