An iterative synthesis of poly-substituted indole oligomers reveals a short effective conjugation length in eumelanin model compounds

Abstract

Eumelanin is a multifunctional biomaterial that colors the skin, hair and eyes of mammals. Despite years of effort, its molecular structure remains unknown, limiting our understanding of its biological function and the design of synthetic mimics. In an effort to address this challenge, we report an Iterative Chain Growth (ICG) of well-defined 5,6-dihydroxyindole (DHI) model compounds that provides direct, experimental evidence of a short effective conjugation length in the resulting oligomers. Our ICG highlights the C2-selective borylation of N–H indoles in complex settings, and the utility of Suzuki–Miyaura Coupling (SMC) to grow the chain. The resulting C2–C7′ linkage is installed selectively with good yields, affording products with up to 5-indole units. Access to these oligomers allows us to probe how DHI chain extension contributes to the emergence of sun screening in eumelanin. Our oligomers guarantee the absence of oxidized by-products that may otherwise complicate analysis, without substantially altering the photophysics of the indolic-backbone. Steady-state absorption and emission spectroscopy coupled with excited-state calculations reveal pronounced vibronic structure and excited state planarization, but only a moderate red shift with increasing chain length because of poor orbital coupling between adjoined π-systems. We conclude that eumelanin's characteristic ability to absorb visible light does not derive from long chains of fully reduced DHI sub-units. Our work takes an important step towards a more systematic exploration of eumelanin's structure through iterative synthesis, with the long-term goal of explaining the molecular origins of its properties.