Literature 12-08-09

The Huisgen 1,3-dipolar cycloaddition reaction of organic azides and alkynes has gained considerable attention in recent years due to the introduction in 2001 of Cu(1) catalysis by Tornøe and Meldal, leading to a major improvement in both rate and regioselectivity of the reaction, as realized independently by the Meldal and the Sharpless laboratories. The great success of the Cu(1) catalyzed reaction is rooted in the fact that it is a virtually quantitative, very robust, insensitive, general, and orthogonal ligation reaction, suitable for even biomolecular ligation and in vivo tagging or as a polymerization reaction for synthesis of long linear polymers. The triazole formed is essentially chemically inert to reactive conditions, e.g. oxidation, reduction, and hydrolysis, and has an intermediate polarity with a dipolar moment of 5 D. The basis for the unique properties and rate enhancement for triazole formation under Cu(1) catalysis should be found in the high ΔG of the reaction in combination with the low character of polarity of the dipole of the noncatalyzed thermal reaction, which leads to a considerable activation barrier. In order to understand the reaction in detail, it therefore seems important to spend a moment to consider the structural and mechanistic aspects of the catalysis. The reaction is quite insensitive to reaction conditions as long as Cu(1) is present and may be performed in an aqueous or organic environment both in solution and on solid support. This review will focus mainly on the Cu(1) catalysis in the Huisgen reaction, broadly known as the azide/alkyne-“click”-reaction or CuAAC-reaction, and will not consider the noncatalyzed thermal versions at any great length. The thermal version of the reaction first described by Michael and later investigated in detail by Huisgen has been reviewed in great detail and analyzed by Frontal Orbital−Pertubation theory by Lwowski.