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Intramolecular OH···fluorine hydrogen bonding in saturated, acyclic fluorohydrins: the γ-fluoropropanol motif

Intramolecular OH···fluorine hydrogen bonding in saturated, acyclic fluorohydrins: the γ-fluoropropanol motif
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 h1JOH...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.
NMR spectroscopy, fluorination, hydrogen bonds, intramolecular interactions, quantum calculations
0947-6539
17808-17816
Linclau, Bruno
19b9cacd-b8e8-4c65-af36-6352cade84ba
Peron, Florent
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Bogdan, Elena
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Wells, Neil
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Wang, Zhong
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Compain, Guillaume
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Fontenelle, Clement Q.
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Galland, Nicolas
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Le Questel, Jean-Yves
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Graton, Jérôme
12432694-552e-4a40-9935-9ff7c77fbf07
Linclau, Bruno
19b9cacd-b8e8-4c65-af36-6352cade84ba
Peron, Florent
f5ae3790-6337-4be0-8d41-9f23154f753b
Bogdan, Elena
bd2b4c26-9ae0-42eb-8397-3c8d95f48060
Wells, Neil
86312185-007b-495b-86da-4e2e5b9b8025
Wang, Zhong
fe914552-33f1-4f0a-b8a1-52b82e8cb89e
Compain, Guillaume
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Fontenelle, Clement Q.
c746c5ea-96bc-46c2-849d-47215ab58c03
Galland, Nicolas
631c189a-ea3e-4149-9f23-abec8e26e47b
Le Questel, Jean-Yves
38aea4ae-64a3-43b7-8049-ea2f351459f2
Graton, Jérôme
12432694-552e-4a40-9935-9ff7c77fbf07

Linclau, Bruno, Peron, Florent, Bogdan, Elena, Wells, Neil, Wang, Zhong, Compain, Guillaume, Fontenelle, Clement Q., Galland, Nicolas, Le Questel, Jean-Yves and Graton, Jérôme (2015) Intramolecular OH···fluorine hydrogen bonding in saturated, acyclic fluorohydrins: the γ-fluoropropanol motif. Chemistry - A European Journal, 21 (49), 17808-17816. (doi:10.1002/chem.201503253).

Record type: Article

Abstract

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 h1JOH...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.

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e-pub ahead of print date: 23 October 2015
Published date: 20 November 2015
Keywords: NMR spectroscopy, fluorination, hydrogen bonds, intramolecular interactions, quantum calculations
Organisations: Organic Chemistry: Synthesis, Catalysis and Flow

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Local EPrints ID: 384493
URI: https://eprints.soton.ac.uk/id/eprint/384493
ISSN: 0947-6539
PURE UUID: 9f32ea6d-8d9b-4c63-b44e-0b19ba4b2e94
ORCID for Bruno Linclau: ORCID iD orcid.org/0000-0001-8762-0170
ORCID for Neil Wells: ORCID iD orcid.org/0000-0002-4607-5791
ORCID for Clement Q. Fontenelle: ORCID iD orcid.org/0000-0002-1630-3407

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Date deposited: 01 Dec 2015 15:04
Last modified: 15 Aug 2019 00:51

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Contributors

Author: Bruno Linclau ORCID iD
Author: Florent Peron
Author: Elena Bogdan
Author: Neil Wells ORCID iD
Author: Zhong Wang
Author: Guillaume Compain
Author: Clement Q. Fontenelle ORCID iD
Author: Nicolas Galland
Author: Jean-Yves Le Questel
Author: Jérôme Graton

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