Acidity of saturated (hetero)cyclic α-fluoro carboxylic acids and lipophilicity of their amide derivatives

• Published in: Journal of fluorine chemistry Vol. 278; p. 110316
• Main Authors: Pidvyshennyi, Oleksii, Melnykov, Kostiantyn P., Liashuk, Oleksandr, Lesyk, Dmytro, Holota, Yuliia, Borysko, Petro, Grygorenko, Oleksandr O.
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01.08.2024
• Subjects: Acidity; Building blocks; Lipophilicity; Saturated rings; α-Fluorination; Acidity; Saturated rings; α-Fluorination; Building blocks; Lipophilicity
• ISSN: 0022-1139
• DOI: 10.1016/j.jfluchem.2024.110316

•Physicochemical properties of saturated (hetero)cyclic α-fluorocarboxylic acids (amides) are studied.•α-Fluorination decreases pKa values by ca. 2 units due to inductive effect of fluorine.•This effect is not additive with that of other heteroatoms (i.e., cyclic ether moiety).•Lipophilicity of model amides is only slightly affected by the α-fluorination. Analysis of the physicochemical parameters of saturated (hetero)cyclic carboxylic acids and their α-fluorinated analogues is described. Measured pKa values revealed a significant influence of the single fluorine substituent on the compound's acidity (pKa decreased by 1.3–2.4 units). This effect did not demonstrate additivity with electronic effects of other heteroatom (i.e., cyclic ether moiety). On the contrary, lipophilicity (LogP) of the corresponding anilides was almost unaffected upon α-substitution with a fluorine atom and mainly governed by the nature of the (hetera)cycloalkyl substituent. The obtained results suggest that polarization of the C–F bonds themselves does not define the fluorine effect on the compound's lipophilicity. [Display omitted]