Imidazole

Structure and properties

Imidazole is a planar 5-membered ring. It exists in two equivalent tautomeric forms, because the positive charge can be located on either of the two nitrogen atoms. Imidazole is a highly polar compound, as evidenced by its electric dipole moment of 3.67 D. It is highly soluble in water. The compound is classified as aromatic due to the presence of a sextet of π-electrons, consisting of a pair of electrons from the protonated nitrogen atom and one from each of the remaining four atoms of the ring. Some resonance structures of imidazole are shown below:

Amphoterism

Imidazole is amphoteric. That is, it can function as both an acid and as a base. As an acid, the pK_a of imidazole is 14.5, making it less acidic than carboxylic acids, phenols, and imides, but slightly more acidic than alcohols. The acidic proton is located on N-1. As a base, the pK_a of the conjugate acid (cited as pK_BH⁺ to avoid confusion between the two) is approximately 7, making imidazole approximately sixty times more basic than pyridine. The basic site is N3. Protonation gives the imidazolium cation, which is symmetrical.

Preparation

Imidazole was first reported in 1858 by the German-British chemist Heinrich Debus, although various imidazole derivatives had been discovered as early as the 1840s. Its synthesis, as shown below, used glyoxal and formaldehyde in ammonia to form imidazole (or glyoxaline, as it was originally named). This synthesis, while producing relatively low yields, is still used for creating C-substituted imidazoles.

In one microwave modification, the reactants are benzil, benzaldehyde and ammonia in glacial acetic acid, forming 2,4,5-triphenylimidazole (lophine).

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 by varying the functional groups on the reactants. 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 catalyst, such as platinum on alumina, is required.The (1,2) and (3,4) bonds can also be formed from N-substituted α-aminoketones and formamide with 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 that is able to give good yields for substituted imidazoles. In essence, it is an adaptation of the Debus method called the Debus-Radziszewski imidazole synthesis. The starting materials are substituted glyoxal, aldehyde, amine, and ammonia or an ammonium salt.

Formation from other heterocycles

Imidazole can be synthesized by the photolysis of 1-vinyltetrazole. This reaction will give substantial yields only 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 formamide, ethylenediamine, and hydrogen over platinum on alumina, and it must take place between 340 and 480 °C. This forms a very pure imidazole product.

Van Leusen reaction

The Van Leusen reaction can also be employed to form imidazoles starting from TosMIC and an aldimine.

Biological significance and applications

Imidazole is incorporated into many important biological molecules. The most pervasive 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. Imidazole-based histidine compounds play a very important role in intracellular buffering. Histidine can be decarboxylated to histamine, which is also a common biological compound. It can cause urticaria (hives), when histamine is produced during allergic reaction. The relationship between histidine and histamine are shown below:

One of the applications of imidazole is in the purification of His-tagged proteins in immobilised metal affinity chromatography (IMAC). Imidazole is used to elute tagged proteins bound to nickel 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 coordination, 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, that stimulates the central nervous system. It is present in the anticancer medication mercaptopurine, which combats leukemia by interfering with DNA activities.

A number of substituted imidazoles, including clotrimazole, are selective inhibitors of nitric oxide synthase, which makes them interesting drug targets in inflammation, neurodegenerative diseases and tumors of the nervous system. Other biological activities of the imidazole pharmacophore relate to the downregulation of intracellular Ca²⁺ and K⁺ fluxes, and interference with translation initiation.

Pharmaceutical derivatives

The substituted imidazole derivatives are valuable in treatment of many systemic fungal infections. Imidazoles belong to the class of azole antifungals, which includes ketoconazole, miconazole, and clotrimazole.

For comparison, another group of azoles is the triazoles, which includes fluconazole, itraconazole, and voriconazole. The difference between the imidazoles and the triazoles involves the mechanism of inhibition of the cytochrome P450 enzyme. The N3 of the imidazole compound binds to the heme iron atom of ferric cytochrome P450, whereas the N4 of the triazoles bind to the heme group. The triazoles have been shown to have a higher specificity for the cytochrome P450 than imidazoles, thereby making them more potent than the imidazoles.

Some imidazole derivatives show effects on insects, for example sulconazole nitrate exhibits a strong anti-feeding effect on the keratin-digesting Australian carpet beetle larvae Anthrenocerus australis, as does econazole nitrate with the common clothes moth Tineola bisselliella.

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 derivatives. 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 that 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 nitrogen of imidazole. These salts have been used as ionic liquids and precursors to stable carbenes. Salts where a deprotonated imidazole is an anion are also well known; these salts are known as imidazolates (for example, sodium imidazolate, NaC₃H₃N₂).

Related heterocycles

Benzimidazole, an analog with a fused benzene ring

Dihydroimidazole or imidazoline, an analog where 4,5-double bond is saturated

Pyrrole, an analog with only one nitrogen atom in position 1

Oxazole, an analog with the nitrogen atom in position 1 replaced by oxygen

Thiazole, an analog with the nitrogen atom in position 1 replaced by sulfur

Pyrazole, an analog with two adjacent nitrogen atoms

Triazoles, analogs with three nitrogen atoms