Azide-alkyne Huisgen Cycloaddition - Copper Catalysis

Copper Catalysis

A notable variant of the Huisgen 1,3-dipolar cycloaddition is the copper(I) catalyzed variant, no longer a true concerted cycloaddition, in which organic azides and terminal alkynes are united to afford 1,4-regioisomers of 1,2,3-triazoles as sole products (substitution at positions 1' and 4' as shown above). The copper(I)-catalyzed variant was first reported in 2002 in independent publications by Morten Meldal at the Carlsberg Laboratory in Denmark and Valery Fokin and K. Barry Sharpless at the Scripps Research Institute. 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, tBuOH 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.

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. 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. 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). The result is an amphiphilic biohybrid. BSA contains a thiol group at Cys-34 which is functionalized with an alkyne group. In water the biohybrid micelles with a diameter of 30 to 70 nanometer form aggregates.