Kinetics and Mechanism of Enantioselective Cu-Catalyzed Alcohol Silylation

The enantioselective Cu-catalyzed dehydrogenative Si-O coupling of secondary benzylic alcohols with (<i>n</i>Bu)₃SiH was investigated using a combination of in situ ¹H/¹⁹F NMR spectroscopic reaction monitoring, isotopic labeling, kinetic modeling, and computational studies. Macrokinetic behavior is governed by substrate-inhibited L*CuOR·ROH resting states: rates rise with conversion when [(<i>n</i>Bu)₃SiH] > [ROH] and fall when [(<i>n</i>Bu)₃SiH] < [ROH]. Alcohols bearing electron-withdrawing substituents are stronger inhibitors and show overall lower macrokinetic reactivity, but react faster than alcohols with electron-donating substituents in intermolecular competitions, indicating that inhibition is more substituent-sensitive than the product-committing step. Divergence between intrinsic enantioselectivity and observed macrokinetic rates of enantiomers in isolation results from enantiomer-dependent inhibition, and a product-committing σ-bond-metathesis step is consistent with measured Eyring activation parameters and a Si-H/Si-D KIE ≤ 1.3. Eyring and Hammett analyses, as well as DFT calculations, support an H-bonding inhibition mode for the L*CuOR·ROH resting state. Stoichiometric styrene as an additive suppresses H₂ generation and mitigates catalyst deactivation, increasing process safety and efficiency. Dynamic kinetic resolution, enabled by addition of a ruthenium racemization cocatalyst, results in reaction rates comparable to those of the faster enantiomer while improving overall efficiency.