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 (pKAHY) when OH•••F intramolecular hydrogenbond (IMHB) interactions occur, as opposed to an increase in pKAHY 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 -sometimes unexpected-observed differences in pKAHY 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 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 Hbond donating capacity.

A Study of Intramolecular Hydrogen Bonding in Levoglucosan Derivatives

“…Bond critical points (BCPs) related to six-membered OH···O IMHB interactions were systematically detected, whereas we were not able to find any BCP along the OH4···F and the OH4···O5 interactions. This latter defines a five-membered IMHB motifs and the AIM methodology is known to fail detecting any BCP in these conditions [ 23 , 24 , 25 ]. The interaction energies E (2) n→σ* computed from the NBO analyses pointed out charge transfer from the oxygen or the fluorine lone pairs to the hydroxyl antibonding orbital whatever the IMHB studied, but they clearly show that these interactions are very weak for the five-membered IMHBs, coherent with the AIM trends.…”

“…IMHB interactions were analyzed through AIM topological analysis of the IEF-PCM/B97-D3 BJ /6-311++G(2d,p) wavefunctions with the AIM2000 program [ 30 ]. In addition to the electron densities ρ b and their Laplacians, the potential energy density V b at the BCP were used to gain additional insights into the strength of a given HB [ 8 , 25 , 31 , 32 , 33 , 34 ]. Indeed, the HB energy can be estimated by using V b according to the established relationship in Equation (3) [ 35 ]: E HB = ½ V b , …”

Synthesis of Fluorine‐Containing Molecular Entities Through Fluoride Ring Opening of Oxiranes and Aziridines

“…Graton et al described ring opening of cyclohexene oxide 88 under these conditions in almost quantitative yield (Scheme ). The reaction proceeded with inversion at the epoxide carbon …”

Photocatalytic Difluoromethylation Reactions of Aromatic Compounds and Aliphatic Multiple C–C Bonds

“…The phosphonodifluoromethylation of alkenes has been documented to proceed through diverse methods such as nucleophilic addition [47][48][49][50][51][52][53][54], transition metal catalysis [55][56][57][58], photoredox catalysis (by oxidative quenching cycles) [59][60][61][62][63], or radical ATRA reactions [64][65][66][67][68][69], as depicted in Scheme 15.…”