Activation and Delivery of Small Molecules by Transition Metal Complexes

Abstract

In nature, the activation and delivery of biologically relevant small molecules such as nitrite (NO2−), nitric oxide (NO•), and dioxygen (O2) represent fundamental processes that play a central role in catalytic reactions and cellular signaling pathways mediated by metalloenzymes. The biological transformations and signaling events are tightly regulated by diverse metalloenzymes to support essential physiological functions. To gain deeper insight into the reactivity and mechanisms of metalloenzymes, synthetic coordination and bioinorganic chemistry have sought to elucidate the fundamental principles of small molecule activation and delivery, while also developing biomimetic complexes capable of reproducing or modulating such reactivity in a controlled manner. This thesis explores the mechanisms not only for the activation and transformation of NO2− and O2 but also for the spatiotemporal delivery of NO•, as observed in biological systems. In chapter 1, a mononuclear iron(II)-nitrite complex is shown to mediate the 2H+/1e− reduction of NO2− to NO• via the {FeNO}6 species proposed as a key reaction intermediate. Spectroscopic and kinetic studies reveal the formation of {FeNO}6 intermediate, including evidence for heterolytic N–O bond cleavage and the involvement of a transient Fe(II)···ONOH2+ adduct. Chemical reduction of {FeNO}6 confirms the generation and release of NO•, providing insight into the stepwise pathway of NO2− reduction relevant to enzymatic and catalytic NO• production. Chapter 2 investigates the photoinduced dissociation of NO• from a nonheme {FeNO}7. In-situ photocrystallographic experiments on crystalline {FeNO}7 provide direct structural evidence of Fe–NO bond elongation under visible light irradiation, capturing real-time snapshots of the excited-state of the {FeNO}7 species. Combined with solution-phase reactivity studies and multiconfigurational CASSCF calculations, the results reveal that NO• release is induced via metal-to-ligand charge transfer (MLCT). Furthermore, electronic modulation of supporting ligand by para-substituted Cl enhances photodissociation efficiency, elucidating key design principles for NO-delivering photoactive systems. Chapter 3 describes a functional model of quercetin 2,4-dioxygenase based on a well-defined nickel(II)-flavonolate complex. Structural, spectroscopic, and computational analyses demonstrate that the complex mimics the enzymatic O2 activation chemistry. Notably, the electronic configuration exhibits SOMO-HOMO inversion, highlighting the flavonolate ligand as the initial site of oxidation. Thermal decomposition of the complex after O2 activation yields benzoic and salicylic acid, supporting an oxygenation mechanism that parallels natural flavonoid degradation pathways. Taken together, all investigations in this thesis demonstrate how transition metal complexes can mediate the activation and delivery of small molecules through finely tuned electronic and structural features. The findings provide a deeper mechanistic understanding of metal-mediated activation and delivery chemistry.