Imidazole

Imidazole is a nitroimidazole.^{[1][2][3][4][5]}

Discovery

Imidazole was first synthesized by H. Debus in 1858, but various imidazole derivatives had been discovered as early as the 1840s. His synthesis, as shown below, used ammonia to form imidazole. This synthesis, while producing relatively low yields, is still used for creating C-substituted imidazoles.

In one ammonia in glacial acetic acid forming 2,4,5-triphenylimidazole (Lophine).^[6]

Preparation

Imidazole can be synthesized by numerous methods besides the Debus method. Many of these syntheses can also be applied to different substituted imidazoles and imidazole derivatives simply by varying the functional groups on the reactants. In literature, these methods are commonly categorized by which and how many bonds form to make the imidazole rings. For example, the Debus method forms the (1,2), (3,4), and (1,5) bonds in imidazole, using each reactant as a fragment of the ring, and thus this method would be a three-bond-forming synthesis. A small sampling of these methods is presented below.

Formation of One Bond

The (1,5) or (3,4) bond can be formed by the reaction of an immediate and an α-aminoaldehyde or α-aminoacetal, resulting in the cyclization of an amidine to imidazole. The example below applies to imidazole when R=R₁=Hydrogen.

Formation of Two Bonds

The (1,2) and (2,3) bonds can be formed by treating a 1,2-diaminoalkane, at high temperatures, with an alcohol, alumina, must be present in the reaction for the imidazole to form. The example below applies to imidazole when R=Hydrogen.

The (1,2) and (3,4) bonds can also be formed from N-substituted α-aminoketones and formamide and heat. The product will be a 1,4-disubstituted imidazole, but here since R=R₁=Hydrogen, imidazole itself is the product. The yield of this reaction is moderate, but it seems to be the most effective method of making the 1,4 substitution.

Formation of Four Bonds

This is a general method which is able to give good yields for substituted imidazoles. The starting materials are substituted glyoxal, aldehyde, amine, and ammonia or an ammonium salt.^[7]

Formation from other Heterocycles

Imidazole can be synthesized by the photolysis of 1-vinyltetrazole. This reaction will only give substantial yields if the 1-vinyltetrazole is made efficiently from an organotin compound such as 2-tributylstannyltetrazole. The reaction, shown below, produces imidazole when R=R₁=R₂=Hydrogen.

Imidazole can also be formed in a vapor phase reaction. The reaction occurs with ethylenediamine, and hydrogen over platinum on alumina, and it must take place between 340 and 480 °C. This forms a very pure imidazole product.

Structure and properties

Imidazole is a 5-membered planar ring, which is soluble in water and resonance structures of imidazole are shown below.

Imidazole is a base and an excellent electrophilic attacks at the carbon atoms, and most of these reactions are substitutions that keep the aromaticity intact. One can see from the resonance structure that the carbon-2 is the carbon most likely to have a nucleophile attack it, but in general nucleophilic substitutions are difficult with imidazole.

Biological significance and applications

Imidazole is incorporated into many important biological molecules. The most obvious is the histamine, which is also a common biological compound. It is a component of the toxin that causes urticaria, which is basically an allergic reaction. The structures of both histidine and histamine are:

One of the applications of imidazole is in the purification of ions attached to the surface of beads in the chromatography column. An excess of imidazole is passed through the column, which displaces the His-tag from nickel co-ordination, freeing the His-tagged proteins.

Imidazole has become an important part of many pharmaceuticals. Synthetic imidazoles are present in many fungicides and DNA activities.

Industrial applications

Imidazole has been used extensively as a corrosion inhibitor on certain transition metals, such as copper. Preventing copper corrosion is important, especially in aqueous systems, where the conductivity of the copper decreases due to corrosion.

Many compounds of industrial and technological importance contain imidazole. The thermostable polybenzimidazole PBI contains imidazole fused to a benzene ring and linked to a benzene, and acts as a fire retardant. Imidazole can also be found in various compounds which are used for photography and electronics.

Salts of imidazole

Salts of imidazole where the imidazole ring is in the cation are known as imidazolium salts (for example, imidazolium chloride). These salts are formed from the protonation or substitution at stable carbenes. Salts where a deprotanated imidazole is an anion are also possible; these salts are known as imidazolide salts (for example, sodium imidazolide).

Related heterocycles

• benzene ring.
• Dihydroimidazole or benzimidazoline, an analog where 4,5-double bond is saturated.
• atom in position 1.
• oxygen.
• sulfur.
• nitrogen atoms.

References

1. ^ Katritzky; Rees. Comprehensive Heterocyclic Chemistry. Vol. 5, p.469-498, (1984).
2. ^ Grimmett, M. Ross. Imidazole and Benzimidazole Synthesis. Academic Press, (1997).
3. ^ Brown, E.G. Ring Nitrogen and Key Biomolecules. Kluwer Academic Press, (1998).
4. ^ Pozharskii, A.F, et.al. Heterocycles in Life and Society. John Wiley & Sons, (1997).
5. ^ Heterocyclic Chemistry TL Gilchrist, The Bath press 1985 ISBN 0-582-01421-2
6. ^ Microwave-Mediated Synthesis of Lophine: Developing a Mechanism To Explain a Product Crouch, R. David; Howard, Jessica L.; Zile, Jennifer L.; Barker, Kathryn H. J. Chem. Educ. 2006 83 1658
7. ^ US6,177,575 (PDF version) (2001-01-23) Anthony J. Arduengo, III Process for Manufacture of Imidazoles 

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