At the heart of this agenda is the tautomeriza=on of the ini=al Tz/TCO click product formed aUer IEDDA liga=on. The fate of this 4,5-dihydropyridazine (4,5-DHP) tautomer is remarkably suscep=ble to both structural and environmental factors , making it the cri=cal determinant for achieving release (Fig. ). Factors that shiU the tautomeriza=on equilibrium towards forma=on of the releasing 1,4-DHP will facilitate cleavage; conversely, mul=ple undesired pathways can hinder the release route. For the combina=on of primary amine leaving groups and alkyl tetrazines, irreversible intramolecular cycliza=on leads to a nonreleasing tricyclic dead-end isomer (Supplementary Fig. ), which can be prevented by N-methyla=on at the TCO-carbamate . Undue persistence of the 4,5-DHP itself is a barrier to release, as are irreversible forma=on of the non-releasing 2,5-DHP and its oxida=on. Hence, naviga=ng the complex cascade of post-click events is the key for designing more efficient bond-cleavage tools.