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.

Halogen bond (X-bond) interactions involving organic iodine have been investigated using data retrieved from the Cambridge Structural Database (CSD) and Density Functional Theory (DFT) calculations. The analysis of the mean normalised intermolecular distances involving Csp–I, Csp²–I and Csp³–I X-bond donors first shows that, for interactions with the same acceptor site, the shortest mean distance is always measured for Csp–I X-bond donors. This experimental trend is rationalised through molecular electrostatic potential calculations on the iodine surface, along the σ-hole of the iodine atom, since Csp–I donors are characterised by the strongest V_S,max values, that is to say the more electron poor iodine atoms. In agreement with the trends revealed from the analysis of the I⋯N distances, the X-bond with Csp–I donors appear more linear (mean of 169.5°) than with Csp²–I and Csp³–I donors, their respective values being close to 164°. From a survey of the geometries of the X-bond contacts observed in the most extended dataset (Csp²–I: 1213), a crystallographic order of X-bond acceptor strength has been obtained through a careful consideration of the chemical functions and subfunctions to which the acceptor atom belongs. This order is in good agreement with the one observed in solution on the diiodine basicity scale pK_BI2. An exception to this trend is thioureas, which show unexpected long (weak) S⋯I distances. However, these observations are rationalised from the sulfur behaviour, which acts simultaneously as a X-bond acceptor and hydrogen-bond (H-bond) acceptor in these structures. Finally, an interesting correlation between the pK_BI2 and the I⋯Y normalised intermolecular distances is found for a wide and varied collection of organic bases, since we have been able to delineate 22 families of organic compounds covering more than four pK units on the pK_BI2 scale.