Crystal structure analysis and computational study of 4,5-dihydro-1,2,4-oxadiazoles

The conformational analysis of three 3,5-disubstituted 4,5-dihydro-1,2,4-oxadiazoles (DHOZs) was investigated using X-ray crystal structure and DFT computations. Mechanistically, nucleophilic attack of either the hydroxy or the amino group of the amidoxime precursor to the re- or si-faces of the aldehyde carbonyl group and the following intramolecular cyclization results normally in the formation of the R/S-enantiomeric pair with the stereocenter on the C5-atom of the heterocyclic ring. Surprisingly, the crystal packing of the investigated compounds revealed the presence of the pure R-enantiomer, pure S-enantiomer, and the racemic mixture. The optical activities of the molecules are confirmed by recording their CD spectra. Crystal packing is explored based on the acting intra- and intermolecular interactions using the quantum theory of atoms-in-molecules (QTAIM), non- covalent interaction plot (NCI plot), reduced density gradient (RDS), Hirshfeld surface (HS) analysis, and twodimensional fingerprint (2D-FP) plots. The computational structural characteristics of the optimized geometries of the considered DHOZs are compatible with those in the crystal packing. Furthermore, the computational conformational analysis of the imino-oxime intermediate, involved in the intramolecular cyclization process, support the experimental findings.