Synthesis, crystal structure, DFT studies and Hirshfeld surface analysis of novel isoxazole derivatives

This article describes firstly the synthesis of a new series of isoxazole 5a-e from p-methoxythymol, extracted from Tetraclinis Articulata, as starting material involving 1,3-dipolar cycloaddition reaction and secondly a detailed study of the molecular packing and intermolecular interactions in crystals of five related 5-((2-isopropyl-4-‑methoxy‑5-methylphenoxy)methyl)-3-phenylisoxazole derivatives. All compounds were synthesized and subjected to solid state characterization by single-crystal X-ray diffraction analysis, and to studies with the use of NMR and Hirshfeld surface analysis. All structures display intermolecular C—H···O hydrogen bonding and C—H···π interactions, forming layers in the crystal lattice. The crystal structures of compounds 5a; 5c and 5d are consolidated by π—π interactions. Hirshfeld surface analysis, the dnorm surfaces, electrostatic potential and two-dimensional fingerprint plots were examined to verify the contributions of the different intermolecular contacts within the supramolecular structure. The most important contributions for the crystal packing are from H···H, H···C/C···H and O···H/H···O interactions. Additionally, DFT calculations have been used to analyze the electronic and geometric frontier molecular orbital and Molecular Electrostatic Potential map analyses of the compounds were produced using the optimized structures.