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 was the first to understand the scope of this organic reaction. American chemist Karl Barry Sharpless has referred to this cycloaddition as "the cream of the crop" of click chemistry and "the premier example of a click reaction".
In the reaction above azide 2 reacts neatly with alkyne 1 to afford the product triazole as a mixture of 1,4-adduct (3a) and 1,5-adduct (3b) at 98 °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 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.
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.
Copper catalysts
The use of a Cu catalyst in water was an improvement over the same reaction first popularized by Rolf Huisgen in the 1970s, which he ran at elevated temperatures. The traditional reaction is slow and thus requires high temperatures. However, the azides and alkynes are both kinetically stable.