Optimization of compound lipophilicity is a key aspect of drug discovery. The aim of this work was to compare the lipophilicity modulations induced by 16 distinct known and novel fluoroalkyl motifs on three parent models. Fifty fluorinated compounds, with 28 novel experimental aliphatic log values, are involved in discussing various lipophilicity trends. As well as confirming known trends, a number of novel lipophilicity-reducing motifs are introduced. Tactics to reduce lipophilicity are discussed, such as "motif extensions" and "motif rearrangements", including with concomitant extension of the carbon chain, as well as one- and two-fluorine 'deletions' within perfluoroalkyl groups. Quantum chemical log calculations (SMD-MN15) based on solvent-dependent three-dimensional (3D) conformational analysis gave excellent correlations with experimental values, superior to log predictions based on 2D structural motifs. The availability of a systematic collection of data based on a small number of parent molecules illustrates the relative lipophilicity modulations of aliphatic fluorination motifs.
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