Physicochemical studies. The pKa values for carboxylic acids 1, 2 and protonated amines 3, 4 were measured by standard acid-base titration (Figure ). As anticipated, introduction of the Oxygen atom into the ring led to a significant decrease in the pKa value that correlated with its inductive effect (i.e., the through-bond distance to the functional group). In particular, the most significant decrease was observed for the 1[1,0]/1[2,0] and 2[0,0]/2[2,0] carboxylic acid pairs. For amines, this effect was even more pronounced, with ΔpKa = 1.7-1.8 units for 3[1,0]/3[3,0] and 4[0,0]/4[3,0] pairs. gem-Difluorination of both alicyclic and O-heterocyclic carboxylic acids and amines also led to an expected pKa decrease, with its absolute value following the trend: β > γ > δ position. Again, acidity of protonated amines was more susceptible to the CF2 group effects, with the largest ΔpKa of 3.1 units observed for the 3[0,0]/3[0,β] and 4[3,0]/4[3,β] pairs. The LogP values were measured for anilides 5, 6 and benzamides 7, 8 (prepared by reaction of carboxylic acids 1, 2 with aniline in the presence of EDC, DMAP, and Et3N, or amines 3, 4 with benzoyl chloride in the presence of Et3N) using the classical shake-flask method combined with HPLC quantitative analysis (Figure ). It was found that introducing the Oxygen atom resulted in lowered lipophilicity (by 0.83-1.57 ΔLogP units), with the largest difference (1.57) for the 7[3,0]/7[0,0] pair. Notably, the effect of gem-difluorination of alicyclic and Oheterocyclic compounds on their lipophilicity was different. In particular, gem-difluorination of cycloalkane derivatives 5-8[0,0] typically resulted in the lipophilicity decrease (by 0.16-0.56 LogP units). The highest ΔLogP values were observed for the ,difluorinated isomers (up to 0.56 for the 7[0,0]/7[0,β] pair). To gain a deeper insight into the nature of the O/CF2 effects on the compound's lipophilicity in the studied series, we calculated average pKa and LogP values for the corresponding amide pairs (i.e., with/without O or CF2 group) for each position of the five-and six-membered rings (2, 3, or 4 for O, and , , or  for CF2). separate fragments in the discussed positions. For example, to evaluate effect of introducing Oxygen atom at the position 2 of the six-membered ring on the COOH group acidity, pKa values of all available tetrahydropyran-3carboxylic acids (1[2,0], 1[2,γ], and 1[2,δ]) were compared to those of cyclohexane counterparts (1[0,0], 1[0,γ], and 1[0,δ]), and average pKa was determined within this subset. The resulting pKa and LogP increments are summarized in Figure , A. This deliberately selected example is given for illustration purposes; see Table for the full dataset.