Surfing the limits of cyanine photocages one step at a time.

Near-infrared light-activated photocages enable controlling molecules with tissue penetrating light. Understanding the structural aspects that govern the photouncaging process is essential to enhancing their efficacy, crucial for practical applications. Here we explore the impact of thermodynamic stabilization on contact ion pairs in cyanine photocages by quaternarization of the carbon reaction centers. This strategy enables the first direct uncaging of carboxylate payloads independent of oxygen, resulting in a remarkable two-orders-of-magnitude enhancement in uncaging efficiency. Our computational analyses reveal that these modifications confer a kinetic instead of thermodynamic effect, reducing ion-ion interactions and allowing complete separation of free ions while inhibiting recombination. We demonstrate that, while thermodynamic stabilization is effective in traditional chromophores operating at shorter wavelengths, it rapidly reaches its thermodynamic limitations in NIR photocages by compromising the photocage stability in the dark. Thanks to these findings, we establish that activation of cyanine photocages is limited to wavelengths of light below 1000 nm. Our work illuminates the path to improving uncaging cross-sections in NIR photocages by prioritizing kinetic trapping and separation of ions.