Benzimidazole
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Through Aromaticity, Organic compound and Benzene
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. 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.
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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.
N,N'-Dialkylbenzimidazolium salts are precursors to certain N-heterocyclic carbenes.
Applications
Benzimidazole derivatives are among the most frequently used ring systems for small molecule drugs listed by the United States Food and Drug Administration. 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.
- 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.