Physicochemical Properties of α-Fluoroalkyl-Substituted Cycloalkylamines and Amino Acids

Kostiantyn P. Melnykov; Oleksandr S. Liashuk; Andrii Koblianskyi; Oleh Smyrnov; Sofiia Slobodianyk; Bohdan V. Bobovskyi; Dmytro Lesyk; Svetlana Valentynivna Shishkina; Andrii Frolov; Petro Borysko; Oleksandr O. Grygorenko

doi:10.26434/chemrxiv.10001985/v1

Physicochemical Properties of α-Fluoroalkyl-Substituted Cycloalkylamines and Amino Acids

Тип публікації :

Препринт

Дата випуску :

5 лютого 2026 р.

Автор(и) :

Kostiantyn P. Melnykov

Oleksandr S. Liashuk

Andrii Koblianskyi

Oleh Smyrnov

Sofiia Slobodianyk

Bohdan V. Bobovskyi

Dmytro Lesyk

Svetlana Valentynivna Shishkina

Andrii Frolov

Petro Borysko

Oleksandr O. Grygorenko

eKNUTSHIR URL :

https://ir.library.knu.ua/handle/15071834/34249

DOI :

10.26434/chemrxiv.10001985/v1

Журнал :

ChemRxiv

Цитування :

[APA 7] Kostiantyn, P. M., Oleksandr, S. L., Andrii, K., Oleh, S., Sofiia, S., Bohdan, V. B., Dmytro, L., Svetlana, V. S., Andrii, F., Petro, B., & Oleksandr, O. G. (2026). Physicochemical Properties of α-Fluoroalkyl-Substituted Cycloalkylamines and Amino Acids. ChemRxiv,. https://doi.org/10.26434/chemrxiv.10001985/v1

[ДСТУ] Physicochemical Properties of α-Fluoroalkyl-Substituted Cycloalkylamines and Amino Acids / P. M. Kostiantyn та ін. ChemRxiv. 2026. DOI: 10.26434/chemrxiv.10001985/v1 (дата звернення: 11.09.2026).

A systematic matched molecular pair analysis of α-fluoroalkyl-substituted alicyclic amines (C 3 –C 6 cycloalkanes and tetrahydropyran) and their benzamide models by benchmarking them against β- and γ-substituted analogues is reported. Experimentally obtained acidity and lipophilicity values (p K a and Log P ) revealed an exceptionally strong and predictable impact of α -fluoroalkyllation on the acid-base properties of the amine moiety with an approximately additive contribution of 1.6 ± 0.1 p K a units per fluorine atom. Lipophilicity trends were more nuanced, yet α -substitution produces distinctive ΔLog P patterns consistent with competing inductive and local polarization effects near the amide fragment. Mapping the obtained dataset in Log P– p K a space highlights the cluster-type localization of the various fluoroalkylated patterns, enabling property tuning via isosteric substitutions. Finally, multigram-scale access to diastereopure α -CF 3 cycloalkyl amino acids was proposed along with quantification of their ionization profiles, supporting application of these scaffolds as versatile fluorinated building blocks for drug discovery.

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