In the last decade bioorthogonal bond-cleavage reactions based on the IEDDA (inverse-electron-demand Diels-Alder) reaction of trans-cyclooctenes and tetrazines have emerged as a promising strategy for potential in vivo release of target molecules. Since their discovery, numerous approaches have been investigated to optimize their performance in terms of bioorthogonal compatibility, kinetics and complete release of desired target compounds. Recently, the scope of pyridazine elimination has been extended in order to cleave further moieties besides carbamates. Suffering from the limitations mentioned, with regard for the release of phenols and primary amines, the known concept of self-immolative linkers (SIL) was introduced as an encouraging approach to enhance pyridazine elimination kinetics. Two different self-immolative linkers for the release of phenols respectively primary amines were sufficiently introduced that both led to release at highly accelerated kinetics. For the first time in literature, it was possible to achieve almost quantitative release of primary amines. In addition, it was possible to determine the pH dependency (pH 4-9) with regard to the reaction rate of released compounds and to determine their optimum. The pH dependency on the kinetics of click-to-release and selfimmolation emphasized again the importance of environmental sensitivity of the whole disassembly cascade.
