Azide-alkyne Huisgen cycloaddition: Difference between revisions

Revision as of 19:20, 14 December 2015

Revision as of 09:48, 7 March 2016

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</ref> was the first to understand the scope of this [[organic reaction]]. American [[chemist]] [[K. Barry Sharpless]] has referred to this [[cycloaddition]] as "the cream of the crop" of [[click chemistry]]<ref>

{{cite journal | author = H. C. Kolb, M. G. Finn and K. B. Sharpless | title = Click Chemistry: Diverse Chemical Function from a Few Good Reactions | year = 2001 | journal = [[Angewandte Chemie International Edition]] | volume = 40 | issue = 11 | pages = 2004–2021 | doi = 10.1002/1521-3773(20010601)40:11<2004::AID-ANIE2004>3.0.CO;2-5 | pmid=11433435}}

</ref> and "the premier example of a click reaction."<ref>{{cite journal|last=Kolb|first=H.C.|author2=Sharpless, B.K.|title=The growing impact of click chemistry on drug discovery|year=2003|volume=8|issue=24|pages=1128-11371128–1137|doi=10.1016/S1359-6446(03)02933-7|pmid=14678739|journal=Drug Discov Today}}</ref>

[[Image:Huisgen.png|center|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]</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 | author = David Amantini, Francesco Fringuelli, Oriana Piermatti, Ferdinando Pizzo, Ennio Zunino, and Luigi Vaccaro| 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.

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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{{cite journal | author = Vsevolod V. Rostovtsev, Luke G. Green, Valery V. Fokin, K. Barry Sharpless| title = A Stepwise Huisgen Cycloaddition Process: Copper(I)-Catalyzed Regioselective Ligation of Azides and Terminal Alkynes | year = 2002 | journal = [[Angewandte Chemie International Edition]] | volume = 41 | issue = 14 | pages = 2596–2599 | doi = 10.1002/1521-3773(20020715)41:14<2596::AID-ANIE2596>3.0.CO;2-4 | pmid=12203546}}

</ref>

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-(benzyltriazolylmethyl)amine]] (TBTA) is used. The reaction can be run in a variety of solvents, and mixtures of water and a variety of (partially) miscible organic solvents including alcohols, DMSO, DMF, ''t''BuOH and acetone. Owing to the powerful coordinating ability of nitriles towards Cu(I), it is best to avoid acetonitrile as the solvent. The starting reagents need not be completely soluble for the reaction to be successful. In many cases, the product can simply be filtered from the solution as the only purification step required.

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===Copper catalysts===

The use of a Cu catalyst in water was an improvement over the same reaction first popularized by [[Rolf Huisgen]] in the 1970s, which he ran at elevated temperatures.<ref>1,3-Dipolar Cycloaddition Chemistry, published by Wiley and updated in 2002</ref> The traditional reaction is slow and thus requires high temperatures. However, the azides and alkynes are both kinetically stable.

As mentioned above, copper-catalysed click reactions work essentially on terminal alkynes. The Cu species undergo metal insertion reaction into the terminal alkynes. The Cu(I) species may either be introduced as preformed complexes, or are otherwise generated in the reaction pot itself by one of the following ways:

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=== Mechanism ===

A mechanism for the reaction has been suggested based on [[density functional theory]] calculations.<ref>{{cite journal | author = F Himo, T Lovell, R Hilgraf, VV Rostovtsev, L Noodleman, KB Sharpless, 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] 3d¹⁰ 4s¹. 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. 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 [[cyclisation]] 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.

In the uncatalysed reaction the alkyne remains a poor electrophile. Thus high energy barriers lead to slow reaction rates.<ref>{{cite journal | author = V. D. Bock, H. Hiemstra, 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>

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</ref>

<ref>

{{cite journal | author = McNulty, J.; 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.]] pages = 5462–5470 | 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 | author = 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 = 6082-60886082–6088 | doi = 10.1039/c1ob05360d | pmid= 21748192}}

</ref>

==References==