Finally, we turned to the highly reac=ve monosubs=tuted H-aryl-Tz 12 (HBAm) and the bis-pyridyl-Tz 1 (Pyr2), which display minimal release with rTCO, encapsula=ng a general and mul=factorial trend in which cleavage efficiency declines as Tz reac=vity increases. Even at high buffer concentra=on (100 mM), HBAmtriggered cleavage is <25%, while Pyr2 reaches only 6% release from rTCO. In notable contrast, iTCO achieves near-complete 96% release with HBAm (12) and quan=ta=ve (>99%) release with Pyr2 (1), erasing the tradeoff between reac=on kine=cs and release yield. The Supplementary Informa=on (Supplementary Fig 4) expands on this selected subset of Tz with addi=onal tetrazines, all of which demonstrate excellent release yields with iTCO, ranging from 92 to 99%. Interes=ngly, the lower end of that range is largely occupied by tetrazines equipped with TDGs, unneeded here, where a subset of click events will place the two TDGs (TCO and Tz) in counterproduc=ve compe==on with each other. This further highlights the value and simplicity of the always-correctly-placed direc=ng OH group on iTCO.