page_title: Click chemistry
section_title: Alkene and tetrazine inverse-demand Diels-Alder
hierarchical_section_title: Click chemistry / Reactions / Reactions of strained alkenes / Alkene and tetrazine inverse-demand Diels-Alder
caption_attribution_description: English: A diagram illustrating the [4+2] Diels-Alder reaction between a tetrazine and an alkene.
context_page_description: In chemical synthesis, "click" chemistry is a class of biocompatible small molecule reactions commonly used in bioconjugation, allowing the joining of substrates of choice with specific biomolecules. Click chemistry is not a single specific reaction, but describes a way of generating products that follow examples in nature, which also generates substances by joining small modular units. In many applications, click reactions join a biomolecule and a reporter molecule. Click chemistry is not limited to biological conditions: the concept of a "click" reaction has been used in pharmacological and various biomimetic applications. However, they have been made notably useful in the detection, localization and qualification of biomolecules.
  Click reactions occur in one pot, are not disturbed by water, generate minimal and inoffensive byproducts, and are "spring-loaded"—characterized by a high thermodynamic driving force that drives it quickly and irreversibly to high yield of a single reaction product, with high reaction specificity. These qualities make click reactions particularly suitable to the problem of isolating and targeting molecules in complex biological environments.
context_section_description: Strained cyclooctenes and other activated alkenes react with tetrazines in an inverse electron-demand Diels-Alder followed by a retro [4+2]  cycloaddition (see figure). Like the other reactions of the trans-cyclooctene, ring strain release is a driving force for this reaction. Thus, three-membered and four-membered cycloalkenes, due to their high ring strain, make ideal alkene substrates.
  Similar to other [4+2] cycloadditions, electron-donating substituents on the dienophile and electron-withdrawing substituents on the diene accelerate the inverse-demand diels-alder. The diene, the tetrazine, by virtue of having the additional nitrogens, is a good diene for this reaction. The dienophile, the activated alkene, can often be attached to electron-donating alkyl groups on target molecules, thus making the dienophile more suitable for the reaction.
caption: A Tetrazine-Alkene reaction between a generalized tetrazine and a strained, trans-cyclooctene
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