Searching for "Greener" Bioequivalents of CF₃ to Lower its Environmental Impact

Considering the broad use of the trifluoromethyl functional group (-CF₃) in medicinal chemistry and taking into account the recent concerns on the negative environmental effects of CF₃ containing compounds, we are searching for "greener" alternatives. Thus, different chemical groups (i. e. iodide, fluoride, cyclopropyl, isopropyl, cyclobutyl, 3-oxetyl, 2-oxetyl, methylsulfide, pentafluorosulfide, methylsulfonyl and sulfonamide) have been considered as potential bioequivalents of -CF₃ aiming to use them in compounds with therapeutic interest instead of the polyfluoride functionality. Different structural (molecular surface and volume) and physicochemical (electronic and lipophilic) aspects of the bioequivalent functionalities proposed have been theoretically calculated and compared to those of -CF₃. Additionally, the corresponding phenyl derivatives carrying these functionalities have been purchased or prepared and their experimental lipophilicity (i. e. LogP) measured using shake-flask experiments and UV-vis spectroscopy.