Deciphering the mechanism of the Ni-photocatalyzed C‒O cross-coupling reaction using a tridentate pyridinophane ligand

Photoredox nickel catalysis has emerged as a powerful strategy for cross-coupling reactions. Although the involvement of paramagnetic Ni(I)/Ni(III) species as active intermediates in the catalytic cycle has been proposed, a thorough spectroscopic investigation of these species is lacking. Herein, we report the tridentate pyridinophane ligands RN3 that allow for detailed mechanistic studies of the photocatalytic C–O coupling reaction. The derived (RN3)Ni complexes are active catalysts under mild conditions and without an additional photocatalyst. We also provide direct evidence for the key steps involving paramagnetic Ni species in the proposed catalytic cycle: the oxidative addition of an aryl halide to a Ni(I) species, the ligand exchange/transmetalation at a Ni(III) center, and the C–O reductive elimination from a Ni(III) species. Overall, the present work suggests the RN3 ligands are a practical platform for mechanistic studies of Ni-catalyzed reactions and for the development of new catalytic applications.

T he carbon-oxygen (C-O) bond-forming reactions are of particular interest in the field of organic synthesis, as C-O bonds are prevalent in many natural products, pharmaceuticals, and agrochemicals [1][2][3] . Although Pd-based C-O crosscoupling catalysts are well established [4][5][6][7] , there has been a great interest in developing sustainable catalytic systems based on earth-abundant nickel. In this regard, photoredox/nickel dual catalysis and light-promoted Ni catalysis have emerged as powerful strategies for challenging C-O bond formations [8][9][10][11] . Accordingly, an in-depth mechanistic understanding of Nimediated photocatalysis is essential for rational reaction design and optimization. From a mechanistic viewpoint, while the photocatalytic cycle is well-understood, the Ni-mediated redox cycle remains elusive as intermediates in various oxidation states (from Ni 0 to Ni IV ) have been proposed 12 . For example, the involvement of paramagnetic Ni I and Ni III species has been commonly implicated, yet such intermediates have not been thoroughly investigated, and the key catalytic steps of oxidative addition, transmetalation, and reductive elimination have rarely been observed directly 10,13,14 .
Our group has employed tetradentate azamacrocycle N,N'dialkyl-2,11-diaza [3.3](2,6)pyridinophanes ( R N4) ligands to isolate and characterize Ni III species capable of C-C [15][16][17][18] and C-heteroatom 15,19,20 bond formation reactions, and to probe the involvement of high-valent Ni species in these reactions. Since the most ubiquitous ligands in Ni cross-coupling and photocatalytic reactions are the bidentate bipyridine ligands [8][9][10][11]21 , the R N4 ligands were thought to be less effective ligands for catalytic applications due to the crowded environment around the Ni center, which is also expected to disfavor the formation of Ni I species. By contrast, a bidentate ligand structure is not suitable for stabilizing high-valent Ni species, thus hampering the investigation of such Ni intermediates 22 . Considering these aspects, we sought to identify an optimal ligand framework positioned in between bipyridine and R N4 ligands in terms of denticity, molecular structure, and functionality, and thus the pyridinophane tridentate R N3 ligands were targeted (Fig. 1a). These R N3 ligands are structurally analogous to the R N4 ligands, possessing a rigid aromatic pyridinophane framework and containing only one flexible chelating arm that allows for either a κ 2 or κ 3 coordination. Surprisingly, such R N3 ligands have never been synthesized to date, likely due to the lack of an efficient synthetic route. Several other well-known fac-capping tridentate N-donor ligands such as tris(pyrazoyl)borate (Tp -) 22 , tris(pyrazolyl) methane (Tpm) 23 , or 1,4,7-trimethyl-1,4,7-triazacyclononane (Me 3 TACN, Fig. 1b) 24 have been reported to stabilize high-valent organometallic Ni complexes, or even an organometallic Ni I complex 25 , yet these ligands do not seem to stabilize mononuclear LNiX 2 (X = halide) complexes, dinuclear halide-bridged or homoleptic 2:1 L:Ni complexes being generated instead [26][27][28] .
In this work, we report the development of N-alkyl-2-aza[3.2] (2,6)pyridinophanes ( R N3, R = Me or i Pr) ligands, which embody our design criteria for photocatalytic applications and mechanistic studies. The corresponding ( R N3)Ni complexes are active C-O cross-coupling catalysts upon light excitation and without an added precious-metal photocatalyst. Importantly, we show that the utilization of the tridentate R N3 ligands allows for a comprehensive examination of the Ni intermediates proposed in the individual steps of the cross-coupling catalytic cycle: oxidative addition, transmetalation/ligand exchange, and reductive elimination, all these steps involving paramagnetic Ni I or Ni III species.

Results and discussion
Ligand development. In 1958, Overberger et al. reported the reduction of N-nitrosodibenzylamines by Na 2 S 2 O 4 to generate the hydrocarbon product with evolution of N 2 29 . However, this reaction has received little attention since then, and only one report by Takemura et al. in 1988 exploited the N-nitroso reduction reaction to obtain [2.2]cyclophane derivatives 30 . We speculated that this N-extrusion reaction would provide an efficient synthetic pathway for tridentate pyridinophane ligands. Our synthesis starts with the unsymmetrical pryridinophane precursor N-tosyl-2,11-diaza [3.3](2,6)pyridionphane ( TsH N4, Fig. 2a) 31 . For the nitrosylation step, TsH N4 was treated with HNO 2 to generate the N-nitroso intermediate TsNO N4 in 85% yield. Subsequent reductive elimination of nitrogen from the N-nitrosoamine was performed with Na 2 S 2 O 4 under basic conditions, converting TsNO N4 to Ts N3 in 75% yield. Additional steps of detosylation and methylation or isopropylation afforded the alkylated ligand variants Me N3 or iPr N3 in~45% overall yields, confirming that further functionalization can be easily achieved. The N-nitroso reduction conditions are mild, suggesting a broad functional group tolerance. Since all reaction steps do not require extensive purification and their yields are high, the development of this synthetic route provides an opportunity to access a variety of ligand structures by further functionalization or starting from different secondary amine precursors. Notably, Levin et al. have recently reported the development of an anomeric amide reagent for the oxidative extrusion of nitrogen from dibenzylamines via a isodiazene intermediate to yield C-C coupled products 32 . By comparison, our approach employs a reduction of the N-nitrosoamine intermediate and only uses simple and commonly available reagents, and thus allowing for bis-2-picolylamines to be used as substrates.
Synthesis and characterization of ( R N3)NiCl 2 complexes. The reaction of Me N3 or iPr N3 with Ni(DME)Cl 2 in CH 2 Cl 2 generated the green Ni II -dichloride complexes ( Me N3)NiCl 2 (1a) and ( iPr N3)NiCl 2 (1b), respectively (Fig. 2b). This is in contrast to other tridentate N-donor ligands such as Tp -, Tpm, or Me 3 TACN, which tend to form dinuclear halide-bridged or homoleptic 2:1 L:Ni complexes instead of LNiCl 2 complexes [26][27][28] . Both complexes 1a and 1b are paramagnetic, as shown by the paramagnetic NMR spectrum of 1b ( Supplementary Fig. 11), and the effective magnetic moment μ eff of 3.03 μ b determined using the Evans method is consistent with a triplet ground state (S = 1), as expected for a high-spin Ni II center 33,34 . The obtained magnetic moment value is similar to those of triplet ground state Ni(bpy)X 2 (X = halide) complexes 35 , although these complexes adopt a tetrahedral geometry 36 . The molecular structures of 1a and 1b were determined by single crystal X-ray diffraction (Fig. 2c), to reveal similar coordination environments around the Ni center, except that the structure of 1b exhibits slight distortions due to the bulkier i Pr substituent ( Supplementary Fig. 55). The structure of 1a reveals a five-coordinate Ni II center in a square pyramidal geometry with a calculated trigonality index parameter τ of 0 37 , with an average Ni-N py bond length of 2.058 Å and an axial Ni-N amine bond length of 2.056 Å, which are similar to those of the related complex ( tBu N4)NiCl 2 38 . A closer look at the space-filling representation of 1a, as shown from the bottom view and along the Ni-N amine axial axis (Fig. 2d), reveals that the Ni center is sterically protected by the H atoms of the ethylene bridge and thus could lead to an increased stability of the high-or low-valent Ni intermediates (see below).
The electrochemical properties of ( R N3)NiCl 2 complexes were investigated by cyclic voltammetry (CV, Fig. 3c, Supplementary  Figs. 13 and 14). The CVs of 1a and 1b in MeCN reveal a pseudoreversible oxidation wave at 0.71 V vs Fc +/0 , which is assigned to the Ni III/II couple, as well as an irreversible reduction wave at −1.20 V vs Fc +/0 for 1a and −1.22 V for 1b, followed by a pseudoreversible reduction wave at −1.60 V vs Fc +/0 for 1a and −1.72 V for 1b, respectively. The first reduction wave is proposed to correspond to the conformation of the Ni complex in which the R N3 ligand adopts a κ 2 binding mode, in line with the flexibility of the pyridinophane ligands observed previously 24,39 . The electrochemical irreversibility of the second reduction event is likely due to the loss of a Cl − ligand and the change in coordination geometry from square pyramidal to tetrahedral upon formation of the Ni I species (i.e., an EC mechanism: an electron transfer followed by a chemical reaction) 40 . It is important to note that the oxidation and reduction potentials for 1a and 1b are similar to those of (dtbbpy)NiCl 2 , which exhibits an oxidation wave at 0.56 V vs Fc +/0 and an irreversible reduction wave at −1.37 V vs Fc +/0 , followed by a pseudoreversible reduction wave at −1.74 V vs Fc +/0 ( Supplementary  Fig. 16). By comparison, while for ( Me N4)NiCl 2 the Ni III/II oxidation event was observed at 0.52 V vs Fc +/0 , no reduction event was observed up to −2.00 V vs Fc +/041 , supporting our hypothesis that tetradantate ligands cannot stabilize Ni I species to a large extent. The accessible reduction events observed for ( R N3) NiCl 2 suggest that for these complexes the Ni I oxidation state is accessible via one-electron reduction with a chemical reductant and thus it can be exploited in reactivity and mechanistic studies. When compared to (dtbbpy)NiCl 2 , the ( R N3)NiCl 2 complexes exhibit similar oxidation and reduction potentials, which is essential for photocatalysis, yet they possess a structural advantage by containing the flexible axial amine arm that is beneficial for characterization of reaction intermediates (see below).
The UV-visible absorption spectra of 1a and 1b were then obtained and also analyzed computationally. The UV-vis absorption spectrum of 1a shows an intense band around 380 nm and a less intense band around 640 nm (Fig. 3a). To probe the nature of the electronic transitions, time-dependent density functional theory (TD-DFT) calculations were performed. As the ground state of 1a has triplet spin multiplicity, the higher energy absorption feature (380 nm) is attributed to a combination of a spin-allowed Cl → R N3 ligand-to-ligand charge transfer ( 3 LLCT) and a Ni → R N3 metal-to-ligand charge transfer , further supporting that the lowest excited state (T 1 ) has primarily MC d-d character. For a qualitative representation of the specified transitions between the ground and excited states, we performed a natural transition orbital (NTO) analysis that provides a localized picture of the transition density matrix (Fig. 3b) 42 . The NTO analysis supports the assignment of the 380 nm transition to a T n excited state with a mixed LLCT/MLCT character, while the 633 nm transition involves an electron excitation between predominantly metal-based orbitals, thus indicating a MC (d-d) transition. For 3d transition metal complexes the MC (d-d) state usually lies lower in energy than the CT state(s), due to the intrinsically low ligand field strength, and thus resulting in the relaxation of the CT state to the lowerlying MC (d-d) state 43,44 . Therefore, we propose that on initial population of the MLCT/LLCT state is followed by fast relaxation to the lower MC (d-d) state with an appreciable Ni-Cl σ* orbital character (Fig. 3d), which then promotes a metal-ligand homolytic bond cleavage 45,46  Photocatalytic C-O coupling reactions mediated by ( R N3) NiCl 2 complexes. To probe the relevance of the ( R N3)NiCl 2 complexes in photocatalysis, we evaluated their light-promoted catalytic activity in C-O cross-coupling without any additional photocatalyst. Our initial efforts focused on optimizing the reaction conditions using methanol and 4-bromoacetophenone (Table 1 and Supplementary Tables 2-8). In the presence of 2 mol% ( Me N3)NiCl 2 (1a) and quinuclidine in THF, the desired C-O coupled product 4-methoxyacetophenone was obtained in 95% yield under purple LED (λ max = 390 nm) irradiation ( The same C-O coupling reaction was also probed under common dual Ni/photoredox catalytic conditions using various Ir or Ru photocatalysts and blue LED light (λ max = 456 nm) ( Table 2). The photocatalyst screening experiments revealed that the Ir photocatalysts tested here gave the desired C-O coupled product in 80-98% yield, while the Ru catalysts showed no reactivity.
EPR and reactivity studies. Several reports have proposed the oxidative addition of an organic halide to Ni I to generate a Ni III species is a key step in the C-O cross-coupling catalytic cycle 13,14,47 , yet minimal evidence was provided and such a step has been underexplored experimentally 50,51 . Our Ni catalysts have accessible Ni II/I redox potentials, thus we aimed to probe the reduction of Ni II to Ni I and the subsequent oxidative addition of an aryl halide to generate a Ni III intermediate by using X-band electron paramagnetic resonance (EPR) spectroscopy. For the EPR studies, 1b was used due to its better solubility vs 1a. Upon the reduction of 1b by 1 equiv decamethylcobaltocene (CoCp* 2 ) at −95°C (Fig. 4a), a Ni I species 2 was formed that exhibits a rhombic EPR spectrum with g x = 2.241, g y = 2.113, and g z = 2.049 (Fig. 4d), and suggesting the presence of a metal-based radical. The detection of an EPRactive mononuclear Ni I species is important since such an intermediate is essential for an efficient oxidative addition step. By comparison, in the catalytic systems involving bidentate bipyridine ligands relatively stable dinuclear Ni I species are formed as side products that hinder catalysis, especially at higher substrate concentrations and catalyst loadings 13,47 . In our case, the Ni I species 2 decays rapidly to EPR inactive species in the absence of substrate, yet no dinuclear Ni I species are formed, suggesting that the tridentate R N3 ligand might prevent the formation of such catalytically inactive species due to the steric hindrance provided by the axial amine arm of the R N3 ligand (see Supplementary Figs. 58 and 59 for the space filling models of 1a and 1b). This behavior might explain why higher concentrations of substrate and catalyst can be employed herein, which is in contrast to the conditions utilized in other reported C-O cross-coupling reactions 10,11,14 . When 20 equiv 4-bromoacetophenone were added to a thawing solution of 2 (Fig. 4b), the resulting EPR spectrum could be simulated with two sets of parameters corresponding to two different species in a 0.6:1 ratio and that were tentatively assigned to the initial Ni I species and a new Ni III species (Fig. 4e and Supplementary  Fig. 32). We tentatively propose that the Ni III species is a transient 6-coordinate ( iPr N3)Ni III (PhAc)BrCl (3) complex generated through the oxidative addition of 4-bromoacetophenone to 2. Moreover, when 40 equiv 4-bromoacetophenone were added to 2 (Fig. 4c), only a rhombic EPR signal with g x = 2.298, g y = 2.197, and g z = 2.037 formed (Fig. 4f), which was assigned to the proposed structure 3 and thus strongly supporting a direct conversion from Ni I (2) to Ni III (3) that is promoted by the excess aryl halide. The observed EPR spectrum for 3 decays quickly upon warming up the solution for seconds at −80°C ( Supplementary Fig. 33), supporting the increased reactivity of 3 and its proposed involvement in catalysis. Finally, while the exact structure of this species 3 is not unambiguously known, it is important to note that to the best of our knowledge the direction observation of the oxidation addition of an aryl halide to a Ni I species to generate a Ni III species has not been reported to date. To further probe the role of various Ni III species in the C-O coupling reaction, we independently synthesized the ( iPr N3)Ni II ( -PhAc)Br complex 4 via oxidative addition of 4-bromoacetophenone   to Ni(COD) 2 in the presence of iPr N3 (Fig. 5a). While 4 is unstable in solution at room temperature, rapidly decomposing to the green ( iPr N3)Ni II Br 2 complex, it is stable at −40°C for several hours. The decomposition of a related nickel complex, (bpy)Ni II PhBr, to (bpy) Ni II Br 2 has been observed previously and proposed to proceed via a bimolecular pathway 52,53 . The instability of 4 in solution prevented us from obtaining X-ray quality crystals, nonetheless since 4 is diamagnetic its structural evidence was provided by 1 H NMR obtained at −40°C, which shows a slight peak broadening due to the flexible amine arm (Supplementary Fig. 2) 24 . Oxidation of 4 with acetylferrocenium hexafluorophosphate ( Ac FcPF 6 ) at −40°C generates the Ni III [( iPr N3)Ni III (PhAc)(Br)] + complex 5 (Fig. 5a). The effective magnetic moment μ eff of 1.98 μ b , determined using the Evans method, is consistent with a S = 1/2 ground state for 5, as expected for a Ni III center 33,34 . The rhombic EPR spectrum of 5 with g x = 2.356, g y = 2.158, g z = 2.059 is significantly different than that of 3 (Fig. 5e vs. Fig. 4f), solidifying the proposed 6-coordinate structure for 3 in Fig. 4c. Complex 5 was stable in solution at −35°C and can be isolated as a red solid, yet it was recalcitrant to form single crystals. Therefore, the presence of a Ni III center was further confirmed by X-ray photoelectron spectroscopy (XPS), which shows an increase of the Ni 2p3/2 and 2p1/2 binding energies of~1.5 eV for 5 versus 4, demonstrating the presence of a more oxidized Ni center ( Supplementary Fig. 60) 54 . The appreciable stability of 5 allowed us to investigate its reactivity. When 5 was reacted with 1 equiv tetraethylammonium chloride (TEACl, Fig. 5b), a rhombic EPR spectrum with g x = 2.363, g y = 2.144, g z = 2.047 and sharper signals than the spectrum of 5 was obtained, indicating the likely formation of the [( iPr N3)Ni III (PhAc)(Cl)] + species 6 ( Fig. 5f vs. Fig. 5e). A similar EPR signal broadening due to superhyperfine coupling to the Br atom (I = 3/2) vs the Cl atom (I = 3/2) was observed in a previous study by our group, where the structural analysis of [( tBu N4)Ni III Ar(X)] + complexes (X = Br or Cl) confirmed the effect of the halide ligand onto the corresponding EPR spectra 15 . Importantly, an EPR spectrum resembling the proposed 6-coordinate species ( iPr N3)Ni III (PhAc)BrCl (3) was not observed, supporting the instability of this sterically hindered species. GC-MS analysis of the solution of 6 after warming up to room temperature in the absence of MeOH reveals Ar-Cl product formation ( Supplementary Fig. 37), while the reaction between ( iPr N3)Ni II (PhAc)Br (4) and PhICl 2 generates an EPR spectrum identical to that of 6 ( Supplementary Fig. 39), providing additional experimental evidence for the halide exchange step. Next, we probed the ligand exchange step with an alkoxide. The addition at −80°C of quinuclidine in MeOH to 5 generates a species assigned as the Ni III -aryl alkoxide complex [( iPr N3) Ni III (PhAc)(OMe)] + (7), which exhibits a rhombic EPR signal with g x = 2.326, g y = 2.151, g z = 2.027 and superhyperfine coupling to the one axial N (I = 1) donor in the g z direction of A z (N) = 19.4 G (Fig. 5g). We posit that replacement of the halides that exhibit superhyperfine interactions (Br or Cl, I = 3/2) by the methoxide ligand resolves the superhyperfine coupling to the N atom along the g z direction, while the weaker π-donor methoxide NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-022-28948-8 ARTICLE leads to a stronger Ni-N axial interaction. The identity of 7 was further confirmed by the treatment of 5 with 1 equiv NaOMe, which generated an identical EPR spectrum ( Fig. 5h and Supplementary Fig. 45). Importantly, to the best of our knowledge this is the first experimental observation of a ligand exchange reaction (either by a halide or alkoxide) occurring at a Ni III metal center, which is typically proposed as a key step in Nimediated C-C and C-heteroatom bond formation reactions 55,56 . Finally, we also note that 5 is a catalytically competent species (Supplementary Table 8) and affords the C-O cross-coupled product in 31% yield, suggesting that 5 can successfully enter the catalytic cycle. In this case, the lower yield is likely due to the slight decomposition of 5 in RT during the catalytic reaction.
Upon warming up to room temperature, species 6 and 7 undergo C-O bond-forming reductive elimination, affording 4-methoxyacetophenone together with different amounts of acetophenone ( Fig. 6 and Supplementary Figs. 49-54), and consistent with a favorable reductive elimination from a Ni III species 57,58 . Moreover, the addition of excess anionic ligands (Cl − or OMe − ) leads to increased yields of the C-O coupled product (Fig. 6) and faster decomposition of 6 and 7, as seen in the fast decay of their EPR signals (Supplementary Figs. 42 and 44). We propose that coordination of an additional anionic ligand in the presence of excess base leads to the formation of a congested 6-coordinate Ni III center due to the steric hindrance of the ethylene bridge that blocks the second axial coordination site (Fig. 2d), and consequently results in accelerated C-O reductive elimination. This is also in line with the observed rapid decay of the 6-coordinate species ( iPr N3)Ni III (PhAc)BrCl (3, Fig. 4c and Supplementary Fig. 33). In addition, the rapid reductive elimination from a 6-coordinate Ni III center may preclude β-hydride elimination (Fig. 6, entry 6), which is likely the source of the formation of b. Overall, these EPR and reactivity studies provide a complete picture of the Ni I /Ni III catalytic cycle for the C-O cross-coupling reaction, with experimental evidence for each essential step in this process: oxidative addition, transmetalation/ligand exchange, and reductive elimination.
Mechanistic considerations. Finally, based on the photoredox/Ni dual catalytic studies under blue LED light (Table 2), we evaluated the thermodynamic feasibility of the photocatalytic process in the C-O coupling reaction. A comparison of the redox potentials of the Ni complexes and photocatalysts implies that a reductive quenching pathway is not operating, as the observed production yields contradicts the trend of the oxidation strength of excited photocatalysts (see Supplementary Discussion). Instead, an oxidative quenching pathway is proposed to be operative, in which the initial step is the single-electron reduction of Ni II by the excited photocatalyst, and this is in line with our results in which all photocatalysts with E(M + /*M) < −0.87 V afford the C-O coupling product. By combining the insights obtained from EPR and reactivity studies and the photoredox/Ni dual catalysis, two photocatalytic mechanisms are proposed (Fig. 7). The ( R N3)Ni II complex is reduced to a Ni I species either by irradiation with purple LED light (Fig. 7a) or via a single  electron transfer (SET) from the excited photocatalyst (Fig. 7b), followed by an oxidative addition of the aryl halide to form a transient ( R N3)Ni III Ar(Br)X species. For both of the direct lightpromoted Ni catalysis and dual Ni/photoredox catalysis, the ( R N3)Ni III species can undergo a ligand exchange with the alcohol substrate in presence of excess base to generate the ( R N3) Ni III Ar(OR)X species, which is then proposed to undergo a subsequent reductive elimination to yield the C-O coupled product and regenerate a ( R N3)Ni I species, completing the catalytic cycle. As the proposed catalytic cycle in Fig. 7a suggests a Ni I / Ni III dark catalytic cycle, then the theoretical quantum yield for the light-promoted Ni catalysis should be above 1 (Φ Ni > 1). The measured quantum yield was determined experimentally to be below 1 (Φ Ni < 0.26, Supplementary information page 32), which is likely due to the less efficient absorption of light in the heterogeneous reaction mixture that contains insoluble material and thus prevents an accurate determination of the number of photons absorbed by Ni under catalytic conditions. In addition, the quantum yield (Φ Ni < 0.26) obtained by actinometry could be significantly overestimated. Given that there are several possible side reactions that would generate off-cycle Ni II species, if Φ Ni ≪ 1, then the dark Ni I /Ni III dark catalytic cycle may not be able to compensate for the deleterious side reactions. While values of Φ > 1 were reported previously for similar photoredox/Ni dual catalysis C-O cross-coupling reactions 13 , a dark Ni I /Ni III cycle cannot be unambiguously ruled out. To provide further evidence for a dark catalytic cycle, we performed a light on/off experiment and employed ReactIR to monitor in real time the consumption of the starting material 4-bromoacetophenone, which exhibits a characteristic IR C=O stretch at 1690 cm −1 (Supplementary information page 34). When the reaction was performed with the light on 25% of the time and the light off 75% of the time, the reaction yield was only marginally lower than when the reaction was performed under continuous illumination (Supplementary Table 9), while the ReactIR monitoring clearly showed the continuous consumption of the substrate during the light-off periods ( Supplementary Fig. 25). Overall, these results strongly support a self-sustained Ni I /Ni III cycle, although continuous irradiation during catalysis seems to be beneficial to regenerate any depleted ( R N3)Ni I species due to a Ni I /Ni III comproportionation process.
To further probe the proposed Ni I /Ni III comproportionation reaction that can generate off-cycle Ni II species, we investigated this process via EPR and NMR spectroscopy. The reaction between 5 and in situ generated 2 (i.e., 1b + CoCp* 2 ) leads to the rapid decay of the EPR signal, indicating the decomposition of 5 and conversion into an EPR inactive species (Supplementary Fig. 26). In addition, NMR analysis of the reaction confirmed the formation of ( iPr N3) Ni II Cl 2 complex 1b as the terminal product of comproportionation, along with several organic products ( Supplementary Figs. 27-30). These EPR and NMR results thus support the deleterious Ni I /Ni III comproportionation leading to off-cycle Ni II -dihalide species, which can re-enter the catalytic cycle upon photoexcitation and is also consistent with previously reported computational 13 and experimental reports 59 . For the proposed dual Ni/photoredox catalysis (Fig. 7b), the ( R N3)Ni I species can directly re-enter the catalytic cycle, or it can be oxidized to the ( R N3)Ni II complex via an SET process with the oxidized photocatalyst Ir IV , thus regenerating the Ir III photocatalyst. Overall, both mechanisms are proposed to involve both Ni I and Ni III intermediates, which are involved in the oxidation addition step, and the ligand exchange/transmetalation and reductive elimination steps, respectively. The main difference between the two pathways is the generation of the catalytically active ( R N3)Ni I species, either through light-promoted reduction of the Ni II precursor (Fig. 7a), or by the excited photocatalyst (Fig. 7b).
In conclusion, herein we report the tridentate pyridinophane R N3 ligands and their Ni complexes, which were employed in mechanistic studies of the photocatalytic C-O cross-coupling reaction. The ( R N3)NiCl 2 complexes are active photocatalysts for the C-O cross-coupling in the absence of a precious metal photocatalyst. Employing these developed R N3 ligands allowed us to directly probe the key steps of the C-O cross-coupling catalytic cycle involving paramagnetic Ni species: the oxidative addition of an aryl halide to a Ni I species to generate a Ni III species, the ligand exchange/transmetalation step at a Ni III center, and the C-O bond forming reductive elimination from a Ni III species. Overall, the present work suggests that the R N3 ligands can lead to the development of improved Ni catalysts, and are also a practical platform for detailed mechanistic studies of related Ni-catalyzed reactions.

Methods
General procedure for the C-O cross-coupling reaction. In a N 2 -filled glovebox, 4-bromoacetophenone (0.4 mmol, 1.0 equiv), quinuclidine (0.44 mmol, 1.1 equiv), MeOH (1.6 mmol, 4 equiv), ( Me N3)NiCl 2 (2 mol%), and a magnetic stir bar were added into 0.4 mL THF in a vial. The vial was irradiated with one Kessil purple LED lamp (λ max = 390 nm, max 52 W) under fan cooling. After 24 h, 1,3-benzodioxole (0.4 mmol) was added to the reaction mixture at a standard, and the reaction mixture was analyzed by 1 H NMR in CDCl 3 and GC-FID to determine the yield of C-O coupled product. Authentic 4-methoxyacetophenone was purchased from AK scientific and used to determine the retention time and response factor for GC-FID quantification.
General procedure for EPR detection of 2 and 3. In a N 2 -filled glovebox, a MeOH solution of 1b was layered on top of a frozen PrCN solution of CoCp* 2 and 4-bromoacetophenone in the EPR tube. The mixture was quickly frozen and taken outside of the glove box. The reaction mixture was mixed at −95°C, quickly frozen at 77 K, and then the sample was warmed up for~10 s to −95°C to allow for a complete reaction.
General procedure for EPR detection of 5, 6, and 7. In a N 2 -filled glovebox, an EPR tube was charged with 1:3 CH 2 Cl 2 :Toluene or CH 2 Cl 2 :PrCN solution of 5 and frozen at 77 K. A MeOH solution of TEACl, quinuclidine, or NaOMe was added over the frozen solution of 5. After taking out the EPR tube from the glovebox, an initial EPR spectrum was taken at 77 K (for 5). After a quick shake of the tube for 10 s at −95°C (for 6 or 7), the sample was frozen at 77 K and the EPR spectrum was collected.

Data availability
The crystallographic data generated in this study have been deposited in the Cambridge Crystallographic Data Center database under deposition numbers CCDC 2085516 (1a) and 2085517 (1b). The synthetic details, spectroscopic and electrochemical characterization of new compounds, computational details, mechanistic studies, and X-ray crystallographic data generated in this study are provided in the Supplementary Information file. Any additional data that support the findings of this study are available from the corresponding author upon request. reactions of (2,2'-Bipyridine)Ni(OCH2CH2CH2CH2). J. Am. Chem. Soc. 115, 2075Soc. 115, -2077Soc. 115, (1993