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Azide alkyne Huisgen cycloaddition



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 [1] 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. [2]

Additional recommended knowledge

In the reaction above [3] 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 °C in 18 hours.

Variants of the Huisgen reaction

A notable variant of the Huisgen 1,3-dipolar cycloaddition is the copper(I) catalyzed variant, in which organic azides and terminal alkynes are united to afford 1,4-regioisomers of 1,2,3-triazoles as sole products. The copper(I)-catalyzed variant was first reported for solid phase synthesis of peptidotriazoles by Morten Meldal and co-workers at the Carlsberg Laboratory in Denmark. 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). But it is certainly a click reaction. 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, tBuOH and acetone work well. Owing to the powerful coordinating ability of nitriles towards Cu(I) it is best to avoid acetonitrile as the solvent.

NH-1,2,3-triazoles are also prepared from alkynes in a sequence called the Banert cascade.

The utility of the Cu(I) catalyzed click reaction has also been demonstrated in the polymerization reaction of a bis-azide and a bis-alkyne with copper(I) and TBTA to a conjugated fluorene based polymer.[4] The degree of polymerization easily exceeds 50. With a stopper molecule such as phenyl azide, well-defined phenyl end-groups are obtained.

The copper mediated azide-alkyne cycloaddition is receiving widespread use in material and surface sciences.[5] Most variations in coupling polymers with other polymers or small molecules have been explored. Current shortcomings are that the terminal alkyne appears to participate in free radical polymerizations. This requires protection of the terminal alkyne with a trimethyl silyl protecting group and subsequent deprotection after the radical reaction are completed. Similarly the use of organic solvents, copper (I) and inert atmospheres to do the cycloaddition with many polymers makes the "click" label inappropriate for such reactions. An aqueous protocol for performing the cycloaddition with free radical polymers is highly desirable.

The CuAAC click reaction also effectively couples polystyrene and bovine serum albumin (BSA) [6]. The result is an amphiphilic biohybrid. BSA contains a thiol group at Cys-34 which is functionalized with an alkyne group. Polystyrene has an azido end-group and the coupling takes place in a THF / phosphate buffer solution with Copper(II) sulfate and ascorbic acid. In water the biohybrid micelles with a diameter of 30 to 70 nanometer form aggregates.

References

  1. ^ Huisgen, R. (1961). "Cenetary Lecture - 1,3-Dipolar Cycloadditions". Proceedings of the Chemical Society of London: 357.
  2. ^ H. C. Kolb, M. G. Finn and K. B. Sharpless (2001). "Click Chemistry: Diverse Chemical Function from a Few Good Reactions". Angewandte Chemie International Edition 40 (11): 2004-2021. doi:10.1002/1521-3773(20010601)40:11%3C2004::AID-ANIE2004%3E3.0.CO;2-5.
  3. ^ Development and Applications of Click Chemistry Gregory C. Patton November 8, 2004 http://www.scs.uiuc.edu Online
  4. ^ D. J. V. C. van Steenis, O. R. P. David, G. P. F. van Strijdonck, J. H. van Maarseveen and J. N. H. Reek (2005). "Click-chemistry as an efficient synthetic tool for the preparation of novel conjugated polymers". Chemical Communications 34: 4333 - 4335. doi:10.1039/b507776a.
  5. ^ R.A. Evans (2007). "The Rise of Azide–Alkyne 1,3-Dipolar 'Click' Cycloaddition and its Application to Polymer Science and Surface Modification". Australian Journal of Chemistry 60: 384 - 395. doi:= 10.1071/CH0645 doi = 10.1071/CH0645.
  6. ^ A. J. Dirks, S. S. van Berkel, N. S. Hatzakis, J. A. Opsteen, F. L. van Delft, J. J. L. M. Cornelissen, A. E. Rowan, J. C. M. van Hest, F. P. J. T. Rutjes, R. J. M. Nolte (2005). "Preparation of biohybrid amphiphiles via the copper catalysed Huisgen 3 + 2 dipolar cycloaddition reaction". Chemical Communications 33: 4172 - 4174. doi:10.1039/b508428h.
 
This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Azide_alkyne_Huisgen_cycloaddition". A list of authors is available in Wikipedia.
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