Quantum chemical investigation and molecular design of coumarin-based heavy-metal-free photosensitizers for one- and two-photon excited fluorescence imaging and photodynamic therapy.

The rational design of heavy-metal-free photosensitizers (PSs) is essential for advancing fluorescence (FL) imaging and photodynamic therapy (PDT). In this work, we present a systematic quantum-chemical investigation of eight coumarin-based derivatives (C1-C8) to elucidate how molecular structure controls excited-state dynamics. Time-dependent density functional theory (TD-DFT), combined with Fermi's Golden Rule, was applied to compute FL emission, internal conversion (IC), and intersystem crossing (ISC) rate constants, enabling quantitative prediction of FL and triplet quantum yields. The results show that C1, C2 and C6 undergo reduced fluorescence due to partial population of the dark 1TICT state, but maintains both moderate fluorescence and appreciable triplet yield, supporting dual applications in imaging and PDT. The heavy-atom derivative C3 achieves nearly unit triplet quantum yield (Φ T ≈ 1.0), confirming the dominant role of sulfur-enhanced ISC and reactive oxygen species generation. In contrast, C4 and C8 favor fluorescence over ISC, while C5 and C7 exhibit the highest emission efficiency by suppressing both TICT state and ISC process, identifying them as optimal imaging probes. Importantly, Herzberg-Teller vibronic coupling was found to dominate ISC efficiency in heavy-atom-free systems but was negligible in heavy-atom-based analogues. In addition, the large two-photon absorption (TPA) cross sections of C1-C8 provide redshifted excitation windows, thereby overcoming the penetration limitations of one-photon absorption (OPA) and enhancing biomedical applicability. Collectively, these insights establish design principles for tailoring radiative and non-radiative pathways in coumarin scaffolds, enabling the targeted development of multifunctional organic PSs.