Laser Photodissociation Action Spectroscopy for the Wavelength-Dependent Evaluation of Photoligation Reactions

The nitrile imine-mediated tetrazole-ene cycloaddition is a widely used class of photoligation. Optimizing the reaction outcome requires detailed knowledge of the tetrazole photoactivation profile, which can only partially be ascertained from absorption spectroscopy, or otherwise involves laborious reaction monitoring in solution. Photodissociation action spectroscopy (PDAS) combines the advantages of optical spectroscopy and mass spectrometry in that only absorption events resulting in a mass change are recorded, thus revealing the desired wavelength dependence of product formation. Moreover, the sensitivity and selectivity afforded by the mass spectrometer enable reliable assessment of the photodissociation profile even on small amounts of crude material, thus accelerating the design and synthesis of next-generation substrates. Using this workflow, we demonstrate that the photodissociation onset for nitrile imine formation is red-shifted by ca. 50 nm with a novel N-ethylcarbazole derivative relative to a phenyl-substituted archetype. Benchmarked against solution-phase tunable laser experiments and supported by quantum chemical calculations, these discoveries demonstrate that PDAS is a powerful tool for rapidly screening the efficacy of new substrates in the quest toward efficient visible light-triggered ligation for biological applications.