Crystal Structure, Hirshfeld Surface Analysis, and Computational Study of Quinolin-8-yl 4-Chlorobenzoate: Insights from Spectroscopic, Thermal, and Antitumor Properties

We report the time-efficient synthesis of quinolin-8-yl 4-chlorobenzoate (3) via an O-acylation reaction between 8-hydroxyquinoline (1) and 4-chlorobenzoyl chloride (2) mediated by triethylamine in acetonitrile under heating at 80 degrees C for 20 min in the Monowave 50 reactor. This protocol is distinguished by its short reaction time, operational simplicity, and clean reaction profile. The structure of 3 was fully characterized through a combination of analytical techniques, including NMR, IR, and UV-Vis spectroscopy, MS spectrometry, differential scanning calorimetry (DSC), thermogravimetry (TG), and crystallographic studies. Interestingly, X-ray diffraction analyses of 3 show that the crystal structure is characterized by C-H center dot center dot center dot N, C-H center dot center dot center dot O, Cl center dot center dot center dot pi, and pi center dot center dot center dot pi interactions. The molecular conformation presents an orthogonal orientation between aromatic rings in the solid state. The calculated interaction energies using the CE-B3LYP model show that dispersion forces act in a higher proportion to build the crystal, which is consistent with the few short hydrogen interactions detected. Electrostatic potential maps suggest the formation of sigma-holes over the Cl atoms. Although they can behave as both Lewis acid and base sites, Cl center dot center dot Cl interactions are absent due to the shallow depth of these sigma-holes. Quantum chemical descriptors and global reactivity descriptors were examined using the B3LYP method with the 6-31G(d,p) basis set implemented in CrystalExplorer. Finally, compound 3 exhibited low activity against HOP-92 and EKVX non-Small-cell lung and UO-31 Renal cancer cell lines, with a growth inhibition percentage (GI%) ranging from 6.2% to 18.1%.

Automated summary

We reported a time-efficient synthesis of quinolin-8-yl 4-chlorobenzoate (3) through an O-acylation reaction between 8-hydroxyquinoline (1) and 4-chlorobenzoyl chloride (2) mediated by triethylamine. The reaction was conducted in acetonitrile at 80 degrees C for 20 minutes in the Monowave 50 reactor. Compound 3 was fully characterized using various analytical techniques, and its crystal structure exhibited unique C-H···N, C-H···O, Cl···π, and π···π interactions.