Hole-mediated PhotoRedox Catalysis: Tris( p -substituted)biarylaminium Radical Cations as Tunable, Precomplexing and Potent Photooxidants.

: Electrochemically-mediated Photoredox Catalysis emerged as a powerful synthetic technique in recent years, overcoming fundamental limitations of electrochemistry and photoredox catalysis in the single electron transfer activation of small organic molecules. However, the mechanism of how photoexcited radical ion species with ultrashort (picosecond-order) lifetimes could ever undergo productive photochemistry has eluded synthetic chemists. We report tri( para -substituted)biarylamines as a tunable class of electroactivated photocatalysts that become superoxidants in their photoexcited states, even able to oxidize molecules (such as dichlorobenzene and trifluorotoluene) beyond the solvent window limits of cyclic voltammetry. Furthermore, we demonstrate that precomplexation not only permits the excited state photochemistry of tris( para -substituted)biarylaminium cations, but enables and rationalizes the surprising photochemistry of their higher-order doublet (D n ) excited states. these complexes could be converged or dissociated. cases, a solvent of MeCN modelled implicitly. I Br atoms Supplementary Intermolecular centroid-to-centroid the Supplementary Hypothesized precomplex matches


Introduction Synthetic Organic Electrochemistry (SOE) (1-5) and visible light PhotoRedox
Catalysis (PRC), (6)(7)(8)(9)(10)(11)(12) which offer entries to single electron transfer (SET) chemistry and radical intermediates under mild conditions, have risen to the fore of contemporary organic synthesis. A key factor underpinning the success of PRC is the host of available photocatalyst structures with well-characterized photophysical and redox data, allowing chemists to match a given excited state to a desired process. Although PRC exhibits a selectivity benefit in transferring the energy of visible light photons to a colored transition metal-based or organic dye photocatalyst, its scope of applications are redox potential-limited by the energy of single photons (ca. 1.8-3.1 eV).
Multiple-photon-accumulating strategies such as consecutive photoelectron transfer (conPET) (13)(14)(15)(16)(17) and triplet-triplet annihilation upconversion (TTA-UC), (18)(19)(20) have represented an elegant means to achieve powerful SET reductions, but their use in oxidations has so far been elusive. However, these techniques place limiting requirements on reactions, such as the requirement in conPET for both ground and radical ion states to be visible-light active. Furthermore, net-oxidative/reductive PRC processes employ excess of a sacrificial oxidant/reductant which is necessary for photocatalyst turnover, but which may (or whose by-products may) i) interfere with the desired downstream chemistry and ii) may require separation from the desired products. The conPET strategy likewise suffers from this requirement. In comparison to PRC processes, SOE can employ uncapped potentials to chemical redox reactions at the turn of a dial. However, electrode surfaces typically (21)(22) cannot discriminate between organic molecules aside from their innate order of thermodynamic redox potentials. Moreover, low electrical conductivity in organic solvents typically require applied potentials to be higher than the redox potential of the target substrate. (23) This encourages deleterious higher order or solvent redox processes especially if target SET processes lie near the solvent electroactive window (+3 to -3 V for typical electrolyte-containing solvents). (23)(24)(25) In addition, mechanistic characterization of the heterogeneous "electrocatalysis" step (referring to heterogeneous SET at the electrode surface) (26) has remained a key challenge in SOE. Screening of electrode materials is often inevitable, despite best efforts to characterize materials by overpotential, electrical resistivity, surface area, stability and cost. (27)(28) As a result of these limitations, in recent years synthetic photoelectochemistry is emerging as a state-of-the-art in SET-mediated chemistry. (29)(30)(31)(32)(33) Different categories for the merger of photochemistry and electrochemistry have been reported, including interfacial photoelectrochemistry (iPEC) involving photoelectrodes (34)(35)(36)(37) and decoupled photoelectrochemistry (dPEC) where photo-and electrochemical steps serve separate roles in the reaction mechanism. (38-39) A third category involves an intimate and synergistic relationship of photo-and electrochemical steps within the same catalytic cycle. (40)(41)(42)(43)(44)(45)(46)(47)(48)(49)(50)(51) A variety of nomenclature has been coined in the literature for this sub-category of PEC, such as: "electrophotocatalysis" (45)(46)(47)51) "photoelectrocatalysis" (46,50) and "electron-primed photoredox catalysis" (51). We coined the general nomenclature "electrochemically-mediated PhotoRedox Catalysis (e-PRC)" as a blanket term to cover both net-oxidative and net-reductive variants (29) and to avoid misunderstanding with iPEC. e-PRC leverages the unique benefits of both parent technologies PRC and SOE in order to i) compile potential and photon energies to achieve photocatalyst excited-state potentials beyond those normally accessible via visible light photons alone (44)(45)(46)51) and to ii) obviate the need for sacrificial oxidants/reductants. (48,50) Pioneering reports on e-PRC realized these benefits in a number of net-reductive/net-oxidative transformations. (44)(45)(46)(47)(48)(49)(50)(51) (Figure 1).

Synthetic Results
We began by screening different TPA e-PRCats (Generation 1, Figure 2) with different half-wave oxidation potentials in the Nicewicz model reaction; (66) the oxidative C-H amination of mesitylene (E p ox = +2.1 V vs. SCE) (66) with pyrazole ( Table 1) No product was observed in the absence of light and only traces in the absence of potential (4%) or TPA e-PRCat (2%), confirming the operation of e-PRC. Generally, the yield of 3aa increased with increasing oxidation half-wave potentials (E1/2) of the TPA (Figure 2 and Table 1, suggesting that the TPA .+ 's excited state potential is more relevant to success than the steady-state concentration of electrogenerated radical cation.    Interestingly, tri([1,1'-biphenyl]-4-yl)amine (TpBPA) afforded a notably higher yield of 3aa than the commercial tris(4-bromophenyl)amine (entry 4) despite having an appreciably lower E1/2.
Comparisons of the UV-visible spectra of TPA .+ revealed a plausible explanation; that TpBPA benefitted from the strongest absorption at 400 nm. Decreasing LED input power by ca. 10x decreased the yield (entry 5). Screening of other protic sources revealed MeOH to be most effective (entry 6). Carbon foam was a superior anodic WE to carbon felt, likely due to its higher surface area (entries 6-7). Gratifyingly, screening of other CE materials revealed copper to be the optimal cathodic CE (entries [8][9]. A decreased TpBPA loading (5%) gave an inferior (but still high) yield (entry 10) and LiClO4 as an electrolyte was inferior (entry 11). While DMF as solvent gave no reaction, we were surprised the reaction performed well in DCM as solvent, despite its lower conductivity (entries [12][13]. The yield of 3aa tracked well with increasing applied constant potential  With optimal conditions in hand, the amination of arenes with a variety of pharmaceutically-relevant N-heterocycles was explored ( Table 2). Halide-bearing and carbonyl (aldehyde, ketone and ester)-bearing pyrazoles, triazole, benzotriazole, and a functionalized derivative of benzimidazole afforded generally good to excellent (50-89%) yields of aminated mesitylenes 3aa-3aj. We note that benzimidazole derivatives have not been reported as nucleophiles in previous photoelectrochemical arene amination or conPET photocatalytic methods. (37,45,67) 6-Chloro-2-fluoropurine afforded a modest yield of 3ak (32%), presumably due to its steric hinderance as a nucleophile. Xylenes and toluene were tolerated to afford aminated arenes 3bb-3fb in moderate to excellent (30-88%) yields. Table 2. e-PRC C-H heteroaminations using TpBPA.
Unless otherwise stated, all reactions used 3.5 eq. arene; isolated yields. Yields in parenthesis determined by 1 H NMR. a A Pt CE was used and AcOH.
Interestingly, the product yields of xylenes followed the order meta-> ortho-> para-xylene, despite the E p ox following the opposite trend. (68) Toluene has an even higher E p ox than xylenes but reacted to give 81% of 3eb. (68) Bromobenzene afforded a 30% yield of 3fb with notable r.s.m., while iodobenzene gave no reaction at all (60% r.s.m.). Benzene and PhCl were unsuccessful, presumably due to their notably higher E p ox (only a 10% yield of 3gb's combined C1/C3 isomers was obtained, even when using a large excess of PhCl and after 72 h). Substitution of Cu for Pt wire cathode increased the yield to 15%; substitution of MeOH for AcOH increased the yield to 35% ( Table 3).
Despite exhaustive efforts, we could not improve the conversion/yield beyond this threshold.   Figure 4. Generation 2 TPA e-PRCats, and the XRD structure of TCPBA. Thermal ellipsoids are set at the 50% probability level. Hydrogen atoms are omitted for clarity. C atoms shown in grey, and N atoms in blue.
Leveraging the facile synthetic customization of TPAs, we synthesized derivatives of TpBPA ( Figure   4) with electron-withdrawing groups to bolster their respective TPA .+ excited state potentials (entries 1-4). Of these, we were delighted to find that tris(4'-cyano-[1,1'-biphenyl]-4-yl)amine (TCBPA) increased the yield of 3gb to 46% ( Table 3). In contrast to TpBPA, the optimal TCBPA catalyst loading was 5 mol% (entries 4-8), increasing the yield of 3gb to 69% with no detected starting material (entry 6). Notably, the reaction was still quite efficient with only 1.5 mol% of TCBPA (entry 8). With these optimal conditions in hand, reactions of PhCl, benzene and even fluorobenzene were enabled, affording 3gb-3ib in modest to good (30-65%) yields (Table 4). Interestingly, under the same applied constant potential Ucell as in Table 2 and in contrast to the use of TpBPA, here toluene underwent benzylic oxidation instead of amination, while a pyrazole-4-carboxaldehyde (either before or after benzene C-H amination) underwent oxidation to its carboxylic acid (Table 4, bottom). Bromobenzene gave a lower yield of 3fb than that in Table 2. The above observations indicate a less oxidizing TPA .+ excited state (such as that from TpBPA .+ ) is beneficial for certain substrates and demonstrates the value of tunability presented by this class of e-PRCats. We further probed the limits of arene SET oxidations with TCBPA .+ , by targeting 1,2-dichlorobenzene and trifluorotoluene, and were encouraged to detect products, albeit in low yields, from each when using TCBPA (17% of 3jb and 7%, respectively). Yields did not increase with extended reaction time (96 h) or higher applied potential (Ucell = +1.8 V), which suggested that we had reached the oxidizing limit of this photoexcited TPA .+ . Gratifyingly, further e-PRCat tuning in the form of the even more electron-deficient tris(2',4'-dicyano-[1,1'-biphenyl]-4-yl)amine (TdCBPA) increased the yield of 3jb to a much more satisfactory 31% (Table 5). Although polyfluorinated arenes were activated to afford 3ob and 3hb in only modest yields (~20%), it should be emphasized that oxidative SNAr-type activation of such challenging substrates with pyrazoles has not to our knowledge been previously accomplished. In  An intriguing theme running through the TPA-mediated e-PRC substrate scope is the apparent influence of steric effects on reactivity. In contrast to a previous report (45) and in line with the trends observed in Table 2 The aforementioned control reaction without applied potential afforded only 4% of 3aa. In contrast to TpBPA, TCBPA is a pale yellow solid that does absorb appreciably at 400 nm. Nevertheless, in the absence of an applied potential for the optimized synthesis of 3gb, only a 12% yield of 3gb was observed. The detection of small amounts of product in the aforementioned control reactions corroborates a conPET-type mechanism (13)(14)(15)(16)(17) where photoexcitation of TpBPA or TCBPA leads to SET reduction of protons or trace O2 (reactions were bubbled by N2 for 5 min during preparation and sealed; no further strict precautions were taken) to generate the corresponding TPA .+ . In any case however, the very substantial yield differences when applied potential is present or absent confirm the pivotal role of the TPA .+ s and that e-PRC is the main product-forming pathway in both reactions. Greatly aiding our mechanistic study of this phenomenon was the fact that TPA .+ s can be preparatively isolated as their bench stable PF6 salts. (65) Their XRD crystal structures revealed a common propeller-type structure, also observed for parent TPAs (Figure 7). However, attempts to investigate quenching of photoexcited TPA .+ s were thwarted by the fact that they do not exhibit respectively, clearly ruling out photochemistry by diffusion-control and bimolecular quenching. It is reasonable to assume that higher order excited states possess even shorter lifetimes, and that precomplexation can therefore be the only rationalization for productive, unimolecular SET and the aforementioned anti-Kasha behaviour.  (Figure 9). In the presence of mesitylene, the spectrum of TpBPA .+ was unchanged.
Gratifyingly, irradiation with 400 nm light effected gradual conversion of TpBPA .+ to TpBPA, corroborating the expected SET from mesitylene to the photoexcited TPA .+ . Interestingly and in contrast, the spectrum of TCBPA .+ was altered by addition of PhCl; a small bathochromic perturbation of the peak at 384 nm to 395 nm occurred, indicating complexation between TCBPA .+ and PhCl. Irradiation with 400 nm led to complete conversion of TCBPA .+ to TCBPA after 5 min.
Given the paramagnetic nature of these species, we reasoned that a change in the EPR spectra of TPA .+ s in the presence of arene substrates (350 eq., mirroring the reaction conditions) would be more conclusive in corroborating precomplexation.    calculations were employed to model precomplexation of various TPA .+ /arene combinations ( Table   6). For unsymmetrical (halo)arene substrates, orientations of the complex with halogen facing both 'in' to the N radical cation and 'out' were explored (see Supplementary Information for full investigations). We assumed that -stacking interactions (81-82) at the TPA .+ 's biphenyl unit could be responsible for precomplexation. Attempts to position PhCl or mesitylene substrates in a sandwich or parallel-displaced - stacking interaction ("-" complex) around the inner N-bearing ring of their respective TPA .+ s led predominantly to dissociation, whereas positioning of the substrates around the terminal aromatic ring identified a local minima for the complexes resembling a T-type stacking interaction ("T-" complex). For this complex, minimal change in the spin density was detected for TpBPA .+ + mesitylene (Figure 12), whereas a large shift in spin density occurred for TCBPA .+ + PhCl where the Cl atom was facing inwards (Figure 13). This is consistent with the changes in EPR and UV-vis spectra, and so we assigned this "T-" complex as the one responsible for the triplet EPR signal and successful reactivity, since the oxidizing power of the N radical cation remains localized on its N atom. On the other hand, for less successful substrate PhBr and unsuccessful PhI (no product, 60% 2b recovered), a "-" complex was presumed to be responsible for the broad singlet EPR signal. Delocalization of the N radical cation over the biphenyl aromatic system would lead to stabilization, presumably decreasing E p ox of the photoexcited TPA .+ . Table 6. Free energies and intermolecular distances for T- or - precomplexes.
Complex a Complexation G (kcal mol -1 ) Intermolecular distance (Å)  Table 4). Iodo-and bromobenzene as substrates gave very high G values for T- complexes and their - complexes were more accessible albeit still highly endergonic. Attempts to obtain a T- complex for TCBPA .+ with 1,4-dichlorobenzene led to dissociation, while its- complex was found to be accessible.   A mechanism is proposed consistent with spectroscopic and computational studies herein ( Figure   16). Anodic SET oxidation generates the TPA .+ from its TPA. Photoexcitation of the TPA .+ to its D1/D2 or higher Dn states followed by bimolecular SET reductive quenching is prohibited by the TPA .+ 's picosecond lifetime. Instead, preassociation occurs to give a reactive T- or an unreactive - precomplex, depending on the sterics of the arene substrate. In the latter case, conjugative stabilization of the N radical cation decreases E p ox of the *TPA .+ below the threshold for productive unimolecular SET such that photoexcitation leads simply to non-radiative photophysical relaxation processes (such as internal conversion). In the former case, photoexcitation yields unimolecular SET reductive quenching of the *TPA .+ , regenerating the TPA and generating the arene radical cation to be intercepted by the N-heterocyclic nucleophile 2b followed by loss of protons and further SET (anodic or by the TPA .+ ) to yield product 3. The prerequisite for precomplexation rationalizes the typical requirement for an excess of arene (3.5 eq. up to 1 mL, ~40 eq. herein) to drive precomplexation equilibrium in arene amination reactions mediated by radical cations (45)(46). particularly an advantage over direct electrolysis, where electrodes typically discriminate between molecules based on redox potentials. In context of the findings herein, we foresee 'Pre-PRC' as an important next evolution of photoredox catalysis, that presents tremendous opportunities in novel reactivity and selectivity to the synthetic chemist.

Acknowledgments
We thank the Alexander von Humboldt Foundation for funding, provided within the framework of the Sofja Kovalevskaja Award endowed by the German Federal Ministry of Education and Research.
We thank Prof. John C. Walton for helpful discussions on the interpretation of EPR spectra. We thank Regina Hoheisel for assistance and training in spectroelectrochemical measurements. We thank Prof.
Patrick Nuernberger and Dr. Roger-Jan Kutta for insightful discussions on the photophysics of