Imidazole is an organic compound with the formula C3N2H4. It is a white or colourless solid that is soluble in water, producing a mildly alkaline solution. In chemistry, it is an aromatic heterocycle, classified as a diazole, and has non-adjacent nitrogen atoms.
3D model (JSmol)
CompTox Dashboard (EPA)
|Molar mass||68.077 g/mol|
|Appearance||white or pale yellow solid|
|Density||1.23 g/cm3, solid|
|Melting point||89 to 91 °C (192 to 196 °F; 362 to 364 K)|
|Boiling point||256 °C (493 °F; 529 K)|
|Acidity (pKa)||6.95 (for the conjugate acid) |
|UV-vis (λmax)||206 nm|
|planar 5-membered ring|
|Safety data sheet||External MSDS|
|H302, H314, H360, H360D|
|P201, P280, P305+351+338, P310, P330 |
|Flash point||146 °C (295 °F; 419 K)|
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
|what is ?)(|
Many natural products, especially alkaloids, 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 antifungal drugs, the nitroimidazole series of antibiotics, and the sedative midazolam.
Structure and propertiesEdit
Imidazole is a planar 5-membered ring. It exists in two equivalent tautomeric forms, because hydrogen can be bound to one or the other nitrogen atom. 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 planar ring containing 6 π-electrons (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:
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 the one bound to nitrogen. Deprotonation gives the imidazole anion, which is symmetrical. As a base, the pKa of the conjugate acid (cited as pKBH+ 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.
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. It was shown that glyoxal, formaldehyde, and ammonia condense to form imidazole (glyoxaline, as it was originally named). This synthesis, while producing relatively low yields, is still used for generating C-substituted imidazoles.
Imidazole can be synthesized by numerous methods besides the Debus method. Many of these syntheses can also be applied to substituted imidazoles by varying the functional groups on the reactants. These methods are commonly categorized by the number of reacting components.
- One component
- Two component
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 R1 = R2 = 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.
- Three component
This method proceeds in good yields for substituted imidazoles. An adaptation of the Debus method, it is 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 R1 = R2 = R3 = 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. The Van Leusen Imidazole Synthesis allows the preparation of imidazoles from aldimines by reaction with tosylmethyl isocyanide (TosMIC). The reaction has later been expanded to a two-step synthesis in which the aldimine is generated in situ: the Van Leusen Three-Component Reaction (vL-3CR).
Biological significance and applicationsEdit
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. Histamine can cause urticaria (hives) when it is produced during allergic reaction. The relationship between histidine and histamine is 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.
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.
Salts of imidazoleEdit
Salts of imidazole where the imidazole ring is in 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 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).
- 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
This article lacks ISBNs for the books listed in it. (November 2017)
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