The Importance of Secondary Coordination Sphere in Nonheme Iron Chemistry
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Date
2016-03-22
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Johns Hopkins University
Abstract
Dioxygen activating nonheme iron enzymes are an important class of enzymes that are responsible for a wide variety of biological organic transformations including hydroxylation of aromatic substrates. Metalloenzymes are able to perform chemo- and regio-selective oxidation reactions by controlling both of their primary and secondary coordination sphere groups around the active metal center. However, biomimetic synthetic model complexes focus mainly on developing the primary coordination sphere to understand the reactivity of these model complexes. The effects of secondary coordination sphere groups on the reactivity of iron complexes remain less explored. This thesis describes synthetic nonheme FeIV(O) mediated aromatic hydroxylation reactions (C−H and C−F hydroxylations), and shows how secondary coordination sphere elements such as substrate orientation and H-bonding interaction are necessary to achieve such reactivity. The thesis provides one of the first experimental examples that supports the idea that an intermediate-spin (S = 1) synthetic FeIV(O) can perform aromatic hydroxylation, provided that the substrate is held in the proper place in the 2nd coordination sphere. A novel photolytic C−F amination reaction by a putative FeIV(N) complex is also discussed.
Chapter 1 provides a general discussion about dioxygen activation in nonheme iron enzymes and recent developments in the O2 activation by synthetic model complexes. Aromatic amino acid hydroxylases, a sub-class of the nonheme iron enzyme family is of particular interest, and respective synthetic model complexes are discussed subsequently. The difficulties associated with a model complex in achieving intermolecular aromatic hydroxylation will be discussed from computational analysis perspective.
Chapter 2 involves synthesis of two new ligands N4Py2Ph and N4Py2Ph,amide. The corresponding iron(II) complexes [FeII(N4Py2Ph)(CH3CN)]2+ and [FeII(N4Py2Ph,amide)]2+ were prepared to study the effects of substrate orientation and H-bonding interactions on the reactivity of these two complexes. Reactivity of both complexes with oxidants (e.g. tBuOOH, ArIO) was analyzed. It was shown that the proper orientation of substrates (phenyl groups) in [FeII(N4Py2Ph)(CH3CN)]2+ is necessary for arene hydroxylation to occur. Interestingly, the presence of a H-bond donor group in [Fe(N4Py2Ph,amide)]2+ allows for the stabilization of an FeIIIOOR intermediate, which was not seen with the other N4Py2Ph ligand.
Chapter 3 discusses modifying of the N4Py2Ph ligand to include fluorine substituents in the ortho-sites of the second coordination sphere phenyl groups. The new ligand, N4Py2PhF2 allows for the key iron(IV)-oxo intermediate to be trapped at low-temperature. This species is capable of performing a novel aromatic C−F hydroxylation reaction. Various spectroscopic techniques were employed to characterize the FeIV(O) intermediate and to follow the C−F hydroxylation reaction. This provides the first example of a spectroscopically characterized nonheme FeIV(O) mediated aromatic C−F hydroxylation reaction.
Chapter 4 describes the characterization of [FeIV(O)(N4Py2PhF2)](BF4)2 by single crystal X-ray diffraction. The electronic structure of the [FeIV(O)(N4Py2PhF2)]2+ complex was studied by variable field Mössbauer spectroscopy. These studies proved the assertion made in chapters 2 and 3 that an intermediate spin (S = 1) FeIV(O) species is capable of performing arene hydroxylation, provided the substrate is in the right orientation. The mechanism of the aromatic C−F hydroxylation reaction was investigated by building two new related ligands. These ligands were synthesized with a methoxy (−OMe) group introduced separately in to the meta or ortho/para positions of the phenyl rings in relation to the C−F bonds in the N4Py2PhF2 ligand. The corresponding FeII complexes [FeII(N4Py2PhF2,m-OMe)(CH3CN)]2+ and [FeII(N4Py2PhF2,o/p-OMe)(CH3CN)]2+ were synthesized. Both complexes were shown to perform C−F hydroxylation via FeIV(O) intermediates. The stability of the respective FeIV(O) complexes, and rates of C−F hydroxylation provided information on the mechanistic pathway for C−F hydroxylation.
Chapter 5 describes the synthesis of an iron(II)-azide complex [FeII(N4Py2PhF2)(N3)](BF4). The structure of this complex was characterized by X-ray crystallography and FTIR spectroscopy. A novel photolytic aromatic C−F amination reaction by the FeII−N3 complex was observed. The resulting iron(II)-amido complex (FeII−NAr) was also crystallographically characterized and was shown to undergo an oxidation reaction when exposed to air. A mechanistic pathway involving an iron(IV)-nitrido (FeIV(N)) has been proposed along with a number of future experiments, that would help to support the proposed mechanism for C−F amination reaction.
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Keywords
bioinorganic, dioxygen activation, nonheme, iron, hydroxylation, iron-oxo,
C−F functionalization, C−H functionalization, Secondary coordination, H-bonding, substrate orientation, amination, S-oxygenation.