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

Abstract

The 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 Co^III-oxo complex, PhB(^AdIm)₃Co^IIIO. Upon oxidation, a transient Co^IV-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.

Figure 1.

Crystal structures of complexes 1-4. Thermal ellipsoids are shown at 50% probability. All H–atoms besides those bound to O are omitted for clarity. Counterions and solvent molecules except for the Et₂O hydrogen-bonding to the O–H in 3 are also omitted.

Figure 2.

(A) ¹H NMR spectrum at −35 °C in THF-d₈ of the reaction of 4 with FcBF₄. Only the aromatic region is shown for clarity. The full spectrum is shown in Figure S19. The resonances associated only with 3 are highlighted in blue and those associated only with 5 are in red. Overlapping resonances from 3 and 5 are in purple. Asterisks indicate toluene and benzene impurities in the THF-d₈. (B) Crystal structure of 5 shown as a ball and stick model. All H–atoms and the counterion are omitted for clarity.

Figure 3.

Perpendicular mode X-band EPR spectrum (15 K) of 4^ox-d₄₅ generated in situ at −105 °C in THF-d₈. Simulation parameters: g = 2.0439, 2.0238, 2.0218; A = 16.6, 76.2, −0.2 MHz. Experimental conditions: microwave frequency 9.6304 GHz, microwave power 0.2 mW. The full spectrum is shown in Figure S48.

Figure 4.

Reaction coordinate for intramolecular C–H activation and rebound from 4ox. The structures shown are the DFT optimized structures of the intermediates (black labels) and transition states, shown as sticks except for Co, O, the transferring H–atom, and the involved C–atom. The energies given are the calculated free energies at −80 °C, relative to 4ox, in kcal/mol including a THF CPCM solvent correction.

Scheme 1.

Synthesis of Complexes 1–4

Scheme 2.

Proposed Reaction Mechanisms Following the Oxidation of 4