Everything about Imidazole totally explained
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Imidazole is a
heterocyclic aromatic organic compound. It is further classified as an
alkaloid. Imidazole refers to the parent compound C
3H
4N
2, whereas 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 the related hormone
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 Heinrich Debus in 1858, but various imidazole derivatives had been discovered as early as the 1840s. 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.
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In one
microwave modification the reactants are
benzil,
formaldehyde and
ammonia in
glacial acetic acid forming
2,4,5-triphenylimidazole (Lophine).
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.
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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.
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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.
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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 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.
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. Some
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 isn't 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 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
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. 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, which stimulates the
central nervous system. It is present in the anticancer medication
mercaptopurine, which combats
leukemia by interfering 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.
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 deprotanated imidazole is an
anion are also possible; these salts are known as
imidazolide salts (for example, sodium imidazolide).
Related heterocycles
Further Information
Get more info on 'Imidazole'.
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