Azide-alkyne Huisgen cycloaddition: Difference between revisions

Revision as of 05:20, 28 August 2017

Revision as of 13:07, 28 August 2017

Line 97:

=== 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] 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|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}}</ref><ref>{{Cite journal|last=Iacobucci|first=Claudio|last2=Reale|first2=Samantha|last3=Gal|first3=Jean-François|last4=De AngelisDe 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}}</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 [[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.