The research proposed herein intends to further expand the depth of our understanding, and our ability to mimic, the active sites of a family of dioxygen activating mono-nuclear non-heme iron containing enzymes. Enzymes in this family facilitate the catalytic conversion of a large range of biologically essential reactions, such as alkylated DMA and RNA repair, penicillin and cephalosporin biosynthesis, and protein modification, and are thus very important to human health. Furthermore, some members catalyze the environmentally friendly removal of toxic aromatic reagents, and even act as anti-cancer drugs. The electronic and reactivity properties of the active iron species are of great interest because these enzymes catalyze the activation of one of the most chemically inert moieties - the C-H bond, in most of the respective conversions they carry-out. A thorough understanding of the catalytic mechanism of these iron-containing active sites is thus of paramount interest, both from a medicinal and an industrial catalysis perspective. The catalytically active species in most of these enzymes is an iron (IV)-oxo complex with iron in the high-spin state (HS). Model Fe (IV)-oxo complexes - synthesized to gain further understanding of the active site, and eventually to produce non-natural catalysts that facilitate the reactions that the enzymes catalyze - have been developed. However, all but one has had iron in the low-spin state (LS). These complexes contained nitrogen rich ligands with four or five N-donors. Conversely, the enzyme active-site contains two histidine and two carboxylate ligands bound to iron (i.e. two N- and two O-donors). It is proposed that by incorporating multiple O-donor ligands it will be possible to synthesize HS-Fe(IV)-oxo complexes. The HS complexes will be characterized with a variety of spectroscopic and structural techniques such as electronic, resonance Raman, infra-red, NMR, Mossbauer, and X-ray diffraction and absorption spectroscopies. The synthesis of HS complexes will allow for a genuine investigation of the electronic properties of Fe(IV)-oxo complexes, and detailed investigation of their reactivity properties with inert alkanes (e.g. cyclohexane, toluene, and even methane) will give us a better understanding of the very complex reaction profiles these enzymes demonstrate.
By developing synthetic model compounds, that show similar properties to a family of iron containing natural systems, we intend to gain a better understanding of the processes these natural systems facilitate in humans and other organisms. Ultimately this will allow us to more efficiently develop medicines to treat certain illnesses, and for the 'clean'natural removal of toxins from the environment.
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|McDonald, Aidan R; Guo, Yisong; Vu, Van V et al. (2012) A Mononuclear Carboxylate-Rich Oxoiron(IV) Complex: a Structural and Functional Mimic of TauD Intermediate 'J' Chem Sci 3:1680-1693|
|McDonald, Aidan R; Bukowski, Michael R; Farquhar, Erik R et al. (2010) Sulfur versus iron oxidation in an iron-thiolate model complex. J Am Chem Soc 132:17118-29|