Design and Mechanistic Investigation of High-Valent Iron Complexes for Enantio and Site-Selective C–H Bond Oxidation

Dey Biswas, Doyel (2026) Design and Mechanistic Investigation of High-Valent Iron Complexes for Enantio and Site-Selective C–H Bond Oxidation. PhD thesis, Indian Institute of Science Education and Research Kolkata.

Text (PhD thesis of Doyel Dey Biswas (20RS026)) 20RS026.pdf - Submitted Version Restricted to Repository staff only Download (14MB)

Abstract

Regio- and stereoselective oxidation of C–H bonds is important from both industrial and environmental perspectives, yet equally challenging due to the high bond dissociation energies (around 100 kcal mol⁻¹). But nature achieves this efficiently via enzymes like Cytochrome P450, Methane monooxygenase and Rieske dioxygenase using high-valent Fe=O species. This high valent iron oxo intermediate first abstracts H-atom (HAA) to form a metal hydroxide and R•, (the rate-determining step), followed by radical rebound to yield R–OH and the reduced metal ion, which goes back into the catalytic cycle. Motivated by these biological systems, synthetic catalysts like iron- and manganese-based complexes supported by both heme and non-heme ligand frameworks such as porphyrin, N₄ and TAML have been evolved, which are capable of mimicking their reactivity. It is also worth noting that synthetic metal oxo complexes are typically associated with oxygenation chemistry, whereas in biological systems, the reaction is often accompanied by their asymmetric transformations. The importance of chiral molecules is highlighted in the pharmaceutical industry in synthesising important drug molecules for medicinal purposes. Beyond metal oxo species, a smaller number of metal complexes bearing alternative ligands (MnX, where X = F, Cl, NO₃, etc.) have also been shown to promote both C–H and O–H bond activation. As with metal oxo systems, their reactivity is largely governed by the strength of the X–H bond formed after HAA. This alternative metal complexes with HAA reactivity has encouraged the exploration of MnX complexes that may enable activation of stronger C–H bonds under suitable conditions, along with a deeper examination of their HAA pathways. In this thesis, the complete mechanistic investigation of the catalytic cycle of cytochrome P450 has been performed through a biomimetic complex commonly named as bTAML-Fe catalyst. The HAA step was earlier discussed by this complex, and here the latter half, i.e., the rebound process, has been studied with the help of a synthesised Fe(IV)OH intermediate, starting from a reported (Et₄N)₂[(Ph, Me-bTAML)FeIIICl] complex. This intermediate was characterised at room temperature with different spectroscopic techniques and found to be reactive towards a carbon radical to yield a hydroxylated product, thus following a rebound mechanism. Not only that, this can perform HAA with a phenolic O–H bond in a concerted proton-electron transfer pathway (CPET). Followed by this, the HAA reactivity by metal non-oxo complex has also been discussed in this thesis, where a metal chloride complex has been synthesised with (Et₄N)₂[(CF³Ph, Me-TAML)FeIIICl] complex. In this case, highly electron-withdrawing -CF₃ groups were incorporated in the phenyl rings of the ligand backbone, which increases the redox potential of this complex tremendously. This causes the higher oxidation state of this catalyst to achieve enhanced reactivity. The Fe(IV)Cl complex, for the first time, has shown HAA with both O–H bonds and relatively weak C–H bonds, including substrates like xanthene (BDFE ≈ 75 kcal mol⁻¹). A complete mechanistic investigation suggested that the Fe(IV)Cl complex can oxidise the O–H and C–H bonds following an oxidative asynchronous CPET pathway. This increased potential makes the oxoiron(V) intermediate a more powerful oxidant towards the C–H bond oxidations. It can oxidize the 3° C–H bonds at least four to ten times faster than other bTAML-Fe complexes and also the 2° C–H bonds in substituted cyclohexane (~ 30%). After understanding the mechanisms of these catalysts towards the oxidations of C–H bonds, the other dimension of catalysis, which is the asymmetric catalysis, has been discussed in this thesis. Here, an oxidative desymmetrization of spirocyclic oxindoles was performed by the former [(Ph,Me)bTAML]FeIIICl catalyst, which gives a high yield (93%) and good enantiomeric excess (67%). A detailed computational investigation suggested that the π-π interaction between the phenyl rings of the catalyst and the substrate is responsible for tuning the enantioselectivity. Collectively, this thesis underscores the complete mechanisms of the C–H bond oxidation by the biomimetic bTAML-Fe complex, followed by extending its reactivity towards both site and enantio-selective oxidations.

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