Benzimidazole Explained

Benzimidazole is a heterocyclic aromatic organic compound. This bicyclic compound may be viewed as fused rings of the aromatic compounds benzene and imidazole. It is a white solid that appears in form of tabular crystals.^[1]

Preparation

Benzimidazole was discovered during research on vitamin B₁₂. The benzimidazole nucleus was found to be a stable platform on which drugs could be developed.^[2] Benzimidazole is produced by condensation of o-phenylenediamine with formic acid, or the equivalent trimethyl orthoformate:

C₆H₄(NH₂)₂ + HC(OCH₃)₃ → C₆H₄N(NH)CH + 3 CH₃OH

2-Substituted derivatives are obtained when the condensation is conducted with aldehydes in place of formic acid, followed by oxidation.^[3]

Reactions

Benzimidazole is a base:

C₆H₄N(NH)CH + H⁺ → [C₆H₄(NH)₂CH]⁺It can also be deprotonated with stronger bases:

C₆H₄N(NH)CH + LiH → Li [C₆H₄N₂CH] + H₂

The imine can be alkylated and also serves as a ligand in coordination chemistry. The most prominent benzimidazole complex features N-ribosyl-dimethylbenzimidazole, as found in vitamin B₁₂.^[4]

N,N-Dialkylbenzimidazolium salts are precursors to certain N-heterocyclic carbenes.^{[5] [6]}

Applications

Benzimidazole derivatives are among the most frequently used ring systems for small molecule drugs listed by the United States Food and Drug Administration.^[7] Many pharmaceutical agents belong to the benzimidazole class of compounds. For example:

• Angiotensin II receptor blockers such as azilsartan, candesartan, and telmisartan.
• Anthelmintic agents such as albendazole, ciclobendazole, fenbendazole, flubendazole, mebendazole, oxfendazole, oxibendazole, triclabendazole, and thiabendazole. These drugs work by binding tubulin, a vital part of the cytoskeleton and mitotic spindle. Benzimidazoles are selectively toxic towards parasitic nematodes, selectively binding and depolymerising their tubulins.^[8]
• Antihistamines such as astemizole, bilastine, clemizole, emedastine, mizolastine, and oxatomide.
• Benzimidazole fungicides such as benomyl, carbendazim, fuberidazole, and thiabendazole. These drugs selectively bind to and depolymerise fungal tubulin.
• Benzimidazole opioids such as bezitramide, brorphine, clonitazene, etodesnitazene, etonitazene, etonitazepipne, etonitazepyne, isotonitazene, metodesnitazene, and metonitazene.
• Proton-pump inhibitors such as dexlansoprazole, esomeprazole, ilaprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole, and tenatoprazole.
• Typical antipsychotics such as benperidol, clopimozide, droperidol, neflumozide, and oxiperomide, and pimozide.
• Other notable pharmaceutical agents which contain a benzimidazole group include abemaciclib, bendamustine, dabigatran, daridorexant, and glasdegib.

In printed circuit board manufacturing, benzimidazole can be used as an organic solderability preservative.

Several dyes are derived from benzimidazoles.^[9]

See also

• Benzimidazoline
• Polybenzimidazole, a high performance fiber

Further reading

• Book: Grimmett, M. R. . Imidazole and benzimidazole synthesis . Academic Press . Boston . 1997 . 0-12-303190-7 .

Notes and References

1. Web site: Benzimidazole CAMEO Chemicals NOAA . 2023-01-11 . cameochemicals.noaa.gov.
2. Bennet-Jenkins . E. . Bryant . C. . 1996 . Novel sources of anthelmintics . International Journal for Parasitology . 26 . 8-9 . 937–947 . 10.1016/s0020-7519(96)80068-3 . 0020-7519 . 8923141.
3. Robert A. Smiley "Phenylene- and Toluenediamines" in Ullmann's Encyclopedia of Industrial Chemistry 2002, Wiley-VCH, Weinheim.
4. H. A. Barker. R. D. Smyth. H. Weissbach. J. I. Toohey. J. N. Ladd. B. E. Volcani. amp. Isolation and Properties of Crystalline Cobamide Coenzymes Containing Benzimidazole or 5,6-Dimethylbenzimidazole. Journal of Biological Chemistry. February 1, 1960. 235. 2. 480–488. 10.1016/S0021-9258(18)69550-X. 13796809. free.
5. R. Jackstell . A. Frisch . M. Beller . D. Rottger . M. Malaun . B. Bildstein . Efficient telomerization of 1,3-butadiene with alcohols in the presence of in situ generated palladium(0)carbene complexes . 2002 . Journal of Molecular Catalysis A: Chemical . 185 . 1–2 . 105–112 . 10.1016/S1381-1169(02)00068-7.
6. H. V. Huynh . J. H. H. Ho . T. C. Neo . L. L. Koh . Solvent-controlled selective synthesis of a trans-configured benzimidazoline-2-ylidene palladium(II) complex and investigations of its Heck-type catalytic activity . 2005 . . 690 . 16 . 3854–3860 . 10.1016/j.jorganchem.2005.04.053.
7. Taylor, R. D.; MacCoss, M.; Lawson, A. D. G. J Med Chem 2014, 57, 5845.>
8. Wang . C. C. . January 1984 . Parasite enzymes as potential targets for antiparasitic chemotherapy . Journal of Medicinal Chemistry . 27 . 1 . 1–9 . 10.1021/jm00367a001 . 0022-2623 . 6317859.
9. Horst Berneth "Methine Dyes and Pigments" in Ullmann's Encyclopedia of Industrial Chemistry, 2008, Wiley-VCH, Weinheim.