Mechanistic Insights into the Origins of Selectivity in a Cu-Catalyzed C–H Amidation Reaction

The
catalytic transformation of C–H to C–N
bonds
offers rapid access to fine chemicals and high-performance materials,
but achieving high selectivity from undirected aminations of unactivated
C(sp3)–H bonds remains an outstanding challenge.
We report the origins of the reactivity and selectivity of a Cu-catalyzed
C–H amidation of simple alkanes. Using a combination of experimental
and computational mechanistic studies and energy decomposition techniques,
we uncover a switch in mechanism from inner-sphere to outer-sphere
coupling between alkyl radicals and the active Cu(II) catalyst with
increasing substitution of the alkyl radical. The combination of computational
predictions and detailed experimental validation shows that simultaneous
minimization of both Cu–C covalency and alkyl radical size
increases the rate of reductive elimination and that both strongly
electron-donating and electron-withdrawing substituents on the catalyst
accelerate the selectivity-determining C–N bond formation process
as a result of a change in mechanism. These findings offer design
principles for the development of improved catalyst scaffolds for
radical C–H functionalization reactions.