IEDDA Click Reaction

Inverse electron-demand Diels-Alder (IEDDA) click reaction was first discovered by Bachmann and Deno in 1949, featuring an electron-rich dienophile reacting with an electron-poor diene to form new chemical bonds and a six-membered ring. It was recognized as a potential "click" reaction by Hilderbrand and Fox in 2008, and had been widely applied in bioorthogonal chemistry and materials science. The schematic diagram of a typical IEDDA click reaction is shown in Scheme 1.

Scheme 1. Schematic diagram of a typical IEDDA click reaction.

Advantages

Like the traditional Diels-Alder click reaction, IEDDA click reaction has proven to be an invaluable addition to the chemist's toolbox. This is because it can join two molecules together quickly and simply under mild conditions with a high yield. In addition, it is also orthogonal to many other reactions, making it highly selective. These advantages provide the possibility for a wide range of applications of IEDDA click reaction.

Mechanism

Although IEDDA click reaction is usually recognized as a formal [4+2] cycloaddition, the actual mechanism is controversial. Both stepwise and concerted mechanisms had been demonstrated in different studies, and the exact mechanism may depend on the steric and electronic factors of reactants.

• Stepwise mechanism

The accepted view is that most IEDDA click reactions occur via a stepwise mechanism. That is, the IEDDA click reaction proceeds through a transition state, but not all chemical bonds are formed or broken at the same time. The reaction of amino-pyrrole and 1,3,5-triazine was thoroughly studied by Rosa's group. As many as five intermediates were identified by H, ¹³C, ¹⁵N and ¹⁹F nuclear magnetic resonance (NMR) spectroscopy. The first intermediate is zwitterion, which can be detected when electronic factors and steric factors inhibit their cyclization^[1]. This study demonstrates the stepwise mechanism of IEDDA click reaction is related to electronic and steric factors.

• Concerted mechanism

In the concerted mechanism, the product is obtained in a single step through a single transition state. In other words, all bonds are formed or broken at the same time in the IEDDA click reaction. Gomez-Bengoa and co-workers studied an IEDDA click reaction between an alkynylboronate and a tetrazine. Compounds 9 and 10 were used as reactants of their respective functional groups, with the cycloaddition adduct formed upon the elimination of nitrogen (Scheme. 2)^[2]. In principle, a bicyclic adduct is formed as an intermediate; in practice, this was never observed.

Scheme 2. Reaction between an alkynylboronate and a tetrazine for mechanism study of IEDDA click reaction.

What Can We Do?

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References

1. Rosa, M.D.; Arnold, D. Mechanism of the inverse-electron demand Diels-Alder reaction of 2-aminopyrroles with 1,3,5-triazines: detection of an intermediate and effect of added base and acid. Tetrahedron Letters. 2007, 17(48): 2975-2977.
2. Gomez-Bengoa, E.; et al. The Participation of Alkynylboronates in Inverse Electron Demand [4 + 2] Cycloadditions: A Mechanistic Study. Journal of the American Chemical Society. 2007, 9(129): 2691-2699.