Deciphering weak hydrogen bonds, halogen bonds, and π-stacking interactions in two fluorinated 2'-hydroxychalcones: insights from experimental and theoretical analysis

Abstract

In this article, we report the synthesis, spectroscopic and X-ray characterization of two fluorinated 2’-hydroxychalcone derivatives (E)-3-(4-fluorophenyl)-1-(2-hydroxyphenyl)prop-2-en-1-one (1) and (E)-1-((2-hydroxyphenyl)-3-[(4-trifluoromethyl) phenyl]prop-2-en-1-one (2). These compounds were synthesized by Claisen–Schmidt condensation between 2’-hydroxyacetophenone and 4-fluorobenzaldehyde and 4-(trifluoromethyl)benzaldehyde under basic conditions to afford the desired compounds in good yields. The structures were fully established using FTIR, UV-visible and 1H and 13C nuclear magnetic resonance (NMR) spectroscopy. The crystallographic analysis reveals that the supramolecular assembly in 1 is mainly governed by C-H···O and C-H···F H-bonds and C-H···O, F···F, and π-stacking interactions were observed in 2. Hirshfeld surface analysis revealed that H···H, H···O/O···H and H···F/F···H contacts dominate the crystal packing of both compounds. Lattice and intermolecular interaction energies for 1, 2, and two related compounds were computed by using the PIXEL procedure. Contact enrichment ratios showed the most favorable intermolecular interactions for all the four compounds. A detailed Density Functional Theory (DFT) computational analyses were performed to evaluate the strength and nature of the intermolecular interactions which stabilize the crystal packing. Finally, possible pharmacological effects, mechanisms of action, metabolism-related actions, and toxic effects are predicted using PASSonline software. The four analyzed 2′-hydroxy-chalcones exhibited high anti-hypoxic activity. Pharmacokinetic properties, as well as absorption, distribution, metabolism, excretion and toxicity properties were also predicted using the online SwissADME software.