In chemical biology, “tagging” is more than a simple color—it can be a powerful way to track, label, and connect molecules under living-system-compatible conditions.

Trans-cyclooctene (TCO) is a highly strained alkene and an important reagent in bioorthogonal chemistry, valued for its exceptional reactivity and biocompatibility. The strong ring strain of its trans double bond enables TCO to react rapidly and selectively with tetrazines (Tzs) under physiological conditions, without the need for metal catalysts.

The reaction between TCO and tetrazine proceeds through an inverse electron-demand Diels–Alder (IEDDA) mechanism. Electron-rich TCO reacts with electron-deficient tetrazine via rapid [4+2] cycloaddition to form a strained bicyclic intermediate, which then undergoes retro-Diels–Alder reaction with release of nitrogen gas (N₂), generating stable dihydropyridazine or pyridazine products. Nitrogen extrusion helps drive the reaction forward and contributes to its fast kinetics and high efficiency.

📌 Reference: https://link.springer.com/article/10.1186/s41181-024-00275-x

Because this click reaction is fast, selective, catalyst-free, and compatible with living systems, TCO-based chemistry has been widely applied in chemical biology, materials science, and biomedical research. Representative applications include protein and cell labeling, molecular imaging, bioconjugation, radiolabeling, pretargeted imaging, and targeted drug delivery.