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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 |
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 |
| pmid = 11975567
| issue = 9}}
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While the copper(I)-catalyzed variant gives rise to a triazole from a terminal alkyne and an azide, formally it is not a 1,3-dipolar cycloaddition and thus should not be termed a Huisgen cycloaddition. This reaction is better termed the Copper(I)-catalyzed Azide-Alkyne Cycloaddition (CuAAC).
While the reaction can be performed using commercial sources of copper(I) such as cuprous bromide or iodide, the reaction works much better using a mixture of copper(II) (e.g. copper(II) sulfate) and a reducing agent (e.g. sodium ascorbate) to produce Cu(I) in situ. As Cu(I) is unstable in aqueous solvents, stabilizing ligands are effective for improving the reaction outcome, especially if [[tris
NH-1,2,3-triazoles are also prepared from alkynes in a sequence called the [[Banert cascade]].
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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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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 |
=== 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===
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 |
== Ruthenium catalysis==
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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==
{{reflist|30em}}
{{Alkynes}}
{{DEFAULTSORT:Azide Alkyne Huisgen Cycloaddition}}
[[Category:Cycloadditions]]
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