Enzyme-Like Hydroxylation of Aliphatic C–H Bonds From an Isolable Co-Oxo Complex

Abstract

Selective hydroxylation of aliphatic C–H bonds remains a challenging but broadly useful transformation. Nature has evolved systems that excel at this reaction, exemplified by cytochrome P450 enzymes which use an iron-oxo intermediate to activate aliphatic C–H bonds with k1 > 1400 s–1 at 4 °C. Many synthetic catalysts have been inspired by these enzymes and are similarly proposed to use transition metal-oxo intermediates. However, most examples of well-characterized transition metal-oxo species are not capable of reacting with strong, aliphatic C–H bonds, resulting in a lack of understanding of what factors facilitate this reactivity. Here, we report the isolation and characterization of a new terminal CoIII-oxo complex, PhB(AdIm)3CoIIIO. Upon oxidation a transient CoIV-oxo intermediate is generated that is capable of hydroxylating aliphatic C–H bonds with an extrapolated k1 for C–H activation >130 s–1 at 4 °C, comparable to values observed in cytochrome P450 enzymes. Experimental thermodynamic values and DFT analysis demonstrate that although the initial C–H activation step in this reaction is endergonic, the overall reaction is driven by an extremely exergonic radical rebound step, similar to what has been proposed in cytochrome P450 enzymes. The rapid C–H hydroxylation reactivity displayed in this well-defined system provides insight into how hydroxylation is accomplished by biological systems and similarly potent synthetic oxidants.

Site-Isolated Main-Group Tris(2-pyridyl)borate Complexes by Pyridine Substitution and Their Ring-Opening Polymerization Catalysis

“…1 Compared with emerging scorpionate ligands, classic tris(pyrazolyl)borates are relatively weak electron donors, 11 a limitation when studying high-valent reactive metals. 12 Tris(2-pyridyl)borate ligands were recently introduced by the Jakle laboratory as a new scorpionate ligand family distinguished both by their highly electron-donating properties and by their exceptional chemical and thermal resilience. 13 On this basis, our laboratory is interested in applying metal tris(2pyridyl)borates as catalysts for polymerization, an application that benefits from well-defined catalysts 14 but typically requires high temperatures industrially.…”

Testing the Limits of Imbalanced CPET Reactivity: Mechanistic Crossover in H-atom Abstraction by Co(III)-oxo Complexes

“…We recently reported an adamantyl (Ad) substituted Co III -oxo complex, PhB( Ad Im)3Co III O, which, given the greater electron donating properties of the Ad groups, is more basic than our previous Co III -oxo complex. 77 Here we demonstrate that this enhanced basicity leads to more highly imbalanced CPET reactivity with C-H substrates. Exploration of activity with acidic phenol substrates reveals a switch from imbalanced CPET to stepwise reactivity featuring initial PT.…”

“…We have previously demonstrated that 1 Ad is more basic and more reducing than 1 tBu , as expected based on the more electron-donating Ad substituents on the imidazol-2-ylidene ligand scaffold. 77 Additionally, the BDFE of 1 Ad is larger than that measured for 1 tBu , providing additional driving force for H-atom abstraction. As 1 tBu Scheme 2.…”

“…For instance, 1 Ad reacts with 10 equivalents of 4-CO2Me-2,6-( t Bu)2C6H2OH (pKa(DMSO) = 11.9) at -100 °C to form a new green intermediate which can be assigned as [PhB( Ad Im)3Co III OH] + (2 Ad ) based on comparison to independently prepared samples (Figure 2B). 77 This suggests that, unlike C-H substrates and less acidic phenols, 1 Ad reacts initially via PT with this substrate at low temperature. The subsequent electron transfer is observed only upon warming to 0 °C, resulting in the formation of 3 Ad (Figure 2C), indicating a slower net rate of product formation.…”

A Quantum-Mechanical Approach to Predicting Carcinogenic Potency of N-nitrosamine Impurities in Pharmaceuticals

“…), and its change along the reaction pathway was shown to control uphill chemical processes (while downhill chemical reactions are typically controlled by a change in molecular hardness). 51 Since the initial C-H activation step is endergonic, 52 we compared  across all 7 nitrosamines (Table Lastly, we briefly considered the electrophilicity of all 7 nitrosamines, which plays an important role downstream in the covalent binding of DNA by alkylating metabolites (Figure 1). It is reasonable to propose that sufficient electronic 'signature' is present in the parent molecules to elucidate differential electrophilic reactivity of their metabolites.…”