Lipophilicity Effects of Monofluorination at the Tertiary Aliphatic Carbon as a Function of alpha-Substituent

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 LogP values strongly depend on the nature of the alpha-substituent present at the C-4 position. In particular, the LogP difference increased with the increase in the substituent’s electronegativity (as described by the 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).