Synthesis and structural elucidation of a trifluoromethylated cyclopentene hydrazone: a combined X-ray and computational study

Abstract

A hybrid compound, benzoylhydrazo-2-trifluoroacetylcyclopent-1-ene (1), was successfully synthesized via the condensation of benzohydrazide and 2-trifluoroacetylcyclopentan-1-one. Structural confirmation was achieved through elemental analysis, NMR spectroscopy and single-crystal X-ray diffraction. Both solution and solid-state analyses confirmed the exclusive formation of the open-chain structure 1, with no evidence of its fused bicyclic derivative (3-hydroxy-3-(trifluoromethyl)-3a,4,5,6-tetrahydrocyclopenta[c]pyrazol-2(3H)-yl)(phenyl)methanone (1′), and the hydrazone form N′-(2-(2,2,2-trifluoroacetyl)cyclopentylidene)benzohydrazide (1″). UV-vis spectroscopy of compound 1 in MeOH and n-heptane revealed a broad absorption band from 210 nm to 300 nm with a pronounced hyperchromic effect in the polar protic solvent, indicating significant solvent-dependent stabilization of the excited state. Thermogravimetric analysis showed that compound 1 is thermally stable up to approximately 190 °C, after which it undergoes a single-step decomposition process. Crystallographic analysis revealed that compound 1 exists as two geometrically distinct molecules in the solid state: a nearly planar form (1a) and a conformation (1b) where the benzoyl group is almost orthogonal to the core. Each molecule is stabilized by an intramolecular N–H⋯O hydrogen bond. These bonds further facilitate intermolecular assembly, whereby molecules of 1b form centrosymmetric dimers that subsequently connect to molecules of 1a, creating an extended 1D supramolecular chain through a network of hydrogen bonds. The DFT calculations corroborated the experimental findings, indicating that the optimized structure aligns with conformation 1b and is energetically more stable than the potential forms 1′ and 1″. Although compound 1 was classified in the low-acute-toxicity Class 4, the model flagged potential risks including neurotoxicity, nephrotoxicity and carcinogenicity, among others. These predicted activities represent key areas requiring rigorous experimental follow-up. On a positive note, the absence of predicted hepatotoxicity and cardiotoxicity is encouraging, as these are common causes of drug candidate attrition. Most significantly, molecular docking studies predicted a strong binding affinity for hemoglobin S (−9.1(0) kcal mol⁻¹), surpassing that of the approved drug Voxelotor (−8.8(0) kcal mol⁻¹). All calculated ligand efficiency scores for 1 fell within the range characteristic of Hit, highlighting its significant potential for development as an inhibitor for sickle cell disease. Although the synthesis of 1 has been reported previously, the present study provides the first comprehensive structural, electronic and in silico pharmacological characterization of this molecule.