Lipophilicity effects of monofluorination at the tertiary aliphatic carbon as a function of α-substituent

Abstract

Effects of monofluorination at the tertiary aliphatic carbon on the compound's lipophilicity were measured for a series of model 4-substituted piperidine-derived benzamides. It was found that the observed ΔLogP values strongly depend on the nature of α-substituent present at the C-4 position. In particular, ΔLogP increased with increasing the substituent's electronegativity (as described by field effect). Using qualitative molecular electrostatic potential surface (MEPS) analysis, we suggested that the fluorine effect on the compound's lipophilicity in the studied systems is defined by electronic distribution modulation at the neighboring atoms (especially Hydrogens).