The Quest for Selectivity in Hydrogen Atom Transfer Based Aliphatic C-H Bond Oxygenation

Area of Science:

• Organic Chemistry
• Catalysis
• Synthetic Methodology

Background:

• Aliphatic C-H bond functionalization is a key area in synthetic chemistry, offering streamlined and cost-effective routes.
• Hydrogen atom transfer (HAT) is a common mechanism, but achieving selectivity among similar C-H bonds is challenging.
• Understanding factors governing C-H bond reactivity is essential for developing selective functionalization strategies.

Purpose of the Study:

• To elucidate the factors controlling selectivity in aliphatic C-H bond functionalization via HAT.
• To demonstrate the predictability and synthetic utility of selective C-H oxidation methodologies.
• To provide insights into the mechanisms of metal-catalyzed C-H oxidations.

Main Methods:

• Kinetic studies using a cumyloxyl radical as a model HAT reagent.
• Oxidation reactions employing hydrogen peroxide (H2O2) with iron or manganese catalysts.
• Analysis of electronic, steric, stereoelectronic, torsional, and medium effects on C-H bond reactivity.

Main Results:

• Congruent reactivity and selectivity patterns were observed between radical-based HAT and metal-oxo species, supporting a common HAT mechanism.
• Amides were identified as key functional groups influencing selectivity through electronic, steric, and stereoelectronic effects.
• Torsional effects and catalyst design were crucial for achieving high chemoselectivity and enantioselectivity in cyclohexane scaffold oxidations.
• Fluorinated alcohols as solvents were shown to deactivate proximal C-H bonds via hydrogen bonding, directing oxidation to remote positions and enabling chemoselective hydroxylations.

Conclusions:

• Clarification of HAT governing factors enables the development of selective C-H functionalization methodologies.
• Metal-catalyzed C-H oxidations exhibit predictable selectivity exploitable in synthesis.
• The findings offer valuable catalytic methods for chemoselective and enantioselective oxidation of nonactivated aliphatic C-H bonds.