AbstractThe conformational preferences of o‐cresols driven by fluorination were thoroughly investigated from a theoretical point of view with quantum‐chemical methods, and the results were compared to those recently reported for benzyl alcohols. The key conformers of both families exhibit a six‐membered intramolecular hydrogen‐bond (IMHB) interaction. A significant enhancement in the strength of the IMHB is observed in α‐fluoro‐o‐cresols, owing to a simultaneous increase in the hydrogen bond (HB) basicity of the aliphatic fluorine and the HB acidity of the aromatic hydroxyl relative to that observed for o‐fluorobenzyl alcohols, which are characterized by aromatic fluorine atoms and aliphatic hydroxyl groups. In the cases of the di‐ and trifluorinated derivatives, the occurrence of a three‐centered HB is emphasized, and its features are discussed. The impact of these structural predilections on the HB properties of o‐cresol was characterized from the estimation of the HB acidity parameter, pK_AHY, weighted according to their conformational populations. We found that α‐fluorination led to a decrease in the HB acidity of the hydroxyl group (in contrast with the o‐fluorination of benzyl alcohols), whereas α,α‐difluorination resulted in no significant variation in pK_AHY. Finally, an increase in the HB acidity was predicted upon methyl perfluorination, which was confirmed experimentally. Theoretical descriptors based on atoms in molecules, noncovalent interactions, and natural bond orbital analyses allowed rationalization of the predicted trends and revealed a relationship with the strength of the established OH⋅⋅⋅F IMHB.