The Diels-Alder cycloaddition between 1,2,4,5-tetrazines and trans-cyclooctenes is a highly e icient and rapid bioorthogonal reaction. After an initial inverse electron demand Diels-Alder reaction, which is the rate limiting step, a retro-Diels-Alder with loss of N2 gives a dihydropyridazine (Figure ). Owing to its biocompatibility and high reactivity, this reaction is used in in vivo applications such as pretargeted radiolabeling and targeted drug release. In these applications, high reactivity is the most crucial property. The kinetics of such reactions have been the focus of intensive investigation in numerous experimental and computational studies, aimed at understanding and improving reactivity. Figure : Mechanism of the bioorthogonal 1,2,4,5-tetrazine/trans-cyclooctene reaction.