Azide-alkyne Huisgen cycloaddition: Difference between revisions

Revision as of 04:17, 7 December 2019

Revision as of 03:10, 20 October 2020

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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 triazole '''3''' as a mixture of 1,4-adduct and 1,5-adduct at 98&nbsp;°C in 18 hours.

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 |lastname-authorlist-ampstyle=yesamp | 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.

Although azides are not the most reactive 1,3-dipole available for reaction, they are preferred for their relative lack of side reactions and stability in typical synthetic conditions.

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| 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 |lastname-authorlist-ampstyle=yesamp | doi = 10.1021/jo011148j

| pmid = 11975567

| issue = 9}}

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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 Et₃N ([[triethylamine]]) are commonly used bases.<ref>{{cite journal |author1=Morten Meldal |author2=Christian Wenzel Tornøe |lastauthorampname-list-style=yesamp | 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 ===

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===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 |lastname-authorlist-ampstyle=yesamp | 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==

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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 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^*RuCl(PPh₃)₂, Cp^*Ru(COD) and Cp^*[RuCl₄] are commonly used ruthenium catalysts. Catalysts containing cyclopentadienyl (Cp) group are also used. However, better results are observed with the pentamethylcyclopentadienyl(Cp^*) version. This may be due to the sterically demanding Cp^* 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>

[[File:RuAAC mechanism.png|center|450px|Mechanism for ruthenium-catalysed click chemistry]]