Intramolecular OHFluorine Hydrogen Bonding in Saturated, Acyclic Fluorohydrins: The gamma -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 OHF intr...

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Bibliographic Details
Published in:Chemistry : a European journal 2015-12, Vol.21 (49), p.17808-17816
Main Authors: Linclau, Bruno, Peron, Florent, Bogdan, Elena, Wells, Neil, Wang, Zhong, Compain, Guillaume, Fontenelle, Clement Q, Galland, Nicolas, LeQuestel, Jean-Yves, Graton, Jerome
Format: Article
Language:English
Subjects:
Aliphatic alcohols
Chains
Constants
Drugs
Fluorination
Fluorine
Hydrogen bonding
Stereochemistry
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Summary: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 OHF 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 OHF IMHBs in acyclic saturated gamma -fluorohydrins, even for the parent 3-fluoropropan-1-ol. The relative stereochemistry is shown to have a crucial influence on the corresponding super(h1)J sub(OHF) values, as illustrated by syn- and anti-4-fluoropentan-2-ol (6.6 and 1.9Hz). The magnitude of OHF 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 OHF IMHB energies. Surprisingly, the predicted OHF IMHB energies are only moderately weaker than these of the corresponding OHOMe. These results provide new insights of the impact of fluorination of aliphatic alcohols, with attractive perspectives for rational drug design. HB source: Intramolecular OHfluorine hydrogen bonding in acyclic, saturated gamma -fluorohydrins is evidenced by the presence of super(h1)J sub(OHF) coupling constants (up to 6.6Hz at 25 degree C). A thorough analysis of the fluorohydrin conformational profile and the OHF intramolecular hydrogen-bond energies is fully consistent with experimental NMR data and provides insight into the competing stabilizing and repulsive interactions that determine the extent of intramolecular hydrogen bonding.
ISSN:0947-6539
1521-3765
DOI:10.1002/chem.201503253