Imidazole (ImH) is an organic compound with the formula . It is a white or colourless solid that is soluble in water, producing a mildly solution. It can be classified as a heterocycle, specifically as a diazole.
Many natural products, especially , contain the imidazole ring. These imidazoles 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 certain , the nitroimidazole series of antibiotics, and the sedative midazolam.
When fused to a pyrimidine ring, it forms a purine, which is the most widely occurring nitrogen-containing heterocycle in nature.
The name "imidazole" was coined in 1887 by the German chemist Arthur Rudolf Hantzsch (1857–1935).[Hantzsch, A. and Weber, J. H. (1887) "Ueber Verbindungen des Thiazols (Pyridins der Thiophenreihe)" (On compounds of thiazole (pyridines of the thiophene series), Berichte der deutschen chemischen Gesellschaft, 20 : 3118–3132, see p. 3119. See also: Hantzsch, A. (1888) "Allegemeine Bemerkungen über Azole" (General observations about azoles), Annalen der Chemie, 249 : 1–6. Hantzsch proposed a reform of the nomenclature of azole compounds, including a proposal to call the heterocyclic ring C3H3(NH)N "imidazole"; see pp. 2 and 4.]
Structure and properties
Imidazole is a planar 5-membered ring, that exists in two equivalent
forms because hydrogen can be bound to one or another
nitrogen atom. Imidazole is a highly polar compound, as evidenced by its electric dipole moment of 3.67
debye,
and is highly soluble in water. The compound is classified as
aromaticity due to the presence of a planar ring containing 6
pi bond (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, which is to say that it can function both as an acid and as a base. As an acid, the p
Ka 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 the one bound to nitrogen. Deprotonation gives the imidazolide anion, which is symmetrical. As a base, the p
Ka of the conjugate acid (cited as p
KBH+ to avoid confusion between the two) is approximately 7, making imidazole approximately sixty times more basic than
pyridine. The basic site is the nitrogen with the lone pair (and not bound to hydrogen). Protonation gives the imidazolium cation, which is symmetrical.
Preparation
Imidazole was first reported in 1858 by the German chemist Heinrich Debus, although various imidazole derivatives had been discovered as early as the 1840s. It was shown that
glyoxal,
formaldehyde, and
ammonia condense to form imidazole (glyoxaline, as it was originally named).
[ From p. 205: "Die gereinigte Substanz stellt das oxalsaure Salz einer Basis dar, die ich mit Glyoxalin bezeichenen werde." (The purified substance constitutes the oxalic salt of a base, which I will designate as "glyoxaline".)] This synthesis, while producing relatively low yields, is still used for generating
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-amino
aldehyde or α-amino
acetal. The example below applies to imidazole when R
1 = R
2 = hydrogen.
Formation of two bonds
The (1,2) and (2,3) bonds can be formed by treating a 1,2-diamino
alkane, 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
1 = R
2 = 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
tetrazole. 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
1 = R
2 = R
3 = 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.
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 compounds. The most pervasive is the
amino acid histidine, which has an imidazole
Side chain. Histidine is present in many
proteins and
enzymes, e.g. by binding metal cofactors, as seen in
hemoglobin.
Imidazole-based histidine compounds play an important role in intracellular buffering.
Pharmaceutical derivatives
Imidazole substituents are found in many pharmaceuticals such as anticancer drug
mercaptopurine. The imidazole group is present in many
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.
A number of substituted imidazoles, including clotrimazole, are selective inhibitors of nitric oxide synthase.
The substituted imidazole derivatives are valuable in treatment of many systemic fungal infections.
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 itself has few direct applications. It is instead a precursor to a variety of agrichemicals, including
enilconazole,
climbazole,
clotrimazole,
prochloraz, and
bifonazole.
It may be useful as a catalyst to depolymerization various and polyurethane plastic materials for recycling.
Coordination chemistry
Imidazole and its derivatives have high affinity for metal cations. One of the applications of imidazole is in the purification of
in immobilised metal affinity chromatography (IMAC). Imidazole is used to elute tagged proteins bound to
nickel 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.
Use in biological research
Imidazole is a suitable buffer for pH 6.2 to 7.8,.
Pure imidazole has essentially no absorbance at protein relevant wavelengths (280 nm),
however lower purities of imidazole can give notable absorbance at 280 nm. Imidazole can interfere with the Lowry protein assay.
Imidazole is often used in protein purification, where recombinant proteins with polyhistidine tags are immobilized onto nickel resins and eluted with a high imidazole concentration.
Salts of imidazole
Salts of imidazole where the imidazole ring is the
cation are known as imidazolium salts (for example, imidazolium
chloride or
nitrate).
These salts are formed from the
protonation or substitution at
nitrogen of imidazole. These salts have been used as
ionic liquids and precursors to
. Salts where a deprotonated imidazole is an
anion are also well known; these salts are known as
(for example, sodium imidazolate, NaC
3H
3N
2).
Related heterocycles
Safety
Imidazole has low acute toxicity as indicated by the of 970 mg/kg (Rat, oral).
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See also
-
1-Methylimidazole
-
4-Methylimidazole
-
Imidazoline (dihydroimidazole)
