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Influence of Alcohol β‐Fluorination on Hydrogen‐Bond Acidity of Conformationally Flexible Substrates
Author(s) -
Graton Jerome,
Compain Guillaume,
Besseau Francois,
Bogdan Elena,
Watts Joseph M.,
Mtashobya Lewis,
Wang Zhong,
WeymouthWilson Alex,
Galland Nicolas,
Le Questel JeanYves,
Linclau Bruno
Publication year - 2017
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201604940
Subject(s) - hydrogen bond , intramolecular force , chemistry , conformational isomerism , diastereomer , electronegativity , alcohol , fluorine , cyclohexanol , computational chemistry , stereochemistry , molecule , organic chemistry , catalysis
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 p K AHY ) when OH⋅⋅⋅F intramolecular hydrogen‐bond (IMHB) interactions occur, as opposed to an increase in p K AHY due 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 p K AHY between 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 V α (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.