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

Lipophilicity and acid-base properties are two key aspects of the optimization of a compound in drug discovery. Using (19)F NMR, we experimentally determined the log D(7.4) of a wide array of 2-thiofluoroalkyl (SR(F)) and 2-sulfonyl fluoroalkyl (SO(2)R(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.