Imidazole is an organic compound with the formula2N(NH)CH.
It is a colourless solid that dissolves in water to give mildly alkaline solution.
In chemistry, it is an aromatic heterocycle, classified as a diazole and as an alkaloid.
Derivatives of imidazole, called imidazoles, form a common family of heterocycles that
share the 1,3-C3N2 ring but feature varied substituents.
This ring system is present in important biological building-blocks, such as histidine, and the
related hormone histamine.
Many drugs contain an imidazole ring, such as antifungal drugs, nitroimidazole, and the
sedative midazolam.
Structure and properties Imidazole is a planar 5-membered ring.
It exists in two equivalent tautomeric forms, because the proton can be located on either
of the two nitrogen atoms.
Imidazole is a highly polar compound, as evidenced by a calculated dipole of 3.61D. 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 pKa 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 pKa of the conjugate acid is approximately 7, making imidazole approximately
sixty times more basic than pyridine.
The basic site is N-3.
Protonation gives the imidazolium cation, which is symmetrical.
Preparation Imidazole was first reported in 1858, 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.
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.
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,, and 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 or 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 and 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 and 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 is a component of the toxin that causes urticaria, which is another name for allergic
hives.
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.
Imidazole is used to elute tagged proteins bound to Ni 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 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 Ca++ 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.
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.
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 possible; these salts are known
as imidazolide or imidazolate salts.
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
See also 1-Methylimidazole
4-Methylimidazole References