Mechanistic Insights into the Origins of Selectivity in a Cu-Catalyzed C

RESULTS AND DISCUSSION

Selectivity of alkyl radical trapping. We began our investigations by probing H-atom transfer (HAT) as the possible selectivity-determining step. It was previously determined that irreversible, turnover-limiting HAT occurs between the tert-butoxy radical and the alkane (Figure 2a). 15 If this step were also selectivity determining, the ratio of amidation products would match the ratio of alkyl radicals generated by the HAT step. To quantify this relationship, we performed trapping experiments in which superstoichiometric quantities of CBr4 were used to intercept the alkyl radicals generated by HAT. The selectivity of the bromination products from reactions under conditions of the amidation process, but with the added CBr4, was compared to that of the amidation reaction in the absence of CBr4. As illustrated in Figure 2a, the ratio of products from reaction of 2,4-dimethylpentane in the presence of CBr4 followed the general trend of 3°>2°>1°, whereas the product from the amidation of this alkane in the absence of CBr4 was solely the 1° N-alkyl benzamide product.

These results illustrate that HAT determines the selectivity of radical generation, but the relative rates of radical trapping controls the ratio of final products. In particular, tertiary alkyl radicals and sterically-hindered secondary alkyl radicals are trapped less efficiently by a putative (phen)Cu(NHBz)2 than by CBr4. We hypothesize that radical decomposition, for instance through b-scission (Figure 2b), outcompetes the productive Cu-mediated process, thereby resulting in the low yields and product distributions containing only primary or non-hindered secondary alkyl amide products. Indeed, analysis of the headspace of the reaction of 2,4-dimethylpentane indicates that propene and isobutene form, revealing that β-scission of the alkyl radicals do occur in competition with productive amidation (see Figure S4). The formation of methane was also observed. Methyl radicals can be generated in the reaction by β-scission of the 2,4-dimethylpentyl radical or by b-scission of tertbutoxy radicals (Figure 2b). [28][29][30] Active copper species. To investigate the selectivity of the combination of these alkyl radicals with the copper catalyst, we first calculated the structure of a putative active catalyst based on previously reported structures of related complexes determined by single-crystal x-ray diffraction. !4 values of 0 and 1 indicate perfect D4h and Td structures of related complexes, respectively. 15 The active Cu(II) bisamidate complex adopts a distorted square planar geometry (Figure 3a) characterized by computed !4 values of 0.25 and 0.15 for benzoyl and phthalimide ligands, respectively

C-H activation nitrene insertion a Mechanistic pathways for C(sp 3 )-H amination H [M] [M] [M] N R H NHR ‡ [M] NR 2 [M] NR 2 radical intermediates b Copper-catalyzed aminations by peroxide Hartwig and others H [Cu] ROOR + H N [Cu I ] [Cu II ] NH OR H [Cu III ] general mechanistic proposal c Key selectivity-determining steps d This work: Origins of reactivity and selectivity = COR, CO 2 R, CONR, Ar, SO 2 R, SOR 2 H 2 N H high yields low yields H H H H + OR H 2 N RO OR NH HN R-H R t-BuOH + + 3° > 2° > 1° C-H bonds (phen)Cu phth phth CyH (t-BuO) 2 t-BuO Cy-phth 1 equiv 70% + stoichiometric reaction known selectivity for HAT: NHBz NHBz H 2 NBz + Cu (2:1) catalytic selectivity: 2° > 1° > 3° C-H bonds Cu II L L X X • Energy decomposition analysis • Kinetics experiments + + • Radical trapping experiments • Computational characterization + HOR HOR + Figure 2. a. Selectivity of alkyl radical trapping indicates that radical formation is more efficient for more substituted radicals, but the substituted radicals are trapped inefficiently by (phen)Cu(NHBz)2. Product yields are reported as the average yield from three experiments, and are normalized for the number of C-H bonds of each type. Error bars denote ±1 s of the mean. Conditions: 0.3 mmol benzamide, 9 μmol CuI, 9 μmol phen, 12 mmol 2,4-dimethylpentane, 0 or 1.5 mmol carbon tetrabromide, 0.6 mmol ( t BuO)2, 1,2-DCB, 120 °C, 24 h. Yields were determined by quantitative 1 H NMR spectroscopy and GC-FID. b. Proposed mechanistic pathways for the formation of propene, isobutylene, and methane in the amidation of 2,4-dimethylpentane.

(Figure 3a and SI Table S3). 31 The Cu d 9 electron count results in a first-order Jahn-Teller distortion to relieve orbital degeneracy in the Td geometry, with further preference for the more planar, D4h-like geometry in part from p backbonding of the phen ligand with the metal d orbitals. [32][33][34][35] Unpaired spin density is localized primarily in a Cu dx 2 -y 2 orbital and the corresponding s* orbitals of the four Cu-N bonds (Figure 3a). Because Cu(I)-mediated reduction of ditert-butyl peroxide produces an equivalent of tert-butanol, heteroleptic Cu(II) species (e.g., (phen)Cu(O t Bu)(NHBz)) may be present in the reaction, along with the bisamidate (phen)Cu(NHBz)2. However, the calculated equilibrium between (phen)Cu(NHBz)2 and (phen)Cu(O t Bu)(NHBz) favors the bisamidate complex (∆G = +4.5 kcal mol -1 , see SI Figure S5), supporting the proposal that (phen)Cu(NHBz)2 is an intermediate in the C-H functionalization reaction. Mechanistic trichotomy. The productive trapping of an alkyl radical by this Cu bisamidate could occur by three distinct mechanistic pathways (Figure 3b). 36,37 The first involves single-electron transfer (SET) in which an alkyl cation, formed by one-electron oxidation by the Cu(II) catalyst, is attacked by an amide nucleophile. Such a radical-polar crossover was suggested to be part of the mechanism for the Cu-catalyzed azidation of benzylic C-H bonds. 37 The second mechanistic possibility, proposed to occur during the analogous oxidation of C-H bonds under Kharasch-Sosnovsky conditions, 38,39 involves inner-sphere coupling of the alkyl radical with the Cu complex, forming a formal Cu(III)-alkyl complex. Subsequent reductive elimination would then produce the N-alkylamide and a Cu(I) monoamidate. A third possible mechanism involves outer-sphere attack by the alkyl radical directly at the nitrogen atom of a bound amidate ligand, forming the N-alkyl amide and reforming the Cu(I) monoamidate in a single step. An analogous outer-sphere mechanism was suggested for an enantioconvergent C(sp 3 )-N bond-forming reaction with a sterically-congested Cu-catalyst. 40 To discriminate between these competing pathways, each mechanism was computed for a set of four alkyl radicals with varying steric and electronic properties (methyl, ethyl, isopropyl and tert-butyl). SET pathway. We first evaluated a potential SET pathway. However, this pathway was quickly ruled out based on the highly endergonic electron transfer between 54.8-114.2 kcal mol -1 (see SI Table S5). We attribute this high energy to the high ionization potentials of these non-stabilized alkyl radicals. 41 The particle-hole interaction in the complex formed between the reduced Cu(phen)(NHBz)2 species and the oxidized alkyl radical (ca. -26 kcal mol -1 for t Bu + ) is insufficient to overcome the thermodynamic cost of electron transfer, leading to the conclusion that the reaction does not occur by an SET mechanism. Inner-sphere pathway. Inner-sphere coupling of each of the four alkyl radicals to the d 9 Cu(II) bisamidate complex is predicted to be endergonic, spanning +3.2 to +12.7 kcal mol -1 from Me • to t Bu • . This association generates a formally Cu(III)-alkyl complex in which the amidate ligands are disposed in a cis configuration (Figure 4a), and is electronically barrierless according to a potential energy scan with methyl radical (see SI Figure S6). Each complex adopts a distorted square pyramidal geometry at Cu, characterized by t5 values ranging from 0.17-0.29 across the series of alkyl radicals studied here (see SI Table S6-S7), in which t5=0 corresponds to a square pyramidal (C4v) geometry and t5=1 corresponds to a trigonal bipyramidal (D3h) geometry. 42 The axial position is occupied by one N atom of the phen ligand, and the long Cu-Nax distance suggests that this interaction Structure and spin density of the active (phen)Cu(NHBz)2 catalyst, calculated at the CPCM(C6H6)-wB97M-V/def2-TZVPP//CPCM(C6H6)-wB97M-V/B1 level (see SI for details). [44][45][46] Spin density plotted at an isovalue of 0.05 a.u. Hydrogen atoms hidden for clarity. b. Competing mechanisms for Cu-catalyzed C-N bond formation.

is weak and exists due to the geometric constraint enforced by the rigidity of the bidentate phen ligand. In a formally d 8 Cu(III) C4v complex, the Cu dx 2 -y 2 orbital is vacant, and this vacancy should favor the square pyramidal geometry. However, analysis of the oxidation state of the copper with the OSLO method 43 suggests an ambiguous assignment of +2 or +3, indicating partial dx 2 -y 2 occupancy through Cu-C covalency. Distortion of the complex towards a trigonal bipyramidal geometry lowers the energy of the dx 2 -y 2 orbital, strengthening the Cu-C bond and lowering the total energy of the structure in the process (vide infra). Ligand steric effects may also contribute to the distortion away from a perfect C4v geometry.

Reductive elimination from the cis Cu(III)-alkyl complexes occurs with barriers ranging from 9.7-13.6 kcal mol -1 (Figure 4b) and is strongly exergonic, with driving forces relative to the preceding Cu(III)-alkyl intermediate spanning -

55.1 to -58.6 kcal mol -1 . However, in all cases, this reductive elimination is outcompeted by a polytopal rearrangement that leads to the corresponding trans Cu bisamidate complex (Figure 4c). This rearrangement is highly asynchronous (Figure 4c, inlay), characterized by initial motion of the alkyl ligand into the vacant axial site of the square pyramidal complex, followed by movement of one amide ligand into the equatorial site vacated by the alkyl ligand. An alternative rearrangement during which an N-bound amidate changes into an O-bound imidate is disfavored by at least 8 kcal mol -1 (see SI Table S8).

The polytopal isomerization process is exergonic for the reaction of each alkyl radical, with driving forces ranging from -1.2 to -5.0 kcal mol -1 (Figure 4d). We suggest that the trans isomer is favored over the cis isomer due to the stabilization from placing the most s-donating ligand (the alkyl ligand) trans to the least s-donating ligand (the phen ligand). This trans influence is manifested by a lengthening of the Cu-Neq bond to the phen ligand by 0.02-0.06 Å in the trans complexes over that in the analogous cis isomers and shortening of the amidate Cu-N bond in the trans complex by 0.05-0.09 Å (see SI Table S6-S7) for complexes formed from each of the alkyl radicals. The large span of t5 values for the trans isomer (0.03-0.33) compared with those of the cis complexes (0.17-0.29) reflects the greater flexibility of the trans structure to accommodate alkyl ligands with varying steric requirements.

Reductive elimination from the trans Cu-alkyl complex of each alkyl ligand occurs with a lower barrier than from the cis complex (Figure 4e, 9.1-11.7 kcal mol -1 ), despite the shorter, stronger Cu-C bond in each case (vide infra). The sole exception to this trend is the complex of the methyl, the least sterically demanding of the alkyl groups.

Analysis of the relationship between the nature of the Cu-C bond, the steric bulk of the alkyl substituent, and the barrier to reductive elimination was conducted with the absolutely localized molecular orbital energy decomposition analysis scheme (ALMO-EDA) for bonded interactions (Figure 5). 47,48 With this method, the interaction between geometrically-distorted and rehybridized open-shell fragments-in this case the alkyl radical and the Cu(II) bisamidate complex-are decomposed into their constituent parts: the 'frozen' interaction (∆EFRZ), which comprises Pauli repulsions, permanent electrostatics, and dispersion interactions; the spin-coupling of these fragments (∆ESC), which describes the covalency of the Cu-C bond; orbital polarization (∆EPOL), which captures contraction and induced electrostatic interactions; and charge-transfer effects (∆ECT), which describe the ionic character of the bond (see SI for further discussion).

The primary source of variance in the total energy for binding of the alkyl group in the cisand trans-(phen)Cu(NHBz)2(R) complexes, ∆EBIND, is described by the strength of the covalent Cu-C interaction (∆ESC, Figure 5a and SI Figure S8), in alignment with the result of the OSLO method that predicts a nonpolar covalent Cu-C bond (vide supra). We hypothesized that a stronger covalent Cu-C interaction will increase the activation barrier for reductive elimination because this bond breaks during the C-N bondforming process. A segmented linear regression plot of ∆E ‡ vs ∆ESC (Figure 5b) reveals a negative correlation for complexes with strong spin coupling (∆ESC < -42.5 kcal mol -1 ). However, for weaker spin coupling (∆ESC > -42.5 kcal mol -1 ) the opposite is true: weaker spin coupling correlates with an increase in the activation barrier. This V-shaped relationship between ∆ESC and the barrier to reductive elimination can be understood as follows: as alkyl radical substitution increases, Cu-C covalency, and, therefore, the strength of the Cu-C interaction, decreases. This bond weakening causes a lower barrier to reductive elimination. However, such an increase in substitution may also inhibit C-N bond formation due to increased steric repulsion with the amide ligand in the TS for reductive elimination. These effects of covalency and steric repulsion act antagonistically, resulting in the observed V-shaped relationship between ∆ESC and ∆E ‡ . Such a relationship is analogous to Sabatier's principle, 49 balance of covalency and steric bulk in the Cu-alkyl complex. This optimal balance occurs with the secondary (isopropyl) radical in the trans Cu complex. Outer-sphere pathway. We next characterized the pathway in which outer-sphere formation of the C-N bond occurs with each alkyl radical (Figure 6). Informed by the calculated spin density of the Cu(II) bisamidate (Figure 3a), TSs corresponding to attack of the alkyl radical on the Cu-N s* orbital were identified. Due to significant open-shell character of each TS, we employed Yamaguchi's approximate spin-projection scheme to estimate the activation barrier to C-N bond formation with the spin-pure singlet states (see SI for details). 50 Counter to the expectation based on the Bell-Evans-Polanyi principle, 51,52 the computed activation barrier for the outer-sphere coupling (17.7-21.0 kcal mol -1 ) decreased as the driving force for C-N bond formation decreased. The driving force for C-N bond formation is lower for more substituted radicals, due to the greater stability from such substitution (Figure 6a).

We investigated the origin of this trend using the bonded ALMO-EDA method (vide infra) in combination with the distortion-interaction/activation-strain model. 53 We Figure 6. a. Outer-sphere alkyl radical addition process to (phen)Cu(NHBz)2. Free energies calculated at the CPCM(C6H6)-wB97M-V/def2-TZVPP//CPCM(C6H6)-wB97M-V/B1 level (393.15 K, 1 M). Hydrogen atoms hidden for clarity. b. Contribution of TS polarity in the outer-sphere addition, characterized by the extent of charge transfer through the metric ∆E ‡ CT/∆E ‡ FRZ. c. An earlier transition state results from an increase in transition state polarity. ∆E ‡ CT and ∆E ‡ FRZ calculated at the wB97M-V/def2-TZVPP level using the ALMO-EDA method for bonded interactions.

hypothesized that the polar character of the transition state will increase as the substitution of the radical increases, and this greater polar character should create an increase in the magnitude of ∆E ‡ CT. Since this term also depends on the position of the TS along the reaction coordinate, we normalized ∆E ‡ CT using the frozen interaction (∆E ‡ FRZ), which increases as the TS becomes more advanced, due to increased non-bonded repulsions. The variation in TS polarity can then be described by the ratio ∆E ‡ CT/∆E ‡ FRZ, whose magnitude will increase as the TS becomes more polar. The positive relationship between ∆E ‡ and ∆E ‡ CT/∆E ‡ FRZ (Figure 6b) supports the interpretation that the barrier to C-N bond formation with a more substituted alkyl radical is lower because of the greater ability of the more substituted radical to stabilize positive charge. The increase in partial charge of the alkyl group at the TS supports this conclusion (see SI Figures S10-S11). The resulting increase in polarity causes an earlier, lower-energy TS, illustrated by the decrease in

8 9 10 11 12 13 14 15 -55 -50 -45 -40 -35 -30 ∆E ‡ / kcal mol -1

∆E SC / kcal mol -1 -23 -21 -19 -17 -15 -13 -11 -55 -50 -45 -40 -35 -30 ∆E BIND / kcal mol -1 ∆E SC / kcal mol -1 Me, trans Et, trans Me, cis i Pr, trans i Pr, cis Et, cis t Bu, trans t Bu, cis Me, trans Et, trans Me, cis i Pr, trans Et, cis i Pr, cis t Bu, trans t Bu, cis t Bu i Pr Et Me Me Et i Pr t Bu c 2.32 2.37 2.42 2.47 2.52 -1.7 -1.5 -1.3 -1.1 -0.9 -0.7 r C-N ‡ / Å ∆E CT / ∆E FRZ Figure 7. Simplified potential energy surface describing the fate of methyl, ethyl, isopropyl and tert-butyl radicals, calculated at the CPCM(C6H6)-wB97M-V/def2-TZVPP//CPCM(C6H6)-wB97M-V/B1 level (393.15 K, 1 M). Limiting activation barriers for each substrate are shown with vertical arrows. For full PES of each radical, see SI Figures S13-S16.

the forming bond length at the TS, r ‡ C-N, as charge transfer decreases (Figure 6c). The increased steric bulk of more substituted radicals, therefore, is relatively unimportant at the TS of this mechanism, due to the longer bond that is forming.

Operative C-N bond-forming pathways. Having characterized each of the potential reaction pathways, we directly compared the relative reactivity of methyl, ethyl, isopropyl and tert-butyl radicals to uncover the dominant mechanism in each case (Figure 7). According to our calculations, the overall trend in barrier for reaction of the alkyl radical with the copper amidate complex is ethyl (11.1) ≈ methyl (11.7) < isopropyl (14.4) < tert-butyl (18.7) [numbers in parentheses are the activation free energies (kcal mol -1 ) relative to the lowest energy intermediate for each substrate]. For reactions with ethyl, isopropyl, and tert-butyl radicals, the lowest-energy intermediate along the reaction coordinate is the combination of the isolated (phen)Cu(NHBz)2 complex and free alkyl radical, but for the methyl radical the minimum energy complex is trans-(phen)Cu(NHBz)2(Me), reflective of the low stability of the methyl radical.

For methyl, ethyl, and isopropyl radicals, the inner-sphere mechanism is dominant, with relative activation free energies (∆∆G ‡ ) 5.1-10.4 kcal mol -1 lower than those of the alternative outer-sphere mechanism. The preference for the inner-sphere pathway decreases as the radical becomes more substituted, and reaction of the tert-butyl radical even favors outer sphere combination of the radical with the amidate (∆∆G ‡ = -5.1 kcal mol -1 favoring the outer-sphere pathway). According to our discussion earlier in this paper (Figure 4 and Figure 5), this change in mechanism results from the interplay of Cu-C covalency, steric bulk, and electrophilicity that accompanies an increase in radical substitution. For the most substituted radicals, the greater degree of substitution leads to steric bulk that inhibits the formation and rearrangement of the inner-sphere complex and stabilizes the outer-sphere TS by enhancing the effects of polarity during C-N bond formation. These effects combine to cause a large enough span in activation barriers to switch the reaction mechanism from inner-sphere to outersphere.In summary, small, alkyl radicals undergo C-N bond formation by an inner-sphere mechanism involving reductive elimination from a copper intermediate containing an alkyl and amidate group, whereas the bulkiest substrates form the C-N bond by an outer sphere mechanism involving direct formation of the C-N bond without a copper-alkyl intermediate because the larger volume inhibits combination with the metal center.

Comparing the limiting activation barriers for each of these radicals to the computed HAT barriers (see SI Figure S12), we find that HAT is turnover limiting for methyl, ethyl and isopropyl radicals, in agreement with the results of previous kinetic isotope experiments with cyclohexane as substrate. 15 However, we predict that HAT from the 3° C-H bonds in isobutane should occur with a lower barrier than outer-sphere trapping of the resulting tert-butyl radical (∆G ‡ = 16.7 vs 18.7 kcal mol -1 , respectively). Therefore, we predict that the turnover-limiting step for the bulkiest alkyl radicals will change from HAT to C-N bond formation. The inefficiency of C-N bond formation likely causes the low yields for reactions of bulky alkanes as radical decomposition becomes faster than formation of the C-N bond.

Effect of ligand electronics. To assess the validity of our computational results, we investigated the effect of the ligand on the rate of C-N bond formation and compared the predictions by computation with experimental results

0.0 22.1 21.1 19.5 18.7 3.2 5.4 5.9 12.7 Me• / Et• / i Pr• / t Bu• 10.6 11.1 14.4 23.8 -1.7 1.3 4.5 7.8 10.0 10.4 12.2 18.2 + Et: 11.1 i Pr: 14.4 Me: 11.7 t Bu: 18.7 N N Cu NHBz NHBz R ∆G / kcal mol -1 (Figure 8). Electron-withdrawing groups are predicted to increase the rate of reductive elimination by destabilizing the formally Cu(III) intermediate, as illustrated by the negative correlation between the predicted activation barrier to reductive elimination from cis-(phen)Cu(NHBz)2(Me) and the Hammett parameter s for the substituents at the 4 and 7 positions of the phen ligand (Figure 8a). 54 Conversely, the polytopal rearrangement is expected to be slower for the ligands that are more electron deficient. We rationalize this trend based on anticipated strengthening and shortening of the Cu-N bond of the migrating amidate ligand as the electron density on Cu decreases. Varying the electronic properties of the ligand for a given substrate will balance these two effects, and we anticipate a V-shaped relationship whereby the limiting step in the formation of the C-N bond switches from the polytopal rearrangement to the reductive elimination step in which the two amide ligands are disposed cis to one another. We predict that either strongly electron-donating or electron-withdrawing ligands will, therefore, enhance the rate of C-N bond formation.

To probe this mechanistic hypothesis, we devised a radical clock experiment with the branched alkane 2,4-dimethylpentane (Figure 8b, see SI for derivation). 55 Measurement of the ratio of yields of the branched 1° product (1-N) and the iso-butyl benzamide ( i Bu-N), formed from b-scission of the 1° branched alkyl radical and subsequent trapping, enables analysis of the relative rate of C-N bond formation versus the rate of b-scission (eq 1). The bidentate ligand 2,2'-bipyrine, symmetrically substituted at the 4 and 4' positions, was selected for this experiment due to the availability of these ligands with varying electronic

Major pathway: cis reductive elimination is selectivity-limiting Major pathway: trans rearrangement is selectivity-limiting 0 20 40 60 80 100 -0.4 -0.2 0 0.2 0.4 0.6 0.8 1 Product ratio (A/B) ! p y = 2.52x + 6.80 R² = 1.00 y = -3.01x + 11.07 R² = 0.99 5 6 7 8 9 10 11 12 13 -0.4 -0.2 0 0.2 0.4 0.6 0.8 1 ∆E ‡ / kcal mol -1 ! p Cis reductive elimination: ∆E ‡ = -3.0 p + 11.1 kcal mol -1 Polytopal rearrangement: ∆E ‡ = 2.5 p + 6.8 kcal mol -1 a Predicted electronic dependence b Radical clock design c Experimental electronic dependence MeO H CF 3 NO 2 N N Cu NHBz NHBz Me X X -NHBz NHBz k k R k R ʹ [Cu(II)] [Cu(I)] [Cu(II)] [Cu(I)] R 2 = 0.99 R 2 = 1.00 MeO H CF 3 t Bu Br 40 equiv BzNH 2 1 equiv 3 mol% CuI/L 2 equiv ( t BuO) 2 1,2-DCB 120 °C, 24 h NHBz NHBz i Bu-N 1-N + + NO 2 N N Cu NHBz NHBz X X Product ratio (1-N/ i Bu-N) i Bu-N 1-N d Selectivity-limiting cases cis-[N-Cu-R] cis RE TS rearrangement TS [Cu(II)] + N-R trans RE TS cis-[N-Cu-R] cis RE TS rearrangement TS [Cu(II)] + N-R trans RE TS Case 1: Strong EDG Case 2: Strong EWG

properties and their similarity to the phen ligand used for the computational studies above.

[

A plot of the ratio of [1-N]/[ i Bu-N] as a function of the Hammett parameter s (Figure 8c) reveals a V-shaped relationship, in which either strongly electron-donating or electronwithdrawing substituents on the ligands lead to increased rates of C-N bond formation. While the yields for iso-butyl benzamide i Bu-N are low (<1%), this observed trend supports our prediction that the selectivity-determining step will change from the polytopal rearrangement with complexes of electron-donating ligands (e.g., X=OMe) to the reductive elimination with complexes of electron-deficient ligands (e.g., X=NO2). Ligands that are neither strongly electron-withdrawing nor electron-donating, for instance X=H or Br, cause the rate of C-N bond formation to be the lowest. The ligand with X=CN was a notable outlier in this series ([1-N]/[ i Bu-N]= 6.1 ± 3.6) and was omitted from the plot.

Overall, these results point to two design principles for the development of novel organometallic catalysts for C-H amidation processes: first, ligand electronic properties can be used to modulate the rate of radical trapping to minimize bscission byproducts, and, second, the catalyst coordination environment can be modified to avoid a high barrier to a required polytopal rearrangement (Figure 8d)