Utilizing MEDT analysis of [3 + 2] cycloaddition reaction: x-ray crystallography of spirooxindole linked with thiophene/furan heterocycles and triazole framework

• Published in: BMC chemistry 2024-11, Vol.18 (1), p.229-16, Article 229
• Main Authors: Alayyaf, Abdulmajeed Abdullah, Ali, M., Alwehaibi, Moayad Abdullah, Al-Muhanna, Muhanna K., Soliman, Saied M., Ríos-Gutiérrez, Mar, Haukka, Matti, Barakat, Assem
• Format: Article
• Language: English
• Subjects: Antifungal agents; Chemistry; Chemistry and Materials Science; Chemistry/Food Science; Crystal structure; Crystallization; Crystallography; Cycloaddition; Drug development; Electron density; Heterocycle; Molecular Electron Density Theory (MEDT); R&D; Research & development; Single crystals; Spirooxindoles; Triazole; Triazoles
• ISSN: 2661-801X; 2661-801X
• DOI: 10.1186/s13065-024-01343-8

Hybridization of spirooxindole with different pharmacophores such as triazole and heterocycle such as thiophene and furan moiety was achieved by the [3 + 2] cycloaddition (32CA) reaction approach. Structural investigations of the compounds 4a and 4b were performed using X-ray single crystal structure determinations and Hirshfeld analysis. Both compounds crystallized in monoclinic crystal system. The space group is P2 1 /c for 4a and P2 1 /n for 4b . The crystal parameters are a  = 10.2619(3) Å, b  = 13.6776(3) Å, c  = 10.9318(3), β  = 116.640(4)° for the former while a  = 13.0012(1) Å, b  = 14.9692(1) Å, c  = 14.1178(1) Å, β  = 97.101(1)° for the latter. In both compounds, the aryl group and the triazole moieties are twisted from one another. The twist angle is 84.75˚for 4a while 86.64˚ for 4b . Based on Hirshfeld calculations, the Cl…H, O…H, N…H and C…H non-covalent interactions in 4a while the O…H interactions in 4b are the most important. The molecular mechanism of the key 32CA reaction between the in situ generated azomethine ylides and the corresponding chalcones has been studied within the Molecular Electron Density Theory (MEDT). The MEDT study reveals that the low activation energies and high experimental selectivity are the result of the supernucleophilic character of the ylides and the strong electrophilicity of the chalcones, which favour the process through a high polar character. This high polar character accounts for the total endo selectivity experimentally found.