Imidazole

Imidazole
General
Systematic name	1,3-diazole
Other names	Imidazole 1,3-Diaza-2,4-cyclopentadiene
Molecular formula	C₃H₄N₂
Molar mass	68.08 g/mol
Appearance	white or pale yellow solid
CAS number	^*
Properties
Density and phase	0.6 g/cm³, solid
Solubility in water	miscible
Melting point	89-91 °C (362-364 K)
Boiling point	256 °C (529 K)
Acidity (pK_a)	pK_a=14.5
Basicity (pK_b)	pK_b=7.0
Structure
Coordination geometry	planar 5-membered ring
Crystal structure	monoclinic
Dipole moment	12.8 Cm*10³⁰
Hazards
MSDS	External MSDS
Main hazards	Corrosive
NFPA 704
Flash point	146 °C
RTECS number	N13325 1985-86
Supplementary data page
Structure and properties	n, ε_r, etc.
Thermodynamic data	Phase behaviour Solid, liquid, gas
Spectral data	UV, IR, NMR, MS
Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa) Chemical infobox

Imidazole is a heterocyclic aromatic organic compound. It is further classified as an alkaloid. Imidazole refers to the parent compound C₃H₄N₂, while imidazoles are a class of heterocycles with similar ring structure but varying substituents. This ring system is present in important biological building blocks such as histidine and histamine. Imidazole can act as a base and as a weak acid. Imidazole exists in two tautomeric forms with the hydrogen atom moving between the two nitrogens. Many drugs contain an imidazole ring, such as antifungal drugs and nitroimidazole.

Discovery

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

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 imidate 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, aldehyde, or carboxylic acid. A dehydrogenating agent, such as platinum with 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 from other Heterocycles

Imidazole can be synthesized by the photolysis of 1-vinyltetrazole. This reaction will only give substacial yields if the 1-vinyltetrazole is made efficiently from a 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 formamide, ethylenediamine and hydrogen over plat- inum on alumina, and it must take place between 340 to 480 ºC. This forms a very pure imidazole product.

Structure and properties

Imidazole is a 5 membered planar ring which is soluble in water and polar solvents. The compound has an aromatic sextet which consists of one π electron from the =N- atom and one from each carbon atom, and two from the NH nitrogen. The resonance structures of imidazole are shown below.

Imidazole is a base and an excellent nucleophile. It reacts at the NH nitrogen, attacking alkylating and acylating compounds. It is not particularly susceptible to 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 amino acid histidine, which has an imidazole side chain. Histidine is present in many proteins and enzymes and plays a vital part in the structure and binding functions of hemoglobin. Histidine can be decarboxylated to histamine, which is also a common biological compound. It is a component of the toxin which causes urticaria, which is basically an allergic reaction. The structures of both histidine and histamine are:

One of the application of imidazole in the purification of His-tagged proteins in immobilised metal affinity chromatography(IMAC). Imidazole is used to elute tagged proteins bound to Ni ions attached to the surface of beads in the chromatography column. Imidazole binds to the Ni with higher affinity than His-tags. As a result, imidazole binds the surface of the bead, freeing the His-tagged proteins.

Imidazole has become an important part of many pharmaceuticals. Synthetic imidazoles are present in many fungicides and antifungal, antiprotozoal, and antihypertensive medications. Imidazole is part of the theophylline molecule, found in tea leaves and coffee beans, which stitmulates the central nervous system. It is present in the anticancer medication mercaptopurine, which combats leukemia by inferring with 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.

Related heterocycles

Benzimidazole, an analog with a fused benzene ring. idem: benzimidazoline
Pyrrole, an analog with only one nitrogen atom in position 1.
Oxazole, an analog with the nitrogen atom in position 1 replaced by oxygen.
Pyrazoles, an analog with two adjacent nitrogen atoms.

References

Katritzky; Rees. Comprehensive Heterocyclic Chemistry. Vol. 5, p.469-498, (1984).
Grimmett, M. Ross. Imidazole and Benzimidazole Synthesis. Academic Press, (1997).
Brown, E.G. Ring Nitrogen and Key Biomolecules. Kluwer Academic Press, (1998).
Pozharskii, A.F, et.al. Heterocycles in Life and Society. John Wiley & Sons, (1997).
Heterocyclic Chemistry TL Gilchrist, The Bath press 1985 ISBN 0582014212

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