Given there is an optimal lipophilicity range for orally bioavailable drugs, structural modifications applied in the drug development process are not only focused on optimizing bioactivity but also on fine-tuning lipophilicity. Fluorine introduction can be used for both purposes. Insights into how fluorine introduction affects lipophilicity are thus of importance, and systematic series of fluorinated compounds with measured octanol-water partition coefficients are a powerful way to enhance our qualitative understanding in this regard and are essential as input for computational log P estimation programs. Here, we report a detailed comparison of all possible vicinal and skipped (1,3-substituted) fluorination motifs when embedded in structurally equivalent environments (X-CF_nH_2-n-CF_mH_2-m-X versus X-CF_nH_2-n-CH₂-CF_mH_2-m-X, with n,m ≠ 0 and X = CH₂OH) to compounds with isolated fluorination (n ≠ 0; m = 0, and including X-CH₂-CF_nH_2-n-CH₂-X, n = 0-2). It is shown that skipped fluorination is more powerful for log P reduction purposes compared to single or vicinal fluorination. Efficient stereoselective syntheses of the compounds with skipped fluorination motifs are reported, which where relevant can be made enantioselective using known chiral building blocks. These compounds, and some intermediates, will be of interest as advanced fluorinated building blocks.

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