![Regioselectivity of 9-chloropyrido[1,2-a]benzimidazole halogenation reaction](/upload/12631c5e396938a702bdd516ae8c4208/issues/cover/d2fc3864dd0e37304717f34bbb6953a6.jpeg)
сотрудник
Ярославль, Ярославская область, Россия
студент
Ярославль, Ярославская область, Россия
This paper describes the SEAr regioselectivity of the 9 chloropyrido[1,2-a]benzimidazole reaction by experimental and quantum chemistry methods. We conducted the halogenation process in sulfuric acid using N-bromosuccin- or N-chlorosuccinimide. Two isomeric products 8-Hal 9 chloropyrido[1,2-a]benzimidazole and 6-Hal-9-chloropyrido[1,2-a]benzimidazole occurred. Predominantly, the introduction of the electrophilic particle occurred at the 8th position of the heterocycle. Using quantum chemistry methods, we found the orbital control of the electrophilic halogenation reaction and determined the orientation of the electrophile particle introduction by the distribution of the boundary electron density in the substrate. This corresponded well with the experimental data.
9-chloropyrido[1,2-a]benzimidazole, N-halogensuccinimide, SEAr reaction, regioselectivity, quantum chemical modelling, DFT method B3LYP/6-31G**, PC GAMESS/Firefly and ORCA 5.0.4 software applications
1. Mayoka, G., Keiser, J., Häberli, C. & Chibale K. (2019) Structure–Activity Relationship and in Vitro Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) Studies of N-aryl 3-Trifluoromethyl Pyrido[1,2-a]benzimidazoles That Are Efficacious in a Mouse Model of Schistosomiasis, ACS Infect. Dis., 5, pp. 418–429. DOI:https://doi.org/10.1021/acsinfecdis.8b00313.
2. Liu, A., Ji, R., Shen, S., Cao, X. & Ge,Y. (2017) A ratiometric fluorescent probe for sensing sulfite based on a pyrido [1, 2-a] benzimidazole fluorophore, New Journal of Chemistry, 41(18), pp. 10096-10100. DOI:https://doi.org/10.1039/C7NJ02086D.
3. Gadde, S., Kleynhans, A., Holien, J.K., Bhadbhade, M., Nguyen, P.L.D., Mittra, R., Yu, T.T., Carter, D.R., Parker, M.W., Marshall, G.M., Cheung, B.B. & Kumar, N. (2023) Pyrimido[1,2-a]benzimidazoles as inhibitors of oncoproteins ubiquitin specific protease 5 and MYCN in the childhood cancer neuroblastoma, Bioorg Chem., 136, 106462. DOI:https://doi.org/10.1016/j.bioorg.2023.106462.
4. Kotovskaya, S.K., Baskakova, Z.M., Charushin, V.N., Chupakhin, O.N., Belanov, E.F., Bormotov, N.I., Balakhnin, S.M. & Serova, O.A. (2005) Synthesis and antiviral activity of fluorinated pyrido[1,2 a]benzimidazoles, Him.-farm. Zhurnal, 39(11), pp. 12–16. DOI:https://doi.org/10.30906/0023-1134-2005-39-11-12-16 (in Russian).
5. Arutyunyan, A.A., Avakimyan, J.A. & Stepanyan, G.M. (2016) Antibacterial properties of some polycyclic heterocycles based on pyrimidine and benzimidazole, Biologicheskij zhurnal Armenii, 68(2), pp. 88-91 [online]. Available at: https://arar.sci.am/dlibra/publication/260297 (accessed 02.02.2024) (in Russian).
6. Koo, H.L. & Dupont, H.L. (2010) Rifaximin: A Unique Gastrointestinal-Selective Antibiotic for Enteric Diseases, Curr. Opin. Gastroenterol., 26, pp. 17–25. DOI:https://doi.org/10.1097/MOG.0b013e328333dc8d.
7. Begunov, R.S., Egorov, D.O., Chetvertakova, A.V., Savina, L.I. & Zubishina, A.A. (2023) Antibacterial Activity of the Halogen- and Nitro Derivatives of Benzimidazole Against Bacillus Subtilis, Antibiotiki i khimioterapiya, 68(3-4), pp. 19-24. DOI:https://doi.org/10.37489/0235-2990-2023-68-3-4-19-24 (in Russian).
8. Andrzejewska, M., Yépez-Mulia, L., Cedillo-Rivera, R., Tapia, A., Vilpo, L., Vilpo, J. & Kazimierczuk, Z. (2002) Synthesis, antiprotozoal and anticancer activity of substituted 2-trifluoromethyl- and 2 pentafluoroethylbenzimidazoles, European Journal of Medicinal Chemistry, 37, pp. 973–978. DOI:https://doi.org/10.1016/S0223-5234(02)01421-6.
9. Tkachenko, P.V., Tkachenko, E.V., Zhuravel, I.A., Kazmirchuk, V.V. & Derbisbekova, U.B. (2017) Synthesis and antimicrobial activity 4-arylsulphonyl-derivatives 5-aminopyrazoles, Vestnik KazNMU, (2), pp. 307–311 [online]. Available at: https://cyberleninka.ru/article/n/sintez-i-protivimikrobnaya-aktivnost-4-arilsulfonilproizvodnyh-5-aminopirazolov (accessed 12.02.2024) (in Russian).
10. Begunov, R.S., Sokolov, A.A., Belova, V.O., Fakhrutdinov, A.N., Shashkov, A.S. & Fedyanin, I.V. (2015) Reaction of substituted pyrido[1,2-a]benzimidazoles with electrophilic agents, Tetrahedron Letters, 56(42), pp. 5701–5704. DOI:https://doi.org/10.1016/j.tetlet.2015.08.014.
11. Begunov, R.S., Ryzvanovich, G.A. & Firgang, S.I. (2004) Simple method for the synthesis of substituted benzo[4,5]imidazo[1,2-a]pyridines, Zhurnal organicheskoj khimii, 40(11), pp. 1740-1742. DOI:https://doi.org/10.1007/s11178-005-0082-5 (in Russian).
12. Bogdanova, D.M., Savina, L.I. & Begunov, R.S. (2022) Synthesis and functionalization of pyrido[1,2 a]benzimidazole amino derivatives, From Chemistry Towards Technology Step-By-Step, 3(4), pp. 30 38 [online]. Available at: http://chemintech.ru/index.php/tor/2022-3-4 (in Russian) (accessed 10.12.2023).
13. Becke, A. D. (1993) Density-functional thermochemistry. III. The role of exact exchange, J. Chem. Phys., 98(7), pp. 5648-5652. DOI:https://doi.org/10.1063/1.464913.
14. Miehlich, B.A., Savin, H.S., Stoll, H. & Preuss, H. (1989) Results Obtained with the Correlation Energy Density Functionals of Becke and Lee, Yang and Parr, Chemical Physics Letters, 157(3), pp. 200-206. DOI:https://doi.org/10.1016/0009-2614(89)87234-3.
15. Mueller, M. (2001) Fundamentals of Quantum Chemistry. Molecular Spectroscopy and Modern Electronic Structure Computation, International Journal of Molecular Sciences, 2(6), pp. 291-292. DOI:https://doi.org/10.3390/i2060291.
16. Granovsky, A.A. (2024) Firefly version 8.8 [online]. Available at: http://classic.chem.msu.su/gran/firefly/index.html (accessed 20.02.2024).
17. Neese, F. (2012) The ORCA program system, Wiley Interdisciplinary Reviews: Computational Molecular Science, 2(1), pp. 73–78. DOI:https://doi.org/10.1002/wcms.81.
18. Fukui, K., Yonezawa, T. & Nagata, C. (1957) MO-Theoretical Approach to the Mechanism of Charge Transfer in the Process of Aromatic Substitutions, Bulletin of the Chemical Society of Japan, 27, pp. 1247–1256. DOI:https://doi.org/10.1063/1.1743986.
19. Breza, M. & Milata, V. (2005) Quantum-chemical studies of the nitration of benzazoles, ARKIVOC, 9, pp. 80 89. DOI:https://doi.org/10.3998/ark.5550190.0006.909.
20. Bode, B.M. & Gordon, M.S. (1998) MacMolPlt: a graphical user interface for GAMESS, J. Mol. Graphics and Modeling, 16(3), pp. 133-138. DOI:https://doi.org/10.1016/s1093-3263(99)00002-9).
21. Zhurko, G.A. (2024) Chemcraft. Version 1.6 [online]. Available at: http://www.chemcraftprog.com (accessed at 12.02.2024).
