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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 |last-author-amp=yes | 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}}
</ref> or alkynes.
| year= 2002
| title = Peptidotriazoles on Solid Phase: [1,2,3]-Triazoles by Regiospecific Copper(I)-Catalyzed 1,3-Dipolar Cycloadditions of Terminal Alkynes to Azides
|author1=Christian W. Tornøe |author2=Caspar Christensen |author3=Morten Meldal |last-author-amp=yes | doi = 10.1021/jo011148j
| pmid = 11975567
| issue = 9}}
Commonly used solvents are polar aprotic solvents such as [[Tetrahydrofuran|THF]], [[Dimethyl sulfoxide|DMSO]], [[Acetonitrile]], [[Dimethylformamide|DMF]] as well as in non-polar aprotic solvents such as [[toluene]]. Neat solvents or a mixture of solvents may be used.
[[DIPEA]] (N,N-Diisopropylethylamine) and Et<sub>3</sub>N ([[triethylamine]]) are commonly used bases.<ref>{{cite journal |author1=Morten Meldal |author2=Christian Wenzel Tornøe |lastauthoramp=yes | title = Cu-Catalyzed Azide-Alkyne Cycloaddition | year = 2008| journal = [[Chemical Reviews]] | volume = 108 | issue = 8 | pages = 2952–3015 | doi = 10.1021/cr0783479 | pmid = 18698735}}</ref>
=== 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 | volume = 127}}</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|last=Rodionov|first=Valentin O.|last2=Fokin|first2=Valery V.|last3=Finn|first3=M. G.|date=2005-04-08|title=Mechanism of the Ligand-Free CuI-Catalyzed Azide–Alkyne Cycloaddition Reaction|url=http://onlinelibrary.wiley.com/doi/10.1002/anie.200461496/abstract|journal=Angewandte Chemie International Edition|language=en|volume=44|issue=15|pages=2210–2215|doi=10.1002/anie.200461496|issn=1521-3773}}</ref><ref>{{Cite journal|last=Worrell|first=B. T.|last2=Malik|first2=J. A.|last3=Fokin|first3=V. V.|date=2013-04-26|title=Direct Evidence of a Dinuclear Copper Intermediate in Cu(I)-Catalyzed Azide-Alkyne Cycloadditions|url=http://science.sciencemag.org/content/340/6131/457|journal=Science|language=en|volume=340|issue=6131|pages=457–460|doi=10.1126/science.1229506|issn=0036-8075|pmc=3651910|pmid=23558174|bibcode=2013Sci...340..457W}}</ref><ref>{{Cite journal|last=Iacobucci|first=Claudio|last2=Reale|first2=Samantha|last3=Gal|first3=Jean-François|last4=De Angelis|first4=Francesco|date=2015-03-02|title=Dinuclear Copper Intermediates in Copper(I)-Catalyzed Azide–Alkyne Cycloaddition Directly Observed by Electrospray Ionization Mass Spectrometry|url=http://onlinelibrary.wiley.com/doi/10.1002/anie.201410301/abstract|journal=Angewandte Chemie International Edition|language=en|volume=54|issue=10|pages=3065–3068|doi=10.1002/anie.201410301|issn=1521-3773}}</ref><ref>{{Cite journal|last=Jin|first=Liqun|last2=Tolentino|first2=Daniel R.|last3=Melaimi|first3=Mohand|last4=Bertrand|first4=Guy|date=2015-06-01|title=Isolation of bis(copper) key intermediates in Cu-catalyzed azide-alkyne "click reaction"|url=http://advances.sciencemag.org/content/1/5/e1500304|journal=Science Advances|language=en|volume=1|issue=5|pages=e1500304|doi=10.1126/sciadv.1500304|issn=2375-2548|pmc=4640605|pmid=26601202|bibcode=2015SciA....1E0304J}}</ref><ref>{{Cite journal|last=Özkılıç|first=Yılmaz|last2=Tüzün|first2=Nurcan Ş.|date=2016-08-22|title=A DFT Study on the Binuclear CuAAC Reaction: Mechanism in Light of New Experiments|url=https://dx.doi.org/10.1021/acs.organomet.6b00279|journal=Organometallics|volume=35|issue=16|pages=2589–2599|doi=10.1021/acs.organomet.6b00279|issn=0276-7333}}</ref><ref>{{Cite journal|last=Ziegler|first=Micah S.|last2=Lakshmi|first2=K. V.|last3=Tilley|first3=T. Don|date=2017-04-19|title=Dicopper Cu(I)Cu(I) and Cu(I)Cu(II) Complexes in Copper-Catalyzed Azide–Alkyne Cycloaddition|url=https://dx.doi.org/10.1021/jacs.6b13261|journal=Journal of the American Chemical Society|volume=139|issue=15|pages=5378–5386|doi=10.1021/jacs.6b13261|issn=0002-7863}}</ref> One copper atom is bonded to the acetylide while the other Cu atom serves to activate the azide. The metal center coordinates with the electrons on the nitrogen atom. The azide and the acetylide are not coordinated to the same Cu atom in this case. The ligands employed are labile and are weakly coordinating. The azide displaces one ligand to generate a copper-azide-acetylide complex. At this point [[cyclization]] takes place. This is followed by [[protonation]]; the source of proton being the hydrogen which was pulled off from the terminal acetylene by the base. The product is formed by dissociation and the catalyst ligand complex is regenerated for further reaction cycles.
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.
===Ligand assistance===
The [[ligand]]s employed are usually labile i.e. they can be displaced easily. Though the ligand plays no direct role in the reaction the presence of a ligand has its advantages.
The ligand protects the Cu ion from interactions leading to degradation and formation of side products and also prevents the oxidation of the Cu(I) species to the Cu(II). Furthermore, the ligand functions as a proton acceptor thus eliminating the need of a base.<ref>{{cite journal |author1=Valentin O. Rodionov |author2=Stanislav I. Presolski |author3=David Dı´az Dı´az |author4=Valery V. Fokin |author5=M. G. Finn |last-author-amp=yes | title = Ligand-Accelerated Cu-Catalyzed Azide-Alkyne Cycloaddition: A Mechanistic Report | year = 2007 | journal = [[J. Am. Chem. Soc.]] | volume = 129 | issue = 42 | pages = 12705–12712 | doi = 10.1021/ja072679d | pmid = 17914817}}</ref>
== Ruthenium catalysis==
The proposed mechanism suggests that in the first step, the [[spectator ligand]]s undergo displacement reaction to produce an [[activated complex]] which is converted, via [[oxidative coupling]] of an alkyne and an azide to the ruthenium containing metallocyle (Ruthenacycle). The new [[carbon-nitrogen bond|C-N bond]] is formed between the more electronegative and less sterically demanding carbon of the alkyne and the terminal nitrogen of the azide. The metallacycle intermediate then undergoes reductive elimination releasing the aromatic triazole product and regenerating the catalyst or the activated complex for further reaction cycles.
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 | authors = Li Zhang, Xinguo Chen, Peng Xue, Herman H. Y. Sun, Ian D. Williams, K. Barry Sharpless, Valery V. Fokin, and Guochen Jia; |lastauthoramp=yes | title = Ruthenium-Catalyzed Cycloaddition of Alkynes and Organic Azides | year = 2005| journal = [[J. Am. Chem. Soc.]] | volume = 127 | issue = 46 | pages = 15998–15999 | doi = 10.1021/ja054114s | pmid = 16287266}}</ref><ref>{{cite journal |author1=Brant C. Boren |author2=Sridhar Narayan |author3=Lars K. Rasmussen |author4=Li Zhang |author5=Haitao Zhao |author6=Zhenyang Lin |author7=Guochen Jia |author8=Valery V. Fokin | title = Ruthenium-Catalyzed Azide−Alkyne Cycloaddition: Scope and Mechanism | year = 2008| journal = [[J. Am. Chem. Soc.]] | volume = 130 | issue = 28 | pages = 8923–8930 | doi = 10.1021/ja0749993 | pmid = 18570425}}</ref>
[[Image:RuAAC mechanism.png|center|450px|Mechanism for ruthenium-catalysed click chemistry]]
== 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. Interestingly, silverSilver(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 | 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 | authors = Proietti Silvestri, I., Andemarian, F., Khairallah, G.N., Yap, S., Quach, T., Tsegay, S., Williams, C.M., O'Hair, R.A.J., Donnelly, P.S., Williams, S.J.| title = Copper(i)-catalyzed cycloaddition of silver acetylides and azides: Incorporation of volatile acetylenes into the triazole core | year = 2011 | journal = [[Organic and Biomolecular Chemistry]] | volume = 9 | issue = 17 | pages = 6082–6088 | doi = 10.1039/c1ob05360d | pmid= 21748192}}
</ref>
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