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{{Short description|1,3-dipolar cycloaddition}}
{{Reactionbox
| Name = Azide-alkyne Huisgen cycloaddition
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}}
The '''azide-alkyne Huisgen cycloaddition''' is a [[1,3-dipolar cycloaddition]] between an [[azide]] and a terminal or internal [[alkyne]] to give a [[1,2,3-triazole]]. [[Rolf Huisgen]]<ref>{{cite journal| journal = Proceedings of the Chemical Society of London| page = 357| year= 1961| title = Centenary Lecture - 1,3-Dipolar Cycloadditions| author = Huisgen, R. | doi = 10.1039/PS9610000357}}</ref> was the first to understand the scope of this [[organic reaction]]. American [[chemist]] [[Karl Barry Sharpless]] has referred to copper-catalyzed version of this [[cycloaddition]] as "the cream of the crop" of [[click chemistry]]<ref>{{cite journal |
[[File:Thermal Huisgen cycloaddition.png|thumb|600px|center|Thermal Huisgen 1,3-dipolar cycloaddition.]]
In the reaction above<ref>''Development and Applications of Click Chemistry'' Gregory C. Patton November 8, '''2004''' [http://www.chemistry.uiuc.edu/research/organic/seminar_extracts/2004_2005/08_Patton_Abstract.pdf http://www.scs.uiuc.edu Online]{{dead link|date=January 2018 |bot=InternetArchiveBot |fix-attempted=yes}}</ref> azide '''2''' reacts neatly with alkyne '''1''' to afford the product triazole
The standard 1,3-cycloaddition between an azide 1,3-dipole and an alkene as dipolarophile has largely been ignored due to lack of reactivity as a result of electron-poor olefins and elimination side reactions. Some success has been found with non-metal-catalyzed cycloadditions, such as the reactions using dipolarophiles that are electron-poor olefins<ref>{{cite journal |author1=David Amantini |author2=Francesco Fringuelli |author3=Oriana Piermatti |author4=Ferdinando Pizzo |author5=Ennio Zunino |author6=Luigi Vaccaro |name-list-style=amp | title = Synthesis of 4-Aryl-1H-1,2,3-triazoles through TBAF-Catalyzed [3 + 2] Cycloaddition of 2-Aryl-1-nitroethenes with TMSN3 under Solvent-Free Conditions| year = 2005 | journal = [[The Journal of Organic Chemistry]] | volume = 70 | issue = 16 | pages = 6526–6529|doi = 10.1021/jo0507845|pmid=16050724 }}</ref> or alkynes.
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| doi = 10.1039/b507776a
| title = Click-chemistry as an efficient synthetic tool for the preparation of novel conjugated polymers
|
| pmid = 16113739
| issue = 34}}
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| doi = 10.1039/b508428h
| title = Preparation of biohybrid amphiphiles via the copper catalysed Huisgen [3 + 2] dipolar cycloaddition reaction
|
| pmid = 16100593
| issue = 33|hdl=2066/32869|hdl-access=free}}
</ref> The result is an [[amphiphilic]] biohybrid. BSA contains a [[thiol]] group at [[cysteine|Cys]]-34 which is functionalized with an [[alkyne]] group. In water the biohybrid [[micelle]]s with a [[diameter]] of 30 to 70 [[nanometer]] form aggregates.
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=== Mechanism ===
A mechanism for the reaction has been suggested based on [[density functional theory]] calculations.<ref>{{cite journal |author1=F Himo |author2=T Lovell |author3=R Hilgraf |author4=VV Rostovtsev |author5=L Noodleman |author6=KB Sharpless |author7=VV Fokin | title = Copper(I)-Catalyzed Synthesis of Azoles, DFT Study Predicts Unprecedented Reactivity and Intermediates | year = 2005 | journal = [[Journal of the American Chemical Society]] | pages = 210–216 | doi = 10.1021/ja0471525 |pmid=15631470 | volume = 127|issue=1 |bibcode=2005JAChS.127..210H |s2cid=20486589 }}</ref> Copper is a 1st row [[transition metal]]. It has the electronic configuration [Ar] 3d<sup>10</sup> 4s<sup>1</sup>. The copper (I) species generated in situ forms a [[pi complex]] with the triple bond of a terminal alkyne. In the presence of a base, the terminal hydrogen, being the most acidic, is deprotonated first to give a Cu [[acetylide]] intermediate. Studies have shown that the reaction is [[second order reaction|second order]] with respect to Cu. It has been suggested that the [[transition state]] involves two copper atoms.<ref>{{Cite journal|
The reaction is assisted by the copper, which, when coordinated with the acetylide lowers the pKa of the alkyne C-H by up to 9.8 units. Thus under certain conditions, the reaction may be carried out even in the absence of a base.
In the uncatalysed reaction the alkyne remains a poor electrophile. Thus high energy barriers lead to slow reaction rates.<ref>{{cite journal |author1=V. D. Bock |author2=H. Hiemstra |author3=J. H. van Maarseveen | title = CuI-Catalyzed Alkyne–Azide "Click" Cycloadditions from a Mechanistic and Synthetic Perspective | year = 2006 | journal = [[European Journal of Organic Chemistry]] | pages = 51–68 | doi = 10.1002/ejoc.200500483 | volume = 2006}}</ref>
[[File:
===Ligand assistance===
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Unlike CuAAC in which only terminal alkynes reacted, in RuAAC both terminal and internal alkynes can participate in the reaction. This suggests that ruthenium acetylides are not involved in the [[catalytic cycle]].
The proposed mechanism suggests that in the first step, the [[spectator ligand]]s undergo displacement reaction to produce an [[activated complex]] which is converted, through [[oxidative coupling]] of an alkyne and an azide to the ruthenium containing
Cp<sup>*</sup>RuCl(PPh<sub>3</sub>)<sub>2</sub>, Cp<sup>*</sup>Ru(COD) and Cp<sup>*</sup>[RuCl<sub>4</sub>] are commonly used ruthenium catalysts. Catalysts containing cyclopentadienyl (Cp) group are also used. However, better results are observed with the pentamethylcyclopentadienyl(Cp<sup>*</sup>) version. This may be due to the sterically demanding Cp<sup>*</sup> group which facilitates the displacement of the spectator ligands.<ref>{{cite journal |
[[File:RuAAC mechanism.png|center|450px|Mechanism for ruthenium-catalysed click chemistry]]
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== Silver catalysis==
Recently, the discovery of a general Ag(I)-catalyzed azide–alkyne cycloaddition reaction (Ag-AAC) leading to 1,4-triazoles is reported. Mechanistic features are similar to the generally accepted mechanism of the copper(I)-catalyzed process. Silver(I)-salts alone are not sufficient to promote the cycloaddition. However the ligated Ag(I) source has proven to be exceptional for AgAAC reaction.<ref>{{cite journal |author1=McNulty, J. |author2=Keskar, K |author3=Vemula, R. | title = The First Well-Defined Silver(I)-Complex-Catalyzed Cycloaddition of Azides onto Terminal Alkynes at Room Temperature | year = 2011 | journal = [[Chemistry: A European Journal]] | volume = 17 | issue = 52 | pages = 14727–14730 | doi = 10.1002/chem.201103244 | pmid= 22125272}}</ref><ref>{{cite journal |author1=McNulty, J. |author2=Keskar, K. | title = Discovery of a Robust and Efficient Homogeneous Silver(I) Catalyst for the Cycloaddition of Azides onto Terminal Alkynes | year = 2012 | journal = [[Eur. J. Org. Chem.]] | doi = 10.1002/ejoc.201200930 | volume=2012 |issue=28 | pages=5462–5470}}</ref>
Curiously, pre-formed silver acetylides do not react with azides; however, silver acetylides do react with azides under catalysis with copper(I).<ref>{{cite journal |
==References==
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