Fluorinated carbohydrates have become indispensable in glycosciences. This contribution provides an overview of how fluorine introduction modifies physical and chemical properties of carbohydrates along with selected examples of its applications.

Property tuning by fluorination is very effective for a number of purposes, and currently increasingly investigated for aliphatic compounds. An important application is lipophilicity (log P) modulation. However, the determination of log P is cumbersome for non‐UV‐active compounds. A new variation of the shake‐flask log P determination method is presented, enabling the measurement of log P for fluorinated compounds with or without UV activity regardless of whether they are hydrophilic or lipophilic. No calibration curves or measurements of compound masses/aliquot volumes are required. With this method, the influence of fluorination on the lipophilicity of fluorinated aliphatic alcohols was determined, and the log P values of fluorinated carbohydrates were measured. Interesting trends and changes, for example, for the dependence on relative stereochemistry, are reported.

Fluorination is commonly employed to optimize bioactivity and pharmaco-kinetic properties of drug candidates. Aliphatic fluorination often reduces the lipophilicity (log P), but polyfluoroalkylation typically increases lipophilicity. Hence, identification of polyfluorinated motifs that nonetheless lead to similar or even reduced lipophilicities is of interest to expand the arsenal of medicinal chemistry tools in tackling properties such as compound metabolic stability or off-target selectivity. We show that changing a CF₃-group of a perfluoroalkyl chain to a methyl group leads to a drastic reduction in lipophilicity. We also show that changing a C–F bond of a trifluoromethyl group, including when incorporated as part of a perfluoroalkyl group, to a C–Me group, leads to a reduction in log P, despite the resulting chain elongation. The observed lipophilicity trends were identified in fluorinated alkanol models and reproduced when incorporated in analogues of a drug candidate, and the metabolic stability of these motifs was demonstrated.

Rewriting the rules as fluorination does not always increase hydrogen‐bond acidity: while the strongly electron‐withdrawing fluorine significantly enhances alcohol H‐bond acidity in anti‐vicinal fluorohydrins, an intramolecular F⋅⋅⋅HO interaction overrules completely the inductive effect. This leads to an overall decrease in alcohol H‐bond acidity, compared to the corresponding nonfluorinated alcohol.