Influence of Alcohol beta-Fluorination on Hydrogen-Bond Acidity of Conformationally Flexible Substrates

International audienceRational 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 pK(AHY)) when OH center dot center dot center dot F intramolecular hydrogen-bond (IMHB) interactions occur, as opposed to an increase in pK(AHY) due to the fluorine electronegativity. This work has now been extended to a wider range of aliphatic beta-fluorohydrins with increasing degrees of conformational flexibility. We show that the observed differences in pK(AHY) between closely related diastereomers can be fully rationalized by subtle variations in populations of conformers able to engage in OH center dot center dot center dot F IMHB, as well as by the strength of these IMHBs. We also show that the Kenny theoretical V-alpha(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 center dot center dot center dot F IMHB in the modulation of alcohol H-bond donating capacity