Oxidation of substrates tethered to N-donor ligands for modeling non-heme diiron enzyme active sites

Abstract

Chapter 1. Modeling Carboxylate-Rich Diiron Sites of Dioxygen-Dependent Non-Heme Enzymes Carboxylate-bridged diiron centers are employed in a variety of biological systems to activate dioxygen for substrate oxidation, and small molecule models have been synthesized to mimic this chemistry outside of the natural systems. In this introductory chapter a brief overview of terphenyl-based carboxylate systems is given and progress toward achieving structural, spectroscopic, and functional models of the protein active sites is reviewed. Chapter 2. Synthesis and Reactivity of Carboxylate-Bridged Diiron(II) Complexes with Primary Alkyl Amine Ligands The synthesis and crystallographic characterization of a series of diiron(II) complexes with sterically hindered terphenyl carboxylate ligands and alkyl amine donors are presented. The compounds ... , where ... 2,6-di(p-tolyl)benzoate, and [...] (L= NH₂(CH₂)₃SMe (4); NH₂(CH₂)₃CCH (5)), where ... is 2,6-di(3,5- dimethylphenyl)benzoate, were prepared as small molecule mimics of the catalytic sites of carboxylate-bridged non-heme diiron enzymes.

(cont.) The compounds with the ... carboxylate form tetrabridged structures, but those containing the more sterically demanding ... ligand have only two bridging ligands. The ancillary nitrogen ligands in these carboxylate-rich complexes incorporate potential substrates for the reactive metal centers. Their oxygenation chemistry was studied by product analysis of the organic fragments following decomposition. Compound 1 reacts with dioxygen to afford PhCHO in [approx.] 30% yield, attributed to oxidative dealkylation of the pendant benzyl group. Compound 3 decomposes by established bimolecular pathways upon exposure to dioxygen at low temperatures. When the ... carboxylate is replaced by the ... ligand, as in 5, this behavior no longer occurs. Instead the six- coordinate iron(III) complex with one bidentate and two monodentate carboxylate ligands, [...] (6), was isolated from the reaction mixture following the oxidation of 5.

(cont.) Chapter 3. C-H Activation with Benzyl- and Ethyl- Substituted Pyridine Ligands in Carboxylate-Bridged Diiron(II) Complexes with Dioxygen In this study benzyl and ethyl groups were appended to pyridine and aniline ancillary ligands in diiron(II) complexes of the type [...], where ... is the sterically hindered 2,6-di(p-tolyl)- or 2,6-di(p-fluorophenyl)benzoate (R = Tol or 4-FPh, respectively). These crystallographically characterized compounds were prepared as models for the diiron(II) center in the hydroxylase component of soluble methane monooxygenase (MMOH). Use of 2- benzylpyridine (2-Bnpy) afforded doubly-bridged [...] (1) and [...] (4), whereas tetra-bridged [...] (3) resulted when 4-benzylpyridine (4-Bnpy) was employed. Similarly, 2-(4-chloro- benzyl)pyridine (2-(4-ClBn)py) and 2-benzylaniline (2-Bnan) were employed as N-donor ligands to prepare [...] (2) and [...](5). Placement of the substituent on the pyridine ring had no effect on the geometry of the diiron(II) compounds isolated when 2-, 3-, or 4-ethylpyridine (2-, 3-, or 4-Etpy) was introduced as the ancillary nitrogen ligand. The isolated [...] (6), [...] (7), [...] (8), and [...] (9) complexes all contain doubly-bridged metal centers.

(cont.) The oxygenation of compounds 1 - 9 was studied by product analysis of the organic fragments following decomposition. Hydrocarbon fragment oxidation occurred for compounds in which the substrate moiety is in close proximity to the diiron center. The extent of oxidation depended on the exact makeup of the ligand set. Chapter 4. A Thermally Sensitive Intermediate Generated in the Reaction of [...] with Dioxygen In this chapter the reaction of [...] (la) with dioxygen at low temperature to form the 02-sensitive intermediate (lb) was investigated. Various spectroscopic methods including UV-visible, resonance Raman (rR), electron paramagnetic resonance (EPR), and M6ssbauer were applied to study the mechanism and the intermediates involved. Chapter 5. Synthesis and Reactivity Studies of Carboxylate-Bridged Diiron(II) Compounds with Dangling Sulfur-Containing Substrates Functional models of the carboxylate-bridged diiron active site in soluble methane monooxygenase are described in which potential substrates are introduced as substituents on bound pyridine ligands.

(cont.) Thiol, sulfide, and sulfoxide moieties tethered to pyridine were allowed to react with the prefabricated diiron(II) complex [...], where ... is a sterically hindered 2,6-di(p-tolyl)benzoate. The resulting diiron(II) complexes were characterized crystallographically. Triply- and doubly-bridged compounds [...] (1), [...] (2), and [...] (3) resulted when 2-phenylthiopyridine (2-PhSpy), 2-methylthio- pyridine (2-MeSpy) and 2-pyridylmethylsulfoxide (2-MeS(O)py), respectively, were employed. Use of 2-mercaptopyridine (2-HSpy) afforded the mononuclear complex [...] (4a). The dioxygen reactivity of these iron(II) complexes was investigated. A dioxygen-dependent intermediate (4b) formed upon exposure of 4a to 0₂, the electronic structure of which was probed by various spectroscopic methods. Exposure of 1 - 3 to dioxygen revealed both sulfide and sulfoxide oxidation. Chapter 6. Effect of Substrate Position in Diphenylphosphinopyridine Ligands on Geometry and Reactivity of Diiron(II) Carboxylate-Bridged Compounds In this chapter the exploration of carboxylate-bridged diiron(II) compounds containing phosphino-derivatized pyridine ligands to mimic aspects of chemistry at the active site of soluble methane monooxygenase (sMMO) is presented.

(cont.) 2-, 3-, or 4-Diphenylphosphino moieties incorporated into a pyridine ligand (2-, 3-, or 4-Ph₂Ppy) were allowed to react with the preassembled diiron(II) complex [...], where ... is a sterically hindered 2,6-di(p-tolyl)- or 2,6-di(p-fluorophenyl)benzoate (R = Tol or 4-FPh). Triply-, doubly-, and tetrabridged compounds [...] (1), [...] (2), [...] (3), [...] (4) resulted and were characterized crystallographically. Exposure of 1 - 4 to dioxygen revealed both stoichiometric and catalytic phosphine oxidation. Oxidation of 4 in CH₂C1₂ affords [...] (6), which contains the biologically relevant [Fe₂([mu]-OH)₂([mu]-O₂CR)] ³⁺ core. This reaction is sensitive to the choice of carboxylate ligands, however, since the p-tolyl analog 1 yielded a hexanuclear species, 5, upon oxidation.