Nitrene transfer from a sterically confined copper nitrenoid dipyrrin complex

Despite the myriad Cu-catalyzed nitrene transfer methodologies to form new C–N bonds (e.g., amination, aziridination), the critical reaction intermediates have largely eluded direct characterization due to their inherent reactivity. Herein, we report the synthesis of dipyrrin-supported Cu nitrenoid adducts, investigate their spectroscopic features, and probe their nitrene transfer chemistry through detailed mechanistic analyses. Treatment of the dipyrrin CuI complexes with substituted organoazides affords terminally ligated organoazide adducts with minimal activation of the azide unit as evidenced by vibrational spectroscopy and single crystal X-ray diffraction. The Cu nitrenoid, with an electronic structure most consistent with a triplet nitrene adduct of CuI, is accessed following geometric rearrangement of the azide adduct from κ1-N terminal ligation to κ1-N internal ligation with subsequent expulsion of N2. For perfluorinated arylazides, stoichiometric and catalytic C–H amination and aziridination was observed. Mechanistic analysis employing substrate competition reveals an enthalpically-controlled, electrophilic nitrene transfer for primary and secondary C–H bonds. Kinetic analyses for catalytic amination using tetrahydrofuran as a model substrate reveal pseudo-first order kinetics under relevant amination conditions with a first-order dependence on both Cu and organoazide. Activation parameters determined from Eyring analysis (ΔH‡ = 9.2(2) kcal mol−1, ΔS‡ = −42(2) cal mol−1 K−1, ΔG‡298K = 21.7(2) kcal mol−1) and parallel kinetic isotope effect measurements (1.10(2)) are consistent with rate-limiting Cu nitrenoid formation, followed by a proposed stepwise hydrogen-atom abstraction and rapid radical recombination to furnish the resulting C–N bond. The proposed mechanism and experimental analysis are further corroborated by density functional theory calculations. Multiconfigurational calculations provide insight into the electronic structure of the catalytically relevant Cu nitrene intermediates. The findings presented herein will assist in the development of future methodology for Cu-mediated C–N bond forming catalysis.


Introduction
Copper-catalyzed amination and aziridination are powerful methodologies for C-H activation with applications in the elaboration of simple chemical feedstocks and the construction of various nitrogen-containing natural products. 1,2Furthermore, the earth-abundance and low toxicity of Cu relative to precious metals render its employment in stereospecic catalysis attractive from an environmental perspective. 3New methods for direct C-H functionalization in lieu of functional group exchange provide the potential for achieving high atom economy and also establish new opportunities for late-stage diversication of complex molecules. 4][10] The bulk of these transformations have been developed for the N-tosylnitrene transfer reagent [(phenylsulfonyl)imino]phenyliodinane (PhINTs), based on the ease of precursor synthesis and the capacity for detosylation to deprotect amines or aziridines. 11In addition, protected amines and aroyl azides have been incorporated into aziridination 12 and amidation 13 reactions.Cu nitrenoid (Cu-NR) species are commonly invoked as the reactive intermediate for C-H bond activation and alkene aziridination (Fig. 1); 5,10, however, the eeting nature of these highly reactive intermediates has precluded their spectroscopic observation and direct analysis of their reactivity proles. In th absence of structural authentication and rigorous characterization, the intermediacy of a copper nitrenoid can be inferred from computational support 37,38 and through kinetic analysis of enantioselective aziridination.39 Reaction optimization is further complicated by the potential redox non-innocence of the nitrene fragment and the capacity of Cu to reside in a variety of spin states, potentially giving rise to different reactivity proles based on the participation of the nitrenoid in the frontier orbital manifold.Consequently, understanding the electronic structure of the Cu nitrenoid intermediate and the distribution of electrons across the Cu-N bond is paramount to understanding its reactivity.
We previously reported structural characterization of the rst bona de copper nitrenoid complex, derived from treatment of a mononuclear Cu(N 2 ) complex with electron-rich arylazides. 40he terminology nitrenoid refers to a general monosubstituted nitrogen motif with no specic claims regarding the valency of the nitrogen center.By contrast, imido (NR 2− ), imidyl ( 2 NR 1− ), and nitrene ( 3 NR or 1 NR) denote specic claims regarding the valency of the nitrene; consequently, prior to acquisition of rigorous spectroscopic data, we elect to employ the descriptor nitrenoid.Due to the heightened reactivity of the resultant Cu nitrene, all syntheses and manipulations were conducted in passivated glassware using solvents with strong C-H bonds and without allowing reaction mixtures to exceed room temperature.Specically, the Cu nitrene species were found to degrade via azoarene formation when solutions were stored at 40 °C or le standing in C 6 D 6 at room temperature over multiple days.The structural metrics of the nitrene adduct as determined by singlecrystal X-ray diffraction revealed dearomatization of the nitrene aryl substituent with bond lengths akin to isolated Cu diketimide complexes obtained by reductive coupling with C(sp 3 )-hybridization at the para-aryl carbon reported by Warren and coworkers 25 and by us. 40Multinuclear X-ray absorption spectroscopy, including Cu K/L 2,3 -edge 41 and N K-edge XANES 42 with further corroboration by multicongurational calculations, revealed the most appropriate electron description as a cuprous triplet nitrene adduct (i.e., Cu I ( 3 NAr)), in lieu of a higher valent cupric imidyl redox isomer (i.e., Cu II ( 2 NAr)), or cupryl imido complex (i.e., Cu III (NAr)). 43While the hydrindacene-substituted dipyrrin allowed for isolation and characterization of the Cu nitrene, modication of the dipyrrin with a less stericallyoccluded anking group allowed for the stoichiometric nitrene transfer reactivity to be rendered catalytic.
The employment of electron-decient arylazides afforded analogous paramagnetically-shied   We herein describe the reactivity prole of a sterically unencumbered Cu complex competent for C-H amination and aziridination using peruorinated electron-decient arylazides, with catalysis exhibited for select substrates including alkenes and C-H bonds adjacent to heteroatoms and arenes.Mechanistic experimental and computational studies are consistent with a stepwise H-atom abstraction and radical recombination with a rate-limiting step assigned as Cu nitrenoid formation, which is in contrast with other dipyrrin amination catalysts which exhibit rate-limiting substrate activation through hydrogen-atom abstraction.
Treatment of ( EMind L)H with mesitylcopper in anhydrous benzene at elevated temperatures afforded ( EMind L)Cu(C 6 H 6 ) with clean conversion to ( EMind L)Cu(N 2 ) (1) upon removal of excess solvent and recrystallization from a concentrated pentane solution under N 2 at −35 °C. 40,55The N 2 adduct in 1 represents one of the least activated isolable metal-dinitrogen complexes (n N 2 = 2242 cm −1 ), reecting an energetic mismatch between the Cu I ion and N 2 p*-orbitals due to poor energetic and spatial overlap and, therefore, minimal p-backbonding.Given the minimal activation of N 2 , we rationalized facile ligand substitution of N 2 for organoazides would be feasible.Treatment of 1 in hexanes with substituted organoazide substrates is accompanied by rapid effervescence and a color change from carrot-orange to red-orange.Analysis by multinuclear NMR spectroscopy ( 1 H/ 13  Bu)] (3-t Bu) as identied by single crystal Xray diffraction (Scheme 1). 40The intermediate prior to copper nitrenoid formation is ascribed to an azide adduct ( EMind L) Cu(N 3 Ar) based on notable perturbations in the azide stretching frequencies.In particular, treatment of 1 with (4-t Bu)C 6 H 6 N 3 results in a signicant changes by infrared spectroscopy (n N 3 Ar = 2121, 2087 cm −1 ) compared to the free arylazide (n N 3 Ar = 2127, 2088 cm −1 ) (Fig. S76 †).The employment of the 15 N a isotopologue (4-t Bu)C 6 H 6 15 NNN corroborated the identity of these resonances (n NN 15 NAr = 2113 cm −1 ; free n NN 15 NAr = 2110, 2066 cm −1 ) (Fig. S12 †).Although the thermal instability of ( EMind L)Cu(N 3 Ar) to yield the subsequent Cu nitrenoid precludes structural characterization and identication of an internal (N a -bound) or terminal (N g -bound) motif, employment of the sterically encumbered alkyl azide 1-azidoadamantane (N 3 Ad) facilitated isolation of the thermally and photolytically robust ( EMind L)Cu(N 3 Ad) (2) with k 1 -ligation to the terminal nitrogen atom (N g ) (Fig. 3a).Employing alkyl azides without quaternary substitution on the carbon adjacent to the nitrogen resulted in rapid formation of a diamagnetic species, consistent with a-elimination to yield the corresponding imine adduct, which has been observed elsewhere for putative late transition metal nitrenoid complexes. 44,45,56Minimal elongation is observed within the azide unit of 2 (N g -N b = 1.129(8)Å, 1.231(9) Å), in accord with the observed infrared spectroscopy data (n N 3 Ad = 2134, 2107 cm −1 ; free n N 3 Ad = 2140, 2088 cm −1 ) (Fig. S14 and S15 †).By analogy, the observed diamagnetic species prior to formation of the Cu nitrenoid intermediate is attributed to a terminal N g -ligated azide adduct, which undergoes gradual rearrangement to an internal N a -ligation with subsequent N 2 expulsion to yield the resulting Cu nitrene.

X-ray absorption spectroscopy
The electronic structures of triplet copper nitrenoid complexes 3-O t Bu and 3-t Bu were ascertained by multinuclear X-ray absorption (XAS) spectroscopy (Fig. 2).The N K-edge XAS data reveal two low-energy pre-edge features at 395.31 eV and 395.91 eV in the case of 3-t Bu, and at 395.36 eV and 395.91 eV in the case of 3-O t Bu (Fig. 2A).The splitting of this pre-edge feature is consistent with two holes localized to the N of the aryl nitrenoid motif, 42 indicating a cuprous triplet nitrene adduct Cu I ( 3 NAr) as the best description of the ground states of both 3-t Bu and 3-O t Bu.Our assignment is further corroborated by Cu L 2,3 -edge XAS (Fig. 2B).The L 3 -and L 2 -edge main lines occur at approximately 931.5 eV and 951.3 eV, respectively, for both 3-t Bu and 3-O t Bu.Experimental estimations of the Cu 3d character in the acceptor orbitals derived from integration of the L 3 -and L 2 -edge main lines (Fig. S85 and S86 †) as previously described 43 place the average 3d character per hole at 21% for 3-t Bu and 25% for 3-O t Bu.The attenuation of Cu 3d character in the acceptor orbitals is consistent with majority hole character contained in N-localized orbitals and a physical oxidation state of Cu I .Similar integration of the pre-edge features arising from the nitrene in the N K-edge spectrum is consistent with more N 2p character in the acceptor orbitals in the case of 3-O t Bu, as well (Fig. S83 and S84 †).Taken together, the N K-edge and Cu L 2,3 -edge XAS suggest that the inuence of the tert-butoxy oxygen heteroatom results in more spin density localized to the Cu-N unit, but that both complexes are best described as Cu I ( 3 NAr) adducts.

Intermolecular amination and aziridination
Whereas 3-O t Bu and 3-t Bu were competent for aromatization of 1,4-cyclohexadiene (BDE C-H = 76 kcal mol −1 ) 57 to yield benzene and the corresponding aniline adduct ( EMind L)Cu(H 2 NAr) as identied by independent synthesis, C-H amination was not observed from the Cu nitrene adducts for more inert substrates such as toluene or cyclohexane.This absence of C-H amination is attributed to steric preclusion of substrates from the EMind substituents and the weak N-H bond of the subsequent Cu anilido intermediate.Thus, we targeted electron-decient nitrene sources for greater N-H bond strengths to enhance the efficacy of nitrene transfer.Treatment of 1 with stoichiometric pentauorophenyl azide (C 6 F 5 N 3 ) in thawing toluene afforded the corresponding benzylic aminated species, albeit in diminished yield (10%) with the predominant organic product identied C 6 F 5 NH 2 (55%) following demetallation through acidication and quantication by 19 F NMR spectroscopy.Inspection of the crude reaction mixture by EPR spectroscopy reveals formation of independently isolated cupric anilido product ( EMind L)Cu(NH(C 6 F 5 )), resulting in poor mass balance. 40e proposed the limited nitrene transfer reactivity was attributable to the steric pressure about the Cu center.Thus, we selected the more sterically exposed variant ( ArF L)Cu (4) with rotationally exible 2,4,6-triphenyl(aryl) anking substituents while maintaining the dipyrrin methine 3,5-bis-triuoromethyl aryl substituent to match the electronic nature of 1 and provide a 19 F NMR handle to assess Cu speciation during nitrene transfer reactions.The synthesis of the dipyrrin platform can be conducted on multi-gram scales with metalation effected by mesitylcopper under prolonged heating (80 °C, 14 h) in  Fc/Fc 1+ ), attributed to the more electron-decient uorinated substituent (Fig. S79 †).The electron-decient nature of 4 yields air-stability, in contrast to 5 which partially ligates O 2 prior to the onset of decomposition into oligomeric Cu-containing species. 54The exchange of the meso arene for 4 relative to 5 yields marked changes by UV/vis spectroscopy (Fig. S77 and S78 †), which has been previously observed by us in a series of ferrous dipyrrin coordination complexes. 58Gratifyingly, treatment of 4 with C 6 F 5 N 3 in thawing toluene afforded the corresponding aminated toluene product (62%) by 19 F NMR spectroscopy as the sole organic species, slightly augmented relative to that of 5 (45%), with the mass-balance identied as Cu II species by integration of the incorporated 19 F NMR ligand substituent.Treatment of either 4 or 5 with (4-t Bu)C 6 H 6 N 3 afforded rapid detection of paramagnetic 1 H NMR spectroscopy resonances akin to those of 3-t Bu without evidence of an organoazide adduct, suggesting Cu nitrene intermediates as viable intermediates in this transformation (Fig. S36 †) (Scheme 2).

Stoichiometric mechanistic analysis
2.4.1 Hammett analysis.The mechanism of nitrene transfer from 4 was probed.For ease of assessing Cu speciation and quantifying product formation, nitrene transfer was monitored by 19 F NMR spectroscopy using C 6 F 5 N 3 as the arylazide source.Intermolecular competition amination experiments with 4 and stoichiometric C 6 F 5 N 3 in an equimolar mixture of toluene and para-substituted toluene derivatives reveals an amination preference for electron-rich substrates (r = −0.82(1)against Hammett s + values, Fig. 4a and Table S1 †) with minimal change in amination yield as a function of toluene substitution.Amination products containing the pentauorophenyl amine moiety were independently synthesized through nucleophilic aromatic substitution of hexauorobenzene with the corresponding alkyl amine, allowing for facile product identication by direct comparison of multinuclear ( 1 H/ 13 C{ 1 H}/ 19 F) NMR resonances.Similar negative r values have been attributed for electrophilic nitrene transfer with accumulation of positive charge at the putative nitrene fragment for intermolecular Co, 59 Cu, 16 and Rh [60][61][62] C-H amination.A similar preference for consumption of electron-rich styrenes over electron-decient styrenes is observed for intermolecular competition aziridination experiments from 4 (r = −0.92(2)against Hammett s + values, Fig. 4b and Table S2 †), akin to values observed for Cu aziridination with iodoimine substrates. 20The linear correlations against s + values for amination (R 2 = 0.99) and aziridination (R 2 = 0.98) contrast those observed for intermolecular nitrene transfer from dipyrrin ( t Bu L)FeCl(Et 2 O) and aziridination both by brominated tris(pyrazolyl)borate and tripodal guanidinato Cu complexes, which required employment of radicaldelocalization parameters (s JJ , s mb ) for satisfactory linear correlations. 16,63,64.4.2Linear free energy relationship.Intermolecular amination experiments using 4 with neat equimolar toluene and competing substrate of various bond dissociation energies reveal a Bell-Evans-Polanyi relationship 65,66 based on the linear relationship between reaction rate and bond dissociation energy, indicating substrate preference to be dictated by bond strength and not by other factors such as oxidation potential or substrate acidity (Fig. 4c).67 Nonetheless, the substrate steric prole was observed to contribute to substrate preference in competition experiments as evidenced by the lower-thananticipated consumption of diphenylmethane (BDE C-H = 84 kcal mol −1 ) 68 to the corresponding amine, attributed to an entropic penalty for large substrates given the large dipyrrin aryl anking substituents.In support of the hypothesis that sterically hindered substrates afford lower reactivity due to their steric bulk, attempted amination of tertiary C-H bonds for triphenylmethane (BDE C-H = 81 kcal mol −1 ) 57 and cumene (BDE C-H = 85 kcal mol −1 ) 69 resulted in no observed product formation by 19 F NMR spectroscopy, attributed to the steric prole of the substrates (Fig. S49 †).Moreover, amination of 2methyltetrahydrofuran with 4 proceeds with exclusive amination of the less substituted a-ethereal carbon in a 2.2 : 1.0 diastereomeric ratio, further supporting a steric preference (Table 1, entry 1).The catalytic amination of 2-methyltetrahydrofuran employing 5 (vide infra) favors formation of the opposite diastereomer as evident by 1 H NMR spectroscopy (1.0 : 1.7), illustrating an inuential role of the meso arene on the resulting chemistry.1, entry 2). Treatent of 4 with C 6 F 5 N 3 in neat 4-ethyltoluene resulted in a mixture of ethyl and methyl aminated products (1.0 : 6.2) favoring the weaker, more sterically precluded C-H bond (Table 1, entry 3).This ratio was similar to that observed for intermolecular amination of an equimolar mixture of toluene and ethylbenzene (1.0 : 7.1).In accord with the inability to functionalize cumene, competition amination using 4-isopropyltoluene proceeds without any detectable functionalization of the tertiary C-H site.
The mechanism of substrate activation was probed through radical clock experiments and kinetic isotope effect measurements.Amination of the radical clock phenyl(cyclopropyl) methane with either 4 or 5 furnishes the corresponding benzylic functionalized product with the cyclopropyl ring intact by 1 H/ 19 F NMR spectroscopy by comparison to an authentic amine sample (Fig. S52 †).This observation is consistent with either a concerted amination process or a H-atom abstraction followed by the radical recombination step faster than the ring opening of the cyclopropyl unit. 70The absence of cyclopropyl ringopening contrasts with amination observed from dimeric Cu b-diketiminate complexes with alkyl azides, 56 attributed to either differences in radical clock lifetimes 71 or mechanistic differences in C-N bond formation.Further consistent with the absence of long-lived radical intermediates, aziridination of (Z)b-deuterostyrene 72 proceeds with retention of stereochemistry in >20 : 1 values based on integration of 1 H NMR spectroscopic  resonances for the resulting aziridine with no diastereomer detected (Fig. S63 †).2.4.4Kinetic isotope effect.Kinetic isotope effect (KIE) measurements, including intermolecular competition amination with equimolar h 8 -toluene and d 8 -toluene as well as intramolecular competition amination with d 1 -ethylbenzene, resulted in values 9.0(7) and 4.4(2), respectively, and consistent with a stepwise hydrogen-atom abstraction step (Fig. S43-S45 †).Minimal changes in intramolecular competition amination kinetic isotope effects were observed for d 1 -ethylbenzene with related arylazides 4-(CF 3 )C 6 F 4 N 3 , and 4-(CO 2 Me)C 6 F 4 N 3 , which respectively yielded values of 8.7(2) and 8.2 (2).Amination of a neat equimolar mixture of h 12 -cyclohexane and d 12 -cyclohexane by 4 with C 6 F 5 N 3 resulted in a measured intermolecular competition kinetic isotope effect of 8.4(4), suggesting no major KIE change as a function of C-H bond strength.
2.5.1 Kinetic analysis.For kinetic analysis, consumption of C 6 F 5 N 3 was monitored by in situ 19 F NMR spectroscopy with 4 or 5 (10 mol%), employing initial rates by monitoring the reaction to 10% consumption of arylazide to obviate potential issues for catalytic degradation (Fig. S55 †) Nonetheless, 4 is retained at 98% with minimal conversion (<2%) to the Cu II anilido species based on integration of meso arene triuoromethyl substituents upon full consumption of C 6 F 5 N 3 , and reaction rates were observed to be identical measuring to greater extents of completion (Fig. 5a).Measurements were repeated in triplicate with average measurements reported and error bars representing the rst standard deviation, and either uorobenzene or 4-uoroanisole was employed as an internal standard for 1 H/ 19 F NMR quantication.Monitoring the reaction by 1 H/ 19 F NMR spectroscopy in d 8 -tetrahydrofuran revealed 4 as the resting state, and titration experiments of 4 with variable quantities of d 8 -tetrahydrofuran in C 6 D 6 revealed no noticeable changes in diamagnetic 1 H NMR resonances, suggesting against a tetrahydrofuran adduct of 4 in accordance with the predicted low oxophilicity of the Cu I oxidation state.The absolute rate of arylazide consumption was equal to the rate of hemiaminal production within error of 19 F NMR measurements.The concentration of arylazide with respect to time was linearized by examining the logarithm of concentration, indicating a pseudo-rst order overall reaction (Fig. 5b).Complex 4 aminates tetrahydrofuran at a slower rate than complex 5 (4: k obs = 8.16(6) × 10 −4 s −1 and t 1/2 = 14.2 minutes; 5: k obs = 4.34(9) × 10 −3 s −1 and t 1/2 = 2.7 minutes).Repeating tetrahydrofuran amination with 4 at various temperatures to extract activation parameters from Eyring analysis revealed a moderate positive enthalpy (DH ‡ = 9.2(2) kcal mol −1 ) and a large negative entropy (DS ‡ = −42(2) cal mol −1 K −1 ) indicative of a bimolecular rate-determining step (Fig. 5c, S66 and S67 †).The free energy (DG ‡ 298K = 21.7(2)kcal mol −1 ) is in accord with the amination of tetrahydrofuran at room temperature.
2.5.2Order analysis.Plotting the slope of arylazide consumption as a function of 4 or arylazide reveals a linear relationship (Fig. 6a and b), indicating both rst-order dependencies (Fig. S68-S71 †).This observation is in accord with the apparent rst-order decay of arylazide under the reaction conditions, given a constant concentration of 4 and the vast excess of substrate under catalysis.No change in C 6 F 5 N 3 consumption was observed in the presence of excess tetrahydrofuran (>500 equiv.)(Fig. S72 and S73 †).Nonetheless, employing reduced equivalents of tetrahydrofuran (<100 equiv.) in C 6 D 6 resulted in an apparent increase in background degradation to yield the corresponding Cu II anilido, preventing an assessment of reaction order on substrate under lower loadings of substrate.
2.5.3Kinetic isotope measurements.Kinetic isotope effect measurements were conducted to identify the involvement of substrate in the overall reaction prole.Intramolecular cyclization of alkyl azides by Fe, 73 Co, 53,74 and Ni 75 dipyrrin complexes showed high sensitivity to the presence of a C-H or C-D bond with large non-classical kinetic isotope effect values.For intermolecular H-atom abstraction or amination reactivity, nonclassical kinetic isotope effects were additionally observed from isolable metal nitrenoid species. 44,46,49By contrast, repeating parallel amination trials in neat h 8 -tetrahydrofuran and d 8tetrahydrofuran resulted in only a minimal change in the overall rate based on the observed kinetic isotope effect of 1.10(2), suggesting against rate-limiting H-atom abstraction, although concerted C-H insertion or an asymmetric transition state cannot be ruled out from this value (Fig. 6c). 76,77 Curiously, a larger absolute kinetic isotope effect was observed from 5 (2.06(1)) with similar changes in the intramolecular and intermolecular amination of 8.1(1) and 10.7(4) (Fig. S75 †), suggesting the mesityl substituent may impact the underlying kinetics and rate-determining step of the overall reaction.
Lastly, noting the capacity of sterically encumbered Cu bdiketiminate species to conduct C-H bond amidation of inert hydrocarbons with aroyl azides, the analogous transformation was targeted with 1 and 4. Interestingly, treatment of 1 (1 mol%) with 4-methoxybenzoyl azide in C 6 D 6 at room temperature afforded the corresponding aryl isocyanate conrmed through independent synthesis.The reaction was completed with ca. 10 minutes in quantitative yield with recovery of 1 (Fig. S82 †).By contrast, treatment of 4 with stoichiometric 4-methoxybenzoyl azide afforded full consumption of 4 and a distinct paramagnetic species as ascertained by 1 H/ 19 F NMR spectroscopy and EPR analysis, attributed to formation of the corresponding Cu II amide species.These results underscore the importance of steric prole on reaction trajectory.

Computations
Calculations were conducted using the Gaussian 16 program 79 to corroborate kinetic measurements for tetrahydrofuran amination by 4 and elucidate the underlying elementary steps  (Fig. 7).Hybrid QM/MM calculations (see Fig. S93 † in the ESI for the QM/MM partition scheme used) utilized the ONIOM method, 80 with the Universal Force Field (the phenyl groups of the quadraphenyl substituent). 81The DFT partition utilized the B3LYP functional, [82][83][84][85] and a two-step sequence involving a geometry optimization plus vibrational frequency step using the 6-31+G(d) basis set, followed by larger basis set single point calculations for more accurate energetics utilizing the 6-311++G(d,p) basis set. 86Calibration and additional details regarding this approach are described in the ESI.† In general, the results of the two-step scheme mirror the one-step approach (using exclusively the larger basis set) results well, with most free energies only varying by ca.±1-2 kcal mol −1 (Table S13 †).
The reference free energy was dened as the separate reactants, consisting of 4, pentauorophenyl azide, and tetrahydrofuran (A, Fig. 7).Two isomers of the organoazide complex of the catalyst were considered, ( ArF L)Cu(k 1 -N g -C 6 F 5 N 3 ) (B) and ( ArF L)Cu(k 1 -N a -C 6 F 5 N 3 ) (C).Calculations favor formation of more sterically exposed B, which is more easily accessible with a relative Gibbs free energy (G rel ) that is 2.8 kcal mol −1 compared to A. Formation of the internal isomer C has G rel = 9.2 kcal mol −1 versus A.
Removal of N 2 affords a copper-nitrenoid intermediate, for which both singlet and triplet spin states were evaluated, 3  , respectively.This indicates that the activation at the 2 position via C-H activation is thermodynamically preferred, consistent with the experimentally observed selectivity.The last step considered in the reaction coordinate is the radical rebound of the amide complex to the organic radical generated by H-atom abstraction of THF, yielding the desired amination product, and recovery of the isolated catalyst.Formation of the amination product results in a relative energy of −62.8 kcal mol −1 versus separated catalyst, organoazide and THF reactants (F).Importantly, we were unable to locate a transition state prior to recombination of the alkyl radical, suggesting a barrierless transition state for radical capture.
To further corroborate the results of the B3LYP calculations, the relative Gibbs free energy was obtained for all stationary points in Fig. 7 using the wB97XD functional, 88 except for the N 2 elimination transition state, which we were unable to get to converge.The wB97XD functional uses a version of Grimme's D2 dispersion model 89 and therefore corrects the long-range behavior of the functional.The results obtained with the wB97XD functional are given in Table S15 in the ESI.† While the G rel for most of the stationary points in the reaction coordinate Additionally, the effects of implicit solvation in THF were considered via DFT calculations.These calculations used the Polarizable Continuum Model (PCM) 90,91 for implicit solvation, 92 as implemented in the Gaussian 16 program. 93The continuum solvent calculations utilized the B3LYP functional, and geometry optimizations were initiated from the previously obtained gas-phase B3LYP geometries.As for the calculations done with the wB97XD functional, some of the stationary points, such as the separated amide and THF radicals, have relative energies that are lower than those obtained with B3LYP (see Table S13 in the ESI †).Again however, all previous conclusions regarding the more stable transition states, etc., remain consistent in the solvation calculations as compared to the energies obtained using B3LYP.For example, the tripletspin transition state for C-H bond activation of tetrahydrofuran remains lower in energy (G rel = −19.4kcal mol −1 ) than the unrestricted singlet-spin N 2 -elimination transition state (G rel = 25.9 kcal mol −1 ), but when implicit solvation is accounted for, this difference is more pronounced (DG = 45.3 kcal mol −1 when implicit solvation is considered, versus DG = 31.8kcal mol −1 without solvation effects).

Electronic structure analysis
Spectroscopy-oriented conguration interaction (SORCI) calculations based on a complete active space self-consistent eld (CASSCF) reference were rst carried out on a truncated model derived from the crystallographic coordinates of 3-O t Bu (Fig. 8).
Hydrogen atom positions were optimized with the B3LYP density functional.The SORCI results indicate a multicongurational triplet ground state (Fig. S89 †) in agreement with previous investigations into the electronic structure of 3-t Bu. 40 The Cu Itriplet nitrene conguration (CFG 1) is the most signicant contributor to the ground state (76%) in which the unpaired electrons reside in the N 2p x and 2p y orbitals (MOs 155 and 156) of the coordinated nitrene.Two other low-weight congurations can be identied as a ferromagnetic Cu II -iminyl conguration (CFG 2; 7%) and a Cu III -imido conguration (CFG 3; 4%); all other congurations contribute less than 1% each to the ground state.
The computed electronic structure of 3-O t Bu corroborates the XAS-derived formulation of the ground state and further supports the assignment of 3-O t Bu as a Cu I ( 3 NAr) adduct, as opposed to higher valent Cu II or Cu III species.The average 3d character per hole estimated from congurations with greater than 1% contribution to the ground state is 27%, consistent with the intensity of the observed Cu L 3 -and L 2 -edge main lines and assignment of the metal center as physically Cu I (Table 3).Similar summation over the calculated N 2p contributions to the acceptor orbitals from congurations with greater than 1% contribution to the ground state are consistent with the slight increase in intensity of the N K-edge pre-edge features observed with 3-O t Bu compared to 3-t Bu.The unpaired electron residing in the N 2p x orbital is conjugated with the aryl nitrene (MO 155) while the unpaired electron resides in the N 2p y orbital, which is orthogonal to the aryl p system, further liing the degeneracy of the N 2p x and 2p y orbitals.The asymmetry of the N K-edge preedge features arising from the nitrene can be understood in  terms of simple single-electron transitions into the N 2p x and 2p y orbitals, explaining both the difference in energy and relative intensity of the observed features.
Due to the reactive nature of 4, we were unsuccessful at the detection of reactive intermediates by NMR spectroscopy with C 6 F 5 N 3 as the azide source.Additional SORCI calculations were conducted to gain insight into the impact of the peruoroarene substituent on the ground state electronic structure.Similar to 3-O t Bu and 3-t Bu, a triplet ground state in which the unpaired electrons principally reside in the N 2p x and 2p y orbitals was predicted (Fig. S90 †).As 4 could not be isolated, it was necessary to obtain the structure from density functional theory (DFT) geometry optimization.Because the ground states of 3-O t Bu and 3-t Bu are highly multicongurational and thus not well described by DFT, we also performed geometry optimizations on these structures and repeated the CASSCF/SORCI procedure for truncated models derived from the DFT-optimized structures (Fig. S91 and S92 †).In both cases, the electronic structure was best described as a Cu I ( 3 NAr) adduct, though the composition of the acceptor orbitals was in weaker quantitative agreement with experiment.Taking this into consideration, a clear trend in arene functionalization and electronic structure could not be unambiguously identied across the series of three Cu I ( 3 NAr) adducts from the multicongurational calculations alone.In all three cases, however, an inverted ligand eld was indicated in which the Cu valence orbitals were lower in energy than the corresponding nitrene valence orbitals, resulting in redox-active MOs of predominantly nitrene character in what has been termed ligand eld inversion. 43,94Conclusions A dipyrrin-supported Cu I synthon was demonstrated to mediate C-H bond amination and aziridination of exogeneous substrates using electron-decient arylazides, proposed to proceed through an intermediate Cu nitrene species (Fig. 9).Arylazide activation involves ligation through the sterically exposed terminal nitrogen (N g ), followed by rearrangement to the internal nitrogen (N a ) with subsequent irreversible expulsion of N 2 .Hammett analyses reveal the Cu nitrenoid intermediate, observable by 1 H NMR spectroscopy for certain electron-decient arylazides, behaves as an electrophilic nitrene reagent, akin to other putative amination reactive intermediates. 28Amination proceeds with a Bell-Evans-Polanyi relationship, although sterically precluded tertiary C-H bonds remain unfunctionalized, likely due to steric clashing with the quadraphenyl motifs of the ligand scaffold.Nitrene transfer to tetrahydrofuran as a model substrate revealed pseudo-rst order decay in arylazide under reaction conditions with order dependence on both Cu and arylazide.Eyring analysis and computations are consistent with rate-limiting Cu nitrenoid formation, contrasting previous dipyrrin amination catalysis in which hydrogen-atom abstraction is measured as the ratedetermining step.This discrepancy can be attributed to the difference in reduction potential between Cu I and more reducing metal ions such as Ni I or Co I .The large barrier may be in part due to the absence of metal-ligand multiple bonding formation during N 2 extrusion.Furthermore, the subsequent radical recombination step is barrierless for Cu, contrasting a Ni intramolecular amination catalyst which exhibit loss of stereochemical information due to a non-negligible radical recombination barrier. 95These results will guide the improvement of future amination catalysts, with detailed computations addressing the impact of the nitrene aryl substituent on the resulting electronic structure underway.

Fig. 1
Fig. 1 (a) Invoked Cu nitrenoid intermediates for H-atom abstraction, C-H amination, nitrene transfer, and aziridination transformations.(b) The isolation of a Cu nitrenoid represents the first structurally validated and spectroscopically authenticated example competent for nitrene transfer.Charges are omitted for clarity in which all presented Cu complexes are formally Cu(III).

2 . 4 . 3
Substrate competition.Competition experiments further elucidated the electronic preference of 4 for C-H amination against aziridination.Treatment of 4 with C 6 F 5 N 3 in the presence of 4-methylstyrene resulted in exclusive formation of the corresponding aziridine without any detectable benzylamine, indicative of a preference for aziridination over C-H amination (Table

Table 2
Yields determined by19 F NMR integration relative to fluorobenzene internal standard over a 12 h time frame in neat substrate a 0.1 mol% catalyst loading for 36 h.b 5.0 mol% catalyst loading.c 0.5 mol% catalyst loading.d Due to overlapping C-F resonances, the yield was determined by 1 H NMR integration relative to an internal standard of uoroanisole.
Nonetheless, measurement of competition intramolecular amination with 2,2d 2 -tetrahydrofuran 78 and competition intermolecular amination with an equimolar mixture of h 8 -tetrahydrofuran and d 8 -tetrahydrofuran revealed larger kinetic isotope effect values of 4.7(1) and 6.2(2) (Fig. S74 †), indicative of a sensitivity of the overall reaction to identity of the C-H or C-D bond of the substrate.
[Cu] = NAr ( 3 D) and 1 [Cu] = NAr ( 1 D).The G rel for closed-shell singlet 1 D and triplet 3 D are respectively DG = −32.4kcal mol −1 and −35.5 kcal mol −1 .Hence, the triplet is predicted to be more stable by ca. 3 kcal mol −1 .Additional B3LYP/6-311++G(d) geometry optimizations with Gaussian 16 and ORCA 4.2.1 87 suggest that the singlet state of 1 D is a closed-shell singlet with unsuccessful attempts to isolate an open-shell singlet analogue of 3 D.The singlet and triplet transition state for C-H bond activation of tetrahydrofuran have either G rel = −2.0kcal mol −1 ( 1 TS2 ‡ ) or −7.3 kcal mol −1 ( 3 TS2 ‡ ), Fig. 7.These free energies represent a calculated C-H activation barrier of DG ‡ = 28.3kcal mol −1 (DS ‡ = 48.4cal mol −1 K −1 at 298 K) for the more stable triplet surface relative to the nitrene intermediate.To activate the C-H bond of THF, a hydrogen is abstracted from the substrate resulting in an anilido ( 2 [Cu]-NHAr) and the activated substrate radical (E).Two radicals were initially considered: one with the C-H activation site proximal to the oxygen atom in THF, and one with the activation site distal to the oxygen atom.The relative free energy for the separated amide and each radical are −35.6 kcal mol −1 and −32.7 kcal mol −1

Fig. 8
Fig. 8 Leading configurations comprising (6,4) subspace of SORCI calculation on a truncated model of 3-O t Bu.Averaged atomic natural orbitals are plotted at an isovalue of 0.03 au. 1

Table 3
Calculated estimations for average Cu and N character per hole a 3-O t Bu b 3-t Bu b,d 3-O t Bu c 3-t Bu c ( ArF L)Cu(NC 6 F 5 ) c a Only congurations contributing greater than 1% to the ground state are considered.b Coordinates employed from truncated solid-state structure.c Coordinates employed from truncated geometry optimized structure.d Average Cu 3d and N Ar 2p character per hole estimated from the two major congurations previously published.