Kinetics and Mechanism of Enantioselective Cu-Catalyzed Alcohol Silylation

The enantioselective
Cu-catalyzed dehydrogenative Si–O coupling
of secondary benzylic alcohols with (nBu)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 [(nBu)3SiH] > [ROH] and fall when [(nBu)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.