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 19F NMR, we experimentally determined the log D7.4 of a wide array of 2-thiofluoroalkyl (SRF) and
2-sulfonyl fluoroalkyl (SO2RF) substituted pyridines
and the pKa 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 D7.4 values. Our results highlight
the influence of fluorination topology in SRF 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 D7.4 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.