Mechanism and Selectivity of Copper-Catalyzed Bromination of Distal C(sp³)-H Bonds

Unactivated C(sp³)-H bonds are the most challenging substrate class for transition metal-catalyzed C-H halogenation. Recently, the Yu group [Liu, T.; Myers, M. C.; Yu, J. Q. Angew. Chem., Int. Ed.2017, 56 (1), 306-309] has demonstrated that a Cu^II/phenanthroline catalyst and BrN₃, generated in situ from NBS and TMSN₃ precursors, can achieve selective C-H bromination distal to a directing group. The current understanding of the mechanism of this reaction has left numerous questions unanswered. Here, we investigated the mechanism of Cu-catalyzed C(sp³)-H bromination with distal site selectivity using density functional theory calculations. We found that this reaction starts with the Br-atom transfer from BrN₃ to the Cu center that occurs via a small energy barrier at the singlet-triplet state seam of crossing. In the course of this reaction, the presence of the N-H bond in the substrate is critically important and acts as a directing group for enhancing the stability of the catalyst-substrate interaction and for the recruitment of the substrate to the catalyst. The required C-centered radical substrate formation occurs via direct C-H dehydrogenation by the Cu-coordinated N₃ radical, rather than via the previously proposed N-H bond dehydrogenation and then the 1,5-H transfer from the γ-(C-H) bond to the N-radical center pathway. The C-H bond activation by the azide radical is a regioselectivity-controlling step. The following bromination of the C-centered radical by the Cu-coordinated bromine completes the product formation. This reaction step is the rate-limiting step, occurs at the singlet-to-triplet state seam of the crossing point, and is exergonic.