On the polarity of partially fluorinated methyl groups

A series of indole and 5-methoxyindole derivatives, substituted at C3 with n-propyl or 4-methylcyclohexyl scaffolds bearing varying degrees of fluorination of the terminal methyl group, have been prepared and studied. These compounds exhibit characteristic polarity patterns, measured either by log P or chromatographic capacity factors, which are consistent with the partially known lipophilicity pattern for the corresponding n-propylbenzene series. Based on a simple C-F bond vector analysis, the polarity increase upon exchange of a terminal methyl by a trifluoromethyl group in an aliphatic substituent should be comparable to that arising from a single H/F exchange at the terminal methyl group, while the volume increase in the former case is three times larger than that in the latter. This may explain the observation that replacement of a methyl by a fluoromethyl group results in a more pronounced lowering of molecular lipophilicity than its replacement by a trifluoromethyl group. The same analysis predicts a difluoromethyl group to exhibit a lipophilicity reduction similar to that of a fluoromethyl group. (C) 2013 Elsevier B.V. All rights reserved.