Dioxygen and Nitric Oxide Activation at Synthetic Copper Complexes: Relevance to Unique Structural Aspects of Metalloprotein Active Sites

The intricacies of metalloprotein chemistry including the fundamentally important mechanistic details of small molecule activation at enzymatic metal centers are studied via synthetic bioinorganic model complexes. The catalytic depiction of dioxygen and nitric oxide activation, for instance, is logically outlined by the identification of different transient intermediates (and the putative active species) and elucidation of the role of secondary sphere functionalities (like proton channels, H-bonding networks etc.) in the reaction cycle. Chapter 1 provides an overview of copper metalloenzymes involved in dioxygen activation and reduction and a brief introduction to nitric oxide reductases due to their relevance in the following chapters. Copper-containing metalloproteins are found in mononuclear, homo-multinuclear (coupled and noncoupled), and hetero-multinuclear (copper plus iron or zinc) copper active sites, which are described in this chapter. The mechanistic aspects of the 2e/2H+ conversion of NO(g) to N2O(g) through the intermediacy of the proposed “hyponitrite” intermediate, with the help of (bi)metallic active sites of NOR enzymes is briefly touched upon and the role of proton channels/H-bonding networks in the reductive coupling chemistry is mentioned. Chapter 2 presents a series of TMPA-based copper(I) complexes (TMPA ≡ tris(2-pyridylmethyl)amine), with and without secondary coordination sphere hydrogen-bonding moieties, which were studied for their O2 reactivity at cryogenic conditions; A systematic stabilization of the metastable cupric-superoxide intermediate was achieved via increasing the strength of the secondary sphere H-bonding groups; electrophilic reactivity of H-bonded cupric superoxides toward O-H bonds also enhanced, thereby elucidating a possible role of secondary sphere designs in catalytic model systems. In Chapter 3, the role of Scys-ligation to the CuM site of copper monooxygenases was probed using the first structurally characterized N3S(thioether)-ligated cupric superoxide complex. Direct evidence for a CuII-S bond is presented (supported by DFT) and an analogous azido complex is crystallographically characterized. Kinetic comparison of O-H oxidation between the N3S-superoxo and it’s N4-analog, along with cyclic voltammetry measurements present a striking difference in the donating ability of the fourth S vs the N atom to the Cu center. Chapter 4 illustrates the role of acidic secondary-sphere H-bonding moieties which was studied by the reactivity of two reduced Cu-models and the stability/reactivity aspects of the putative hyponitrite (N2O22-) unit were probed spectroscopically and product analyses. Our study provides the first example of a copper-only complete NOR model system outlining the cruciality of fine-tuned acidities of active site components and/or proximal water molecules in the NOR active site. Chapter 5 illustrates characterization of several new intermediates in the Cu-mediated NO(g)-reductive coupling scheme; a stepwise formation of an N,N’-hyponitrite intermediate and it’s isomerization to the O,O’ analog is depicted via detailed spectroscopic analyses. The role of second sphere H-bonding motifs and H-bonding solvents in differentiating the reductive coupling and disproportionation pathways is outlined in detail