Skip to content
Licensed Unlicensed Requires Authentication Published by De Gruyter (O) March 28, 2015

Crystal and molecular structures of two 1H-2-substituted benzimidazoles

Pilar Cabildo, Rosa M. Claramunt, Fco. Javier Zuñiga, Ibon Alkorta and Jose Elguero

Abstract

The X-ray molecular structure of two benzimidazoles unsubstituted on the nitrogen atoms (2-ethyl-1H-benzimidazole and 2-propyl-1H-benzimidazole) has been determined and analysed in the context of crystallographic and solid-state NMR data of seven substituted benzimidazoles. The first compound presents polymorphism, and two polymorphs [forms 3a and 3c] were obtained from different solutions of dichloromethane/hexane. Polymorph (3a) contains two independent molecules differing in the conformation of the ethyl group. Polymorph (3c) contains only one molecule in the asymmetric unit, with similar configuration as the ordered molecule of polymorph (3a). Another polymorphic form (3b) is obtained by cooling form (3a) below 179 K. The transition is related to an order-disorder process and involves a change in the hydrogen-bonding scheme. The second compound (4) presents enantiomorphism and its asymmetric unit contains four independent molecules that differ in the conformation of the 2-propyl group. For form (3a), the splitting of NMR signals is almost perfectly consistent with the features of the crystal structure, whereas not splitting is observed for compound (4). Agreements between NMR and X-ray crystallography techniques are also observed in other simple 2-R-1H-benzimidazoles (R = C4H9, CH2C6H5 and C6H5), but disagreements are found for R = H, CH3.


Corresponding author: Fco. Javier Zuñiga, Fac. Ciencia y Tecnología, Dpto. Física Materia Condensada, Universidad del Pais Vasco, APDO. 644, 48080 Bilbao, Spain, E-mail:

Acknowledgments

Authors thanks to Prof. T. Breczewski for helping in DSC measurements. This work has been financed by Ministerio de Ciencia e Innovación (CTQ2010-16122) and Ministerio de Economía y Competitividad of Spain (CTQ2012-35513-C02-02) and Comunidad Autónoma de Madrid (Project MADRISOLAR2, ref. S2009/PPQ-1533). This work was also supported by the Basque Government (project IT779-13).

References

[1] C. J. Moody, Advances in Nitrogen Heterocycles, in: C. J. Moody, (Ed.), Prefaced, Vol. 3, JAI Press, Stamford, USA, 1998.Search in Google Scholar

[2] A. Gomtsyan, Heterocycles in drugs and drug discovery. Chem. Heterocycl. Comp.2012, 48, 7.Search in Google Scholar

[3] R. Dua, S. Shrivastava, S. S. K. Sonwane, S. K. Srivastava. Pharmacological significance of synthetic heterocycles scaffold: a review. Adv. Biolog. Res.2011, 5, 120.Search in Google Scholar

[4] J. Velík, V. Baliharová, J. Fink-Gremmels, S. Bull, J. Lamka, L. Skálova, Benzimidazole drugs and modulation of biotransformation enzymes. Res. Vet. Sci.2004, 76, 95.Search in Google Scholar

[5] S. L. Khokra, D. Choudhary, Benzimidazole an important scaffold in drug discovery. Asian J. Biochem. Phar. Res.2011, 3, 476.Search in Google Scholar

[6] R. G. Ingle, D. D. Magar, Heterocyclic chemistry of benzimidazoles and potential activities of derivatives. Int. J. Drug. Res. Technol.2011, 1, 26.Search in Google Scholar

[7] R. Walia, M. Hedaitullah, S. F. Naaz, K. Iqbal, H. S. Lamba, Benzimidazole derivatives – An overview. Int. J. Res. Pharm. Chem.2011, 1, 565.Search in Google Scholar

[8] K. P. Barot, S. Nikolova, I. Ivanov, M. D. Ghate, Novel research syrategies of benzimidazole derivatives – A review. Mini Rev. Med. Chem.2013, 13, 1421.Search in Google Scholar

[9] J. Elguero, A. Fruchier, S. Mignonac-Mondon, Etude RMN en série hétérocyclique. IX. Dérivés méthylés et dinitro-2,4- phénylés du benzimidazole et de l’imidazo[4,5-b]pyridine. Bull. Soc. Chim. Fr.1972, 2916.Search in Google Scholar

[10] A. Fruchier, L. Pappalardo, J. Elguero, Etudes RMN en chimie hétérocyclique. XXII. Etude par RMN du carbone-13 de dérivés du benzimidazole. An. Quim.1980, 76C, 79.Search in Google Scholar

[11] J. de Mendoza, J. Elguero, Systèmes aromatiques à 10 électrons π dérivés de l’aza-3a pentalène. X. Série du s-triazolo[4,3-a]benzimidazole. Bull. Soc. Chim. Fr.1974, 1675.Search in Google Scholar

[12] J. de Mendoza, J. Elguero, Systèmes aromatiques à 10 électrons π dérivés de l’aza-3a pentalène. XVI. Recherches dans la série du benzimidazo[1,2-a]benzimidazole. Bull. Soc. Chim. Fr.1974, 2987.Search in Google Scholar

[13] J. Elguero, A. Fruchier, L. Knutsson, R. Lazaro, J. Sandström, Systèmes aromatiques à 10 électrons π dérivés de l’aza-3a pentalène. XI. Etude par RMN de l’imidazo[1,2-b]pyrazole et du pyrazolo[1,5-a]benzimidazole. Can. J. Chem.1974, 52, 2744.Search in Google Scholar

[14] A. Maquestiau, Y. Van Haverbeke, R. Flammang, M. C. Pardo, J. Elguero, Fragmentation d’azoles sous l’impact electronique. V. Isomerisation du benzimidazole avant degradation. Org. Mass Spectrom.1974, 8, 1188.Search in Google Scholar

[15] A. Maquestiau, Y. Van Haverbeke, R. Flammang, M. C. Pardo, J. Elguero, Fragmentation d’azoles sous l’impact electronique. VII. N-Ethyl-benzimidazoles. Org. Mass Spectrom.1975, 10, 313.Search in Google Scholar

[16] E. Escande, J. Lapasset, R. Faure, E. J. Vincent, J. Elguero, Les benzazoles (indazole, benzimidazole, benzotriazole): Structure moléculaire et propriétés fondamentales. Tetrahedron1974, 30, 2903–2909.10.1016/S0040-4020(01)97464-2Search in Google Scholar

[17] L. Infantes, O. Mó, M. Yáñez, M. V. Roux, P. Jiménez, J. Z. Dávalos, M. Temprado, M. A. V. Ribeiro Da Silva, M. D. M. C. Ribeiro Da Silva, L. M. P. F. Amaral, P. Cabildo, R. M. Claramunt, J. Elguero, Substituent effects on enthalpies of formation of nitrogen heterocycles: 2-Substituted benzimidazoles and related compounds. J. Phys. Chem. A2006, 110, 2535.10.1021/jp055954wSearch in Google Scholar PubMed

[18] J. Elguero, G. Llouquet, C. Marzin, Annular tautomerism of benzimidazoles: effect of a hydrogen bond on the prototropic rate. Tetrahedron Lett.1975, 16, 4085.Search in Google Scholar

[19] J. Catalán, J. Elguero, R. Flammang, A. Maquestiau, The relative basicities of imidazole and benzimidazole. Angew. Chem. Int. Ed.1983, 22, 323.Search in Google Scholar

[20] P. Jiménez, M. V. Roux, J. Z. Dávalos, M. Temprado, M. A. V. Ribeiro Da Silva, M. D. M. C. Ribeiro Da Silva, L. M. P. F. Amaral, P. Cabildo, R. M. Claramunt, O. Mó, M. Yáñez, J. Elguero, Substituent and ring effects on enthalpies of formation: 2-methyl- and 2-ethyl-benzimidazoles vs. benzene- and imidazole-derivatives. Mol. Phys.2004, 102, 711.Search in Google Scholar

[21] M. A. V. Ribeiro Da Silva, M. D. M. C. Ribeiro Da Silva, L. M. P. F. Amaral, P. Jiménez, M. V. Roux, J. Z. Davalos, M. Temprado, P. Cabildo, R. M. Claramunt, J. Elguero, O. Mó, M. Yáñez, Experimental thermochemical study of two 2-alkylbenzimidazole isomers (alkyl = propyl and isopropyl). J. Chem. Thermodyn.2004, 36, 533.Search in Google Scholar

[22] M. A. V. Ribeiro Da Silva, M. D. M. C. Ribeiro Da Silva, L. M. P. F. Amaral, J. Elguero, P. Jiménez, M. V. Roux, J. Z. Davalos, M. Temprado, P. Cabildo, R. M. Claramunt, O. Mó, M. Yáñez, Thermochemical properties of two benzimidazole derivatives: 2-phenyl- and 2-benzylbenzimidazole. J. Chem. Thermodyn.2005, 37, 1168.Search in Google Scholar

[23] S. Horiuchi, F. Kagawa, K. Hatahara, K. Kobayashi, R. Kumai, Y. Murakami, Y. Tokura, 2012. Above-room-temperature ferroelectricity and antiferroelectricity in benzimidazoles. Nature communications Online Edition: 2012/12/18, doi:10.1038/ncomms2322.10.1038/ncomms2322Search in Google Scholar PubMed PubMed Central

[24] I. Alkorta, G. Sánchez-Sanz, C. Trujillo, J. Elguero, R. M. Claramunt, A theoretical study of the parent NH-benzazoles (benzimidazoles, indazoles and benzotriazoles): geometries, energies, acidity and basicity, NMR properties and molecular electrostatic potentials. ARKIVOC2012, ii, 85.10.3998/ark.5550190.0013.209Search in Google Scholar

[25] J. Elguero, I. Alkorta, R. M. Claramunt, P. Cabildo, P. Cornago, M. Á. Farrán, M. Á. García, C. López, M. Pérez-Torralba, D. Santa María, D. Sanz, Structure of NH-benzazoles (1H-benzimidazoles, 1H- and 2H-indazoles, 1H- and 2H-benzotriazoles. Chem. Heterocycl. Comp.2013, 177.10.1007/s10593-013-1237-xSearch in Google Scholar

[26] M. Litt, C. Hsu, P. Basu, S. M. Aharoni, Scanning for ferroelectricity in polycrystalline materials, J. Appl. Phys.1975, 46, 3250.Search in Google Scholar

[27] F. H. Allen, The Cambridge Structural Database: a quarter of a million crystal structures and rising. Acta Crystallogr. Sect. B2002, 58, 380.10.1107/S0108768102003890Search in Google Scholar PubMed

[28] F. H. Allen, W. D. S. Motherwell, Applications of the Cambridge Structural Database in organic chemistry and crystal chemistry. Acta Crystallogr. Sect. B2002, 58, 407; Cambridge Structural Database (CSD), version 5.34, updated May 2013. http://www.ccdc.cam.ac.uk.10.1107/S0108768102004895Search in Google Scholar PubMed

[29] F. J. Zúñiga, L. Palatinus, P. Cabildo, R. M. Claramunt, J. Elguero, The molecular structure of 2-phenylbenzimidazole: a new example of incommensurate modulated intramolecular torsion. Z. Kristallogr.2006, 221, 281.Search in Google Scholar

[30] J. D. Dunitz, J. Bernstein, Disappearing polymorphs. Acc. Chem. Res.1995, 28, 193.Search in Google Scholar

[31] R. K. Harris, NMR studies of organic polymorphs & solvates. Analyst2006, 131, 351.10.1039/b516057jSearch in Google Scholar PubMed

[32] A. Altomare, M. C. Burla, M. Camalli, G. Cascarano, C. Giacovazzo, A. Guagliardi, A. G. G. Moliterni, G. Polidori, R. Spagna, R. SIR97. A Package for Crystal Structure Solution by Direct Methods and Refinement, Bari, Rome, Italy, 1997.Search in Google Scholar

[33] V. Petricek, M. Dusek, L. Palatinus, Jana2006. Structure Determination Software Programs. Institute of Physics, Praha, Czech Republic, 2006.Search in Google Scholar

[34] J. L. Farrugia, WinGX and ORTEP for Windows: an update. J. Appl. Crystallogr.2012, 45, 849.Search in Google Scholar

[35] Diamond 3.2, Crystal Impact GbR, Bonn, Germany.Search in Google Scholar

[36] J. M. Pérez-Mato, D. Orobengoa, M. I. Aroyo, Mode crystallography of distorted structures. Acta Crystallogr. A2010, 66, 558.10.1107/S0108767310016247Search in Google Scholar PubMed

[37] B. Ojha, G. Das, Molecular recognition of 2-alkylbenzimidazole: photophysical and structural studies. J. Photochem. Photobiol. A: Chem.2010, 211, 176.Search in Google Scholar

[38] L. B. Alemany, D. M. Grant, T. D. Alger, R. J. Pugmire, Cross polarization and magic angle sample spinning NMR spectra of model organic compounds. 3. Effect of the 13C-1H dipolar interaction on cross polarization and carbon-proton dephasing. J. Am. Chem. Soc.1983, 105, 6697.Search in Google Scholar

[39] R. K. Harris, NMR crystallography: the use of chemical shifts. Solid State Sci.2004, 6, 1025.Search in Google Scholar

[40] R. K. Harris, R. E. Wasylischen, M. J. Duer, NMR Crystallography, Eds. Wiley, Chichester, 2009.Search in Google Scholar

[41] J. C. Facelli, D. M. Grant, Determination of molecular symmetry in crystalline naphthalene using solid-state NMR. Nature1993, 365, 325.10.1038/365325a0Search in Google Scholar PubMed


Supplemental Material:

The online version of this article (DOI: 10.1515/zkri-2015-0004) offers supplementary material, available to authorised users.


Received: 2014-11-19
Accepted: 2015-2-23
Published Online: 2015-3-28
Published in Print: 2015-6-1

©2015 by De Gruyter

Scroll Up Arrow