:Imidazole

Imidazole is a planar 5-membered ring, that exists in two equivalent tautomeric 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 D,{{cite journal|last1=Christen|first1=Dines|last2=Griffiths|first2=John H.|last3=Sheridan|first3=John|date=1981|title=The Microwave Spectrum of Imidazole; Complete Structure and the Electron Distribution from Nuclear Quadrupole Coupling Tensors and Dipole Moment Orientation|journal=Zeitschrift für Naturforschung A|volume=36|issue=12|pages=1378–1385|doi=10.1515/zna-1981-1220|bibcode=1981ZNatA..36.1378C|s2cid=3522351|doi-access=free}} and 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:

:File:Resonance-imidazole.svg

Imidazole is amphoteric, which is to say that it can function both as an acid and as a base. As an acid, the pK_a 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 pK_a of the conjugate acid (cited as pK_BH⁺ 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 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).{{cite journal |title= Ueber die Einwirkung des Ammoniaks auf Glyoxal |trans-title= On the reaction of ammonia upon glyoxal |first= Heinrich |last= Debus |journal= Annalen der Chemie und Pharmacie |volume= 107 |issue= 2 |pages= 199–208 |year= 1858 |url= https://babel.hathitrust.org/cgi/pt?id=njp.32101044011045;view=1up;seq=211 |doi= 10.1002/jlac.18581070209 |access-date= 2016-10-01 |archive-date= 2020-05-30 |archive-url= https://web.archive.org/web/20200530234014/https://babel.hathitrust.org/cgi/pt?id=njp.32101044011045&view=1up&seq=211 |url-status= live }} 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.

:File:Imidazole_from_glyoxal_aldehyde_ammonia.svg

In one microwave modification, the reactants are benzil, benzaldehyde and ammonia in glacial acetic acid, forming 2,4,5-triphenylimidazole ("lophine").{{cite journal|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.|date=2006|volume=83|issue=11|page=1658|doi=10.1021/ed083p1658|bibcode=2006JChEd..83.1658C}}

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.

The (1,5) or (3,4) bond can be formed by the reaction of an imidate and an α-aminoaldehyde or α-aminoacetal. The example below applies to imidazole when R₁ = R₂ = hydrogen.File:Imidazole_one-bond-method.svg

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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.

:File:Imidazole_two-bond-method.svg

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.

::File:(1,2)(3,4)_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 the Debus-Radziszewski imidazole synthesis. The starting materials are substituted glyoxal, aldehyde, amine, and ammonia or an ammonium salt.{{US patent reference|number=6,177,575|y=2001|m=01|d=23|inventor=Arduengo, A. J.|title=Process for Manufacture of Imidazoles}}

:File:Debus-Radziszewski_imidazole_synthesis.svg

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.

:File:Imidazole_synthesis_from_vinyltetrazole.svg

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.{{cite journal|last1=Van Leusen|first1=Albert M.|last2=Wildeman|first2=Jurjen|last3=Oldenziel|first3=Otto H.|date=1977|title=Chemistry of sulfonylmethyl isocyanides. 12. Base-induced cycloaddition of sulfonylmethyl isocyanides to carbon, nitrogen double bonds. Synthesis of 1,5-disubstituted and 1,4,5-trisubstituted imidazoles from aldimines and imidoyl chlorides|journal=Journal of Organic Chemistry|volume=42|issue=7|pages=1153–1159|doi=10.1021/jo00427a012|bibcode=1977JOrgC..42.1153A}} 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).

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.{{cite book|last1=Hochachka|first1=P. W.|first2=G. N.|last2=Somero|date=2002|title=Biochemical Adaptation: Mechanisms and Process in Physiological Evolution|location=New York|publisher=Oxford University Press}} Histidine can be decarboxylated to histamine. Histamine can cause urticaria (hives) when it is produced during allergic reaction.

Imidazole substituents are found in many pharmaceuticals such as anticancer drug mercaptopurine. The imidazole group is 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.

A number of substituted imidazoles, including clotrimazole, are selective inhibitors of nitric oxide synthase.{{cite journal|last1=Castaño|first1=T.|last2=Encinas|first2=A.|last3=Pérez|first3=C.|last4=Castro|first4=A.|last5=Campillo|first5=N. E.|last6=Gil|first6=C.|date=2008|title=Design, synthesis, and evaluation of potential inhibitors of nitric oxide synthase|journal=Bioorg. Med. Chem.|volume=16|issue=11|pages=6193–6206|pmid=18477512|doi=10.1016/j.bmc.2008.04.036|url=https://digital.csic.es/bitstream/10261/87090/1/accesoRestringido.pdf|type=Submitted manuscript|hdl=10261/87090|access-date=2018-07-24|archive-date=2023-03-06|archive-url=https://web.archive.org/web/20230306094210/https://digital.csic.es/bitstream/10261/87090/1/accesoRestringido.pdf|url-status=live}}{{cite journal|last1=Bogle|first1=R. G.|last2=Whitley|first2=G. S.|last3=Soo|first3=S. C.|last4=Johnstone|first4=A. P.|last5=Vallance|first5=P.|date=1994|title=Effect of anti-fungal imidazoles on mRNA levels and enzyme activity of inducible nitric oxide synthase|journal=Br. J. Pharmacol.|volume=111|issue=4 |pages=1257–1261|pmc=1910171|pmid=7518297|doi=10.1111/j.1476-5381.1994.tb14881.x}} Other biological activities of the imidazole pharmacophore relate to the downregulation of intracellular Ca²⁺ and K⁺ fluxes, and interference with translation initiation.{{cite journal|last1=Khalid|first1=M. H.|last2=Tokunaga|first2=Y.|last3=Caputy|first3=A. J.|last4=Walters|first4=E.|date=2005|title=Inhibition of tumor growth and prolonged survival of rats with intracranial gliomas following administration of clotrimazole|journal=J. Neurosurg.|volume=103|issue=1 |pages=79–86|pmid=16121977|doi=10.3171/jns.2005.103.1.0079}}

The substituted imidazole derivatives are valuable in treatment of many systemic fungal infections.{{cite book |title= Comprehensive Pharmacy Review |author= Leon Shargel |year= 2007 |edition= 6th |pages= 930|publisher= Lippincott Williams & Wilkins | isbn=9780781765619}} 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.{{cite book |title= Veterinary Pharmacology and Therapeutics |edition= 9th |pages= 1019–1020 |last1= Davis |first1= Jennifer L. |last2= Papich |first2= Mark G. |last3= Heit |first3= Mark C. |year= 2009 |chapter= Chapter 39: Antifungal and Antiviral Drugs |editor1-last= Riviere |editor1-first= Jim E. |editor2-last= Papich |editor2-first= Mark G. |chapter-url= https://books.google.com/books?id=ievLulSqwBAC |publisher= Wiley-Blackwell |isbn= 978-0-8138-2061-3 }}

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.{{cite journal|last1=Sunderland|first1=M. R.|last2=Cruickshank|first2=R. H.|last3=Leighs|first3=S. J.|date=2014|title=The efficacy of antifungal azole and antiprotozoal compounds in protection of wool from keratin-digesting insect larvae|journal=Textile Res. J.|volume=84|issue=9|pages=924–931|doi=10.1177/0040517513515312|s2cid=135799368}}

Imidazole itself has few direct applications. It is instead a precursor to a variety of agrichemicals, including enilconazole, climbazole, clotrimazole, prochloraz, and bifonazole.{{Ullmann|author=Ebel, K., Koehler, H., Gamer, A. O., & Jäckh, R.|title=Imidazole and Derivatives|year=2002|doi=10.1002/14356007.a13_661}}

image:Prochloraz.svg is one of several imidazole-derived agrichemicals.]]

Polyethylene terephthalate (PET) is a widely used plastic found in clothing, food packaging, beverage bottles, and thermoplastic resins. The massive accumulation of PET waste, mostly from single-use beverage bottles and food packaging, creates serious environmental problems.{{Cite web |title=Visual Feature {{!}} Beat Plastic Pollution |url=https://www.unep.org/interactives/beat-plastic-pollution/ |access-date=2025-01-02 |website=unep.org |language=EN}} As a type of polyester, PET can be broken down through a process called depolymerization which involves breaking its molecular chains using chemical methods.

A method of depolymerization called "imidazolysis," uses imidazole and similar compounds to break down PET. When PET reacts with an excess of imidazole, it produces 1,1′-terephthaloylbisimidazole (TBI).{{Cite journal |last=Bepari |first=Mousumi R. |last2=Sullivan |first2=Lauren R. |last3=O’Harra |first3=Kathryn E. |last4=Barbosa |first4=Gabriel D. |last5=Turner |first5=C. Heath |last6=Bara |first6=Jason E. |date=2024-07-12 |title=Depolymerizing Polyethylene Terephthalate (PET) via “Imidazolysis” for Obtaining a Diverse Array of Intermediates from Plastic Waste |url=https://pubs.acs.org/doi/10.1021/acsapm.4c01525 |journal=ACS Applied Polymer Materials |volume=6 |issue=13 |pages=7886–7896 |doi=10.1021/acsapm.4c01525}} TBI can be further processed into smaller products, including amides, benzimidazoles, and esters, or even reused to create new polymers. TBI is a flexible intermediate compound, meaning it can be stored and later transformed into specific products as needed. This may allow manufacturers to delay deciding on the final products until after the depolymerization process, providing flexibility to meet different industrial demands.

Imidazolysis can also be used to break down other polyesters and polyurethanes, making it a versatile approach for recycling plastics.

{{main|Transition metal imidazole complex}}

Imidazole and its derivatives have high affinity for metal cations. 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 is a suitable buffer for pH 6.2 to 7.8,.{{cite book | last=Dawson | first=R. M. C. | title=Data for biochemical research | publisher=Clarendon Press | publication-place=Oxford | year=1986 | isbn=978-0-19-855299-4 | oclc=11865673 | page=325}} Pure imidazole has essentially no absorbance at protein relevant wavelengths (280 nm),{{cite web |title=1H-Imidazole |url=https://webbook.nist.gov/cgi/cbook.cgi?ID=C288324&Mask=400 |access-date=13 May 2021 |archive-date=25 April 2021 |archive-url=https://web.archive.org/web/20210425154408/https://webbook.nist.gov/cgi/cbook.cgi?ID=C288324&Mask=400 |url-status=live }}{{cite web |title=Optimizing Purification of Histidine-Tagged Proteins |url=https://www.sigmaaldrich.com/technical-documents/protocols/biology/affinity-chromatography-tagged-proteins/optimizing-purification-of-histidine-tagged-proteins.html |access-date=13 May 2021 |archive-date=13 May 2021 |archive-url=https://web.archive.org/web/20210513212432/https://www.sigmaaldrich.com/technical-documents/protocols/biology/affinity-chromatography-tagged-proteins/optimizing-purification-of-histidine-tagged-proteins.html |url-status=live }} however lower purities of imidazole can give notable absorbance at 280 nm. Imidazole can interfere with the Lowry protein assay.{{cite journal | last1=Molina | first1=F | last2=Rueda | first2=A | last3=Bosque-Sendra | first3=J.M | last4=Megias | first4=L | title=Determination of proteins in the presence of imidazole buffers | journal=Journal of Pharmaceutical and Biomedical Analysis | publisher=Elsevier BV | volume=14 | issue=3 | year=1996 | issn=0731-7085 | doi=10.1016/0731-7085(95)01615-5 | pages=273–280| pmid=8851751 }}

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.

File:Imidazolium salt.svg

Salts of imidazole where the imidazole ring is the cation are known as imidazolium salts (for example, imidazolium chloride or nitrate).{{Cite journal|last1=Zolfigol|first1=Mohammad A.|last2=Khazaei|first2=Ardeshir|last3=Moosavi-Zare|first3=Ahmad R.|last4=Zare|first4=Abdolkarim|last5=Kruger|first5=Hendrik G.|last6=Asgari|first6=Zhila|last7=Khakyzadeh|first7=Vahid|last8=Kazem-Rostami|first8=Masoud|date=2012-04-06|title=Design of Ionic Liquid 3-Methyl-1-sulfonic Acid Imidazolium Nitrate as Reagent for the Nitration of Aromatic Compounds by in Situ Generation of NO2 in Acidic Media|journal=The Journal of Organic Chemistry|volume=77|issue=7|pages=3640–3645|doi=10.1021/jo300137w|pmid=22409592|issn=0022-3263}} 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 the 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

Imidazole has low acute toxicity as indicated by the {{LD50}} of 970 mg/kg (Rat, oral).

• 1-Methylimidazole
• 4-Methylimidazole
• Imidazoline (dihydroimidazole)

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Category:Alkaloids

Category:Simple aromatic rings

Category:Aromatic bases