Azide-alkyne Huisgen cycloaddition
[3] In the reaction above[4] 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.
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[6] and Valery Fokin and K. Barry Sharpless at the Scripps Research Institute.
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.
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.
The CuAAC click reaction also effectively couples polystyrene and bovine serum albumin (BSA).
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 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.
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.
The proposed mechanism suggests that in the first step, the spectator ligands undergo displacement reaction to produce an activated complex which is converted, through oxidative coupling of an alkyne and an azide to the ruthenium containing metallacycle (Ruthenacycle).
The new 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.
