tetrazines

Tetrazines are a class of heterocyclic compounds characterized by a six-membered ring containing four nitrogen atoms, commonly referred to as 1,2,4,5-tetrazine. The core ring is highly electron-poor and aromatic, and a wide range of substitutions on the ring modulate reactivity and stability. Substituted tetrazines include aryl, alkyl, and heteroatom-containing groups, with electron-withdrawing substituents generally enhancing reactivity in the ring.

A defining feature of tetrazines is their role as electron-poor dienes in inverse-electron-demand Diels–Alder reactions. They readily react with electron-rich dienophiles such as strained alkenes and alkynes, including trans-cyclooctene and norbornene derivatives. The cycloaddition is typically followed by extrusion of nitrogen gas, yielding a dihydropyridazine or related products. This fast, selective reactivity under mild conditions has made tetrazines central to bioorthogonal chemistry, particularly in labeling and imaging applications in living systems.

Synthesis of tetrazines commonly involves construction of the heterocycle from smaller precursors followed by oxidation. Routes include condensation or cyclization of dihydro- or amidrazone relatives with nitrile-type substrates, producing dihydrotetrazines that can be oxidized to the 1,2,4,5-tetrazine core. Practical methods emphasize access to substituted derivatives that balance stability with reactivity for the intended application.

Applications span bioconjugation, fluorescent labeling, and materials science. In biology, tetrazine ligation enables rapid, selective tagging of biomolecules in cells and organisms. In materials chemistry, tetrazines are used for crosslinking and functionalization, and fluorogenic tetrazines provide turn-on signals upon reaction, aiding imaging and sensing.