α‐Fluoro‐o‐cresols: The Key Role of Intramolecular Hydrogen Bonding in Conformational Preference and Hydrogen‐Bond Acidity

Abstract

The conformational preferences of o-cresols driven by fluorination have been thoroughly investigated from a theoretical point of view with quantum chemical methods and compared to those recently reported for benzyl alcohols. Key conformers of both families exhibit a 6-membered intramolecular hydrogen-bond (IMHB) interaction. A significant enhancement of IMHB strength is observed in -fluoro-o-cresols, owing to the simultaneous increase of the aliphatic fluorine hydrogen-bond (HB) basicity and of the aromatic hydroxyl HB acidity, compared to o-fluorobenzyl alcohols, which are characterized by aromatic fluorine atoms and aliphatic hydroxyl groups. In the case of di-and trifluorinated derivatives, the occurrence of a three-centre hydrogen-bond is emphasised and its features discussed. The impact of these structural predilections on ocresol HB properties has been characterised from the estimation of the HB acidity parameter, pKAHY, weighted according to their conformational populations. We find that -fluorination leads to an HB acidity decrease of the hydroxyl group (in contrast with o-fluorination of benzyl alcohols), whereas ,-difluorination results in no significant variation of pKAHY. Finally, an increase of HB acidity is predicted upon methyl perfluorination, which has been confirmed experimentally. Theoretical descriptors based on AIM, NCI and NBO analyses allows rationalizing the predicted trends, and reveal a relationship with the strength of the established OHF IMHB.

Influence of Alcohol β‐Fluorination on Hydrogen‐Bond Acidity of Conformationally Flexible Substrates

“…AIM analysis may lead to the localization of a bond critical point (BCP) between the fluorine and the hydroxyl hydrogen atoms. From the potential energy densities ( V b ) computed at the BCP, the energy ( E HB ) of the corresponding IMHB interaction can be estimated . Unfortunately, these analyses systematically failed to find any BCP in the β‐fluorohydrin series, which is in agreement with literature reports of similar 5‐membered IMHB motifs…”

“…Regardless of the series, the highest V α (r) values are computed for the trifluorinated alcohols, followed systematically by the difluorinated alcohols, and finally the monofluorinated derivatives. As already depicted and rationalized for other fluorohydrin derivatives, it is worth noting that the values calculated for non‐fluorinated compounds are located between the mono‐ and the difluoroalcohols (except in series 5 , see Table S7 in the Supporting Information).…”

“…Hence, with one exception, this clearly demonstrates the validity of the Kenny electrostatic descriptor V α (r) in probing the hydrogen‐bond donating capacity of fluorohydrins, the effects of fluorination being well‐reflected. An excellent correlation between p K AHY and V α (r) for all hydroxyl H‐bond donors studied so far (78 compounds), including the current series of 15 alcohols, is shown in Figure . The resulting sample yields a robust correlation equation, [Eq.…”

“…A full description of the H‐bond properties of functional groups is innately connected with their thorough conformational analysis, which was undertaken for the compounds under study by density functional theory (DFT) calculations. For a proper description of their structural features and the relative populations of the various conformers, the solvent effects (CCl 4 in the current experiments) were accounted for during geometry optimization.…”

A Study of Intramolecular Hydrogen Bonding in Levoglucosan Derivatives

“…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 , …”