Azide-alkyne Huisgen cycloaddition: Difference between revisions

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Revision as of 03:56, 13 January 2019

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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 |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|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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=== 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 }}</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.<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|pmid=15693051|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|pmid=25614295|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|pmid=28394586|issn=0002-7863|url=http://www.escholarship.org/uc/item/1p87h7fj}}</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.

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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 | 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>