Influence of Fluorination on the Conformational Properties and Hydrogen-Bond Acidity of Benzyl Alcohol Derivatives

The effect of fluorination on the conformational and hydrogen-bond (HB)-donating properties of a series of benzyl alcohols has been investigated experimentally by IR spectroscopy and theoretically with quantum chemical methods (ab initio (MP2) and DFT (MPWB1K)). It was found that o-fluorination generally resulted in an increase in the HB acidity of the hydroxyl group, whereas a decrease was observed upon o,o′-difluorination. Computational analysis showed that the conformational landscapes of the title compounds are strongly influenced by the presence of o-fluorine atoms. Intramolecular interaction descriptors based on AIM, NCI and NBO analyses reveal that, in addition to an intramolecular OH⋅⋅⋅F interaction, secondary CH⋅⋅⋅F and/or CH⋅⋅⋅O interactions also occur, contributing to the stabilisation of the various conformations, and influencing the overall HB properties of the alcohol group. The benzyl alcohol HB-donating capacity trends are properly described by an electrostatic potential based descriptor calculated at the MPWB1K/6-31+G(d,p) level of theory, provided solvation effects are taken into account for these flexible HB donors.

1 Nomenclature applied to distinguish the various benzyl alcohol conformations: Two gauche_gauche conformations can be distinguished: the so-called g_g, and the g_g (2), which is actually never observed owing to the repulsion of the OH and CH groups..

With substitution:
When the orientation of the OH group is towards the ortho-substituent, as in A, then it is proximal, in the other case (B), it is distal. The ortho-substituent has priority over the meta-substituent (C). With no, or two equal ortho-substituents, the relative orientation of the OH-group is referred to the position of the metasubstituent (D). See I and II for examples.

Substituent in-plane conformations
The O-Me group is typically located in the plane of the aromatic ring, due to the presence of the resonance structure III. In analogy with amide E and Z isomers, the E/Z nomenclature is applied here, cf E and F.
See IV and V for examples. In IV, the alcohol is distal with the OMe group, and the OMe conformation is E. In V, the ortho-substituent has priority for the alcohol conformation, but the OMe remains E.

Substituent out-of-plane conformations
In contrast to a OMe group, the trifluoromethoxy group is typically located out-of-plane, with the O-CF3 bond perpecdicular to the plane of the aromatic ring. Hence, syn/anti nomenclature now indicates their position relative to the CH2OH group, if the latter is in the gauche or perpendicular conformation: a syn conformation is when both are oriented on the same side of the ring, anti when different (see G, H). By convention, the BnOH alcohol orientation is indicated first. Hence, here it is not specified that the CF3 is perpendicular.
With the bezylic alcohol group in the planar conformation, and the trifluoromethyl group in the perpendicular conformation, the syn/anti nomenclature cannot be used any more. As shown for I, the proximal/distal nomenclature is required to indicate the relative position of the OH group, and now we do indicate that the CF3 is perpendicular (as opposed to E or Z).
Finally, when both OH and trifluoromethyl groups are perpendicular, it needs to be indicated whether they are syn or anti. Again, we do indicate that the CF3 is perpendicular (see J) For the trifluoromethyl substituted compounds, conformations can be distinguished where one of the C-F bonds is in the plane of the aromatic ring (eclipsed, K), or out-of-plane with the ring (perpendicular, L). For the former, it is indicated whether the in-plane C-F bond is distal or proximal to the CH2OH group. For the latter, it is indicated whether the out-of-plane C-F bond is syn or anti with an out-of-plane C-OH bond.
For the nitro compounds, : Though the nitro group is always planar in the non fluorinated and monofluorinated nitrobenzyl alcohol, in the difluoro derivative, it is just out of plane because of the repulsion with the fluorine atom, leading to two distinct conformations. When the C-OH is out-of-plane, reference is made with the nitro oxygen nearest to the adjacent fluorine atom. The syn descriptor is used for when this oxygen and the C-OH bond are on the same side of the aromatic ring (M), and anti when on different sides (N)., Table S1. Absolute (a.u.) and relative Gibbs free energies (kJ mol -1 ), calculated at the IEF-PCM/MPWB1K/6-31+G(d,p) and IEF-PCM/MP2/6-311++G(2d,p) levels of theory.
Electrostatic potential values V(r) for each conformer, and weighted value V(r) (in a.u.) and calculated H-bond acidity values pKAHY.

2-Fluoro-5-methoxylbenzyl alcohol
The 2-Fluoro-5-nitrobenzyl alcohol was obtained using the same procedure described for the 2-Fluorobenzyl alcohol starting from 3.0 g of starting material (

2,6-difluoro-3-nitrobenzyl alcohol
To a suspension of NaBH4 (1.9eq, 25.1mmol) in 44 mL of THF at 0 ᵒC was added the carboxylic acid (13.2mmol) dissolved in 12mL of THF over a period of 30 minutes. Then, 4.45mL of boronetrifluoride etherate were added dropwise over a period of 30 minutes. The mixture was stirred at room temperature for 15 hours and was then quench by adding dropwise HCl 1N until no gas comes out anymore. The solution is diluted with water and extract 3 times with ethyl acetate. The organic layer is dried and the solvent was evaporated. The crude mixture was purified by flash chromatography using the petrol ether / ethyl acetate (86/14 to 82/18) as eluent and the fractions were purified by HPLC (Hexane/Ethyl acetate: 78/22) which permitted to afford 1.23 g of the 2,6-difluoro-3-nitrobenzyl alcohol as a white solid (53%) and the 2-fluoro-5nitrobenzyl alcohol (35%).  Med. Chem. 1999, 7, 2647-2666 The unexpected selective monodefluorination was observed when the reduction reaction was also carried out starting with the corresponding ester using the sodium boron hydride or lithium aluminium hydride. The procedures are described below.

Procedure using LiAlH4:
To a solution of methyl 2,6-difluoro-3-nitrobenzoate (2.15g, 10.6mmol) in freshly distilled diethyl ether (100mL) was added LiAlH4 (2eq., 21.2mmol, 805mg) over a period of 10 minutes at room temperature. The mixture was stirred overnight, cooled at 0ᵒC and then quench by adding 2.2 mL of water over a period of 1 hour. The solid was filtered on celite and the solvent was evaporated under reduced pressure. The crude mixture was purified by flash chromatography using petroleum ether/ethyl acetate: 86/14 as eluent which permitted to afford the 2-fluoro-5nitrobenzyl alcohol (35%).