Mechanism and Selectivity of Copper-Catalyzed Bromination of Distal C(sp(3))–H Bonds

[Image: see text] Unactivated C(sp(3))–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 BrN(3), generated in situ from NBS and TMSN(3) 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(sp(3))–H bromination with distal site selectivity using density functional theory calculations. We found that this reaction starts with the Br-atom transfer from BrN(3) 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 N(3) 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.