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| Names | |||
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| Preferred IUPAC name 1H-Imidazole[1] | |||
| Other names 1,3-Diazole Glyoxaline (archaic) | |||
| Identifiers | |||
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3D model (JSmol) | |||
| 103853 | |||
| ChEBI | |||
| ChEMBL | |||
| ChemSpider |
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| DrugBank | |||
| ECHA InfoCard | 100.005.473 | ||
| EC Number |
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| 1417 | |||
| KEGG |
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| RTECS number |
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| UNII | |||
| UN number | 3263 | ||
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| Properties | |||
| C3H4N2 | |||
| 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) | ||
| 633 g/L | |||
| Acidity (pKa) | 6.95 (for theconjugate acid)[2] | ||
| UV-vis (λmax) | 206 nm | ||
| Structure | |||
| Monoclinic | |||
| Planar 5-membered ring | |||
| 3.61D | |||
| Hazards | |||
| Occupational safety and health (OHS/OSH): | |||
Main hazards | Corrosive | ||
| GHS labelling:[4] | |||
   | |||
| Danger | |||
| H302,H314,H360D | |||
| P263,P270,P280,P301+P310,P305+P351+P338,P308+P313[3] | |||
| Flash point | 146 °C (295 °F; 419 K) | ||
Except where otherwise noted, data are given for materials in theirstandard state (at 25 °C [77 °F], 100 kPa). | |||
Imidazole (ImH) is anorganic compound with the formula(CH)3(NH)N. It is a white or colourless solid that is soluble in water, producing a mildlyalkaline solution. It can be classified as aheterocycle, specifically as adiazole.
Many natural products, especiallyalkaloids, 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 ashistidine and the related hormonehistamine. Many drugs contain an imidazole ring, such as certainantifungal drugs, thenitroimidazole series ofantibiotics, and the sedativemidazolam.[5][6][7][8][9]
When fused to apyrimidine ring, it forms apurine, which is the most widely occurring nitrogen-containingheterocycle in nature.[10]
The name "imidazole" was coined in 1887 by the German chemistArthur Rudolf Hantzsch (1857–1935).[11]
Imidazole is a planar 5-membered ring, that exists in two equivalenttautomeric forms because hydrogen can be bound to one or anothernitrogen atom. Imidazole is a highly polar compound, as evidenced by itselectric dipole moment of 3.67 D,[12] and is highly soluble in water. The compound is classified asaromatic due to the presence of a planar ring containing 6π-electrons (a pair of electrons from the protonated nitrogen atom and one from each of the remaining four atoms of the ring). Someresonance structures of imidazole are shown below:
Imidazole isamphoteric, which is to say that it can function both as an acid and as a base. As an acid, thepKa 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 pKa of the conjugate acid (cited as pKBH+ to avoid confusion between the two) is approximately 7, making imidazole approximately sixty times more basic thanpyridine. 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 chemistHeinrich Debus, although various imidazole derivatives had been discovered as early as the 1840s. It was shown thatglyoxal,formaldehyde, andammonia condense to form imidazole (glyoxaline, as it was originally named).[13] This synthesis, while producing relatively low yields, is still used for generatingC-substituted imidazoles.
In onemicrowave modification, the reactants arebenzil,benzaldehyde andammonia inglacial acetic acid, forming 2,4,5-triphenylimidazole ("lophine").[14]
Imidazole can be synthesized by numerous methods besides theDebus method. Many of these syntheses can also be applied to different substituted imidazoles and imidazole derivatives by varying thefunctional 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.
The (1,5) or (3,4) bond can be formed by the reaction of animidate and an α-aminoaldehyde or α-aminoacetal. The example below applies to imidazole when R1 = R2 = hydrogen.
The (1,2) and (2,3) bonds can be formed by treating a 1,2-diaminoalkane, at high temperatures, with analcohol,aldehyde, orcarboxylic acid. A dehydrogenating catalyst, such asplatinum onalumina, is required.
The (1,2) and (3,4) bonds can also be formed fromN-substituted α-aminoketones andformamide 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.
(3%2c4)_formation_imidazole.svg)
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 theDebus-Radziszewski imidazole synthesis. The starting materials are substituted glyoxal, aldehyde, amine, and ammonia or an ammonium salt.[15]
Imidazole can be synthesized by thephotolysis of1-vinyltetrazole. This reaction will give substantial yields only if the 1-vinyltetrazole is made efficiently from anorganotin 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 withformamide,ethylenediamine, and hydrogen overplatinum onalumina, and it must take place between 340 and 480 °C. This forms a very pure imidazole product.
TheVan Leusen reaction can also be employed to form imidazoles starting fromTosMIC and analdimine.[16] 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).
Imidazolin-5-one derivatives can be synthesized from Oxazolidin-5-ones via amidification followed by dehydration. in this reaction, the Oxazolidin-5-ones were condensed with primary amines like aniline, sulfonamides etc. in the presence of various of catalysts like dry pyridine or glacial acetic acid + sodium acetate or glacial acetic acid + red brick powder to yield Imidazolin-5-one derivatives.
Imidazole is incorporated into many important biological compounds. The most pervasive is theamino acidhistidine, which has an imidazoleside-chain. Histidine is present in manyproteins andenzymes, e.g. by binding metal cofactors, as seen inhemoglobin.
Imidazole-based histidine compounds play an important role in intracellular buffering.[17] Histidine can bedecarboxylated tohistamine. Histamine can causeurticaria (hives) when it is produced duringallergic reaction.
Imidazole substituents are found in many pharmaceuticals such as anticancer drugmercaptopurine. The imidazole group is present in manyfungicides andantifungal,antiprotozoal, andantihypertensive medications. Imidazole is part of thetheophylline molecule, found in tea leaves and coffee beans, that stimulates thecentral nervous system.
A number of substituted imidazoles, includingclotrimazole, are selective inhibitors ofnitric oxide synthase.[18][19] Other biological activities of the imidazolepharmacophore relate to the downregulation of intracellularCa2+ andK+ fluxes, and interference with translation initiation.[20]
The substituted imidazole derivatives are valuable in treatment of many systemicfungalinfections.[21] Imidazoles belong to the class ofazole antifungals, which includesketoconazole,miconazole, andclotrimazole.
For comparison, another group of azoles is the triazoles, which includesfluconazole,itraconazole, andvoriconazole. The difference between the imidazoles and the triazoles involves the mechanism of inhibition of thecytochrome 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.[22]
Some imidazole derivatives show effects on insects, for examplesulconazole nitrate exhibits a strong anti-feeding effect on thekeratin-digesting Australian carpet beetle larvaeAnthrenocerus australis, as doeseconazole nitrate with the common clothes mothTineola bisselliella.[23]
Imidazole itself has few direct applications. It is instead a precursor to a variety of agrichemicals, includingenilconazole,climbazole,clotrimazole,prochloraz, andbifonazole.[24]
It may be useful as a catalyst todepolymerize variouspolyesters andpolyurethane plastic materials forrecycling.[25]
Imidazole and its derivatives have high affinity for metal cations. One of the applications of imidazole is in the purification ofHis-taggedproteins inimmobilised metal affinity chromatography (IMAC). Imidazole is used to elute tagged proteins bound tonickelions attached to the surface of beads in thechromatography column. An excess of imidazole is passed through the column, which displaces the His-tag from nickel coordination, freeing the His-tagged proteins.
Imidazole is a suitable buffer for pH 6.2 to 7.8,.[26] Pure imidazole has essentially no absorbance at protein relevant wavelengths (280 nm),[27][28] however lower purities of imidazole can give notable absorbance at 280 nm. Imidazole can interfere with theLowry protein assay.[29]
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 where the imidazole ring is thecation are known as imidazolium salts (for example, imidazoliumchloride ornitrate).[30] These salts are formed from theprotonation or substitution atnitrogen of imidazole. These salts have been used asionic liquids and precursors tostable carbenes. Salts where a deprotonated imidazole is ananion are also well known; these salts are known asimidazolates (for example, sodium imidazolate, NaC3H3N2).
Imidazole has low acute toxicity as indicated by theLD50 of 970 mg/kg (Rat, oral).[24]
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