1245tetrazine

1,2,4,5-tetrazine is a six-membered heteroaromatic ring that contains four nitrogen atoms at positions 1, 2, 4 and 5 and two carbon atoms at positions 3 and 6. The ring is highly electron-deficient and planar, making it a versatile scaffold for chemical modification. Substituted derivatives of the 1,2,4,5-tetrazine core are commonly prepared, with the 3 and 6 positions often bearing functional groups to tune reactivity and solubility.

A defining feature of 1,2,4,5-tetrazines is their reactivity in inverse electron-demand Diels–Alder (IEDDA) reactions. They react rapidly with strained alkenes and alkynes, such as trans-cyclooctene and related dienophiles, to form dihydropyridazine adducts and release nitrogen gas. The reaction is notable for proceeding under mild, often aqueous, conditions and at low reagent concentrations, which underpins its wide use in bioorthogonal chemistry. Reactivity can be modulated by substituents on the tetrazine ring; electron-withdrawing groups generally increase the rate of reaction with dienophiles.

Applications of the tetrazine motif include bioorthogonal labeling, imaging, and pretargeting strategies in biomedical research. Tetrazine derivatives are frequently incorporated into fluorescent probes, bioconjugates, and polymers to enable rapid, selective ligation to strained alkenes in complex biological environments. In addition to biological uses, tetrazine-containing compounds find roles in materials science and catalysis where rapid, selective cycloadditions are advantageous. Safety and handling depend on the specific derivatives, as with many energetic heterocycles, and should follow appropriate chemical hygiene practices.