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

Abstract

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(sp 3 )−H bonds remains an outstanding challenge. We report the origins of the reactivity and selectivity of a Cucatalyzed 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.

Catalytically Relevant Organocopper(III) Complexes Formed through Aryl-Radical-Enabled Oxidative Addition

“…In particular, limited experimental evidence exists that supports the formation of organo-Cu III complexes via the stepwise oxidative addition of alkyl electrophiles to Cu I catalysts. Consequently, such an inner sphere Cu III pathway remains largely hypothetical and is mainly supported by computational chemistry . Indeed, recent calculations by Lan have cast doubts on the participation of Cu III intermediates in coupling reactions .…”