Lipophilicity. LogP values were measured for benzamides 13ao (prepared by benzoylation of amines 7c and 11a-o under the standard reaction conditions) using the classical shake-flask method combined with HPLC quantitative analysis as reported previously (Figure ). The 3,3-diFox substituent slightly increased the lipophilicity upon introduction into parent piperidine derivative 13a (LogP = 1.6 vs 1.1, respectively); this effect was similar to those of methyl or CHF2CH(OMe) groups. Notably, gem-difluorination of the oxetane ring resulted in nearly the same LogP increase (1.6 vs 1.1 for 13c and 13c, respectively), which is contrary to the case cycloalkane derivatives where gemdifluorination typically led to increased hydrophilicity. Analysis of the remaining data presented in Figure revealed that the 3,3-diFox substituent had intermediate position between lipophilic (cyclo)alkyl or CF3-substituted compounds and hydrophilic derivatives bearing polar groups (e.g., ester, amide, or 1,3dioxolane). Therefore, according to these results, the 3,3-diFOx moiety can be considered as a possible replacement for both substituent types to fine-tune the compound's lipophilicity in the desired direction. Linear free energy relationships. A quantitative relationships between the structure and reactivity of benzene derivatives was formulated by L.P. Hammett in 1937 and is still actively used in QSAR studies. In its essence, the Hammett equation states that there is a linear relation between the reaction rates and equilibrium constants for a similar series of compounds (e.g., benzoic acid derivatives):