Aromatic hybrid guanidine-stabilized copper complexes and their application as tyrosinase model systems

Paul, Melanie; Herres-Pawlis, Sonja (Thesis advisor); Oppel, Iris Marga (Thesis advisor)

Aachen : RWTH Aachen University (2021)
Dissertation / PhD Thesis

Dissertation, RWTH Aachen University, 2021


The design of environmentally friendly and efficient catalysts for oxidation processes represents a longstanding research goal. The natural copper protein tyrosinase efficiently activates molecular oxygen, forming reactive copper-oxygen intermediates which catalyze phenolase and catecholase transformations. Inspired by nature, synthetic model systems are designed to imitate the active site of tyrosinase, exploring the structure-reactivity relationship of the copper protein. This doctoral thesis deals with the development of tyrosinase model systems based on aromatic hybrid guanidine ligands. These tailored ligand systems combine strong σ-donor properties of the bulky guanidine moiety with spatially smaller, weaker amine donor moieties, which are bridged by an aromatic spacer to rigidify the ligand backbone. Five structurally related hybrid guanidine ligands were developed to examine correlations between ligand structure and reactivity of the corresponding copper complexes. 29 copper(I) and copper(II) species with weakly coordinating and halide anions were synthesized, of which 15 were structurally characterized by single crystal X-ray diffraction. Oxygenation of suitable copper(I) complexes resulted exclusively in the formation of bis(µ-oxido) dicopper(III) complexes, which were characterized by UV/Vis, resonance Raman and X-ray absorption spectroscopy, cryo-UHR-ESI mass spectrometry as well as DFT simulations. Additionally, the formation of the bis(µ-oxido) species was quantified by spectrophotometric titration with ferrocene monocarboxylic acid. Formation and thermal decay kinetics were studied extensively by UV/Vis spectroscopy to investigate the influence of the ligand system, present anions and different additives on the model system. Several decomposition products were successfully isolated. The hybrid guanidine-stabilized bis(µ-oxido) dicopper(III) complexes are well-suited for tyrosinase-like oxygenation reactions of aromatic alcohols, as the hybrid ligands balance stabilization of the Cu2O2 core and accessibility for external substrates. A library of substrate classes was investigated to exceed the established substrate scope. Many new polycyclic aromatic alcohols including pyridinols, naphthols, quinolinols and indolols were introduced into tyrosinase chemistry. Substrates were hydroxylated and oxidized selectively to generate quinones which were captured exclusively as bent phenazine derivatives. The selectivity of the oxygenation reaction was confirmed by DFT calculations using the Fukui function, enabling a prognosis of the favored hydroxylation position. A simple salt metathesis of the catalyst allowed oxygenation reactions under mild conditions at room temperature, increasing the turnover of the system. Catalytic reactivity and selectivity of the model system were sustained despite enhancing the steric demand of the supporting ligand system. This systematic study opens the door to future developments on tyrosinase model systems to gain deeper insights into molecular mechanisms of the activation and transfer of dioxygen in biological systems.