We observed second-order rate constants for the click reaction (PBS, 37 °C) of the bis-hydroxypyridyl-Tz 5 with rTCO and cTCO of 1500 M -1 s -1 and 3400 M -1 s -1 , respectively, remarkably faster than prior bis-alkyl-Tz benchmarks. Compared to 2 (PA2), which triggers complete release of primary or secondary amines, this represents a ≥120-fold increase in reactivity. Relative to Tz 1 (capable of complete release only with secondary amines), click reactivity is increased 18-(rTCO) to 28-fold (cTCO). Notably, post-click elimination was also substantially accelerated, overall enabling fast and efficient release at low micromolar concentrations (cf. Fig. ). Applying these findings, we achieved efficient in situ activation of a cTCO-caged prodrug and intramitochondrial cleavage of an rTCO-caged fluorogenic probe in live cells, clearly demonstrating the superior click-to-release performance of the 'yellow' bis-hydroxypyridyl-Tz 5.