Bio-inspired Oxidation of C–H Bonds: Development of Peroxide Activating Cytochrome P450 Mimics

Jana, Sandipan (2023) Bio-inspired Oxidation of C–H Bonds: Development of Peroxide Activating Cytochrome P450 Mimics. PhD thesis, Indian Institute of Science Education and Research Kolkata.

Text (PhD thesis of Sandipan Jana (17RS052)) 17RS052.pdf - Submitted Version Restricted to Repository staff only Download (15MB)

Abstract

C-H bond activation is an extremely significant process in daily life. Starting from the simplest hydrocarbon, methane (a greenhouse effect), can be tamed and converted into several value-added products starting from methanol. This finds application not only in the development of petroleum industries but also in pharmaceutical industries and drug discoveries. Taking inspiration from Nature, selective functionalization or oxidation of ubiquitous yet inert C-H bonds and C=C bonds is achieved by the formation of high-valent metal-oxo intermediates which is crucial for metabolism and other biological activities, including biosynthesis of hormones. For example, using earth-abundant first-row transition metal like iron, nature has designed several enzymes such as Cytochrome P450 (CYPs), Methane monooxygenase (MMOs), Rieske dioxygenase, etc. which performs efficient and highly selective oxidation of C-H bonds in various complex settings. In this context, CYPs utilize an oxoiron(IV) cation radical, Compound I, in its active site, for strong C-H bond oxidation. However, their reactivities cannot be studied invitro as the active site of these enzymes are deeply buried inside the protein scaffold, resulting in the urge to mimic systems which can replicate the reactivities of the enzymes in aqueous media using natural oxidants like dioxygen or hydrogen peroxide as the terminal oxidant. Historically, scientists have developed heme and non-heme iron model complexes for C-H oxidation. However, heme or porphyrin systems have, in general, failed as an oxidation catalyst, due to catalyst decomposition and free radical pathways which limit the selectivities and efficiencies of these systems. On the other hand, in the last 15 years, non-heme model complexes, have shown a resurgence in selective and efficient C-H oxidation using hydrogen peroxide albeit in the presence of acids. Our group has developed a more robust iron framework bearing biuret modified electron-rich tetraamide macrocycle (Fe-bTAML), which can replicate the reactivities of reported non-heme complexes, in the absence of acids, via the formation of oxoiron(V) intermediate. The aim of my thesis is to understand the role of high-valent oxo-iron intermediates involved in C-H oxidation, via the development of structural and functional mimic of Cytochrome P450 or other peroxidases. Using our Fe-bTAML framework, we have developed three intermediates, namely, oxoiron(V), oxoiron(IV), and oxoiron(IV) cation radical, where each one of them has different role towards C-H oxidation. Here, for the first time, we have been able to synthesize a valence tautomer of oxoiron(V), i.e., oxoiron(IV) cation radical, which can oxidize strong aliphatic C-H bonds at faster rates in comparison to regular Fe-bTAML. Also, we have developed two systems which can perform C-H oxidation in a biomimetic fashion efficiently and selectively. Initially, we developed an iron complex, [Fe(NO2-bTAML)], by nitro group substitution in the equatorial (head) position of bTAML system, which in the presence of meta-chloroperbenzoic acid or sodium hypochlorite, oxidizes C-H and C=C bonds in acetonitrile-water medium at room temperature. The second one involves the formation of [Fe(Ph,Me-bTAML)] complex by phenyl group substitution in ligand framework. This complex can not only activate strong C-H bonds in water, but also give rise to oxoiron(V) species in presence of a natural oxidant like hydrogen peroxide, thereby mimicking the peroxide shunt pathway of catalytic C-H oxidation in CYPs via the formation of Compound I. So, for the first time, a TAML based iron complex is generated which can prevent dimer formation, activate hydrogen peroxide towards oxoiron(V) formation (without the need of any acids), and most importantly, oxidize C-H bonds in water at room temperature in a very efficient and regioselctive manner unknown to previously reported non-heme iron complexes. Chapter I deals with the comprehensive study of the significance of C-H bond oxidation in sustaining biological processes and thereby life. Here, the natural enzymes, such as iron containing Cytochrome P450 and Rieske dioxygenases, play a critical role by catalyzing a plethora of oxidation reactions via the generation of high-valent metal-oxo intermediates, which is key to activate small molecules like dioxygen (O₂), hydrogen peroxide (H₂O₂) and water (H₂O). A brief history of the research done on synthelic model complexes towards iron catalyzed C-H oxidation as well as on the reactivities of the iron-oxo intermediates has been revealed here. Theoretical analysis of oxoiron(IV) and oxoiron(V) reactivity toward hydrogen atom abstraction and olefin epoxidation is also covered in this chapter. The influence of axial and equatorial ligands of iron complexes on the oxygenation reactivity of heme and nonheme model complexes is demonstrated in this chapter. Chapter II involves the formation of an oxoiron(IV) cation radical belonging to the biuret-modified TAML (bTAML) system, which is a valence tautomer of oxoiron(V) intermediate, and can be termed as a structural mimic of Compound I. It is generated upon two-electron oxidation of an iron(III) complex bearing electron-rich methoxy substituted bTAML framework and thoroughly characterized through multiple spectroscopic techniques and density functional theory. Although there are a handful of oxoiron(IV) cation radical species in the literature, this is the first example where we have compared oxoiron(IV) cation radical and oxoiron(V) belonging to the same ligand framework. Reactivity studies demonstrate that the radical oxidizes strong aliphatic sp3 C-H bonds at faster rates than previously reported iron bTAML complexes. Chapter III demonstrated the selective oxidation of secondary alcohols and activated primary alcohols to their corresponding aldehydes or ketones using Fe-bTAML as the catalyst and sodium hypochlorite (NaOCl) as the terminal oxidant. Good to excellent yields of 80% to 99% for the carbonyl compounds and turnover numbers up to ~500 was obtained with this catalytic system. The yield and turnover number were dependent on the pH of the reaction and this difference was attributed to the different reactive intermediates that were formed at pH 7 and pH 12, oxoiron(V) and oxoiron(IV), respectively. Reactions involving the oxoiron(V) intermediate oxidize secondary alcohols more efficiently than its oxoiron(IV) analogue. This trend was reversed for the oxidation of activated primary alcohols where reactions involving oxoiron(IV) afforded much higher TONs. This reactivity trend can be explained by the differences in bond dissociation energy (BDE) of their corresponding one electron reduced species ([FeIV-OH], ~99 kcal/mol; [FeIII-OH], ~83 kcal/mol) as well as their relative stabilities in the solvent during the reaction. This catalytic system was found to be unsuitable for unactivated primary alcohol due to the formation of the non-reactive FeIV(OMe) intermediate after one catalytic cycle. Chapter IV involves the use of a peroxidase-mimicking iron complex based on an electron-withdrawing nitro-group substituted bTAML macrocyclic ligand framework [Fe(NO2-bTAML)] as a catalyst to perform selective oxidation of unactivated 3° C−H bonds and activated 2° C−H bonds including natural products. Low catalyst loading (1-2 mol%), high product yield (excellent mass balance) under near-neutral conditions and broad substrate scope (18 substrates which include arenes, heteroaromatics, and polar functional groups) are the highlighted features of this work. Aliphatic C−H oxidation of 3° and 2° sites of complex substrates was achieved with predictable selectivity using steric, electronic, and stereoelectronic rules that govern site selectivity, which included oxidation of (+)-artemisinin to (+)-10β-hydroxyartemisinin. Mechanistic studies indicate oxoiron(V) to be the active oxidant during these reactions. Chapter V demonstrates the development of a fully functional Cytochrome P450 mimic, which performs highly regioselective oxidation of aliphatic C-H bonds in water using hydrogen peroxide as the terminal oxidant. By modifying the bTAML framework, we have been successful in altering the reactivity of the corresponding iron complex toward C-H bond oxidation. For the first time, a non-heme complex is generated that exhibits the peroxide shunt pathway for selective C-H bond oxidation using water as the solvent. The 3° selectivities of the oxidation reactions are enhanced in comparison to oxoiron(V) catalyzed oxidation belonging to the nitro-substituted bTAML framework. Mechanistic studies suggest the involvement of FeV(O) as the active oxidant. Chapter VI shows the synthesis and characterization of a modified bTAML complex, (Et₄N)₂[FeIII(CYH-bTAML)Cl] where two cyclohexyl groups are attached to the ligand framework in place of four methyl groups. This complex acts as peroxidase mimic as it helps in dye degradation, and also can be used for oxygenation reactions as it forms a room temperature stable FeV(O). Chapter VII discusses the conclusion of the overall work as given in the thesis. The future directions are also depicted in this chapter.

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