Impact of Fluorine Pattern on Lipophilicity and Acid–Base Properties of 2-(Thiofluoroalkyl)pyridines: Insights from Experiments and Statistical Modeling

Abstract

Lipophilicity and acid–base properties are two key aspects of the optimization of a compound in drug discovery. Using ¹⁹F NMR, we experimentally determined the log D^7.4 of a wide array of 2-thiofluoroalkyl (SR_F) and 2-sulfonyl fluoroalkyl (SO₂R_F) substituted pyridines and the pK_a values of their protonated counterparts. Statistical modeling based on constitutional and DFT descriptors provided further insights into the structure–property relationship, explaining the experimental observations and predicting log D^7.4 values. Our results highlight the influence of fluorination topology in SR_F fragments and demonstrate the dual effect of fluorine on molecular polarity, increasing the hydrophobic surface and the polarity of the sulfur moiety. By analyzing methyl- and ethyl-derived fragments, we found a gradient in log D^7.4 values influenced by the oxidation state of the sulfur atom and fluorination pattern. Our findings emphasize the context-dependent impact of fluorination and offer insights to better understand the impact of thiofluoroalkyl chains on these physicochemical properties.