Azide-alkyne Huisgen cycloaddition
| Azide-alkyne Huisgen cycloaddition | |
|---|---|
| Named after | Rolf Huisgen |
| Reaction type | Ring forming reaction |
| Identifiers | |
| Organic Chemistry Portal | huisgen-1,3-dipolar-cycloaddition |
| RSC ontology ID | RXNO:0000269 |
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 K. 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 triazole 3 as a mixture of 1,4-adduct and 1,5-adduct 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.
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).
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