An Unexpected and Significantly Lower Hydrogen‐Bond‐Donating Capacity of Fluorohydrins Compared to Nonfluorinated Alcohols

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

“…26 This modulation is actually closer to the variations previously observed in the case of cyclic fluorohydrins. 21 Therefore, this study reports new qualitative and quantitative features of OHF IM H-bonding in -fluoro-o-cresols and its impact on the hydroxyl group ability to behave as hydrogenbond donor with an external acceptor. These findings will be of interest in the various fields where intermolecular hydrogen bonding are key interactions, for example in protein-ligand binding and in catalyst ligand design.…”

“…In recent studies, we have confirmed the interest of V(r), initially introduced by Kenny,33 to appropriately estimate the HB acidity of hydroxyl compounds, 27 as well as to take into account the fluorine influence on this property. 21,26 We have therefore calculated V(r) for the current series of cresol derivatives. The conformational analysis carried out above allows us to calculate weighted values of V(r), reported in Table 3 with the estimated pK AHY values, and illustrated in Figure 7.…”

“…After the debate about the effective ability of fluorine to act as a hydrogen-bond (H-bond, HB) acceptor, [11][12][13][14][15] the occurrence of intermolecular OHF H-bonding is now clearly established through experimental and theoretical evidences. [16][17][18][19][20] The existence of intramolecular hydrogen bonds (IMHBs) involving fluorine has also been scrutinised and highlighted experimentally through NMR techniques for conformationally constrained, [21][22][23] partially flexible, 24 and even fully flexible fluorohydrins. 25 We have recently reported that the intermolecular hydroxyl H-bond donating capacity (or HB acidity) in conformationally fixed fluorohydrins (eg 1, Figure 1) 21 and partially flexible benzyl alcohols (eg 2) 26 is deeply influenced by the conformational preferences dictated by the presence of such IMHBs.…”

“…[16][17][18][19][20] The existence of intramolecular hydrogen bonds (IMHBs) involving fluorine has also been scrutinised and highlighted experimentally through NMR techniques for conformationally constrained, [21][22][23] partially flexible, 24 and even fully flexible fluorohydrins. 25 We have recently reported that the intermolecular hydroxyl H-bond donating capacity (or HB acidity) in conformationally fixed fluorohydrins (eg 1, Figure 1) 21 and partially flexible benzyl alcohols (eg 2) 26 is deeply influenced by the conformational preferences dictated by the presence of such IMHBs. Thus, the H-bond acidity of 1 was significantly decreased, and attributed to a rather strong IMHB (6-membered ring motif).…”

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

“…[5] On the other hand, the fluorine influence on H-bond properties of adjacent functional groups has been shown to be less chemically intuitive. While the strong increase in H-bond donating capacity (H-bond acidity) of polyfluorinated alcohols such as hexafluoroisopropanol (HFIP) and trifluoroethanol (TFE) has been well-documented, [6] our work involving stereochemically defined, conformationally rigid fluorohydrins [7] ( Figure 1) shows that monofluorination can lead to a decreased OH H-bond acidity on the pKAHY scale, [6c] and that β,β-difluorination only leads to a modest increase. The Hbond acidities were measured in CCl4 at 25°C by FTIR spectroscopy.…”