Institution: | 1. Department of Medicinal Chemistry, Maj Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, 31-343 Kraków, Poland
Faculty of Chemistry Jagiellonian University, Gronostajowa 2, 30-387 Kraków, Poland;2. Department of Medicinal Chemistry, Maj Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, 31-343 Kraków, Poland;3. Faculty of Chemistry Jagiellonian University, Gronostajowa 2, 30-387 Kraków, Poland;4. Faculty of Chemistry Jagiellonian University, Gronostajowa 2, 30-387 Kraków, Poland
Jagiellonian Centre for Experimental Therapeutic (JCET), Jagiellonian University, Bobrzynskiego 14, 30-348 Kraków, Poland;5. Faculty of Mathematical and Natural Sciences, University of Applied Sciences in Tarnów, Mickiewicza 8, 33-100 Tarnów, Poland |
Abstract: | A series of 4-halogeno aniline derivatives was studied employing combined theoretical and experimental methods (i. e. crystal structure analysis and vibrational spectroscopies). This simplified model system was selected to shed light on the impact of fluorine substitution on the formation of noncovalent interactions such as halogen bonds (XBs) and hydrogen bonds (HBs), which are key interactions in fluorinated/halogenated drug-protein complex formation. Comparative analysis of three previously reported and five newly determined crystal structures indicated that, in most cases, 2-fluoro and 2,6-difluoro substitution of 4-X anilines increases the ability of adjacent amine to form strong N−H⋅⋅⋅N HBs. Additionally, fluorine substituents in the difluorinated derivatives are competitive and attractive HB and XB acceptors and increase the probability of halogen-halogen contacts. A peculiar observation was made for 4-iodoaniline and 2,6-difluoro-4-iodoaniline, which form distinct interaction patterns compared to the corresponding 4-Cl and 4-Br analogs. The observed intramolecular N−H⋅⋅⋅F interactions lead to additional NH bands in the FT-IR spectra. |