Electrochemical Activation of Diverse Conventional Photoredox Catalysts Induces Potent Photoreductant Activity

Abstract

Herein, we disclose that electrochemical stimulation induces new photocatalytic activity from a range of structurally diverse conventional photocatalysts. These studies uncover a new electron primed photoredox catalyst capable of promoting the reductive cleavage of strong C(sp²)–N and C(sp²)–O bonds even when reduction potentials hundreds of mV more negative than Li⁰ are required. We illustrate several examples of the synthetic utility of these deeply reducing but otherwise safe and mild catalytic conditions. Finally, we employ electrochemical current measurements to perform a reaction progress kinetic analysis. This technique reveals that the improved activity of this new system is a consequence of an enhanced catalyst stability profile.

Graphical Abstract

Electrochemical activation of numerous conventional photocatalysts was found to induce potent photoreductant activity. These studies resulted in the discovery of an electron-primed photoredox catalyst capable of cleaving strong aryl C–N and C–O bonds to aryl radical intermediates. Mechanistic experiments revealed that enhanced activity relative to previously developed electron-primed photoredox systems was a result of improved catalyst stability.

Introduction

Reductive activation of organic molecules through single electron transfer (SET) is a fundamental elementary step at the heart of a myriad of synthetically useful transformations.^[1–4] In recent years, photoredox catalysis has emerged as a mild and chemoselective method to induce redox events.^[5–10] Unfortunately, while 400 nm light possesses sufficient energy for a maximum driving force of 3.1 eV, this energy is diminished by 25–50% through vibrational relaxation, internal conversion, and intersystem crossing.^[11] As a consequence, many abundant but thermodynamically stable molecules remain inert to photoredox activation.^[12],[13] Indeed, in the context of reductions, alkali metals have remained reductants of unparalleled potency for over a century. These reagents continue to be used in both academic^[14,15] and industrial^[16] settings despite their implicit hazards, poor chemoselectivity, and inextricable chemical waste. To address this, the development of new strategies to deliver extreme reduction potentials (significantly more negative than –2 V vs. SCE) with the safety and chemoselectivity profile of photoredox catalysis is an emerging area of considerable contemporary interest.^[11,17–22]

Over the past several years, numerous groups,^[23–28] including ours,^[26] have examined catalytic systems designed to leverage mildly reducing radical species as a new family of photocatalysts (Figure 1, top). We have dubbed these reductively activated species electron-primed photoredox catalysts to distinguish them from more conventional photocatalytic reductants. Pioneering work from König used a consecutive photoinduced electron transfer (conPET) approach to photochemically generate an electron-primed photocatalyst, albeit one that did not possess an excited state reduction potentials more negative than –2 V vs. SCE.^[29] The conPET strategy requires a carefully balanced system; both catalyst oxidation states must engage in excited state intermolecular SET under a single set of reaction conditions.^[19] Additionally, the byproducts of catalyst activation, which are typically reactive amine radical cations and easily reduced iminium ions, must not deactivate the catalyst or interfere in subsequent steps.^[30] These fundamental challenges associated with catalyst generation and turnover have resulted in only a small collection of electron-primed photocatalytic systems being identified in the subsequent years^[29,31] despite photophysical studies establishing that numerous persistent radical anions absorb visible light.^[32–36]

Figure 1:

(top) established catalysts known to promote reductive SET events through electron-primed photoredox catalysis and (bottom) electrochemically driven electron-primed photoredox catalysis and a new catalyst discovered in this work derived from 4-DPAIPN. Ar = 2,6-diisopropylphenyl. R = p-OMePh. R' = 2-ethylhexyl.

We envisioned that electrochemistry would offer a flexible approach to generate electron-primed photoredox catalysts as cathodic reduction is highly tunable and divided cell electrolysis excludes interfering oxidized byproducts.^[37–39] Indeed, we previously used this approach to introduce a novel electron-primed photocatalyst capable of reducing aryl chloride substrates with E_red negative than Li⁰.^[26] Contemporaneous efforts by Lambert and Lin disclosed that 9,10-dicyanoanthracene, an electron-primed photoredox catalyst previously accessed via conPET,^[31] exhibits enhanced reactivity towards aryl chloride substrates when driven electrochemically.^[25] However, while these two discoveries validated the use of electrochemistry to generate potent photoreductants, both of these electrophotocatalysts remained structurally analogous to established conPET-based photocatalysts. While rapid progress has been made in net-oxidative electrophotocatalytic transformations,^[40–48] electrophotocatalytic reductions remain comparatively underdeveloped.^[49,50] Herein, we employ cathodic reduction to elicit new photocatalytic activity from numerous organic and inorganic structures. These studies reveal a new electron-primed photoredox catalyst that enables cleavage of strong C(sp²)–N and C(sp²)–O bonds.

Results and Discussion

The generation of aryl radical intermediates is a well-established arena to benchmark new photoreductants. Bench-stable^[51–54] trialkylanilinium salts and activated phenols are readily accessible and can be reductively cleaved to aryl radical intermediates through deeply reducing direct electrolysis or alkali metal reductants, however, they remain difficult to activate under photocatalytic conditions.^[55,56] Within the past year, Larionov and König illustrated that anilide and thiolate photocatalysts are capable of promoting the borylation of anilinium salts and activated phenols via photoreduction.^[57,58] However, boron plays a non-innocent role in these processes and photochemical net-reductive transformations of these substrates remains limited. Reductive defunctionalization is a powerful synthetic tactic to leverage aniline and phenol activating groups in a traceless manner.^[59–62] Current methods to remove these directing groups rely on harsh dissolving metal conditions^[63,64] or palladium catalysis.^[65,66] We envisioned that cleavage of these strong bonds was a perfect arena to explore new potent reductants given recently reported halogen-atom transfer strategies, which in some cases can circumvent deeply reducing potentials,^[67] are unlikely to be amenable to the cleavage of these less polarizable heteroatoms.^[68,69]

We initiated our studies with the reductive cleavage of an N,N,N-trimethyl anilinium salt, 1 (Table 1). We anticipated that the thermodynamic and kinetic challenges presented by aryl C(sp²)–N bond cleavage would expose the limitations of current electron-primed photocatalysts. We found that NpMI, the electron-primed photoredox catalyst we recently reported,^[26] could cleave the C(sp²)–N bond in 42% yield under a constant cathodic potential and visible light irradiation. This result validated that an electron-primed photoredox system is capable of engaging this substrate but also highlighted the need for improved catalysts. We next evaluated a collection of structures related to the NpMI core. Electrochemistry facilitated rapid catalyst evaluation in two primary ways: (1) cyclic voltammetry studies established the minimum cathodic potential to generate the radical anion photocatalyst and (2) evaluation of wavelength dependent photocurrent established the optimal irradiation wavelength (see SI for details).^[70] These studies revealed that various derivatives of NpMI including NpDI, PMI, and NpImz each provided the defunctionalized product, albeit in reduced yield relative to NpMI. Given these data, we concluded that a fundamentally different catalyst scaffold was likely necessary to efficiently promote these challenging reductions.

Table 1:

Evaluation of Electrochemically-Generated Persistant Radical Anions for Photocatalytic Activity^a,b

^aReactions were conducted on a 0.2 mmol scale in DMF (0.1 M ⁿBu₄NPF₆) with RVC cathode and anode. Reaction were run for 12 hours. Yields provided are of 2, determined by GC analysis.

^ball redox potentials reported relative to SCE.

^cAr = 2,6-diisopropylphenyl.

^dReaction was conducted with 1 mol % catalyst. See the supportlng information (SI) for further details.

We next targeted more structurally diverse persistent radical anion precursors that have not been explored as electron-primed photocatalysts.^[36,71–74] We found that phenazine, fluorenone, and fluorescein each promote reduction of 1 in comparable yields to NpMI under appropriate electrophotocatalytic conditions. Control reactions revealed that no conversion is observed in the absence of electrolysis indicating that the photoactivity of the neutral structures is insufficient to drive defunctionalization of 1. These data suggest that electrochemical reduction can coax potent photocatalytic activity out of a much broader range of molecules than previously appreciated. Next, we recognized that nearly all photoredox catalysts, by design, undergo reversible redox events and many possess persistent radical anion congeners.^[6,10,75] We questioned whether the structural features that render molecules effective as conventional photoredox catalysts would translate to the electron-primed photoredox manifold.^[76,23,77] Intriguingly, we found that electrolysis at the Ered of several commonly employed photoredox catalysts Ru(bpy)₃,^[78] Ir(dF-CF₃-ppy)₂(dtbpy),^[78] and 4-CzIPN^[79] turned on photocatalytic activity in this challenging reduction.^[80] While there is a sole report proposing photochemical activity of the reduced congener of an Ir-based photoredox catalyst,^[81] these are the first data consistent with either Ru-based or isophthalonitrile structures acting as electron-primed photoredox catalysts. Given that cathodic reduction of 4-CzIPN resulted in a meaningful improvement in photochemical deamination yield, we examined other isophthalonitrile catalysts. This investigation revealed that 4-DPAIPN^[82] promotes the reduction of model substrate 1 in nearly quantitative yield under electrophotocatalytic conditions. Overall, the structural diversity of the potent photocatalysts identified through these studies suggest that reductively induced photoactivity is a general phenomenon and provides a clear link between catalyst structure and reaction outcome.

We next evaluated whether 4-DPAIPN was promoting this reaction through excitation of a cathodically generated species. Under electrochemical stimulation 4-DPAIPN acts as a far more potent photoreductant than anticipated by its established redox potentials (E_1/2 PC+/PC*) = −1.3 V and E_1/2 (PC/PC•-) = −1.5 V vs. SCE)^[82] (Figure 2). First, we conducted a series of control experiments and found that catalyst, electrolysis, and light were all required for product formation. Next, we examined whether electrochemical reductio no f4-DPAIPN was necessary to promote the defunctionalization reaction. Inspired by an elegant experiment conducted by Lambert and Lin,^[25] we measured the defunctionalization yield at varied cathodic potentials. Overlaying these data with the cyclic voltammogram of 4-DPAIPN illustrates that reactivity is observed only when a sufficient potential to reduce 4-DPAIPN is applied. These data are fully consistent with cathodic catalyst reduction and subsequent excitation as necessary steps for this difficult reductive transformation.^[83]

Figure 2:

Reactions were conducted on a 0.2 mmol scale in DMF (0.1 M ⁿBu₄NPF₆) and run for 12 hours. ^aCV is of 4-DPAIPN. See Supporting Information (SI) for more details.

We next probed the scope of this catalytic C(sp²)–N cleavage process (Table 2). We found ethers (4), free alcohols (5), esters (6), and amides (7) as well as heterocycles such as piperazine (7), pyrrolidine (8), and morpholine (9) were all welltolerated. Notably, this reaction enables a molecular editing strategy wherein an N-aryl ring can be replaced by an alkyl group through an alkylation/reductive cleavage sequence (11) as both aryl and amine fragments can be recovered after C(sp²)–N reduction. Given the promising activity of this catalytic system in the cleavage of anilinium salts, we turned our attention to more difficult to reduce C(sp²)–O bonds. Phenol derivatives (e.g. triflates and phosphates) possess deep reduction potentials (typically <–2.7 V vs. SCE).^[84–86] Despite the energetic demands of C(sp²)–O cleavage, phosphate ester substrates bearing a range of functional groups such as esters (13), amides (14), ethers (15), benzylic amines (16), unprotected alcohols and tertiary amines (18) as well as heterocycles such as imidazole (17) and piperazine (19) each underwent productive C(sp²)–O cleavage. While each of these reactions are conducted far below the cathodic potential required to reduce the substrate, we questioned whether deeply reducing electrolysis could recapitulate this electrophotocatalytic activity. To probe this, we carried out direct electrolysis reactions on two substrates bearing functional groups to investigate the role of the catalyst in preserving chemoselectivity. Under constant current conditions in the absence of catalyst, 16 and 19 showed significant conversion to an intractable mixture containing <20% product. By promoting reduction through a photocatalytic mediator under mild electrochemical potentials, chemoselectivity and functional group tolerance can be vastly improved compared to direct electrolysis conditions.

Table 2:

Scope of Aryl C(sp²)-N and C(sp²)-O Bond Cleavage^a

^aReactions were conducted on a 0.2 mmol scale and run for 12 h in a divided celi with RVC electrodes. Et₃N (2 equiv) was added to the anodic chamber as a terminal reductant.

^bThe counter ion is OTf unless otherwise noted.

^c1 used as the iodide salt.

^dNMR yield.

^eGC yield. See the SI for experimental detalls.

Phenols are electron-donating groups that enable a wide range of reactions at the arene core.^[87–91] We envisioned that the scope of products accessible using these processes could be expanded through a chemoselective excision of the phenolic activating group via an electrophotocatalytic system (Figure 3). For example, this strategy allows selective formation of meta-substituted products inaccessible via direct Friedel–Crafts reactions.^[92] To illustrate this strategy, we prepared a suite of meta-substituted arene products from simple precursors using a phenol-directed alkylation-defunctionalization sequence (20–23). As a direct comparison, we subjected 23 to constant current conditions in the absence of catalyst and observed high conversion with substantially diminished yield. To demonstrate the value of a phenol-directed alkylation-defunctionalization approach, we targeted the synthesis of a tricyclic resorcinol derivative that was developed as a conformationally restricted cannabinoid agonist. The route, devised by Makriyannis,^[93] hinged on phenol-enabled Friedel–Crafts alkylation followed by a Li⁰-promoted excision of the phenol activating group. In our hands, the Friedel–Crafts process and subsequent phosphorylation proceeded smoothly to deliver tricyclic intermediate 24. Gratifyingly, electron-primed photoredox C(sp²)–O cleavage furnished intermediate 25 despite a nearly 2 V underpotential supplied at the cathode. Global demethylation furnished 26 in 18% yield over 4 steps. These data demonstrate how this new catalytic platform can directly fit into synthetic sequences and circumvent the need for more hazardous chemical reductants in the preparation of complex biologically active molecules.

Figure 3:

Phenol as a traceless directing group enabled by electron-primed photoredox catalysis. ^a Yields reported are for the phosphate defunctionalization step. ^b NMR yield. ^c Isolated yield, (a) 70% aq MeS0₃H, 70 °C, 12 h (45% yield), (b) CIP(0)(0Et)₂, DABCO, MeCN, 18 h (70% yield), (c) BBr₃, DCM, -78 °C, 12 h, (91% yield). Conversion of 24 to 25 was accomplished under conditions analogous to those in Table 2. See SI for experimental details.

We next questioned whether the aryl radical intermediates generated upon reductive cleavage of anlinium salts and phosphate esters could be intercepted by classic aryl radical traps. We investigated several aryl radical coupling reactions: phosphonylation, borylation, and heteroarylation (27-29). We found that both C(sp²)–N and C(sp²)–O radical precursors were amenable to each of these radical coupling reactions (Figure 4).

Figure 4:

redox neutral coupling reactions from aryl C(sp²)-N and C(sp²)-O bonds. All reactions conducted on a 0.2 mmol scale and reported as NMR yields. ^aNMR yield. ^bCatalyst loading was 2.5 mol%. See the SI for details.

Having established that 4-DPAIPN is a broadly effective electron-primed photoredox catalyst with immediate synthetic utility, we next aimed to understand the origin of the improved performance of 4-DPAIPN relative to prior electron-primed photoredox catalysts. Specifically, we questioned whether 4-DPAIPN possessed enhanced reactivity, superior catalyst stability,^[94] or both. To address this question, we envisioned that electrochemical current could be employed as a non-invasive in situ rate monitoring technique to unlock tools from reaction progress kinetic analysis (RPKA).^[95] This method can reveal phenomena such as catalyst decomposition and product inhibition typically invisible to classic initial rate kinetics because the analysis is conducted under typical preparative conditions. We conducted a "same excess” experiment with both our previously reported electron-primed photocatalyst, NpMI, and 4-DPAIPN to compare the extent of catalyst deactivation in each case (Figure 5). We selected aryl chloride 30 as the model substrate because both catalysts can engage this substrate under constant potential conditions and preliminary investigations indicated it exhibited a well-behaved kinetic profile.^[96,97] We carried out two separate constant potential experiments for NpMI at different initial concentrations of 30 (traces a and b). When the conversion rate of 30 is plotted as a function of ^[30], the two curves do not overlay. This indicates either catalyst death or product inhibition.^[98] Inhibition by the arene product was excluded by addition of 31, which did not restore overlay between the curves. Furthermore, NpMI exhibited an unusual kinetic profile consistent with decomposition into a new catalytically active species that subsequently decomposes. These data implicate rapid deactivation of NpMI under these conditions. In stark contrast, an analogous “same excess” experiment with 4-DPAIPN resulted in clean first order reaction profiles that nearly overlay. These data are consistent with turnover limiting photoreduction of 30 and minimal catalyst decomposition or product inhibition (see SI for details). As with NpMI, addition of 31 excluded product inhibition and suggests 4-DPAIPN decomposition occurs^[99–102] but is attenuated relative to NpMI. These data indicate that the improved performance of 4-DPAIPN can be attributed to it forming a more robust electron-primed photoredox catalyst. Indeed, the initial rate of dehalogenation promoted by NpMI is faster than 4-DPAIPN but rapid decomposition of this catalyst renders it ineffective for more challenging substrates that are slower to fragment following reduction.

Figure 5:

Reactions performed on a 0.4 mmol scale.Trace a and d: [ArCI]₀ = 0.08 M {standard reaction concentration), Trace b and e: [ArCI]₀ = 0.052 M, Trace c and f: [ArCI]₀ = 0.052 M, [ArH]₀ = 0.028 M. See the SI for details

Conclusion

Overall, we have demonstrated that electrochemistry is an effective tool to explore structurally diverse electron-primed photoredox catalysts. These investigations revealed electrochemical reduction can induce potent photoreductant behavior from structurally diverse catalyst precursors. Among these, a common photoredox catalyst, 4-DPAIPN, is an exceptionally reducing electron-primed photoredox catalyst. This discovery enabled a new catalytic system to promote the reductive cleavage of diverse C(sp²)–N and C(sp²)–O bonds, which we anticipate will enable an array of synthetic sequences that previously would have mandated alkali metal reductants. Finally, we illustrated how principles from RPKA could be directly employed in electrophotocatalysis, using electrochemical current to monitor reaction rate in situ throughout a reaction. We anticipate radical anions will serve as a structurally diverse family of photoredox catalysts for challenging reductive processes and that these studies will provide a roadmap for the use of electrochemistry to both drive and interrogate such systems.