Scott T. Laughlin

Hydrogen sulfide (H 2 S), one of the most important gasotransmitters, plays a critical role in endogenous signaling pathways of many diseases. However, developing H 2 S donors with both tunable release kinetics and high release efficiency for subcellular delivery has been challenging. Here, we describe a click and release reaction between pyrone/pyranthiones and bicyclononyne (BCN). This reaction features a release of CO 2 /COS with second‐order rate constants comparable to Strain‐Promoted Azide‐Alkyne Cycloaddition reactions (SPAACs). Interestingly, pyranthiones showed enhanced reaction rates compared to their pyrone counterparts. We investigated pyrone biorthogonality and demonstrated their utility in protein labeling applications. Moreover, we synthesized substituted pyranthiones with H 2 S release kinetics that can address the range of physiologically relevant H 2 S dynamics in cells and achieved quantitative H 2 S release efficiency in vitro . Finally, we explored the potential of pyranthiones as H 2 S/COS donors for mitochondrial‐targeted H 2 S delivery in living cells.