Azide-alkyne Huisgen cycloaddition: Difference between revisions

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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 | authors author1= H. C. Kolb, |author2=M. G. Finn and |author3=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| doi-access = free }}</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=1128–1137|doi=10.1016/S1359-6446(03)02933-7|pmid=14678739|journal=Drug Discov Today|doi-access=free}}</ref>

[[File:Thermal Huisgen cycloaddition.png|thumb|600px|center|Thermal Huisgen 1,3-dipolar cycloaddition.]]

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| doi = 10.1039/b507776a

| title = Click-chemistry as an efficient synthetic tool for the preparation of novel conjugated polymers

| authors author= D. J. V. C. van Steenis, |author2=O. R. P. David, |author3=G. P. F. van Strijdonck, |author4=J. H. van Maarseveen and |author5=J. N. H. Reek

| 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

| authors author= A. J. Dirks, |author2=S. S. van Berkel, |author3=N. S. Hatzakis, |author4=J. A. Opsteen, |author5=F. L. van Delft, |author6=J. J. L. M. Cornelissen, |author7=A. E. Rowan, |author8=J. C. M. van Hest, |author9=F. P. J. T. Rutjes, |author10=R. J. M. Nolte

| 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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=== 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] 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|last1=Rodionov|first1=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|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|last1=Worrell|first1=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|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|last1=Iacobucci|first1=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|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|last1=Jin|first1=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"|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|last1=Özkılıç|first1=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|journal=Organometallics|volume=35|issue=16|pages=2589–2599|doi=10.1021/acs.organomet.6b00279|issn=0276-7333}}</ref><ref>{{Cite journal|last1=Ziegler|first1=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|journal=Journal of the American Chemical Society|volume=139|issue=15|pages=5378–5386|doi=10.1021/jacs.6b13261|pmid=28394586|bibcode=2017JAChS.139.5378Z |osti=1476482 |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.

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:CuAAC_mechCuAAC_Catalytic_Cycle.png|center|600px|Mechanism for Copper-catalysed click chemistry.]]

===Ligand assistance===

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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 metallocylemetallacycle (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 author= Li Zhang, |author2=Xinguo Chen, |author3=Peng Xue, |author4=Herman H. Y. Sun, |author5=Ian D. Williams, |author6=K. Barry Sharpless, |author7=Valery V. Fokin, and |author8=Guochen Jia | 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|bibcode=2005JAChS.12715998Z }}</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|bibcode=2008JAChS.130.8923B }}</ref>

[[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 | authors vauthors= Proietti Silvestri, I., Andemarian, F., Khairallah, G.N.GN, Yap, S., Quach, T., Tsegay, S., Williams, C.M.CM, O'Hair, R.A.J.RA, Donnelly, P.S.PS, Williams, S.J.SJ | 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>

==References==