Mechanistic insights into the origins of selectivity in a Cu-catalyzed C–H amidation reaction

08 December 2023, Version 1
This content is a preprint and has not undergone peer review at the time of posting.

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(sp3)–H bonds remains an outstanding challenge. We report the origins of 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.

Keywords

Catalysis
C–H functionalization
Computation
Energy decomposition analysis

Supplementary materials

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Description
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Experimental and computational supporting information
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Computational methods, experimental methods, supplementary figures and tables, NMR data (PDF)
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Computational data
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Cartesian coordinates and energies of computed structures (zip)
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