Generation and Reactivity of Bio-Inspired Heme-Peroxo-Copper Model Complexes
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Date
2017-08-17
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Johns Hopkins University
Abstract
A major theme across many fields of science is the goal of understanding how structure begets function. This dissertation explores such relationships utilizing synthetic inorganic and coordination chemistry to interrogate an essential biological phenomenon, namely, the four-proton/four-electron reduction of dioxygen to water. Aerobic life relies
on this seemingly simple reaction, yet, its successful completion requires the efficient collaboration of many components. Heme-copper oxidases (HCOs) are the terminal electron acceptors along the mitochondrial electron transport chain, which contain the heterobinuclear heme-copper active site where O2 binds and is reduced; this reaction is importantly coupled to transmembrane proton-pumping and oxidative phosphorylation. The model systems explored herein aim to understand in detail, the factors which result in
O2 reduction to water by drawing structural inspiration from the binuclear active site. Although it has never been observed during catalytic turnover in HCOs, a metal-bridging peroxide formulation, (heme)FeIII-(O22−)-CuII, has been investigated via computations (DFT) and, in any case, is an informative starting point from a modeling perspective.
In the chapters that follow, the rational design and spectroscopic characterization of new heme-peroxo-copper constructs is discussed, and the reactivities of these species
towards H+/e− sources are reported. The results obtained highlight important aspects of connecting the structural and electronic properties of the model complex with those of the
substrates and elucidating how these properties determine mechanistic outcomes. Overall, this discussion of synthetic model systems proposes insights into biological O2-reduction.
Chapter 1 provides an overview of dioxygen chemistry including bioinorganic O2 reactions, and the current understanding of the enzymatic mechanism of HCOs is reviewed. Synthetic modeling is introduced as a valuable approach for investigating structure-function relationships, and a brief account of the evolution of heme-Cu models is presented.
In chapter 2, a novel synthetic approach is reported which broadens the potential structural scope of heme-O2-Cu complexes by building upon a “naked” synthon. A new pair of species, bearing three or four imidazole donors around copper, are characterized and the stage is set for an investigation into their comparative reactivities in chapter 3.
Chapter 3 details aspects of separate H+ and e− transfer events leading to complete reduction to water rather than release of reactive oxygen species (ROS; i.e., H2O2), while
also demonstrating the importance of H-bonding interactions in O2-activation by a weak phenolic acid.
A mechanistic study based on collaborative efforts in computational and experimental methods is reported in chapter 4, substantiating the above results despite focusing on an analogous complex reacting with phenol. Implications for HCOs are
established.
In chapter 5, the use of catecholic substrates, which can provide up to 2H+/2e−, uncovers a mechanistic pKa-dependence. Spectroscopic, kinetic, and DFT analyses distinguish
double proton-electron-transfer or double proton-transfer pathways, and not HAT.
Finally, chapter 6 presents final conclusions and thoughts, and some future directions for heme-O2-copper model complex reactivity studies are briefly outlined.
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Keywords
heme, copper, peroxos, inorganic chemistry, biomimetic chemistry, heme-copper-oxidases, reactivity