Synthesis, Reactions and Medicinal Uses of Imidazole

Imidazole

Synthesis

Debus method - According to the Debus Method published in 1858, glyoxal, formaldehyde, and ammonia produce imidazole (glyoxaline). 2- and 3-mono- and 4,3-disubstituted imidazoles are available in this product.

Radiszewski synthesis - By combining glyoxal with an aldehyde (e.g., benzaldehyde), benzaldehyde is formed. Formamide can replace ammonia.


Wallach synthesis - Nitroxamide is formed by the reaction between phosphorus oxychloride and N,N'-disubstituted oxamide, which is then reduced with hydroiodic acids to produce nitrogen-containing intermediates. Chloroimidazoles containing 1,2-disubstituted substituents are produced.


Marckwald synthesis - 3-mercaptoimidazoles react with H-imidazoline-2-thiones generated from cyanate, isothiocyanate, or thiocyanate reactions. Dehydrogenation can make imidazole readily available.

From aminonitrile and aldehyde


Maquenne synthesis -



An imidazole derivative is formed by a reaction between alkenes, carbon monoxide, and ammonia.

Reactions

Reaction with acids - The protonation of N3-atoms in imidazole produces stable salts with strong acids.



The proton on the N1 atom of imidazole can be removed by a strong base, but it acts as an acid. There are therefore two properties of the compound: acidic and basic. Pyrole is acidic, while pyridine is basic.

Electrophilic substitution reaction

N – alkylation and N – acylation




Halogenation


Nitration


Sulfonation


Reaction with aldehydes and ketones

Action of oxidizing agents - Imidazole is resistant to auto-oxidation, chromic acid, and hydrogen peroxide, but is attacked by perbenzoic acid.



Reaction with nucleophilic reagents - It is not possible to substitute imidazole with nucleophiles. Nucleophilic substitution readily attacks the C2 position if electron-withdrawing groups are present.

A halogen may be replaced by a nucleophile in the nucleophilic substitution reaction of 2-haloimidazoles.

Medicinal Uses

In histidine and histamine, imidazole is an amino acid parent skeleton. ketoconazole (antifungal), midazolam (sedative), and metronidazole (antibiotic) are all important drugs with imidazole rings. Biotin (vitamin), nucleic acids, and a variety of alkaloids contain this structure. Losartan, Eprosartan, and Neomycin are examples of medications that contain imidazole nucleus, as well as Clotrimazole (anticancer).

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