Editing Imidazole (section)

==Preparation==
Imidazole was first reported in 1858 by the German chemist [[Heinrich Debus (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).<ref>{{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".)</ref> This synthesis, while producing relatively low yields, is still used for generating ''C''-substituted imidazoles.
:[[File:Imidazole_from_glyoxal_aldehyde_ammonia.svg||none|250px]]
In one [[microwave chemistry|microwave]] modification, the reactants are [[benzil]], [[benzaldehyde]] and [[ammonia]] in [[glacial acetic acid]], forming 2,4,5-triphenylimidazole ("[[lophine]]").<ref>{{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}}</ref>

Imidazole can be synthesized by numerous methods besides the [[Debus-Radziszewski imidazole synthesis|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<sub>1</sub> = R<sub>2</sub> = hydrogen.[[File:Imidazole_one-bond-method.svg|none|447x447px|Formation of one bond]]
:

===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 (chemistry)|alcohol]], [[aldehyde]], or [[carboxylic acid]]. A dehydrogenating catalyst, such as [[platinum]] on [[alumina]], is required.
:[[File:Imidazole_two-bond-method.svg|none|400px|Formation of two bonds]]
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<sub>1</sub> = R<sub>2</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.
::[[File:(1,2)(3,4)_formation_imidazole.svg|none|400px|Formation of three bonds]]

===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.<ref>{{US patent reference|number=6,177,575|y=2001|m=01|d=23|inventor=[[Anthony Joseph Arduengo III|Arduengo, A. J.]]|title=Process for Manufacture of Imidazoles}}</ref>
:[[File:Debus-Radziszewski_imidazole_synthesis.svg|none|500px|Arduengo imidazoles]]

===Formation from other heterocycles===
Imidazole can be synthesized by the [[photolysis]] of [[tetrazole|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 R<sub>1</sub> = R<sub>2</sub> = R<sub>3</sub> = hydrogen.
:[[File:Imidazole_synthesis_from_vinyltetrazole.svg|none|500px]]
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.

The [[Van Leusen reaction]] can also be employed to form imidazoles starting from [[TosMIC]] and an [[aldimine]].<ref>{{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}}</ref> 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).