View source for Imidazole

{{chembox
|   Name = Imidazole
|   ImageFile = Imidazole_chemical_structure.png
|   ImageSize = 345px
|   ImageName = Chemical structure of imidazole
|   IUPACName = Imidazole
|   OtherNames = 1,3-diazole<br/>1,3-diazacyclopenta-2,4-diene
| Section1 = {{Chembox Identifiers
|   InChI = 1/C3H4N2/c1-2-5-3-4-1/h1-3H,(H,4,5)
|   StdInChI = 1S/C3H4N2/c1-2-5-3-4-1/h1-3H,(H,4,5)
|   InChIKey = RAXXELZNTBOGNW-UHFFFAOYAS
|   StdInChIKey = RAXXELZNTBOGNW-UHFFFAOYSA-N
|   CASNo = 288-32-4
|    CASNo_Ref = {{cascite}}
|   EC-number = 206-019-2
|   ChemSpiderID = 773
|   RTECS = NI3325000
|   SMILES = n1c[nH]cc1
  }}
| Section2 = {{Chembox Properties
|   Reference = <ref name="ICSC">{{ICSC-ref|1721|name=Imidazole|date=November 2008}}.</ref>
|   Formula = C<sub>3</sub>H<sub>4</sub>N<sub>2</sub>
|   MolarMass = 68.077 g/mol
|   Appearance = white or pale yellow solid
|   Density = 1.03 g/cm<sup>3</sup>, solid
|   Solubility = miscible
|   MeltingPt = 89 °C (362 K)
|   BoilingPt = 268 °C (541 K)
|   pKa = 14.5
|   pKb = 6.993
|   Dipole = 3.61 D
|   LogP = −0.02
|   Viscosity = 2.617 cP (100 ºC)
  }}
| Section3 = {{Chembox Structure
|   Coordination = planar 5-membered ring
|   CrystalStruct = [[monoclinic]]
  }}
| Section7 = {{Chembox Hazards
|   Reference = <ref name="ICSC"/>
|   ExternalMSDS = {{ICSC-small|1721}}
|   EUIndex = not listed
|   GHSPictograms = {{GHS corrosion|Skin Corr. 1}}{{GHS exclamation mark|Acute Tox. (oral) 4}}{{GHS health hazard|Repr. Tox. 2}}
|   GHSSignalWord = DANGER
|   HPhrases = {{H-phrases|314|302|361}}
|   FlashPt = 145 °C (293 ºF)
|   Autoignition = 480 ºC (896 ºF)
  }}
}}
'''Imidazole''' is an [[organic compound]] with the formula C<sub>3</sub>H<sub>4</sub>N<sub>2</sub>.  This [[aromatic]] [[heterocyclic]] is classified as an [[alkaloid]].  Imidazole refers to the parent compound  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 serve as a [[base (chemistry)|base]] and as a weak [[acid]]. Many drugs contain an imidazole ring, such as [[antifungal drug]]s and [[nitroimidazole]].<ref>{{citation | editorlink1 = Alan R. Katritzky | editor1-first = Alan R. | editor1-last = Katritzky | editor2-last = Rees | editor2-first = Charles W. | title = Comprehensive Heterocyclic Chemistry | publisher = Pergamon | volume = 5 | pages = 469–98 | year = 1984}}.</ref><ref>{{citation | last = Grimmett | first = M. Ross | title = Imidazole and Benzimidazole Synthesis | publisher = Academic Press | year = 1997}}.</ref><ref>{{citation | last = Brown | first = E. G. | title = Ring Nitrogen and Key Biomolecules | publisher = Springer | year = 1998 | isbn = 0412835703}}.</ref><ref>{{citation | last1 = Pozharskii | first1 = Alexander F. | first2 = Anatoly T. | last2 = Soldatenkov | first3 = Alan R. | last3 = Katritzky | authorlink3 = Alan R. Katritzky | title = Heterocycles in Life and Society: An Introduction to Heterocyclic Chemistry and Biochemistry and the Role of Heterocycles in Science, Technology, Medicine and Agriculture | publisher = Wiley | location = New York | year = 1997 | isbn = 0471960349}}.</ref><ref>{{citation | title = Heterocyclic Chemistry | first = Thomas L. | last = Gilchrist | publisher = Prentice Hall | location = New York | year = 1987 | isbn = 0-582-01421-2}}.</ref>

==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.<ref>{{citation | title = Ueber die Einwirkung des Ammoniaks auf Glyoxal | first = Heinrich | last = Debus | journal = Ann. Chem. Pharm. | volume = 107 | issue = 2 | pages = 199–208 | year = 1858 | doi = 10.1002/jlac.18581070209}}</ref> This synthesis, while producing relatively low yields, is still used for creating C-substituted imidazoles.
:[[Image:DiketRouteHIm.png|300px]]
In one [[microwave chemistry|microwave]] modification the reactants are [[benzil]], [[formaldehyde]] and [[ammonia]] in [[glacial acetic acid]] forming ''2,4,5-triphenylimidazole'' (Lophine).<ref>{{citation | title = Microwave-Mediated Synthesis of Lophine: Developing a Mechanism To Explain a Product | last1 = Crouch | first1 = R. David | last2 = Howard | first2 = Jessica L. | last3 = Zile | first3 = Jennifer L. | last4 = Barker | first4 = Kathryn H. | journal = J. Chem. Educ. | year = 2006 | volume = 83 | page = 1658}}.</ref>

==Structure and properties==
Imidazole is a 5-membered planar ring, which is soluble in water and other [[Chemical polarity|polar]] solvents. It exists in two equivalent [[tautomer]]ic forms because the [[hydrogen]] [[atom]] can be located on either of the two [[nitrogen]] atoms.  Imidazole is a highly polar compound, as evidenced by a calculated dipole of 3.61&nbsp;[[debye|D]], and is entirely soluble in water. The compound is classified as [[aromaticity|aromatic]] due to the presence of a sextet of [[pi bond|π-electron]]s, 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:
<center>[[Image:Resonance-imidazole.png|550px]]</center>

===Amphotericity===
Imidiazole is [[amphoteric]], ''i.e.'' it can function as both an acid and as a base. As an acid, the p''K''<sub>a</sub> 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 p''K''<sub>a</sub> of the conjugate acid (cited above as p''K''<sub>BH<sup>+</sup></sub> to avoid confusion between the two) is approximately 7, making imidazole approximately sixty times more basic than [[pyridine]]. The basic site is N-3.

==Preparation==
[[Image:Imidazole-ball-and-stick.png|right|thumb|150px|A ball-and-stick model of imidazole, showing carbon-carbon and a carbon-nitrogen double bonds.]]
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 [[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=R<sub>1</sub>=Hydrogen.

:[[Image:Onebondmethod.gif|Formation of one bond]]

;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 catalyst, such as [[platinum]] on [[alumina]], is required.

:[[Image:RCO2HrouteImH.png|Formation of two bonds|300px]]
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=R<sub>1</sub>=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.

:[[Image:1,2--3,4-formation.gif|Formation of three bonds]]

;Formation of Four Bonds
This is a general method which is able to give good yields for substituted imidazoles. It is essentially 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.<ref>{{citation | country-code = US | patent-number = 6177575 | year = 2001 | inventor1-first = Anthony J., III | inventor1-last = Arduengo | inventor2-last = Gentry | inventor2-first = Frederick P., Jr. | inventor3-last = Taverkere |inventor3-first = Prakash K. | inventor4-last = Simmons | inventor4-first = Howard E., III | assignee = E. I. du Pont de Nemours & Co. | title = Process for Manufacture of Imidazoles}}.</ref>

:[[Image:Arduengo imidazoles.png|400px|Arduengo imidazoles]]

;Formation from other Heterocycles
Imidazole can be synthesized by the [[photolysis]] of [[tetrazole|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=R<sub>1</sub>=R<sub>2</sub>=Hydrogen.

[[Image:Ringformation.gif]]

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&nbsp;°C. This forms a very pure imidazole product.

==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]]. Histidine can be [[carboxyl|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 [[allergy|allergic]] hives.  The relationship between histidine and histamine are shown below:

<center>[[Image:Histidine decarboxylase.svg]]</center>

One of the applications of imidazole is in the purification of [[His-tag]]ged [[protein]]s in [[Chromatography#Immobilized metal ion affinity chromatography|immobilised metal affinity chromatography]](IMAC). Imidazole is used to elute tagged proteins bound to [[nickel|Ni]] [[ion]]s 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 [[fungicide]]s 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 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 which are used for photography and electronics.

==Salts of imidazole==
[[Image:Imidazolium salt.png|left|60px|Simple imidazolium cation]]
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 carbene]]s. Salts where a deprotonated imidazole is an [[anion]] are also possible; these salts are known as '''imidazolide salts''' (for example, sodium imidazolide).

==Related heterocycles==
* [[Benzimidazole]], an analog with a fused [[benzene]] ring.
* [[Dihydroimidazole]] or benzimidazoline, 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.

==References==
{{reflist}}

==Further reading==
*{{OrgSynth | first1 = H. R. | last1 = Snyder | first2 = R. G. | last2 = Handrick | first3 = L. A. | last3 = Brooks | title = Imidazole | prep = cv3p0471 | collvol = 3 | collvolpages = 471 | volume = 22 | pages = 65 | year = 1942}}.
*{{SIDS-ref | title = Imidazole | id = 288324 | date = August 2005}}.

==External links==
*{{ICSC|1721}}
*{{Biodegradability JP|id=1643|name=imidazole|date=2003-10-14}}

{{Antifungals}}

[[Category:Imidazoles|*]]

{{Imported from Wikipedia|name=Imidazole|id=296636458}}