Preprint of "Photoinduced Electron Transfer in a Bilirubin–Oxygen Complex: the Triplet-Reactant Computational Challenge"

Although bilirubin photochemistry is central to neonatal jaundice phototherapy, the mechanism of bilirubin photooxidation remains unclear. Here, we use a comprehensive computational approach to investigate whether this mechanism might be initiated by photoinduced electron transfer (PET) to molecular oxygen (O2). For this purpose, we employed a simplified bilirubin model compound–tetramethyldipyrrinone (TMD). We use a combination of multireference, coupled cluster methods, and density functional theory techniques to assess the feasibility of the TMD–O2 complex formation and PET from TMD to O2. Our results support the existence of PET in the bilirubin decomposition pathway, generating superoxide which causes the oxidation of bilirubin. Beyond the bilirubin case, this work underscores the need for efficient and accurate protocols to compute binding free energies of weak O2 encounter complexes with organic chromophores in solution, and it highlights the broader challenge of modeling triplet photochemistry with dense manifolds of near-degenerate states, crossings, and strongly state-specific solvent response.