The Conformational electrostatic potential as predictor for the influence of fluorination on alcohol hydrogen bonding: Identification of a CF2H-mediated cooperative effect

Abstract

Hydrogen bonding is the most important noncovalent interaction involved in molecular binding events. Herein, how γ-fluorination alters the hydrogen bond (HB)-donating capacities of aliphatic alcohol groups is described. Herein, it is shown that the increase in HB-donating capacity due to the fluorine electronegativity can be significantly attenuated by 6-membered F•••HO intramolecular HB (IMHB), to the point where even in acyclic structures a decrease in alcohol HB-donating capacity is observed. The correlation of experimental HB-donating capacities (pKAHY-scale) with an easily computed descriptor, the Kenny molecular electrostatic potential Vα(r), is discussed. It is shown that F•••HO IMHB leads to a Vα(r) reduction which, in the case of highly populated IMHB conformers, leads to an underestimation of HB-donating capacities. The use of conformational electrostatic potentials, however, was found to be very useful to describe OH•••F IMHB, as well as to explain variations in experimental alcohol HB-donating capacities. Notably, Vα(r)-analysis allowed the identification of the importance of conformational equilibria in explaining HB-donating capacity variations of identical fluorohydrin motifs, and notably it also reveals a cooperative effect involving a difluoromethyl group (CF2H) on alcohol HB-donating capacity.

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ORCID for Bruno Linclau: orcid.org/0000-0001-8762-0170

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