View source for Chemistry:Japp–Klingemann reaction

{{Reactionbox
| Name = Japp–Klingemann reaction
| Type = Coupling reaction
| NamedAfter = Francis Robert Japp <br/> Felix Klingemann
| Section3 = {{Reactionbox Identifiers
 | RSC_ontology_id = 0000158
 }}
}}
The '''Japp–Klingemann reaction''' is a [[Chemistry:Chemical reaction|chemical reaction]] used to synthesize [[Chemistry:Hydrazone|hydrazone]]s from β-keto-acids (or β-keto-esters) and [[Chemistry:Aryl|aryl]] diazonium salts.<ref>{{cite journal | title = Ueber Benzolazo- und Benzolhydrazofettsäuren | author = Francis Robert Japp, Felix Klingemann | journal = Berichte der deutschen chemischen Gesellschaft | volume = 20 | issue = 2| pages = 2942–2944 | year =  1887| url =  https://zenodo.org/record/1425485 | doi = 10.1002/cber.188702002165}}</ref><ref>{{cite journal | title = Zur Kenntniss der Benzolazo- und Benzolhydrazopropionsäuren (p 3284-3286)|author1=F. R. Japp |author2=F. Klingemann | journal = Berichte der Deutschen Chemischen Gesellschaft | volume = 20 | issue = 2| pages = 3284&ndash;3286 | year =  1887 | url = https://zenodo.org/record/1425489| doi = 10.1002/cber.188702002234}}</ref><ref>{{cite journal | title = Ueber sogenannte »gemischte Azoverbindungen |author1=F. R. Japp |author2=F. Klingemann | journal = Berichte der deutschen chemischen Gesellschaft | volume = 20 | issue = 2 | pages = 3398–3401 | year =  1887 | url =  https://zenodo.org/record/1425491 | doi = 10.1002/cber.188702002268}}</ref><ref>{{cite journal | title = Ueber die Constitution einiger sogenannten gemischten Azoverbindungen |author1=F. R. Japp |author2=F. Klingemann | journal = Liebigs Annalen der Chemie | volume = 247 | issue = 2 | pages = 190–225 | year =  1888 | doi = 10.1002/jlac.18882470208|url=https://zenodo.org/record/1427427 }}</ref><ref>Phillips, R. R. ''Org. React.'' '''1959''', ''10'', 143.</ref><ref>Reynolds, G. A.; VanAllan, J. A. ''Org. Synth.'', Coll. Vol. 4, p.633 (1963); Vol. 32, p.84 (1952)([http://www.orgsyn.org/orgsyn/prep.asp?prep=cv4p0633 Article] {{Webarchive|url=https://web.archive.org/web/20120716191722/http://www.orgsyn.org/orgsyn/prep.asp?prep=cv4p0633 |date=2012-07-16}})</ref> The reaction is named after the chemists Francis Robert Japp and Felix Klingemann.

:[[File:Japp-Klingemann Reaction Scheme.png|500px|The Japp-Klingemann reaction]]

The hydrazone products of the Japp–Klingemann reaction are most often used as intermediates in [[Chemistry:Organic synthesis|syntheses]] of more complex organic molecules.  For example, a phenylhydrazone product can be heated in the presence of strong acid to produce an [[Chemistry:Indole|indole]] via the [[Chemistry:Fischer indole synthesis|Fischer indole synthesis]].<ref>{{cite journal | title =  1,3,4,5-Tetrahydrobenz[''cd'']indoles and related compounds. Part I. A new synthesis of 3,4-dihydrobenz[''cd'']indol-5(1''H'')-one (Uhle's ketone) |author1=Bowman, R. E. |author2=Goodburn, T. G. |author3=Reynolds, A. A. | journal = J. Chem. Soc. Perkin Trans. 1 | pages = 1121 | year = 1972 | doi = 10.1039/P19720001121}}</ref><ref>{{cite journal | title =  Ergoline synthons: Synthesis of 3,4-dihydro-6-methoxybenz[''cd'']indol-5(1''H'')-one (6-methoxy-Uhle's ketone) and 3,4-dihydrobenz[''cd'']indol-5(1''H)''-one (Uhle's ketone) via a novel decarboxylation of indole-2-carboxylates |author1=Meyer, M. D. |author2=Kruse, L. I. | journal = J. Org. Chem. | volume = 49 | issue = 17 | pages = 3195–3199 | year = 1984| doi = 10.1021/jo00191a028}}</ref>

:[[File:Japp-Klingemann Fischer Indole Combination.png|550px|The Japp-Klingemann reaction used to synthesize indoles]]

If there is a [[Chemistry:Leaving group|leaving group]] elsewhere in the Japp–Klingemann product, the hydrazone instead can cyclize at that site via a [[Chemistry:Substitution reaction|substitution reaction]] to give a [[Chemistry:Pyrazole|pyrazole]]. This process is a key part of the synthesis of {{ill|pyraclofos|de}} and related compounds:<ref>{{cite journal |title= An improved procedure for the preparation of 1-aryl-4-hydroxy-1''H''-pyrazoles |first= Clemens |last= Lamberth |pages= 98–102 |journal= Organic Preprarations and Procedures International |volume= 34 |issue= 1 |year= 2002 |doi= 10.1080/00304940209355748 }}</ref>

[[File:Arylpyrazole via Japp-Klingemann.png|700px]]

==Reaction mechanism==
To illustrate the mechanism, the Japp-Klingemann ester variation will be considered. The first step is the [[Chemistry:Deprotonation|deprotonation]] of the β-keto-ester. The [[Chemistry:Nucleophilic addition|nucleophilic addition]] of the [[Chemistry:Enolate|enolate]] anion '''2''' to the diazonium salt produces the [[Chemistry:Azo compound|azo compound]] '''3'''.  Intermediate '''3''' has been isolated in rare cases. However, in most cases, the hydrolysis of intermediate '''3''' produces a tetrahedral intermediate '''4''', which quickly decomposes to release the carboxylic acid '''6'''.  After [[Chemistry:Hydrogen|hydrogen]] exchange, the final hydrazone '''7''' is produced.

[[File:Japp-Klingemann Ester Mechanism.png|center|1440px|The Japp-Klingemann reaction mechanism]]

==References==
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[[Category:Substitution reactions]]
[[Category:Name reactions]]

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