Tetrazine

Tetrazine refers to a family of heterocyclic compounds containing a six-membered ring in which four nitrogen atoms occupy alternating positions, with the parent compound commonly referred to as 1,2,4,5-tetrazine. The core ring is aromatic and highly electron-deficient, and many derivatives are accessible by substituting carbon-based groups onto the ring. Substituents modulate properties such as reactivity, stability, and solubility, enabling a range of practical applications.

A defining feature of tetrazines is their reactivity in inverse electron-demand Diels–Alder (IEDDA) cycloadditions. They react rapidly with strained alkenes and alkynes, especially trans-cyclooctenes, to form dihydropyridazine adducts with concomitant extrusion of nitrogen gas. This highly selective, fast ligation under mild conditions is central to bioorthogonal chemistry, where tetrazines are used to label biomolecules in living systems or to build modular, labeled constructs for imaging and sensing.

Synthesis and availability of tetrazines typically involve constructing the ring from suitable precursors such as diaminomaleonitrile derivatives, followed by cyclization and oxidation to furnish the aromatic core. A wide variety of substituted tetrazines are known, with substituents chosen to tune electronic effects and reactivity. Electron-withdrawing groups generally increase IEDDA reactivity but can affect stability and handling.

Applications extend beyond bioorthogonal labeling to polymer science, materials chemistry, and medicinal chemistry. Tetrazines appear in fluorescent probes, radiolabeling strategies, and pretargeted imaging approaches, where rapid and selective conjugation is advantageous.

Safety considerations depend on the specific derivative; some tetrazine compounds can be sensitive to heat, shock, or friction and should be handled with standard laboratory precautions.