Lipophilicity trends upon fluorination of isopropyl, cyclopropyl and 3-oxetanyl groups

• Benjamin Jeffries,
• Zhong Wang,
• Robert I. Troup,
• Anaïs Goupille,
• Jean-Yves Le Questel,
• Charlene Fallan,
• James S. Scott,
• Elisabetta Chiarparin,
• Jérôme Graton and
• Bruno Linclau

Beilstein J. Org. Chem. 2020, 16, 2141–2150, doi:10.3762/bjoc.16.182

• isopropyl substituent led to larger lipophilicity modulation compared to fluorination of the cyclopropyl substituent. Keywords: aliphatic fluorination; cyclopropane; isopropyl; isostere; lipophilicity; oxetane; Introduction The introduction of small alkyl groups onto bioactive compounds as space filling

• -position (5), the introduction of the oxetanyl group leading to 6 induces a significant pKa(H) decrease. While the reduction in logP is still observed, the larger proportion of unprotonated substrate leads to a logD7.4 increase. Aliphatic fluorination can also be employed to decrease lipophilicities [6][19

Polarity effects in 4-fluoro- and 4-(trifluoromethyl)prolines

• Vladimir Kubyshkin

Beilstein J. Org. Chem. 2020, 16, 1837–1852, doi:10.3762/bjoc.16.151

• orientation of the groups, while in the (trifluoromethyl)prolines the orientation is similar. This is reflected in the acidity values. Lipophilicity Another parameter, which may be sensitive to the orientation of the dipoles within a molecule is the lipophilicity. It is well known that single aliphatic

• fluorination usually increases polarity of a molecule due the newly introduced polar C–F bond. A CF3 group introduces a dipole of a similar size (see Figure 2), however, due to its high molar volume it increases the hydrophobicity of a molecule [75]. The overall outcome may appear paradoxical: a CF3 group can