1963

Dipolar Cycloadditions

Rolf Huisgen (b. 1920)

The Diels-Alder reaction is the classic example of a cycloaddition (a chemical reaction that leads to a ring formation in a compound), but there are many others. Over the decades, several were discovered that made five-membered rings instead of the Diels-Alder’s six-membered ones. One partner in the reaction was an alkene (an unsaturated hydrocarbon containing a double bond), as usual, but the other side could be an array of three-atom species. German chemist Rolf Huisgen brought all of these reaction types under one tent in a series of papers, which he summarized in a 1963 overview.

What they all had in common was that the three-atom partner could be thought of as a dipole (a species with a negatively charged end and a positively charged one). Some of these dipoles are relatively stable, but many of them form transiently and react quickly. Huisgen’s work established that these cycloadditions really were taking place through a concerted (all-at-once) mechanism like the Diels-Alder reaction, rather than through stepwise intermediates or free radicals (as put forth by competing theories), and he provided a framework to predict the orientation of the products.

For example, if there are very polar intermediates involved, then the reaction should be sensitive to changes in the polarity of the solvent (which could strongly stabilize or destabilize the transition states of such species), but concerted cycloadditions are not. If the two new bonds are being formed at the same time, then the arrangement of substituents around the alkene (the “dipolarophile”) should be preserved, since they don’t have time to rotate and scramble. And if free radicals are involved, then those could be intercepted by flooding the reaction with compounds that react quickly with them, stopping the reaction in its tracks.

The dipolar cycloadditions make a wide variety of five-membered heterocycles that are useful in drug structures, agricultural chemicals, and more. The most famous use of the Huisgen reactions, though, is probably the azide/alkene click chemistry made famous by Barry Sharpless.

Trees of the genus Aspidosperma are found throughout South America and contain a number of very complex alkaloids. Synthesis of these in the lab has often required dipolar cycloaddition as a key step, since the compounds' structures include several fused rings.