Physicochemical Properties of gem-Difluorinated Saturated Bicyclic Amines – Advanced Building Blocks for Drug Discovery

Impact of gem-difluorination on the physicochemical properties of bicyclic saturated amines with 6 to 8 atoms in the largest ring is discussed. The fluorination effect on the acidity of protonated species (pKa) correlated with intuitive predictions based on the inductive effect of the electron-deficient substituent. In contrast, lipophilicity (LogP) could be either increased or decreased by the gem-difluorination. The observed effect depended on the structure of the bicyclic core and was affected by the spatial orientation of the C−F and neighboring C−H bonds.