title: Influence of Alcohol β-Fluorination on Hydrogen-Bond Acidity of Conformationally Flexible Substrates.
abstract: Rational modulations of molecular interactions are of significant importance in compound properties optimization. We have previously shown that fluorination of conformationally rigid cyclohexanols leads to attenuation of their hydrogen-bond (H-bond) donating capacity (designated by pKAHY) when OH⋅⋅⋅F intramolecular hydrogen-bond (IMHB) interactions occur, as opposed to an increase in pKAHYdue to the fluorine electronegativity. This work has now been extended to a wider range of aliphatic β-fluorohydrins with increasing degrees of conformational flexibility. We show that the observed differences in pKAHYbetween closely related diastereomers can be fully rationalized by subtle variations in populations of conformers able to engage in OH⋅⋅⋅F IMHB, as well as by the strength of these IMHBs. We also show that the Kenny theoretical Vα(r) descriptor of H-bond acidity accurately reflects the observed variations and a calibration equation extended to fluorohydrins is proposed. This work clearly underlines the importance of the weak OH⋅⋅⋅F IMHB in the modulation of alcohol H-bond donating capacity.
authors.affiliation: 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.
authors.forename: Jerome
authors.initials: J
authors.lastname: Graton
authors.affiliation: Chemistry, University of Southampton, Highfield, Southampton, SO17 1BJ, UK.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Compain
authors.affiliation: 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.
authors.forename: Francois
authors.initials: F
authors.lastname: Besseau
authors.affiliation: 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.
authors.forename: Elena
authors.initials: E
authors.lastname: Bogdan
authors.affiliation: Chemistry, University of Southampton, Highfield, Southampton, SO17 1BJ, UK.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Watts
authors.affiliation: Chemistry, University of Southampton, Highfield, Southampton, SO17 1BJ, UK.
authors.forename: Lewis
authors.initials: L
authors.lastname: Mtashobya
authors.affiliation: Chemistry, University of Southampton, Highfield, Southampton, SO17 1BJ, UK.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Dextra Laboratories Ltd, The Science and Technology Centre, Earley Gate, Whiteknights Road, Reading, RG6 6BZ, UK.
authors.forename: Alex
authors.initials: A
authors.lastname: Weymouth-Wilson
authors.affiliation: 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.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Galland
authors.affiliation: 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.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Le Questel
authors.affiliation: Chemistry, University of Southampton, Highfield, Southampton, SO17 1BJ, UK.
authors.forename: Bruno
authors.identifier: http://orcid.org/0000-0001-8762-0170
authors.initials: B
authors.lastname: Linclau
keywords: FTIR spectroscopy; H-bond acidity; alcohols; fluorination; quantum chemistry