Photons or Electrons? A Critical Comparison of Electrochemistry and Photoredox Catalysis for Organic Synthesis

Abstract

Redox processes are at the heart of synthetic methods that rely on either electrochemistry or photoredox catalysis, but how do electrochemistry and photoredox catalysis compare? Both approaches provide access to high energy intermediates (e.g. radicals) that enable bond formations not constrained by the rules of ionic or 2 electron (e) mechanisms. Instead, they enable 1e mechanisms capable of bypassing electronic or steric limitations and protecting group requirements, thus enabling synthetic chemists to disconnect molecules in new and different ways. However, while providing access to similar intermediates, electrochemistry and photoredox catalysis differ in several physical chemistry principles. Understanding those differences can be key to designing new transformations and forging new bond disconnections. This review aims to highlight these differences and similarities between electrochemistry and photoredox catalysis by comparing their underlying physical chemistry principles and describing their impact on electrochemical and photochemical methods.

Graphical Abstract

1. INTRODUCTION

Electronic perturbation of molecules for selective bond construction and cleavage is the modus operandi of chemical synthesis, with polar or 2 electron (e) bond disconnections historically dominating retrosynthetic analyses used by organic chemists to construct complex molecules from smaller, simpler building blocks (Scheme 1A).¹ This synthetic tradition stems from the perception that radical intermediates are difficult to control, but the recent renaissance of one electron bond disconnections (Scheme 1B) in organic synthesis highlights the importance of radical-based logic.^2,3,4,5,6,7 In fact, one electron disconnections have been shown to greatly simplify the synthesis of complex organic structures as traditional protecting and functional group interconversions or redox manipulations can be avoided.⁸ As a result, synthetic methods based on radical intermediates often provide a more direct access to a desired product as well as enable new strategies to assemble complex organic structures. A number of complex total syntheses have already demonstrated the use of one electron bond disconnections as a key strategy.^9,10

Scheme 1.

Illustration of 2e vs 1e disconnection approaches for retrosynthesis.

Photoredox and electrochemical synthetic methods have emerged as reliable tools to control the reactivity and selectivity of radical intermediates. Their methods leverage one electron disconnections, either by relying on the innate reactivity of radicals and coupling partners, or by intercepting these radicals with a catalyst, often a transition metal-based catalyst,^11,12,13 to achieve a desired bond formation. Additionally, photoredox and electrochemical methods can access radical-polar cross-over mechanisms (Scheme 1) which enable bond formations between both a radical and a polar building block.

Prior to discussing synthetic examples comparing electrochemical and photochemical methods, some nomenclature related to interpreting synthetic schemes is presented. The electrode materials are depicted under the reaction arrow in synthetic schemes and the polarity of the electrode is denoted a (+) sign for the anode, a (−) sign for the cathode; the use of one or two vertical lines (“|” or “||”) denotes an undivided or divided cell setup, respectively. For example, “Zn(+) | Pt(−)” indicates the electrolysis uses an Zn anode and a Pt cathode in an undivided cell. For electrochemical methods using a carbon-based electrode, we use the following nomenclature: GRC for graphite carbon, GLC for glassy carbon, RVC for reticulated vitreous carbon, in order to distinguish between them. Additionally, a current (i) or current density (j) is provided for electrolysis performed under constant current electrolysis (CCE); an electrode potential (E_c or E_a, for the cathode or anode potential, respectively) is provided for constant potential electrolysis (CPE), and cell potential (U_cell) for constant voltage electrolysis. A complete list of abbreviations and symbols is provided at the end of this review.

2. SCOPE OF REVIEW

With both photoredox catalysis and electrochemistry taking center stage in the field of radical chemistry, organic chemists may wonder how photoredox catalysis and electrochemistry differ and in which cases one approach might be advantageous over the other. Individually, the topics of photochemistry^{14,15,16,17,18} and electrochemistry^{19,20,21,22,23,24,25,26,27} have been extensively reviewed. In contrast, reviews of direct comparisons between photoredox catalysis and electrochemistry are limited.^28,29 This review aims to provide a critical comparison between photoredox catalysis and electrochemistry by: (1) discussing and comparing the basic concepts of photoredox catalysis and electrochemistry in Section 3, and (2) by comparing photoredox and electrochemical approaches of selected synthetic transformations in Section 4. We specifically aim to highlight how the choice of either photoredox or electrochemical approach can impact the reaction outcome of a given functional group conversion or bond formation/cleavage step. Therefore, transformations for which only one approach has been reported are not discussed herein. Additionally, photochemical transformations which do not proceed via a redox mechanism (e.g. energy transfer) are out of scope, and only those that involve photoredox catalysis will be included in our comparison with electrochemical synthetic transformations. We also note that electrochemical and photochemical transformations involving enzymes/biocatalysts are out of scope of this review and the reader should consult these references for insight on this field of catalysis.^{30,31,32,33,34,35,36} Finally, Section 5 focuses on emerging topics along with an outlook. We believe that the community will benefit from insights into these similarities and differences, thus being able to leverage either method to their advantage, as well as realize new or unique opportunities for the development of new transformations,³⁷ including asymmetric reactions^{38,39,40,41,42,43,44,45,46,47,48,49}

3. BASICS OF ELECTROCHEMISTRY & PHOTOREDOX CATALYSIS

How do photoredox and electrochemistry compare? What are their similarities and differences? To begin answering these seemingly simple questions, we first need to think about how radicals are formed, as well as realize that their lifetime⁵⁰ and reactivity can differ greatly (i.e. radicals may behave as nucleophiles or electrophiles).^51,52,53,54 In photoredox catalysis, radicals are generated via the interaction of the photocatalyst with the substrate/intermediate. Thus, the concentration of radicals in solution is relatively low compared to direct electrolysis – in the absence of a redox mediator⁵⁵ – where high concentration of radicals can be achieved at the interface of the solution and working electrode. This fundamental difference in the generation of radicals in photoredox and electrochemical reactions impacts how redox processes in either field are designed. In the following sections, we will review the basic principles of electrochemical and photoredox mechanisms to highlight the advantages and disadvantages of either approach when performing overall (a) redox neutral, (b) net reductive, or (c) net oxidative transformations.

3.1. Basics of Electrochemistry

Electrolysis experiments utilize electrical energy to apply a potential across a pair of electrodes immersed into a solution containing the components to be electrolyzed (Scheme 2A). In conventional electrolysis experiments, four key features are always present: (1) an oxidation reaction occurs at the anode, (2) a reduction reaction occurs at the cathode, and (3) conservation of charge in solution implies that the rates of interfacial electron transfer at the anode and cathode must be equal, leading to a balanced, redox-neutral net reaction, (4) the solution must have an electrical resistance low enough to enable current flow between the two electrodes — this typically requires the use of a soluble supporting electrolyte in the reaction mixture. In many organic electrochemical transformations, only one of the two electrodes (the working electrode) generates a useful product. On the counter electrode, a non-productive reaction takes place. For net oxidative reactions, hydrogen evolution (i.e. proton reduction to H₂) at the counter-electrode is the most common non-productive reaction. For net reductive reactions, sacrificial oxidation of an amine or the anode itself (e.g. Zn, Mg, Al, Cu) are commonly encountered counter-electrode reactions. Later sections will discuss details of each of the above topics. While many electrolysis can be performed using an undivided cell (Scheme 2A), the separation of the two half reactions (oxidation at anode and reduction at the cathode) may be desirable if a starting material, intermediate, or product is susceptible to undesired reaction at the opposite electrode relative to where it is generated or consumed. Separation of the two half-reaction can be accomplished via the use of a divided cell (Scheme 2B). Nonetheless, in order to maintain conservation of charge in solution, a method to accommodate the movement of ions from one half cell to the other is required. This can is achieved by interfacing the two solutions from the two half cells via a salt bridge, or more commonly, by directly interfacing the solutions by using a separator, such as a sintered-glass frit, a porous ceramic, a porous polymer sheet, or a semi-permeable ion-selective membrane (e.g. Nafion^™). Polymeric membranes can exhibit selective transport⁵⁶ of either cations (cation exchange membranes)⁵⁷ or anions (anion exchange membranes).^58,59 For example, Nafion^™ — a perfluorinated sulfonic acid-based membrane — is one of the most frequently used cation exchange membrane in divided cell electrolysis for organic synthesis due to its excellent thermal and mechanical stability. Other cation exchange membrane materials include sulfonated polymers based on polystyrenes, polyimides, and poly(arylene ethers). Anion exchange membranes include those based on polyketones, poly(arylene)s or polyolefins linked to alkyltrimethylammonium, cyclic ammonium, multi-substituted imidazolium, tetrakis-aminophosphonium and cobaltocenium cations, as well as complexes between crown ethers or terpyridine with a metal cation-based salt.

Scheme 2.

Schematic representation of an electrolysis experiment illustrating the two half-reactions. Note that the overall reaction is a linear combination of the two half-reaction, illustrating that redox neutrality must be maintained for (A) an undivided cell and (B) a divided cell.

3.2. Common Mechanisms in Electrochemistry

In the context of electrolysis, various reaction mechanisms exist including those outlined in Scheme 3. The nomenclature introduced by Testa and Reinmuth is commonly used in classifying mechanisms of electrochemical transformations by using the letters E and C to denote steps involving electron transfer and chemical steps, respectively.^60,61 The presence or absence of a chemical step (C) either before or after the electron transfer step (E), as well as whether the step is reversible or irreversible are all options. Subscripts r and i are used to denote whether the E or C step is reversible or irreversible, respectively (e.g. C_i for an irreversible chemical step).

Scheme 3.

Illustration of various electrode mechanisms. O and R are the oxidized and reduced form of the substrate undergoing a reduction event, e is an electron, Z is a generic intermediate formed during a chemical step, Y and P are a starting material and a product, respectively. The subscripts r and i are used to denote whether the E or C step is reversible or irreversible, respectively. C_i^’ denotes an irreversible chemical step that regenerates a catalytic mediator.

Cyclic voltammetry (Figure 1) is an excellent method to measure the potential at which a redox event takes place but also gain insight in the mechanism and reversibility of the reaction.⁶² Figure 1 illustrates cyclic voltammetry data for a reversible reduction event, along with several key descriptors: peak anodic current (i,_pa), peak cathodic current (i_p,c), anodic peak potential (E_p,a), cathodic peak potential (E_p,c). Finally, the half-wave potential (E_1/2) for reversible systems is simply obtained by taking the average between the anodic and cathodic peak potential, explicitly, E_1/2 = 0.5•(E_pa + E_pc). The Nernst equation (equation 1a) describes the partitioning between the oxidized (O) and reduced (R) form of an analyte undergoing a reversible redox process at an electrode in an unstirred solution at a given applied potential (E) based on its standard potential (E°), where R is the ideal gas constant (R = 8.31447 J•mol⁻¹•K⁻¹), F is Faraday’s constant (note F = 96487 C•mol⁻¹) and n is the number of electrons involved in the redox event (A + n e → Aⁿ⁻). E_1/2 can provide an approximation for E°. We refer the reader to tutorial reviews⁶³ and books^64,65 for a more detailed treatise of the topic.

$$E=E^{°}+\frac{RT}{nF}\ln (\frac{[O]}{[R]})$$ (1a)

Figure 1.

Simulated cyclic voltammogram data (2^nd cycle) for a reversible reduction event illustrating several key parameters: anodic peak current (i_p,a), cathodic peak current (i_p,c), anodic peak potential (E_p,a), cathodic peak potential (E_p,c), and the half-wave potential (E1/2).

Returning to the topic of cyclic voltammetry as a tool to discern reaction mechanism,^63,66 Figure 2 illustrates various simulated cyclic voltammograms corresponding to the prototypical mechanisms outline in Scheme 3.⁶³ The ratio of i_p,a to i_p,c from the cyclic voltammograms measured at various scan rates (ν) as well as the peak separation between E_p,a and E_p,c can provide insight into the reversible nature of the redox process and information regarding the underpinning mechanism such as those in Scheme 3. For example, a reversible redox event (E) with no subsequent chemical step (Scheme 3, scenario a), will have i_p,a/i_p,c = 1, such as shown in Figure 1. Scheme 3, scenario b illustrates a mechanism in which a chemical step is followed by an electron transfer step (CE mechanism), where the faster the forward rate constant of the reversible chemical step (C_r), the more reversible the voltammogram becomes (i.e. i_p,a/i_p,c approaches 1), as shown the color progression from blue to dark green to lime green to orange in Figure 2, middle. Figure 2, top, illustrates the scenario where a reversible electron transfer step precedes the chemical step (E_rC_i mechanism, Scheme 3, scenario c), where increasing the scan rate restores reversibility. Scenarios c and d in Scheme 3 differ based on whether the electrochemical step is reversible (E_rC_i, Scheme 3, scenario c) or irreversible (E_rC_r, Scheme 3, scenario d). Multielectron transfer processes via sequential redox events can occur, such as two reversible redox events (E_rE_r) shown in Figure 2, bottom. More elaborate mechanisms exist, such as an ECE mechanism in which a second electron transfer event occurs after the initial EC events. Variations of the ECE mechanism exist where the 2^nd electron transfer event (E₂) may occur at a potential that is more or less thermodynamically facile than the first electron transfer event (E₁), again which require cyclic voltammetry experiments to discern them apart. Scenario e in Scheme 3 illustrates an EC’ mechanism in which the catalytic species utilized in the first step is regenerated in the 2^nd step.

Figure 2.

(Left) Simulated cyclic voltammograms using DigiElech simulation software for three common mechanisms. The currents are normalized. (Top) E_rC_i mechanism: increasing the scan rate (from ν = 0.1 (red) to 1 (green) to 10 V•s⁻¹ (blue)) restores reversibility (rate constant for the C_i step k = 5 s⁻¹). (Middle) C_rE_r mechanism: the faster the forward rate constant of the C_r step, the more reversible the voltammogram (K_eq = 0.1, k_f = 1 (blue), 10 (dark green), 100 (lime green), 1000 s⁻¹ (red)). (Bottom) E_rE_r mechanism: as the separations between the two reduction potentials (ΔE_1/2) decreases, the peaks merge to become a single two-electron peak. ΔE_1/2 = −0.05 (dark blue), 0 (light blue), 0.05 (dark green), 0.1 (lime green), 0.15 (orange), and 0.2 V (red). Figure reproduced from ref 63. Copyright 2018 American Chemical Society.

We note that the cyclic voltammetry data shown in Figure 1 and 2 are for freely diffusing species at the electrode but scenarios where the starting material or product of the redox event is adsorbed onto the electrode are also possible. The peak separation between E_p,a and E_p,c, as well as the effect of scan rate on each of these potential provides insight into discerning between these scenarios. For a fully reversible redox event involving free diffusing species, the following three criteria should be met: (1) the peak anodic and cathodic currents (i_p,a and i_p,c, respectively) should be of equal magnitude (specifically, i_p,a = −i_p,c); (2) a plot of i_p vs ν^1/2 should be linear; and (3) the peak anodic and cathodic potentials (E_p,a, and E_p,c) should be independent of the scan rate. Deviations from linear behavior for plots of i_p vs ν^1/2 may be indicative that either (a) the electrochemical process is quasi-reversible, or (b) the species undergoing the redox event is surface-adsorbed (not freely diffusing). The peak to peak separation between E_p,a, and E_p,c will change as a function of scan rate for quasi-reversible processes, in contrast to a surface adsorbed species which will have this value constant.⁶³

Advanced electrochemical and spectroscopic techniques can be useful to characterize these electrocatalytic systems.^{67,68,69,70,71,72} While this nomenclature was originally developed to describe mechanistic scenarios in the context of electrochemistry, the reader should realize that these classifications may be useful for describing photoredox reactions, as well as those that rely on stoichiometric redox reagents, thus enabling ease of comparison between these systems.

It is not uncommon that only the oxidation or only the reduction process is of interest, while the balancing redox event pertains to redox chemistry on the solvent, electrolyte, or a sacrificial species (reagent or electrode); these are termed unpaired electrolysis. Towards maximizing energy use and minimizing waste, electrochemical reactions can be designed in which both the reduction and oxidation events lead to useful chemistry (paired electrolysis).^73,74,75,76 Scheme 4 illustrates common electrolysis reaction manifolds whereby the overall reaction can be broken down into a combination of oxidation and reduction reactions (half-reactions).⁷⁷ Scheme 4A illustrates divergent paired electrolysis whereby the starting material can either be oxidized or reduced, leading to two different products. An example is the oxidation of glucose to gluconate accompanied by the reduction of glucose to sorbitol, a process that has been utilized on industrial scale.^78,79 Parallel paired electrolysis (Scheme 4B) utilizes two different starting materials, one being oxidized and the other being reduced, in which the intermediates generated at each electrode do not interact with one another and leads to two different products (P¹ and P²). An example of parallel paired electrolysis is the BASF synthesis of phthalide from dimethyl phthalate, where the cathodic reduction of dimethyl phthalate is paired with the simultaneous oxidation of various organic anodic depolarizers (e.g. 4-tert-butyltoluene).⁸⁰ Convergent paired electrolysis (Scheme 4C) brings intermediates generated from both electrodes together to form one product. To enable the convergent reactivity, convergent paired electrolysis usually utilizes a 2e redox event to generate an ionic intermediate which have longer lifetimes than radicals. The Shono oxidation^81,82 is one such example. An amine undergoes 2e oxidation at the anode to generate the corresponding iminium, which then reacts with an alkoxide nucleophile that was generated at the cathode through the reduction of protons (hydrogen generation) from an alcohol solvent. Sequential paired electrolysis (domino electrolysis) processes (Scheme 4D) are reactions that utilize redox events at both electrodes in a linear, sequential mechanism to generate the desired product. An example of a sequential paired electrolysis is the oxidation of oximes to nitrile oxides followed by their reduction to the corresponding nitrile.^83,84 We note that the sequential paired electrolysis illustrated in Scheme 4D is shown to initiate at the anode with an oxidation process. The opposite scenario in which the initial redox event occurs at the cathode followed by a redox event at the anode falls into the same category (we chose to arbitrarily illustrate only one of the two scenarios for simplicity).

Scheme 4.

Illustration of several common electrolysis reaction manifolds: (A) divergent paired electrolysis, (B) parallel paired electrolysis, (C) convergent paired electrolysis, (D) sequential paired electrolysis (domino electrolysis), (E) anodically coupled electrolysis (F) cathodically coupled electrolysis, (G) sequential anodic electrolysis, and (H) sequential cathodic electrolysis. [All redox events are shown as single electron transfer events but redox events involving more than one electron also fall into these categories].

Anodically coupled electrolysis (Scheme 4E) illustrates a type of EEC mechanism whereby two different substrates (A and B) each individually undergo an oxidation event at the anode and their subsequent bimolecular coupling results in the desired product (P). The analogous cathodically coupled process is illustrated in Scheme 4F. The reaction mechanism illustrated in Scheme 4E relies on the individual oxidation potentials of A and B to be close to one another in order to appropriately match the rate of production of radicals A^• and B^•. The analogous statement is true for the reducing potentials of A and B in the context of Scheme 4F). Lin's chlorotrifluoromethylation of alkenes⁸⁵ discussed in Section 4.8.1 is an example of a reaction proceeding via an anodically coupled electrolysis mechanism, while the electrochemical hindered amine synthesis⁸⁶ discussed in Section 4.10 is an example of a cathodically coupled electrolysis mechanism. Sequential anodic and sequential cathodic electrolysis (Scheme 4G and Scheme 4H, respectively) highlight an example of the classic ECEC mechanism. This approach has been utilized for numerous vicinal difunctionalization of alkenes (see Section 4.8).

3.3. Basics of Photoredox Catalysis

In contrast to electrochemistry, photoredox catalysis cannot physically separate the two half reactions of a redox process since both half reactions have to occur at the same photocatalyst, and not at two different electrodes that are spatially separated. A photoredox catalyst (PC) can absorb a photon of appropriate wavelength to generate an excited state (PC*) which can then interact with a substrate via: (1) energy transfer⁸⁷ (which is out of scope of this review), (2) photoinduced electron transfer (PET), or (3) atom transfer. PET is achieved by PC* participating in either an oxidative or reductive quenching process (Scheme 5). This quenching process occurs via single electron transfer (SET) with an electron acceptor (A) or donor (D), where the acceptor and donor can be any combination of a substrate, an intermediate or a terminal oxidant/reductant.

Scheme 5.

Illustration of (A) an oxidative and (B) a reductive quenching photoredox cycle.

3.4. Common Mechanisms in Photoredox Catalysis

In an oxidative quenching cycle (Scheme 5A), SET from PC* to an acceptor (A) results in ground state PC^•+ and the reduced form of the acceptor (A⁻). A subsequent SET from a donor (D) to PC^•+, results in the regeneration of the photocatalyst (PC) and the oxidized form of the donor (D⁺). Alternatively, in a reductive quenching cycle (Scheme 5B), SET from the donor (D) to PC* results in ground state PC^•− and the oxidized form of the donor (D⁺). A subsequent SET from PC^•−, to an acceptor (A) results in the regeneration of the photocatalyst and A⁻. Productive chemistry is leveraged from these (radical) intermediates A⁻ and D⁺ via direct reaction or interception of these radicals with other catalysts (e.g. transition-metal catalyst for cross coupling reactions). Photoredox reactions fall into one of three categories: (scenario 1, Scheme 5) redox neutral process (where radical A⁺ and D⁻ combine or originate from the same structure), or (scenario 2, Scheme 5) a net oxidative, or (scenario 3, Scheme 5) net reductive transformation where the radicals may react with a different starting material. Net oxidative transformations rely on a terminal oxidant (sacrificial acceptor of electrons) whereas net reductive process requires a terminal reductant (sacrificial source of electrons).

Scheme 6 illustrates a common reaction manifold observed in photoredox catalysis, namely radical-polar crossover mechanisms,^88,89 which again is classifiable into either an oxidative or a reductive quenching variation (Scheme 6A and Scheme 6B, respectively). In this reaction manifold, the generation of the radical is followed by radical reactivity, generating a new radical intermediate which then undergoes SET with the photocatalyst to generate a cationic or an anionic intermediate primed for downstream polar reactivity. The polar reactivity can be as simple as loss of a proton/leaving group to generate an alkene, or reaction with a nucleophile/electrophile to generate a new bond. Radical-polar crossover is a common strategy for vicinal alkene difunctionalization, including ring formation reactions where a nucleophile or an electrophile is tethered to the substrate to facilitate intramolecular reactivity from a cationic or an anionic intermediate, respectively.

Scheme 6.

Illustrations of radical-polar crossover mechanisms via (A) an oxidative quenching cycle and (B) a reductive quenching cycle. RP = radical progenitor, PC = photocatalyst, SET = single electron transfer, using alkenes as the radical acceptor in the initial radical-substrate bond forming event. E and C denote electron transfer and chemical steps, respectively, in the mechanism.

3.5. Comparison Between Electrochemistry and Photoredox Mechanisms

Having introduced the various common electrochemical and photoredox mechanisms, we can now draw analogies between the two systems. Redox neutrality in the overall balanced equation is required for both photoredox and electrochemistry (Scheme 5 and Scheme 2, respectively). In electrochemistry the half-reactions (oxidation at the anode and reduction at the cathode) must add to a balanced, redox neutral process to obey the conservation of charge principle. In photoredox, redox neutrality is necessary in order to regenerate the photocatalyst (i.e. catalyst turnover). As a result, direct comparison between the various mechanisms discussed in section 3.2 and 3.4 are possible.

The redox neutral photocatalytic cycle shown in Scheme 5, scenario 1, where both the acceptor and donor in are used in productive manner and are both incorporated into the same product, is analogous to the convergent paired electrolysis (Scheme 4C). Redox neutral processes are more challenging in electrochemistry since the reduction and oxidation events occur at different electrodes and would require diffusion of the radical from one electrode to the other, usually unlikely given the short lifetime of a radical and the relatively long required for it to traverse the inter-electrode distance in a typical bulk electrolysis cell. A handful of examples on how to solve this problem have begun to emerge using microflow electrochemistry and alternating polarity electrolysis (see Section 5.1.2). To address this limitation, radical intermediates can be intercepted by a catalyst (such as a transition-metal catalyst) to generate a longer-lived intermediate for downstream chemistry. Scheme 5, scenario 2 illustrates a net oxidative process, in which the unproductive process is the reduction of an acceptor. This is analogous to an unpaired electrolysis in which a non-productive reduction occurs at the cathode, (e.g. proton reduction to generate hydrogen). Analogously, the net reductive process form scenario 3 in Scheme 5 in which the oxidation reaction (D to D⁺) is an unproductive reaction (e.g. oxidation of an amine) is analogous to an unpaired reduction electrolysis (e.g. using a sacrificial anode as the unproductive oxidation half reaction). The radical-polar cross over reactions from Scheme 6B correspond to the sequential paired electrolysis illustrated in Scheme 4D. The opposite polarity to Scheme 4D (i.e. the cathodic event preceding the anodic event) would be the direct analogy to the radical-polar crossover mechanism in Scheme 6A. Therefore, these radical-polar crossover mechanisms can also be classified as ECEC mechanisms.

In direct electrolysis, redox events occur at the interface of the electrode and solution (typically a heterogenous process) which can lead to a localized, high concentration of radicals. In contrast, redox chemistry in photoredox catalysis occurs in solution (homogenous) and provides a low concentration of radicals. As a result, coupling of two transient radicals is feasible in electrochemistry if they are generated at the same electrode, whereas this is more challenging in photoredox catalysis. Thus, anodically and cathodically coupled electrolysis shown in Scheme 4E & Scheme 4F, respectively, are commonly achieved using electrochemistry. In contrast, these are rarer in photoredox catalysis as it would require the use of at least one persistent radical (increased radical lifetime) to increase the likelihood of the bimolecular encounter event for radical-radical couplings.⁵⁰ Finally, doubly reductive (or doubly oxidative) processes such as the sequential electrolysis mechanisms shown in Scheme 4G & Scheme 4H, are typically unfeasible in photoredox due to the low statistical chance that the radical lifetime is long enough for encountering the low concentration of the redox agent (e.g. photoexcited photocatalyst). In contrast, such events can be achieved more easily in electrochemistry, since both the rate of redox events can be much higher (high current density) and the radical is generated at the electrode-solution interface (highly localized). For noteworthy examples of doubly reductive processes via photoredox catalysis, see Section 5.2.

Radical-polar crossover mechanisms are another strategy widely used in photoredox whereby radical intermediates undergo a redox event to generate an ionic (cationic/anionic) intermediate that affords increased lifetime and the ability to react orthogonally to the radical manifold. In contrast, redox neutral processes are simpler to achieve with photoredox since the photocatalyst can act both as reductant and oxidant in the same cycle which can occur in the same spatial location (within diffusion distance attainable in one turnover of the photocatalyst). Examples of sequential redox chemistry with one redox event occurring at each electrode on the path to product generation do exist but are usually limited to an intermediate traversing between the two electrodes being a closed-shell species (i.e. not a radical) generated via a net 2e electron redox event instead of a net 1e redox event.

3.6. Terminal Oxidants & Reductants

In order to carry out net-oxidative and net-reductive transformations (Scheme 5, scenarios 2 & 3 in photoredox, and unpaired anodic oxidation & unpaired cathodic reductions), the use of terminal oxidants and terminal reductants are required. Some common terminal reductants employed in photoredox include Hantzsch ester,⁹⁰ 1-benzyl-1,4-dihydronicotinamide (BNAH), 1,4-dihydronicotinamide adenine dinucleotide (NADH), amines (Et₃N, i-Pr₂NEt, i-Pr₂NH, Cy₂NMe, Ar₃N), i-PrOH, ascorbic acid, PPh₃,⁹¹ and oxalate (via (C₂O₄)²⁻ → 2 CO₂ + 2e⁻). Common terminal oxidants⁹² include alkyl peroxides (e.g. DTBP), H₂O₂,⁹³ O₂, BrCCl₃,^94,95 oxoammoniums, peracids (e.g. peracetic acid), persulfates (e.g. (NH₄)₂S₂O₈, Na₂S₂O₈), Cu^II salts^96,97 (e.g. Cu(OAc)₂ and Cu(O₂CCF₃)₂). In the context of electrochemistry, in addition to the above redox reagents, the anode can also be used as a terminal reductant if oxidation of the anode material is sufficiently facile. Materials like Zn, Al, Mg, Cu can be used as sacrificial anodes.⁹⁸ Upon donating one or more electrons from the sacrificial (metal) anode to a species at the cathode, the oxidized form of the anode metal will desorb from the anode into solution. The cation may dissolve into the solution or precipitate out as a salt (Scheme 7A), and results in the anode losing mass. In either photoredox or electrochemistry settings, the byproduct of these terminal oxidants/reductants is not always innocent. For example, oxidation of amines typically results in iminium or enamine formation (Scheme 7B) which can interfere with the desired chemistry.⁹⁹ In electrochemistry, the use of a sacrificial metal anode will release metal cations that may participate (enhance) in the catalysis^{100,101,102,103} (e.g. acting as a Lewis-acid), or plate out on the cathode via reductive processes and ultimately decrease the current efficiency. Proton reduction to generate hydrogen is a common sacrificial reduction process at the cathode (Scheme 7C) which can result in the pH increasing in the reaction mixture as the reaction progresses. Electrochemical proton reduction generally relies on the use of a cathode with low overpotential for proton reduction (e.g. Pt) to minimize the cell potential and avoid side reactions. The use of divided cells to isolate the unproductive half-reaction, including its byproducts, can be a useful strategy to avoid it from interfering in the productive half-reaction. Hydrogen evolution has also been employed in the context of photoredox catalysis to turn over the catalyst via a non-productive reduction, for example by using a cobaloxime catalyst (Scheme 7D).^{104,105,106,107}

Scheme 7.

Illustration of a few common sacrificial half-reactions: (A) sacrificial anode (oxidation of metals), (B) sacrificial oxidation of amines, (C) reduction of protons to evolve hydrogen, and (D) proton reduction to evolve hydrogen via cobaloxime catalyst.

3.7. Driving Forces for Electron Transfer and Related Considerations

In section 3.1 to 3.5, we highlighted the similarities and differences between photoredox and electrochemical reaction mechanisms by emphasizing their advantages and disadvantages. This basic overview should enable the reader to select one or the other approach for their synthetic transformation of choice. However, in order to design a photoredox or an electrochemical process, a deeper understanding of the fundamentals of electron transfer and their driving force is useful, as it informs selection of photocatalyst, or electrode material and electrolyte.

Given that these two fields focus on the conversion of electron energy to chemical energy, its relevance to organic chemistry is that electrical and light energy can be converted to chemical energy (in kcal•mol⁻¹) via interconversions of electron volt (eV) and light wavelength (λ) using the Nernst and Planck-Einstein equations respectively. Thus, we believe that developing an understanding of the relationships between eV, λ, and kcal•mol⁻¹ (Scheme 8) will help organic chemists to appreciate and develop new ways of using electrochemistry and photoredox catalysis for chemical synthesis. Despite this similarity, the mechanisms for electron transfer in both methods are quite different, namely, that photoredox is typically limited to single electron transfer events, while electrochemistry can leverage multi-electron redox steps.

Scheme 8.

The relationship between chemical, electrical, and light energy. Insert shows a comparison of these relationships for three commonly-used wavelengths for photoredox catalysis. UV and NIR stand for ultraviolet (< 400 nm) and near-infrared (> 700 nm) respectively.

3.7.1. Photophysical and Electrochemical Considerations for Photoredox Catalysts

The photophysical processes of photoredox catalysts are arguably the most important factors in determining their photochemical reactivity (e.g. redox potentials, excited state lifetime). The behavior of the electronically excited photocatalyst dictates the feasibility and rates of electron transfer (ET), which in turn impacts substrate activation. Thus, any improvements to the efficiencies of reaction methodologies, or developments in catalyst design usually stem from a thorough analysis and understanding of photochemical mechanisms. While covering these photophysical processes in detail is beyond the scope of this review, this section will highlight the fundamentals of excited-state electron transfer and summarize the practical considerations that factor into choosing an appropriate transition-metal or organic photoredox catalyst. Readers interested in a deeper examination of the photophysics involving photoredox catalysis should consult a recent review by McCusker.¹⁰⁸

A representation of the photophysics associated with the electron transfer processes for a general photocatalyst in its ground state (¹A) is illustrated in a simplified state energy diagram (Figure 3A). ¹A is electronically excited upon absorption of light (+hν), which then promotes an electron from its ground state (S₀) to a higher energy singlet state. Vibrational relaxation of the promoted electron by non-radiative pathways leads to the lowest energy singlet excited state (S₁) of ¹A (¹A*). The fate of this electron in ¹A* is dependent on its radiative (light emission) and non-radiative (heat emission) pathways. Relaxation of the S₁ via the fluorescence (radiative, −hν) or internal conversion (non-radiative) returns the excited electron to S₀. Alternatively, the electronically excited electron in ¹A* can transition to a lower energy triplet excited state (T₁) by a spin-forbidden, non-radiative process called intersystem crossing (ISC) to form triplet species ³A*. Because ISC is a spin-forbidden transition, the lifetime for the triplet state ³A* is usually longer than its excited state singlet state ¹A*. If no ET occurs, ³A* can relax to ¹A via similar radiative (phosphorescence) and non-radiative pathways. Alternatively, energy transfer (EnT) mechanisms — Förster and Dexter — may be operative for a photocatalyzed transformation whereby an energy acceptor molecule (e.g. substrate) quenches a photoexcited chromophore. Distinguishing EnT and ET mechanisms typically requires time-resolved experiments, namely transient absorption spectroscopy.¹⁰⁸ For the remainder of this review, we will assume ET as the major contributor to photocatalyzed transformations but also highlight examples where energy transfer mechanisms are invoked. Additionally, Figure 3B illustrates the merger between electrochemical potentials and the energies associated with the electronically excited and ground states of photoredox catalysis. The following discussions of the mathematical principles of electron transfer will use the energy state diagrams in Figures 3A and 3B as a graphical representation.

Figure 3.

The intersection between photophysical (A) and electrochemical (B) properties of photocatalyst A. Diagram adapted from Romero and Nicewicz.¹⁸

In photoredox catalysis, obtaining appreciable substrate activation depends on effective PET. One important factor is the lifetime of the photoexcited catalyst, as the short-lived catalytic photo-oxidant or -reductant may be unable to engage in appreciable electron transfer. Thus, the empirical generalization is that the longer the lifetime of ¹A* and ³A*, the greater the likelihood that photoexcited ¹A* will undergo PET. For the excited state singlet ¹A*, its lifetime $\left({\tau }_{{\text{S}}_1}\right)$ is best approximated as its fluorescence lifetime (τ_f), which is measured using time-resolved emission spectroscopy. This assumption holds that photon emission occurs on faster time scales than non-radiative pathways, and in general, PET is observed when τ_f ≥ 1 ns because the rate of excited state decay is greater than the rate of diffusion.¹⁸ However, to accurately determine the likelihood of PET from the ¹A* state, the fluorescence quantum yield (ϕ_f) must be measured as it reveals the likelihood of non-radiative deactivation pathways (i.e. internal conversion) or the prevalence of ISC from ¹A* to ³A*. Confirmation of the latter mechanism is obtained if a high ISC quantum yield (ϕ_ISC) is observed and would suggest that PET occurs from the ³A* state. Since decay from the triplet state via phosphorescence or internal conversion is much slower (a consequence of symmetry-forbidden transitions), the lifetime of ³A* $\left({\tau }_{{\text{T}}_1}\right)$ will be several orders longer than that of ¹A*.

Another important consideration is a thermodynamically favorable redox potential match between the donor and acceptor species associated with the reaction shown in equation 1b.

$${\mathrm{A}}^{*}+\mathrm{D}\to {\mathrm{A}}^{-•}+{\mathrm{D}}^{+•}$$ (1b)

In order to quantify the excited state and the ground state redox potentials for photoredox catalysts, both spectroscopy and electrochemistry are used. Equation 2, better known as the Gibbs energy of photoinduced electron transfer (ΔG_PET), is a generalized equation typically used to determine the thermodynamic favorability of PET from A* to D (equation 1) and considers both the excited state (E_0,0) and ground state (E°) energies of the species involved in photoinduced electron transfer (Figure 4). F in equation 2 is the Faraday constant (23.061 kcal•V⁻¹•mol⁻¹), while E_1/2(A/A^•−) and E_1/2(D^•+/D) are the reduction and oxidation potentials respectively for a single electron acceptor (A) and single electron donor (D).

$$\Delta G_{\text{PET}}=-F•\left[E_{1/2}\left(\text{A}/{\text{A}}^{•-}\right)-E_{1/2}\left({\text{D}}^{•+}/\text{D}\right)\right]$$ (2)

Figure 4.

Illustration of how one estimates E_0,0 of a photoredox catalyst from overlaid normalized absorption and emission spectra.

The excited state energy of the S₁ state can be experimentally estimated from either 1) the intersection between the normalized absorption and emission spectra or 2) the midpoint between the absorption and emission maxima. The excited state energy of the T₁ state is less trivial to determine and is often estimated using the phosphorescence maximum obtained under cryogenic temperatures.¹⁸ The work term (w) in equation 3 considers the solvent-dependent Coulombic attractions, but is typically omitted due to its relative insignificance in polar solvents. However, these Coulombic interactions have nontrivial impact on redox potentials in nonpolar solvents.¹⁰⁹ Nevertheless, a good first approximation of ΔG_PET can be obtained through this relationship between ground and excited state redox properties.

$$\Delta G_{\text{PET}}=-F•\left[E^{°}\left({\text{D}}^{•+}/\text{D}\right)-E^{°}\left(\text{A}/{\text{A}}^{•-}\right)\right]-w-E_{0,0}$$ (3)

Electrochemistry is an invaluable tool for measuring ground-state redox potentials of organic and inorganic species. The free energy of electron transfer in the ground state is given by equation 1, where F is the Faraday constant (23.061 kcal•V⁻¹•mol⁻¹), and E_1/2(A/A^•−) and E_1/2(D^•+/D) are the reduction and oxidation potentials respectively for a single electron acceptor A and single electron donor D. We use the convention of writing half reactions as net single electron reductions; thus, oxidation potential of a donor refers to the half reaction D → D^•+ + e, whereas the reduction potential of an acceptor molecule refers to the half reaction A + e → A^•−.

In photoredox catalysis, the excited state chromophore (A*) acts as either an oxidant or as a reductant, and thus it is important to obtain its excited state reduction and oxidation potentials (Figure 3B). These values can be derived from equations 4 and 5, which describe the relationship between the energies of A and A*_.

$${E^{*}}_{\text{red}}\left({\mathbf{A}}^{*}/{\mathbf{A}}^{•-}\right)\approx E_{\text{red}}\left(\mathbf{A}/{\mathbf{A}}^{•-}\right)+E_{0,0}$$ (4)

$${E^{*}}_{\text{ox}}\left({\mathbf{A}}^{•+}/{\mathbf{A}}^{*}\right)\approx E_{\text{ox}}\left({\mathbf{A}}^{•+}/\mathbf{A}\right)-E_{0,0}$$ (5)

With ${E^{*}}_{\text{red}}\left(\mathbf{A}*/{\mathbf{A}}^{•-}\right)$ and ${E^{*}}_{\text{ox}}\left({\mathbf{A}}^{•+}/\mathbf{A}*\right)$, we can finally determine the thermodynamic favorability of PET in photoredox catalysis. For A* and a generic substrate B, equation 2 can be further generalized for the two redox events by merging with equations 4 and 5. Equations 6 and 7 describe the free energy of PET for an excited state photooxidant and photoreductant respectively. If photoinduced oxidation of B is favorable, then $\mid {E^{*}}_{\text{red}}\left({\mathbf{A}}^{*}/{\mathbf{A}}^{•-}\right)|>|E_{\text{ox}}\left({\mathbf{B}}^{•+}/\mathbf{B}\right)\mid$. Similarly, if photoinduced reduction of B is to be thermodynamically allowed, then $\left|{E^{*}}_{\text{ox}}\left({\mathbf{A}}^{•+}/{\mathbf{A}}^{*}\right)\right|>\left|E_{\text{red}}\left(\mathbf{B}/{\mathbf{B}}^{•-}\right)\right|$.

$$\Delta G_{\text{PET}}=-F•\left[{E^{*}}_{\text{red}}\left({\mathbf{A}}^{*}/{\mathbf{A}}^{•-}\right)-E_{\text{ox}}\left({\mathbf{B}}^{•+}/\mathbf{B}\right)\right]$$ (6)

$$\Delta G_{\text{PET}}=-F•\left[E_{\text{red}}\left(\mathbf{B}/{\mathbf{B}}^{•-}\right)-{E^{*}}_{\text{ox}}\left({\mathbf{A}}^{•+}/{\mathbf{A}}^{*}\right)\right]$$ (7)

An important consideration for productive electron transfer is a hypothetical overpotential intrinsic to a photoexcited photoredox catalyst and the corresponding substrate. A moderate overpotential likely accelerates electron transfer, with Marcus theory predicting that the rate of electron transfer is at its maximum when −ΔG_ET = λ (i.e. the reorganization energy associated with reorganization of the nuclei from the equilibrium geometry of the reactants to the equilibrium geometry of the products, including reorganization of the solvent).¹¹⁰ However, drops in ET rates are observed at more negative free energies (the Marcus inverted region), with a nonadiabatic back electron transfer process being a putative relaxation mechanism (see next section for details).^{111,112,113,114,115} This observation also holds for proton-coupled electron transfer mechanisms (PCET).¹¹⁶

3.7.2. Comparison of Electron Transfer in Electrochemistry and Photoredox

The theory underlying electron transfer has been established for many decades and we draw attention to Marcus theory in particular and the reviews that discuss this topic in greater detail.^{117,118,119,120,121,122,123} A fundamental premise of Marcus theory is that the kinetics of single electron transfer can be derived from the potential energy wells associated with reactants and products. For a generic single electron donor and acceptor, there are three hypothetical scenarios for SET: (1) the donor being in the excited state and the acceptor being in the ground state (equation 1), (2) the acceptor being in the excited state and the donor in the ground state, and (3) both donor and acceptor are in their electronic ground states. Figure 5A illustrates the scenario for an ergoneutral SET, namely when the Gibbs free energy for electron transfer is zero, which leads to the barrier for SET (ΔG^ǂ) being the energy difference between the intersection of the substrate and product parabolas on the reaction coordinate and their absolute minima (ΔG^ǂ = λ/4). The ΔG^ǂ values for exergonic and endergonic SET processes vary (Figures 5B and 5C respectively) and are best determined using equation 8, which describes the barrier ΔG^ǂ as a function of the Gibbs free energy, ΔG, associated with the SET, and the reorganization energy (λ).

$$\Delta G^{‡}=\frac{{(\lambda +\Delta G)}^2}{4\lambda }$$ (8)

Figure 5.

Graphical depiction of Marcus theory for (A) ergoneutral, (B) exergonic, and (C) endergonic single electron transfers. (D) A comparison of the potential energy curves for exergonic electron transfer involving the Marcus normal region (blue), a barrierless SET process (green), and slowed SET in the Marcus inverted region (red).

The rate of electron transfer predicted by Marcus theory is determined using equation 9. Note: ħ is Planck’s constant, H_A,B represents the electronic coupling between the initial and final states, λ is the reorganization energy, k_B is the Boltzmann constant (1.38064852 × 10⁻²³ m²•kg•s⁻²•K⁻¹), T is temperature (in Kelvin), and ΔG is the Gibbs free energy for SET. We encourage the reader to consult the aforementioned reviews for detailed analyses of SET using this equation.

$$k_{ET}=\frac{2\pi }{\hslash }{\left|H_{A,B}\right|}^2\frac{1}{\sqrt{4\pi \lambda k_{b}T}}\exp \left(\frac{-{(\lambda +\Delta G)}^2}{4\lambda R{k}_{b}T}\right)$$ (9)

Figure 5D illustrates the relationship between ΔG^ǂ and ΔG for SET through a comparison of three exergonic SET processes: (1) one with a small driving force (ΔG₁ somewhat negative, as is shown in Figure 5B) which has a small barrier (ΔG^ǂ₁) and is within in the Marcus normal region; (2) a barrierless SET event (ΔG^ǂ₂ = 0) when the reaction driving force of ΔG₂ = −λ, resulting in barrierless ET; (3) a scenario where a highly exergonic reaction (ΔG₃ extremely negative, ΔG₃ < −λ) will slow down SET — namely, the Marcus inverted region. This last situation is unique as it appears counterintuitive: reaction rates, including those for electron transfer, usually increase with decreasing ΔG values. However, in the Marcus inverted region for electron transfer, SET rates become slower, even if the reaction is highly exergonic, such that ΔG^ǂ₃ > ΔG^ǂ₁.

Scheme 9 illustrates the frontier molecular orbital of a substrate and those of a photocatalyst, and the Fermi level associated with the potential of the electrode, as well as the Gibbs free energy driving forces related to electron transfer (ΔG_ET). Equation 10 illustrates the relationship between the change in Gibbs free energy (ΔG) and the thermodynamically required cell potential (E_e), Faraday’s constant (F), and the number of electrons transferred (n) per molecule.¹²⁴

$$\Delta G=-nF{E}_e$$ (10)

Scheme 9.

Illustration of various scenarios for associated with electron transfer events in electrochemistry and photoredox catalysis. For photoredox catalysis, only excited state electron transfer is illustrated. Additionally, unproductive back electron transfer can be operative, but is omitted from this figure for clarity.

In the context of an electrochemical reduction event, when the electron transfer from the electrode to the substrate (reduction) is favorable, the Fermi level of the cathode is at a higher energy than that of the LUMO of the substrate. Analogously the singly occupied molecular orbital (SOMO) containing the electron in the photocatalyst to be transferred to substrate should be higher than the LUMO of the substrate. For oxidation of a substrate, the Fermi level on the anode should be lower than that of the HOMO of the substrate. Analogously, the SOMO of the catalyst accepting the electron from the substrate should be lower in energy than that of the HOMO of the substrate. We note that the above criteria result in a negative change in Gibbs free energy, which at first hand the reader may think always implies it is spontaneous, but this is not always the case. Orbital overlap restrictions associated with the electron transfer can lead to cases (inverted Marcus regime) where the electron transfer becomes more challenging due to the change in Gibbs free energy being too negative.^{117,118 121} We also note that small positive Gibbs free energy associated with electron transfer can still lead to electron transfer if it is coupled with a subsequent irreversible chemical step (EC mechanism Scheme 3C).

Loosely speaking, electrochemistry has an advantage of being able to render any redox process thermodynamically favorable since it is possible to adjust the Fermi level of the electrode (Scheme 9) by simply adjusting the potential through external controls using a potentiostat (limitations on the electrochemical operating window do exist based on the choice of solvent, electrolyte, and electrode). In contrast, the analogous change in photoredox catalysis requires utilizing a different photocatalyst which has a set of more favorable redox properties, or varying the photocatalyst counterion (applicable only to solvents with low dielectric constants).¹⁰⁹ An additional key difference is that the Fermi level of the electrodes can be adjusted in a continuous manner (Scheme 10A), whereas this variable cannot be adjusted in a continuous manner in photoredox catalysis, nor is it as simply adjusted (Scheme 10B). Careful choice of the photoredox catalyst is required in order to achieve the desired driving force (ΔG_SET) for electron transfer from the photocatalyst to the substrate since the oxidizing or reducing potential of the photocatalyst are intrinsic properties (as discussed in Section 3.7.1). In order to achieve different redox potentials, a new catalyst must be chosen. This may require synthesis of a new catalyst or potentially there may be no catalyst structure known to have the desired redox potential. Thus, electrochemistry enables control over the electrochemical potential at each electrode, whereas photoredox catalysts do not allow for impromptu changes of its reduction and oxidation potentials since both are intrinsic properties of its different redox states. Finally, unlike photoredox catalysis which typically only enables a single electron to be transferred, electrochemistry usually enables multi-electron transfers as well as single electron transfer events (for a discussion of sequential single electron transfers, see Section 5).

Scheme 10.

Illustration of how control over the redox potentials differs between (A) electrochemistry and (B) photochemistry. Note: E_F(cathode) is the applied potential at the cathode and E_F(anode) is the applied potential at the anode. E_red = E(PC*/PC^•−) or E(PC^•+/PC), and E_ox = E(PC*/PC^•+) or E(PC^•−/PC), depending on the situation.

An underappreciated difference between electrochemistry and photoredox catalysis is the relationship between the energy source and its flux (rate). In photoredox catalysis, the energy inputted (wavelength) is decoupled from the photon flux (rate). In contrast, these are not decoupled in electrochemistry as evident from Ohm’s law (see section 3.7.7). For example, a large negative potential can be applied at the cathode potential but the only way to control the flux rate (current) is to either increase or decrease the resistance of the solution (solved with modifications to supporting electrolyte concentration or mass transport conditions). In contrast, photoredox catalysis enables the use of high-energy photons alongside a photocatalyst capable of being strongly reducing in its excited state, while still being able to control the rate externally via the photon flux by the selection of the light source’s power (Watts; e.g. 0.1 W vs 10 W).

3.7.3. Common Classes of Photocatalysts

Photoredox catalysts used in organic synthesis are typically transition-metal complexes or organic dyes. Ruthenium¹²⁵ and iridium¹²⁶ catalysts are often preferred due to their long-lived, redox-active triplet metal-to-ligand charge transfer (³MLCT) states and high reaction stabilities (Scheme 11A). However, the relative scarcity of these precious metals has invigorated the search for reliable alternatives that center on the more-abundant first-row transition metals.^127,128,129 Alternatively, organic dyes^{18,130,131,132,133,134} provide a main-group centered solution, with customizable scaffolds enabling divergent oxidative and reductive PET (Scheme 11B). Several of the most commonly used photocatalysts and their respective redox potentials are shown in Scheme 11.¹³⁵ Readers interested in alternate catalysts are highly encouraged to consult aforementioned references.

Scheme 11.

Selected photoredox catalysts along with their photochemical and electrochemical proprieties. All potentials are measured versus the saturated calomel electrode (SCE).

3.7.4. Electrode Materials

A key additional feature of electrochemistry, compared to photoredox catalysis, is the use of electrodes to facilitate redox processes at the electrode-solution interface (Scheme 2). The choice of electrode material can influence the reaction outcome in terms of yield, current efficiency, chemoselectivity, stereoselectivity, mechanism of electron transfer, and the number of electrons transferred to the substrate.^{136,137,138,139} Thus, the choice of electrode can be a critical parameter in optimizing electrochemical transformations. Electrodes can range from metals to carbon materials and beyond. Carbon based electrodes come in various forms, graphite (GRC), glassy carbon (GLC), reticulated vitreous carbon (RVC),¹⁴⁰ and carbon felt are all commonly available. Graphite is one of the most commonly used anode material. RVC is a porous form of glassy carbon but suffers from being brittle, thus substitutes such as carbon felt are sometimes used, particularly on larger scale. Electrode selection may be influence in part by their robustness to the reaction condition. Electrode degradation of Pt,¹⁴¹ graphite,^142,143 glassy carbon, ¹⁴⁴ and boron doped diamond (BDD)¹⁴⁵ anodes have been characterized in the literature. Cathodic corrosion can also result in degradation of cathodes and details on its process and mitigation strategies have been recently reviewed.¹⁴⁶

Electrodes can be either passive or active. Active electrode materials have electrocatalytically active species on the surface of the electrode and akin to immobilized redox-active catalyst. These active electrodes can impart unique reactivity/selectivity beyond simple electron transfer. Active electrodes include NiOOH generated through the in situ oxidation of a Ni anode^{147,148,149,150} under alkaline conditions, and PbO₂ anodes can be generated under acidic conditions. Waldvogel has demonstrated active anodes using Mo in hexafluoroisopropanol (HFIP),¹⁵¹ as well as active Ni in HFIP, for dehydrogenative arene couplings.¹⁵²

The choice of electrode can play a key role in the energy required to facilitate electron transfer processes. Figure 6 illustrates the concept of overpotential for a redox event under a given set of conditions. Namely that even if the change in Gibbs free energy associated with a certain reaction is negative (thermodynamics), it is not given that the reaction will proceed at an appreciable rate (kinetics) – reaction barriers must be taken into account. Thus, additional potential, beyond the thermodynamically required potential (E_1/2), is used to drive the reaction forward at an appreciable rate. This additional potential is referred to as the overpotential (η) and is given by equation 11:

$$\eta =E_{app}-E_{1/2}$$ (11)

where E_app is the applied potential and E_1/2 is the half-potential (thermodynamically required potential), each quantified relative to the same reference potential (E_ref). The overpotential associated with the reaction occurring at the electrode is dependent on the electrode material (as well as reaction conditions). The overpotential associated with key sacrificial transformations such as hydrogen evolution reaction (HER, equation 12) and oxygen evolution reaction (OER, equation 13) is dependent on the electrode material (see Table 1 for a summary).

$$\text{HER:}2{\text{H}}^{+}+2\text{e}\to {\text{H}}_2$$ (12)

$$\text{OER:}2{\text{H}}_2\text{O}\to {\text{O}}_2+4{\text{H}}^{+}+4\text{e}$$ (13)

Figure 6.

Illustration of the breakdown of the cell potential as a function of the thermodynamic potentials and overpotentials for oxidation (left hand side) and reduction (right hand side) processes.

Table 1.

Conductivity and overpotential (HER and HOR) associated with various electrode materials.

Electrode Material	Conductivity[a] /104 S•cm−1	η for H2 Evolution[b] in H2O /V	η for H2 Evolution in MeOH /V	η for O2 Evolution[d] in H2O /V
Ag	68.17	−0.59,172 −0.46,159 −0.444[h]154	−0.21172	0.61173
Al	41.37	−0.58159
Au	48.76	−0.12,172 −0.430[h]154	−0.20172	0.96173
Be	33.11	−0.63160
Bi	0.93	−0.33172	−0.32172
Cd	14.71	−0.99,159 −1.225[i]154		0.80173
Co	17.86	−0.3 to −0.4174		0.39173
Cu	64.81	−0.46,155 −0.57,160 −0.60,159 −0.720[j] 154	−0.32155, −1.1[m]137c	0.58173
Fe	11.67	−0.40159		0.41173
Ga	7.35	−0.63[c] 175
Hg	1.04	−1.04,159 −1.475[k] 154
In	12.50	−0.80160
Ir	21	−0.030[j] 154
Mg	24.7
Mo	20.62	−0.13,172 −0.30160	−0.28172
Nb	6.58	−0.65,160 −0.80[k] 154
Ni	16.32	−0.32,160 −0.434[h] 154		0.61173
Pb	5.21	−0.85,160 −0.91,159 −1.311[k] 154	−1.7[m] 139	0.80173
Pd	10.22	−0.01,172 −0.09,161 −0.044[h] 154	−0.01172	0.89173
Pt	10.42	−0.27,172 −0.09,159 −0.043[k] 154	−0.19172	1.11173
Pt Plated	NA	−0.01172	−0.01172	0.46173
Rh	23.3	−0.08,159 −0.042[l] 154
Sn	8.70	−0.81176, −0.877[l] 154	−1.3[m]
Ta	8.20	−0.20,172 −0.41160	−0.36172
Ti	2.6	−0.767[h] 154
Tl	6.67	−0.61,172 −1.05160	−0.44172
W	20.75	−0.11,172 −0.27159	−0.32172
Zn	18.3	−1.092[k] 154
Stainless Steel	1.40177	−0.42178		0.28178
Graphite	0.0003, 0.4, 2.6	−0.47159		0.50173
BDD	10−6 to 0.002	−1.5[e]179		1 to 2 [f] 179,180, 181
Glassy Carbon (RVC)	0.02 to 0.10	−1.13[g]182
Leaded Bronze CuSn7Pb15			−1.5[m] 139
PbO2				−0.996[l] 154

^[a]conductivity data from reference 183 and 184, measured at 273 K (except Hg, glassy carbon, BDD which were measured at 298 K), unless stated otherwise.

^[b]HER overpotentials measured at measured in 1 M HCl or H₂SO₄ in solvent at 298 K and 1 mA•cm⁻², unless stated otherwise

^[c]measured at 2 × 10⁻⁴ A•cm⁻².

^[d]OER measured at 1 mA•cm⁻² 298 K, 1 M KOH in H₂O, unless stated otherwise.

^[e]0.5 M H₂SO₄.

^[f]Value significantly depends on electrode doping and pre-treatment procedure.

^[g]pH 3.4.

^[h]measured in 1 M H₂SO₄ at 298 K and 200 mA•m⁻².

^[i]measured in 0.25 M H₂SO₄ at 298 K and 200 mA•m⁻².

^[j]measured in 0.5 M H₂SO₄ at 298 K and 200 mA•m⁻².

^[k]measured in 1 M HCl at 298 K and 200 mA•m⁻².

^[l]measured in 4 M H₂SO₄ at 298 K and 200 mA•m⁻².

^[m]recorded in 2% H₂SO₄ in MeOH at 2 mA•cm⁻².

We note that data for various electrodes based on alloy materials is available.^153,154 It should be emphasized that these overpotentials are also dependent on other reaction parameters such concentration of the analyte/intermediate undergoing the redox event, solvent,^{155,156,157,158} supporting electrolyte,¹⁵⁹ current density,^160,161 temperature,¹⁶² as well as additional additives.^137,163,164 Both the HER and the OER can be used as a non-productive reaction at the counter electrode when performing organic electrosynthesis. Experimentalist leverage electrode materials with low overpotential for these reactions if HER or OER is desired. In contrast, if the HER or OER is undesirable, choosing an electrode which has a high overpotential for these unproductive reactions may be desirable. Electrodes with high overpotential for proton reduction include Pb, leaded bronze,¹³⁹ PbO₂,^165,166 Hg, Cd, Zn, as well as BDD.^{138,167,168,169} Hence, these are common choices in reductive electrolysis such as reductive dimerization of acrylonitrile to adiponitrile (Cd cathode),¹⁷⁰ reduction of oximes (Hg, Pb or leaded bronze cathodes),¹⁷¹ deprotection of Ts groups on nitrogen (Hg cathode, see Section 4.18.2). For example, Lehnherr and Rovis leveraged the use of a Zn cathode, associated with a high overpotential for the HER, to avoid unproductive H⁺ reduction and favor productive reduction of substrates to access hindered primary amines via a reductive coupling of iminiums and cyanoheteroarenes (see Section 4.10). The authors demonstrated that other cathode materials with lower HER overpotential, such as Pt, were less efficient due to competing proton reduction.

The choice of electrode, electrolyte, and solvent can also influence the stereochemical outcome of reactions. An example of that is the electrochemical reduction of oximes (e.g. 12.1) to generate amines (Scheme 12),¹⁷¹ where the use of a Hg cathode favors the formation of diastereomer 12.2, whereas the use of a Pb cathode favors formation of diastereomer 12.3.

Scheme 12.

Illustration of diastereoselectivity change upon using different reaction conditions.

The product selectivity can also be influenced by the choice of electrode. The classic example is the use of graphite vs Pt in the oxidation of alkyl carboxylic acid. Pt favors the 1e oxidation process leading to Kolbe¹⁸⁵ electrolysis, a 1e decarboxylative oxidation process leading to the generation of an alkyl radical, ultimately resulting in the dimerization of the alkyl radical. In contrast, the use of graphite results in a 2e oxidation process (Hofer-Moest reaction),^186,187 forming an alkyl carbocation which can be trapped by nucleophiles such as acetate to afford an ester product (Scheme 13). While the photoredox catalyzed (1e) oxidative decarboxylation is well precedented, examples of dimerizing the resulting radical is not well precedented due to the low concentration of radicals in photoredox catalysis. A noteworthy photochemical example exists where dimerization of the radical generated from a carboxylic acid occurs, but it leverages a high-photon density light source (500 W Xenon lamp) which may provide atypically high concentration of the key radical.¹⁸⁸

Scheme 13.

Illustration of 1e vs 2e oxidation of carboxylates.

Product selectivity in reduction chemistries can also arise based on the choice of electrode. For example, the reduction of acetone under protic conditions will result in mixtures that are dominated by isopropanol or propane depending on whether a Pb or Cu cathode is utilized. The reduction of acetone using lead cathode in acidic solution, predominantly leads to isopropanol formation, whereas the use of a zinc or copper cathode results in formation of propane.¹⁸⁹

Finally, it is also possible to alter the regioselectivity outcome of reactions through the choice of an electrode material. One example is the reductive coupling of allyl chlorides and aldehydes shown in Scheme 14 which can be carried out in a micro-flow reactor.¹⁹⁰ The use of Pt vs Ag cathode results in a reversal in regioselectivity, namely a 41:59 γ:α selectivity (14.1:14.2) with Pt whereas Ag cathode under identical conditions affords a reversal in the major isomer, specifically obtaining a 87:13 γ:α selectivity (Scheme 14A). Additionally, the use of laminar flow is demonstrated to be critical in achieving this selectivity reversal. It has been observed that the electrochemical allylation with aldehydes that have a higher reduction potential than the allylic halides results in predominantly the γ-adduct; in contrast, the α-adduct is obtained when the aldehyde is more easily reduced than the allylic chloride. By using laminar flow, streams of the two incoming reagents via inlet 1 and inlet 2 (Scheme 14A), can afford a choice as to which reagent is first exposed to the cathode, thus facilitating its preferential reduction to amplify this effect in flow mode A; in contrast flow mode B is unable to reverse the selectivity due to the aldehyde being reduced preferentially over the allylic chloride (Scheme 14C). For comparison to fully mixed reaction mixtures, the batch conditions using Pt cathode provide 29:71 ratio of 14.1:14.2 products in a combined 69% yield, highlighting the selectivity effect by using Laminar flow mode.

Scheme 14.

Illustration of regioselectivity change upon using different electrode materials as well as the effect on selectivity as a result of leveraging laminar flow delivering either allylic chloride or benzaldehyde reagent to the cathode.

3.7.5. Electrolytes and the Electric Double Layer

The addition of a supporting electrolyte (a salt) is typically required in order to minimize the resistance of the solution in organic electrosynthesis to enable the passage of an electrical current between the electrodes. The electrolyte should ideally be highly soluble and completely dissociate into cations and anions in the reaction mixture. Common cations in electrolytes include Li⁺, K⁺, tetraalkylammonium (R₄N⁺) and sometimes tetraalkyl phosphonium (R₄P⁺). Common anions in electrolytes include Cl⁻, Br⁻, PF₆⁻, BF₄⁻, TsO⁻, BzO⁻, AcO⁻, TfO⁻, ClO₄⁻, (SO₂CF₃)₂N⁻, B(Ar^F)₄⁻ and MeOSO₂⁻. The electrolyte composition and concentration, as well as the pH of the mixture, all can influence the nature of the electrode-electrolyte interface which can influence rates of electron transfer as well as product selectivity outcomes. The interface between the electrode and the bulk solution features a unique environment. Not only is the solution experiencing a potential gradient which can induce polarization effects (e.g. alignment of dipole of the substrate) but this also leads to the formation of an electric double layer (EDL), also referred to as the Helmholtz double layer (Scheme 15A). While a number of models have been put forward (e.g. Helmholtz, Stern, Gouy-Champan),¹⁹¹ the details can depend on experimental conditions such as electrode material, solvent and electrolyte composition. The negative potential of the cathode provides a driving force for cations to self-assemble on the surface of the cathode, with a second layer of ions comprising of anions to balance charge, thus forming the EDL. In cases where large excess of supporting electrolyte is present relative to substrate, the electrolyte comprises of significant portion of these cations and anions in the EDL, in which the substrate may be interspersed. The choice of the electrolyte can govern whether solvent, protons, or a specific substrate can interpenetrate this EDL, thus imparting selectivity in which substrate may be closer to the electrode and thus facilitating electron transfer with those substrates. Tuning the atomic/molecular radii of the electrolyte’s cation and anion can impart effects on the redox potential of species in solution as well as the reaction outcome in part due to changing the polarity of the EDL (polar vs greasy) as well as ion-pairing strengths.^192,193 Small cations have a higher charge density, which leads to stronger interaction with anions in solution. Tetraalkyl ammonium cations can be tuned in size simply by changing the alkyl chain length (e.g. NMe₄, NEt₄, NBu₄ cations, Scheme 15B).¹⁹⁴ Analogously smaller anions, such as chloride, interact strongly with cationic species unlike large, non-coordinating anions such as tetrakis(3,5-trifluoromethylphenyl)borate (B(Ar^F)₄) anions (Scheme 15C). Solubility considerations in choosing an electrolyte are critical in order to ensure it can contribute to lowering the resistance of the reaction mixture.^195,196

Scheme 15.

(A) A simplified representation of the electric double layer at the anode and cathode. (B) Schematic representation of cation size increasing with longer alkylchains on tetraalkylammonium derived electrolytes. (C) Schematic representation of increasing anion radii size from Cl to PF₆ to B(Ar^F)₄ anions.

Quaternary ammonium salts are often used to avoid proton reductions at the cathode, as these can help exclude protons from the EDL and effectively aid in increasing the overpotential for proton reduction associated with the electrode material used.¹⁶³ These EDL related effects can loosely be thought of analogous to solvent effects imparting changes in reactivity behavior and the EDL is a unique aspect not present in photoredox catalysis. The choice of electrolyte also influences the double layer capacitance which can impact current efficiency in electrochemical transformation, and this double layer capacitance¹⁹⁷ can play an important role in optimizing parameters for alternating current electrolysis.^198,199,200 It is therefore no surprise that the choice of electrolytes can influence the reaction outcomes (yield, selectivity, current efficiencies,²⁰¹ etc.),²⁰² including in bioelectrochemistries in part related to the Hofmeister effect.²⁰³ Advances in the interfacing of analytical techniques have even allowed for in situ probing of electrode-electrolyte interface by time-of-flight secondary ion mass spectrometry (ToF-SIMS),²⁰⁴ as well as understanding electrode fouling in situ.²⁰⁵ Other recent advances in photoelectron-based spectroelectrochemical methods are enabling the study of these electrode/electrolyte interface effects.²⁰⁶

3.7.6. Mechanisms of Catalyst-Mediated Electrolysis

Electrocatalysis is the term traditionally used to refer to reactions in which the electrode is chemically involved in the catalytic process.²⁰⁷ The properties (e.g. chemical, crystallographic features, surface defects) of the electrode material may impart catalytic efficiency and selectivity, the bulk properties of the electrode may not be as important as its surface properties which directly interface with the reaction mixture. In contrast, the use of molecular catalysts refers to the use of molecule either in solution or immobilized on the electrode surface (monolayer or multilayer) to impart catalytic properties on the reaction.²⁰⁷ The use of a catalyst in electrochemical transformations can facilitate either an electron transfer step and/or chemical step.²⁰⁸ Schemes 16A–E illustrates various scenarios in which the catalysts itself may be redox-innocent (Scheme 16A–C) or redox active (Scheme 16D–E).²⁰⁹ Scheme 16A illustrates how a catalyst may bind to substrate to increase the HOMO energy of the substrate, analogously a catalyst can bind substrate and lower the LUMO energy thus facilitating reduction (Scheme 16B). Another example of redox innocent catalysis may involve catalyzing chemical steps after the redox event (Scheme C). In contrast, redox-active catalysts undergo redox events.^210,211,212 Scheme 16E illustrates the use of a redox mediator to oxidize a substrate (facilitating only redox events), whereas (Scheme 16D) illustrates a redox-active catalyst also participating in catalyzing chemical steps (Scheme 16E). While Scheme 16A, 16C–E illustrate anodic processes, the analogous cathodic scenarios are also possible scenarios.

Scheme 16.

Illustration of several common catalyzed manifolds of electrochemical reactions using redox-innocent catalysts (A, B) and redox-active catalysts (C, D, E). (A) HOMO-activation of substrate by a catalyst (facilitates oxidation), (B) LUMO-activation of substrate by a catalyst (facilitates reduction), (C) catalyst only facilitates redox events (outer sphere electron transfer) (D) and (E) catalyst only facilitates redox event (either outer or inner-sphere electron transfer), (F) catalyst facilitates both redox and chemical events. [All redox events are shown as single electron events but redox events involving >one electron also fall into these categories].

The use of a redox-active catalyst in electrochemical transformations can impart a number of benefits.^210,211 The passivation of electrode surfaces commonly observed in direct electrolysis can be suppressed. Passivation or electrode fouling can lead to significant increase in resistance during electrolysis and hamper scalability of such reactions. Redox reactions at electrodes are often slow electron transfer processes, particularly when the redox event imparts a bond breaking/forming event and involves more than one reactant/product and subsequent redox events, due to the presence of a large overpotential. In order to drive reactions at meaningful rate a large excess of energy must be applied to overcome this overpotential.²¹⁰ This overpotential problem (and associated increased energy consumption) is exacerbated upon scaling up direct electrolysis, thus the use of a redox mediator is often sought to decrease this overpotential (and reduce energy consumption), typically resulting in improved selectivity for the functional group targeted to undergo the redox event as a result of the lower cell potential. The selectivity and reactivity between the various functional groups in the substrate is mainly controlled by the difference in the redox potentials of the various groups and that of the electrode potential. In contrast, the use of redox mediator may bind substrate to facilitate redox at a specific functional group (inner sphere electron transfer) thereby impart further improved selectivity. It should be emphasized that it is not uncommon to use a redox mediator with a standard potential that is significantly lower (up to ca. 600 mV) than that of the substrate’s standard potential if the redox process on the substrate is followed by a fast and irreversible chemical reaction, highlighting how to render the process milder compared to direct electrolysis. The number of electrons in the redox event associated with the substrate can be controlled by the choice of the redox mediator, which can be beneficial when aiming for selectively performing a 1e vs 2e redox process (e.g. ferrocene vs quinone, respectively).²¹³ From a green chemistry perspective, the use of stoichiometric redox reagents is problematic not only in terms of the waste generated from these reagents at the end of the reaction but also the additional waste/energy required to separate these from the products. In contrast to reactions using a stoichiometric redox reagent where the concentration of that reagent varies as a function of the extent of reaction, this is not the case in electrochemical reactions using a redox mediator where its relative concentration can be maintained at an optimized concentration. The partitioning of the total concentration of the redox mediator can be estimated by using the Nernst equation⁶⁴ which takes into account both the applied potential and the standard half-cell potential associated with the redox mediator. Direct electrolysis faces a related problem of having a significant concentration gradient as a function of distance from the electrode which may be problematic in some context. Given the above benefits, it is of no surprise that significant efforts have been devoted in the development of redox-active catalysts for electrochemical transformations. Redox mediators should have the following desirable characteristics: (1) both its oxidized and reduced form should be chemically stable, else catalytic activity will be lost, (2) the electron transfer with the electrode and the substrate should be fast and reversible, (3) redox events with solvent or other compounds in the reaction mixture, aside from the targeted substrate, should not occur, and (4) both the oxidized and reduced form of the mediator should be soluble in the reaction mixture (except if it is a biphasic system). A variety of methods have been developed for simulating and interpreting experimental data, including cyclic voltammetry, towards elucidating reaction mechanism of catalyzed (and uncatalyzed) electrochemical transformations.^{68,214,215,216,217}

A few redox mediators are highlighted here in Scheme 17, but a more comprehensive list can be found in other reviews.^{55,210,211,212,218,219} Polycyclic aromatic hydrocarbons and viologens serve as redox mediators for electrochemical reductions, while quinones (typically used in the presence of a proton source)^220,221 metallocenes (e.g. ferrocene derivatives),^{222,223,224,225} and triarylamines²²⁶ are used for oxidation chemistries. Aminoxyl derivatives like TEMPO and ketoABNO are prototypical oxidation catalysts via their oxidized oxoammonium form for hydride abstraction in alcohol oxidation chemistries.^212,227 TEMPO and structurally related analogs have also been used in the diazidation of alkenes,²²⁸ as well as Pd-catalyzed Wacker oxidation of alkenes.²²⁹ N-hydroxyphthalimides (typically used in the presence of base) have been used for hydrogen atom transfer (HAT) catalysts for generation of benzylic and allylic radicals from their corresponding C–H precursors. Other commonly used HAT catalysts include quinuclidine (and related structures like DABCO and 3-acetoxyquinuclidine),^230,231,232 thiols,²³³ benzoate salts (Na or Bu₄N as the cation),²³⁴ thiobenzoates,²³⁵ sulfonamides,²³⁶ phosphates,^237,238 halides,¹⁷ zwitterionic amidates, or alcohols,^239,240 as well as others,^{241,242,243,244,245} all of which can be oxidized either by the anode or a photoredox catalyst to generate their oxidized form capable of doing hydrogen atom abstraction. These method of indirect HAT are in contrast to direct HAT approaches such as those using photocatalysts like decatungstate derivatives (e.g. Na₄W₁₀O₃₂, (Bu₄N)₄W₁₀O₃₂) which can rely on triplet reactivity for HAT.^246,247 Other prototypical redox mediators include halides, metallocenes (ferrocenes and cobaltacenes) and more recently the use of organic dyes more commonly associated with photocatalysis are emerging as useful classes as well (e.g. methylene blue, acridiniums, cyclopropeniums, dicyanoanthracene, perylenediimides).

Scheme 17.

Structures of some key redox mediators along with their redox potentials (in V vs SCE).^{211,226,231,248,249,250,251,252,253,254,255}

3.7.7. Quantifying Efficiency and Other Key Metrics

The internal energy efficiency of photo and electrochemical reactions are captured by the quantum yield^256,257,258 and faradaic efficiency,^64,259,260 respectively. The quantum yield of a radiation-induced process refers to the number of times a specific event occurs per photon absorbed by the system.²⁶¹ For a photochemical reaction, the quantum yields can be calculated for product formation or for starting material consumption. The quantum yield for product formation (ϕ_product) is defined the number of product molecules generated divided by the number of photons absorbed by the starting material (equation 14b). Analogously, the quantum yield for starting material consumption (ϕ_reactant) is defined the number of reactant molecules consumed divided by the number of photons absorbed by the reactant.

$$\varphi =\frac{numberofevents}{numberofphotonsabsorbed}$$ (14a)

$$\varphi =\frac{amountofreactantconsumedorproductformed}{amountofphotonsabsorbed}$$ (14b)

A quantum yield less than 1 is the result of non-productive consumption of photons. This can arise from numerous types of events such as the photocatalyst excited state relaxing to ground state via either an internal conversion mechanism (e.g. conversion of energy into heat via vibrational modes of the molecule), luminescence (e.g. fluorescence from a singlet excited state or phosphorescence from a triplet excited state), back electron transfer (e.g. electron transfer from the acceptor back to the ground state oxidized form of the photocatalyst after a reductive quenching event), or other side reactions which by definition do not lead to product formation. A quantum yield greater than 1 can indicate the presence of a chain reaction mechanism (e.g. radical chain, hole catalysis).²⁶² Finally we note that the quantum yield can depend on reaction conditions, such as concentration, temperature, as well as the extent of conversion.²⁶³

To quantify the efficiency of electrochemical reactions, we can either measure the instantaneous current efficiency (${\varphi }_{\text{instantaneous}}$, equation 15), or the overall charge efficiency (${\varphi }_{\text{overall}}$), as known as the Faradaic efficiency (equation 16.^25,264 The instantaneous current efficiency can be thought of as a ratio of the current that participates in generating desired product, the productive current ($i_{\text{productive}}$), and the total current which takes into account the current that participates in unproductive reactions, the unproductive current ($i_{\text{unproductive}}$). In contrast, the overall charge efficiency (${\varphi }_{\text{overall}}$), sometimes referred to as coulometric efficiency,²⁶⁵ is the $Q_{\text{productive}}$ is the charge consumed to form the desired product and $Q_{\text{total}}$ is the total charge consumed. Thus, the current efficiency and Faradaic efficiency are each a number between 0 and 1. Although these metrics each can be reported as a percentage.^25,264 A current efficiency of unity represents perfect current efficiency, where only the desired process is occurring for each charge transfer event at the electrode. For most electrochemical reactions, current consumption efficiency is usually < 100%, with side reactions or non-faradaic processes (e.g. double layer charging) consume current parasitically.

$${\varphi }_{instantaneous}=\frac{i_{productive}}{i_{productive}+i_{unproductive}}$$ (15)

$${\varphi }_{overall}=\frac{Q_{productive}}{Q_{total}}$$ (16)

The relationship between current and charge is described below using Ohm’s law, where the potential of a cell ($U_{cell}$, given in volts [V]) is equal to the product of the current (i, given in amperes [A]) and its resistance (R, given in ohms [Ω]), as shown by equation 17. We note that the cell potential is the difference between the anode and cathode potential ($E_{\text{a}}$ and $E_{\text{c}}$, respectively).

$$U_{cell}=E_a-E_c=i•R$$ (17)

From equation 17 it becomes clear that if the electrical resistance of a reaction is changing over the course of the reaction (e.g. as starting material is consumed, electrical resistance increases are common), then it is impossible to keep both the current and the potential constant for the entire duration of the reaction. Hence, organic electrochemical transformations are typically performed using one of the following techniques: (a) constant current electrolysis (CCE), also known as galvanostatic electrolysis, in which the current is constant throughout the duration of the reaction (the potential is allowed to vary); (b) constant cell voltage, in which the cell voltage ($U_{\text{cell}}$) is constant throughout the duration of the reaction (the current is allowed to vary); or (c) constant potential electrolysis (CPE), also known as potentiostatic electrolysis, in which the potential of the working electrode is held constant throughout the duration of the reaction (either the potential of the anode ($E_{\text{a}}$) is kept constant, or the potential of the cathode ($E_{\text{c}}$) is kept constant) while the current is allow to vary over time.

Constant current electrolysis is operationally simpler when exploring new substrates/reactions because no prior knowledge is required with regards to the threshold potential required to affect a redox event. The potential will dynamically adjust until a redox event occurs at each of the electrode-solution interface to enable current flow through the solution. These experiments will usually exhibit an increase in the cell potential ($U_{cell}$) as the reaction progresses due to a gradual decrease in concentration of the starting materials (species able to undergo the more facile redox events), as illustrated in Figure 7. As a result, the increased cell potential can lead to undesired side reactions, particularly near the end of electrolysis. In contrast, using constant potential electrolysis not only requires the user to know what potential is necessary to affect the redox event targeted but also requires the use of a reference electrode to accurately achieve this electrode potential. Constant potential electrolysis does have the advantage of being able to dial in a potential that is just enough to reduce or oxidize the functional group of interest, while keeping the magnitude of the potential small enough to minimize side reactions. Improved selectivity can be achieved with CPE but can require significantly longer reaction times to achieve the same level of starting material consumption compared to CCE.

Figure 7.

Illustration of how the electrode potential (anodic potential in this example) rises as a function of conversion in a constant current electrolysis in order to adjust to the depletion of substrate using an anodic oxidation as the example. Figure reproduced from ref 266. Copyright 2020. Wiley-VCH Verlag GmbH & Co. KGaA.

Faraday’s Law (equation 18) illustrates that the total charge, Q (given in Coulombs [C]; note 1 C = 1 A•s), passing through the electrochemical cell is proportional to the absolute amount of analyte ($N_{\text{A}}$, given in moles), where n is the number of electrons per molecule of analyte required for the redox event, and F is the Faraday constant (given in faradays [F]; note 1 F = 96487 C•mol⁻¹). The charge is given by equation 19 which is the integral of the current as a function of time (t, given in seconds [s]) from t = 0 (start of electrolysis) to the end of the electrolysis ($t_{\text{e}}$).

Faraday’s Law:

$$Q=nF{N}_A$$ (18)

$$Q={\int }_0^{t_e}idt$$ (19)

For CCE:

$$Q=i{t}_e$$ (20)

Using equation 19, it is apparent that total charge is the integration area of the change in current over time (Figure 8B and 8D). As a corollary, when the current is constant for the entire duration of the electrolysis, such as in CCE, equation 19 simplifies to equation 20 (Figure 8A):

Figure 8.

Temporal profile of the current and charge for constant current electrolysis (A and B, respectively) and constant potential electrolysis (C and D, respectively).

Since the consumption of starting materials (analyte) is directly proportional to the total charge passed through the solution (Faraday’s law), the rate of starting material consumption will differ whether operating the reaction under CCE or CPE. For a unimolecular process where the electron transfer is the rate determining step (charge transfer limiting regime), CCE will result in the rate of starting material consumption being zeroth order since current is directly proportional to the rate (Figure 8C). In contrast, the same reaction operated using CPE will exhibit 1st order kinetics due to the current exponentially decreasing as the extent of reaction increases (Figure 8D). Equation 21 describes this exponential decay, where $i_{\text{o}}$ is the limiting current at the onset of electrolysis, and k is a rate constant that is directly proportional to both the surface area of the electrode immersed in solution and mass transport parameters, and inversely proportional to the volume of the solution, and t is time.²⁶⁷

For CPE:

$$i=i_0{e}^{-kt}$$ (21)

Analogous to how the total charge is a useful metric in electrochemistry, the concept of photon equivalents^268,269,270 is a useful metric for scaling up photochemical reactions. The absorption spectrum of a reaction may change with time (e.g. darkening of reaction mixture is common), which in turn can impact the yield by changing the instantaneous photoabsorption efficiency and quantum yield. To empirically account for these deviations, the cumulative value of photon equivalents is determined with respect to product yield. This correlation establishes photon equivalents as a scaling factor to enable translation between different photoreactors of the same scale, or between different scales of the same reactor. We refer the reader to published works on this topic for further details.²⁶⁸

3.7.8. Mass Transfer

Both photochemistry and electrochemistry reactions are interfacial in nature, thus aspects of mass transport will influence their reaction rate. In the context of electrochemistry there are three types of mass transport¹²⁴ phenomena: diffusion, convection, and migration. Diffusion relates to the movement of a species due to a concertation gradient. Transport of a species from a region of higher concentration to one of lower concentration occurs naturally to minimize concentration gradients. Convection is the movement of a species due to an external mechanical force (e.g. stirring of the solution, shaking of the reaction vessel, moving the electrodes (or an immersed light source) through the reaction mixture, sparging the reaction mixture in which the bubbles of the gas being sparged into the solution provides mixing). Migration is the movement of charged species along the electric gradient due to coulombic forces (e.g. positively charged ions are attracted to the cathode, and negatively charged ions are attracted to the anode). Migration becomes an insignificant contributor to mass transport in electrolysis when a high concentration of an inert electrolyte is present relative to the substrate concentration since the electric field imparted by the applied potential between the two electrodes is “screened” by the electrolyte (i.e. the charge will be transported mainly by the electrolyte). As for photochemical reactions, only convection and diffusion contribute to the mass transport mechanisms since there are no externally applied electrical gradients, thus migration is not a contributor to mass transport.

In the context of electrochemistry, the substrate (reactant, intermediate, or redox mediator) will have to migrate from the bulk phase of the solution to the electrode-solution interface region in order to undergo a redox event, and subsequently diffuse back into the bulk solution (Figure 9A). In some cases, redox events may require that the substance be adsorbed on the electrode, thus adsorption/desorption rates may come into play as well. Mass transfer regime or charge transfer regimes may dominate, as in the rate determining step may vary depending on the transformation, the reactor design, the mode of operation (e.g. CCE vs CPE), or reaction parameters (e.g. current density or electrode potential). In the extreme scenario, as the electrode polarization increases, the ratio of starting material to product in the electrode surface region (as governed by the Nernst equation) will be increasingly biased towards product, and in the extreme scenario, mass transport will dominate the rate. Thus, the improved mixing available in a flow reactor can be greatly beneficial compared to batch reactors for reducing material processing times (Figure 9B). In a contrasting scenario, when the electrode polarization is barely sufficient for charge transfer with the substrate, then charge transfer will dominate and govern rates of reaction (charge transfer controlled regime).

Figure 9.

A) Illustration of mass transport of the substrate into the Nernst layer, adsorption, electron transfer to the substrate generating the product, desorption of the product, and its mass transport out of the Nernst layer. (B) Illustration of two extreme rate determining step scenarios, namely charge-transfer controlled or mass-transport controlled regimes. Figure reproduced from ref 272. Copyright 2019 American Chemical Society.

Given that the redox event occurring at the electrode cannot occur faster than the analyte reaches the electrode surface (quantified by the mass transfer coefficient, k_m), this implies that a mass transfer limited regime governs the limiting rate of such reactions. The cell current ($i_{\text{cell}}$) is for reactions that are mass transfer controlled (assuming a current efficiency of 1 for the desired reaction) is given by equation 22²⁷¹:

$$i_{cell}=nF{A}_e{k}_{m}c$$ (22)

where A_e is the electrode area, c is the concentration of the analyte (reactant) in the cell. The fractional conversion (for mass transfer limited reactions) as a function of time (t) can be obtained from equation 23:²⁷¹

$$X=1-\exp [\frac{-k_m{A}_{e}t}{V_r}]$$ (23)

where $k_{\text{m}}$ is mass transfer coefficient, $A_{\text{e}}$ is the electrode area, and $V_r$ is the total reaction volume. From the above equation it becomes clear that efficient mass transport to the electrode as well as a high ratio of electrode surface area to reaction volume lead to faster conversion. An important parameter in optimizing electrolysis reactions is the current density (j), which is given by equation 24 (valid for cells with uniform current density), where i is the current (in amperes) passed through the electrode and $A_{\text{e}}$ is the geometric surface area of the electrode exposed to the solution (given in cm²).

$$j=\frac{i}{A_e}$$ (24)

In order to maximize productivity, high current densities are desirable, but this can lead to side reactions and thus decreased yields of the desired product, therefore it is usually necessary to optimize for this tradeoff. For example, if the redox event occurring at the electrode leads to radical formation, then a high current density equates to a high concentration of radicals formed at the electrode. This high current density may facilitate dimerization processes or multi-electron transfer events associated with the same substrate. The use of a redox mediator is a useful strategy to minimize such undesired reaction pathways by enabling redox events to occur in the bulk solution (homogeneous) instead of occurring at a heterogeneous interface (solid-liquid interface of the electrode with the solution). Redox mediators also enable control of the number of electrons transferred to substrate (e.g. this is an effective strategy to favor single electron transfer in cases where attempting to avoid multi-electron transfer events that occur in the absence of the mediator due to the high current density at the electron-solution interface).

Scaling up electrochemistry in batch naturally faces significant challenges since the ratio of the solution-exposed electrode surface area to the reactor volume is difficult to maintain as the scale increases; in contrast, flow electrochemistry can enable scaling up of the reaction via simple cell stacking in order to maintain very high electrode surface area to reactor volume ratios. Similarly, scaling up photochemistry is best suited for flow setups instead of batch in order to maximize the ratio of the surface area that is impinged by light relative to the reaction volume.

3.8. Flow Chemistry and Its Benefits for Scaling Up

Flow chemistry can provide significant advantages compared to batch mode reactions when it comes to scaling up photochemical or electrochemical reactions.²⁷² Numerous reasons exist to use flow chemistry for conducting photoredox catalysis or electrochemistry, including: (1) improved irradiation of the reaction mixture (applicable to photochemistry), (2) reliable scale-up, (3) improved reaction selectivity and increased reproducibility, (4) fast mixing, (5) fast heat-exchange, (6) improved mass transfer for multiphase chemistry (e.g. gas-liquid), and (7) increased safety of operation.²⁷³

The high surface area-to-volume ratio of flow reactors not only provides excellent heat transfer and control over mixing, but more importantly can address mass transfer limitations encountered in batch, as mentioned in the previous section. For example, Beer’s law and its implication for light penetration^269,274 into the solution for photochemical reactions can limit the reaction rate due to being in a photon-limited regime where only a fraction of the solution is exposed to light to excite the photocatalyst, as illustrated in Figures 10A and 10B. The distance, or path length (L), to which light can penetrate into the solution achieving a certain level of transmittance (T), is governed by the concentration (c) and molar absorptivity (ε) of the photocatalyst as illustrated by equation 25, for reactions when the only absorbing specie in solution at that wavelength is the photocatalyst. We note that transmittance of a solution is the transmitted intensity (I) divided by the incident intensity (I_o), and this is sometimes expressed as a percentage (%T). The absorbance of a solution is simply the product of the concentration (c), molar absorptivity (ε) and the path length.

$$L=\frac{-\log (T)}{\epsilon •c}=\log (\frac{I_o}{I})$$ (25)

Figure 10.

(A) Top: Attenuation of light as a function of pathlength through a solution containing Ru(bpy)₃(PF₆)₂ (ε = 13000 cm⁻¹•M⁻¹ at λ = 452 nm)²⁷⁵, bottom: generic effect of light attenuation with increasing concentration of catalyst or using catalysts with increasingly larger e. (B) Comparison of light transmission between batch and (C) flow photochemistry.

The use of reactors with large volume to surface area ratio (typical of batch reactors) results in only a small portion being illuminated due to the light attention as shown in Figures 10A and 10B. The result is non-homogenous illumination of the batch, with excess-photon regions (bright zones) and photon-starved regions (dark zones). In order to drive the reaction to complete, over-irradiation is necessary leading to increased reaction times, which can cause the formation of byproducts. In contrast, the use of flow reactors for photochemistry can enable lower volume to surface area ratios, providing nearly homogenous illumination of the reaction mixture with no dark zones (no photon-starved regions), thus leading to efficient reactions (Figure 10C). The use of continuous stirred tank reactors (CSTRs) interfaced with a laser and a lens for light diffusion have been explored²⁷⁶ as a way to address these light penetration challenges towards scaling up photochemistry on commercial scale. This approach is attractive from the point of view of being compatible with heterogenous mixtures in contrast to photo-flow which are best suited for homogenous conditions.

Below we illustrate several key benefits imparted by flow chemistry for performing electrosynthesis compared to batch operation. Based on Ohm’s law, equation 29 illustrates the ohmic potential drop ($E_{\text{ohmic}}$) between electrodes is equal to the product of the ohmic resistance ($R_{\text{ohmic}}$) and the current (i). The ohmic resistance of an electrochemical cell is linearly proportional to the inter-electrode distance (d) where a is the cross-sectional area between the two electrodes where current is flowing and ρ is the resistivity (given in ohms•meter). The alternate form of this equation is shown on the far right-hand side of equation 26 using solution conductivity, κ, given in siemens (S) per meter; the siemens is the reciprocal of the ohm (Ω), i.e., 1 S = 1•ohm⁻¹).

$$E_{ohmic}=i{R}_{ohmic}=i\frac{d}{a}\rho =i\frac{d}{a}\frac{1}{\kappa }$$ (26)

Equation 26 illustrates why minimizing the inter-electrode separation distance is critical to minimizing the ohmic resistance and thus the ohmic potential drop. An increase in inter-electrode distance, will result in increased resistance which in turn increases the cell potential. Undesirable side reaction may occur as a result of loss of selectivity associated with larger cell potentials. In typical laboratory scale batch electrolysis experiments, such as those utilizing the popular Electrasyn 2.0 setup by IKA equipped with 5 mL or 10 mL reaction volume vial sizes, the inter-electrode distance is typically ca. 0.5 cm. The use of additional electrolyte may be required to offset the increased resistance imposed when increasing the inter-electrode spacing or when introducing a separating material (e.g. semi-permeable membrane, sintered-glass frit) such as in divided cell electrolysis. Flow chemistry for organic electrosynthetic chemistry can enable advantages such as smaller inter-electrode spacing (e.g. <1 mm) which in turn has been demonstrated to enable significant decrease, and even elimination, of supporting electrolytes, highlighting benefits compared to batch mode operations.^{271,277,278,279,280,281,282}

The electrical resistance associated with the ohmic drop results in heating of the solution when current passes through it, resulting in a phenomenon known as Joule heating. The classical description of Joule heating involves the conversion of electrical current energy converted into heat as it flows through a resistor, and this concept can be adapted to electrochemistry by assuming that the solution is the bulk resistor. According to Joule’s first law, the Joule heat is directly proportional to the ohmic drop resistance ($R_{\text{ohmic}}$), the magnitude of the current passing through the solution, and the time duration (t) for which current is passed, as shown in equation 27.²⁸³ Flow chemistry provides the benefit of efficient heat-transfer, and given the smaller inter-electrode spacing compared to traditional batch setups, Joule heating is minimized.

$$Jouleheat=R_{ohmic}•i^2•t$$ (27)

A benefit of using electrochemistry is that electrons are used as the redox reagent instead of traditional redox reagents with significantly higher molecular weights and potentially toxic and/or hazardous properties. This green chemistry aspect must be considered in conjunction with the total energy required for running the process. The energy consumption for the cell is mainly dictated by the cell resistance and the operating current density. Equation 28 illustrates how the cell potential ($U_{\text{cell}}$) is the sum of the thermodynamically required potential ($E_{\text{e}}$), the sum of the overpotential (η) associated with the redox process at each electrode, and the potential associated with the ohmic cell resistance ($R_{\text{ohmic}}$) and the current (i).

$$U_{cell}=-\sum E_e-\sum \mathrm{\eta }-\sum i{R}_{ohmic}$$ (28)

The energy consumption for an electrochemical reactor, given in units W•s•mol⁻¹, can be obtained from the instantaneous current efficiency and the cell potential ($U_{\text{cell}}$) using equation 29,²⁸⁴ where n is the number of electrons per molecule of analyte (stoichiometry), and F is the Faraday constant; thus it becomes clear that minimizing the cell potential and maximizing the current efficiency are desirable towards minimizing the energy consumption.

$$energyconsumption=\frac{n•F•U_{cell}}{currentefficiency}$$ (29)

Electrochemical flow reactions are typically carried out at constant current using the optimal conditions for the analogous batch reaction (e.g. the choice of electrode, solvent, electrolyte, current density, etc.) as a starting point. These parameters enable fast translation of the batch reaction to a flow system. The total charge (Q) is given by equation 30,²⁸⁵ where i is the current in amperes, $\dot{V}$ is the flow rate in mL•min⁻¹, c is the concentration of the substrate in solution in Molar units and F is Faraday’s constant (1608.0889 min•A•mol⁻¹). This equation can be used to determine the ratio of the flow rate to current.

$$Q=\frac{i}{\dot{V}cF}$$ (30)

Flow cell operation can be either be in single-pass mode (continuous processing), or in recirculating mode (semi-batch process), as illustrated in Figure 11.^271,285 In single-pass mode, high conversion must be obtained through the flow cell. In order to achieve this, the flow rate and current need to be adjusted to achieve such outcome and has the drawback of potentially having difficulties in handling gas formation (e.g. H₂ evolution). On the other hand, recirculating mode can easily handle gas as the flow rate can be adjusted high enough that saturation of the solution is not reached and venting of the gas is allowed in the tank that holds the reaction mixture outside of the flow cell. Recirculating mode requires that the reaction mixture be recirculated until high conversion is reached and is usually easier to develop into a process than single pass operation (which requires full conversion upon exiting the cell after a single pass).

Figure 11.

An illustrative comparison between (A) single-pass mode flow cell operation and (B) recirculation-mode flow cell operation.

In a flow setting, the relationship between the cell current ($i_{\text{cell}}$), assuming 100% current efficiency for the desired reaction, and the fractional conversion (X) can be estimated using Faraday’s law by translating equation 30 to arrive at equation 31:²⁷¹

$$i_{cell}=nF\dot{V}{c}_{in}X$$ (31)

where $\dot{V}$ is the volumetric flow rate, $c_{\text{in}}$ is the concentration of the reactant at the cell inlet, and X is the fractional conversion. The fractional conversion can be estimated using equation 32:²⁷¹

$$X=1-\frac{c_{\text{out}}}{c_{\text{in}}}=1-\exp [\frac{-k_{\text{m}}wL}{\dot{V}}]$$ (32)

Where $c_{\text{out}}$ and $c_{\text{in}}$ are the concentrations of the reactant at the inlet and outlet of the cell, k_m is the mass transfer constant, w and L are the width and length of the solution channel, respectively.

A key metric to measure productivity of a continuous-processing reactor, including those for photochemical and electrochemistry transformations, is the space-time yield (STY).^124,286,287 This metric is used across all of flow chemistry. Equation 33 illustrates how to calculate the space-time yield (${\rho }_{\text{st}}$), which is the mass of product (m_p) formed per unit of time, t, and reactor volume (V_r):²⁸⁸

$$space-timeyield=STY={\rho }_{st}=\frac{1}{V_r}\frac{d{m}_p}{dt}$$ (33)

A range of reactor designs^271,289 can be leveraged for continuous processing of electrochemical reactions, from microreactors,^290,291 parallel plate flow reactors,²⁹² pipe cell (cylindrical electrode rod inside a tube) reactor (ideal for high pressure/high temperature reactions),²⁹³ solid polymer electrolyte (SPE) (also called MEA) reactor, ^271,294 bipolar disk stack cell,²⁷¹ rotating electrode reactors (various electrode geometries include rotating cylinder, rotating cone, rotating hemispherical electrodes, with cylindrical geometries being most common),^295,296 and continuous stirred tank reactors (CSTR) connected in series.^271,291 Similarly, continuous processing reactors for photochemistry range in design from plug flow reactors (PFR), CSTR, packed bed reactors, falling film reactors and even tube in tube reactors.²⁹⁷ Depending on the type of reaction, each reactor may afford advantages as well as disadvantages associated with the reaction conditions required (homo vs heterogenous reaction mixture, high pressure vs ambient, high vs low temperature, single vs multi-phasic systems, etc.). Other unique reactor design have also successfully been implemented on large scale such as in the use of stacked (graphite) disks in the anodic methoxylation of toluene derivatives by BASF (14 tons/batch),^298,299 or the use of Swiss-roll³⁰⁰ reactors in an alcohol oxidation (diacetone-L-sorbose to diacetone-2-keto-L-gulonic acid, 2 tons per day) as part of the production of Vitamin C.

The application of electrochemistry on large scale in the context of industrial chemistry has been realized for decades and a summary of such examples has been reviewed.^{170,298,291,301,302,303} Additional green chemistry aspects can exist when using electrochemistry,^{304,305,306,307,308,309,310,311} and in some cases circumvent the use of stoichiometric, potentially hazardous/toxic redox agents by relying on electricity as the source of the most economical reduction/oxidation agent, the electron, simply by adjusting the potential at the working electrode.

3.9. Tools for Studying Reaction Mechanisms

The approaches for gaining insight into the reaction mechanism for a photoredox³¹² or electromediated^{313,314,315,316} process share similarities. Characterization of ground state species by common analytical techniques such as NMR and IR spectroscopy can provide structural and quantitative information, insight into equilibria distribution of starting materials, persistent intermediates and products. UV-Vis absorption spectroscopy can provide insight into the absorption features of the individual substrates and catalyst, but just as importantly experiments where combinations of substrate and catalysts aid in gaining insight whether (1) electron donor-acceptor (EDA)³¹⁷ complexes are forming, or (2) whether a bathochromic shift occurs in the substrate absorption as a result of interacting with a catalyst,³¹⁸ or (3) increased absorption occurs upon complexation to the catalysts.³¹⁹ Cyclic voltammetry^63,320 enables the measurement of redox potentials of starting materials as well as photocatalysts. Steady-state and time-resolved emission spectroscopy are useful for obtaining Stern-Volmer plots,^108,321 which provide insight into which species quench the excited state and the mechanism by which quenching occurs (static vs dynamic quenching, or combination of both).^108,312 It is important to emphasize that the observation of quenching of an excited state via Stern-Volmer luminescence quenching alone cannot conclusively discern between electron transfer and energy transfer mechanisms.¹⁰⁸ Repeating these experiments using solvents of varying polarities can help discern between electron and energy transfer since electron transfer involved charge separation while energy transfer does not. Thus, rates of quenching are largely solvent independent for energy transfer unlike electron transfer processes. Other experiments such as the observation (or lack thereof) a correlation between the rate of quenching vs the triplet energy of the sensitizer, or measurement of redox potentials of the photocatalyst and the substrate quenching the excited state of the photocatalyst can aid in delineating between the two mechanisms.^108,312 Transient absorption spectroscopy via time-resolved pump–probe experiments is another great technique for understanding electron and energy transfer processes. Transient absorption spectroscopy enables the characterization of events occurring on the picosecond timescale and has been used to understand metallaphotoredox catalysis (e.g. dual catalysis based on a transition metal, such as Ni, and a photoredox catalyst) – particularly in differentiating between photoinduced electron transfer and energy transfer mediated processes in reductive elimination events.^322,323,324 Recently transient laser spectroscopy, in combination with steady state photochemical measurements as well as electrochemical methods enabled for the experimental characterization photoredox chemistry involving α-aminoarylation.³²⁵

Reaction progress kinetics (RPK)^326,327,328 can be particularly useful in elucidating reaction mechanism and tools such as in situ LED-NMR^329,330 spectroscopy (Figure 12) and in situ electrochemistry-NMR^{331,332,333,334,335,336,337,338,339,340} (Figure 13) spectroscopy not only provide kinetic but structural information while being intrinsically quantitative. Critical advances from the original design by Berliner³⁴¹ were made by Gschwind³⁴² through improvements in the illumination strategy. These methods can be especially useful for compounds that are formed only under the presence of light or an electric potential as well as those which are volatile (e.g. CO). ³⁴³ The measurement of quantum yields can also be done via in situ LED-NMR spectroscopy³⁴⁴ towards understanding mechanistic aspects such as whether the reaction is photocatalyzed or photoinduced³⁴³ and obtaining evidence of a chain reaction process. The collection of both NMR and UV-vis absorption spectroscopy via in situ LED-NMR has been developed by Gschwind³⁴⁵ providing a tool for characterizing species which may be difficult to observe via NMR spectroscopy (e.g. signal broadening due to paramagnetic species or characterization of species that are NMR silent). Analogous to in situ LED-NMR spectroscopy tools and techniques, in situ electrochemistry-NMR (EC-NMR) has been developed.³³¹ A variety of approaches in the realization of the setup exist, some place the working electrode in the NMR detection zone (in the cross-sectional path of the radiofrequency coil) (Figure 12A), while others minimize interference by having the working electrode directly above this region (Figure 12B). The setup shown in Figure 12A has been used to measure cyclic voltammetry of benzoquinone and simultaneously record ¹H NMR spectra. The setup in Figure 12B has been used to study the electrooxidiation of ascorbic acid to dehydroascorbic acid. There are drawbacks to in situ NMR-based tools, including that they cannot stir the reaction mixture and face challenges in studying heterogenous reactions.

Figure 12.

(A,B) in situ LED-NMR spectroscopy setup and (C,D) in situ UV-LED-NMR spectroscopy setup. (A) Schematic diagram illustrating fiber optic cable inserted into a coaxial insert which centers the illumination in a 5 mm NMR tube. (B) Schematic diagram illustrating the power supply, LED-source and NMR spectrometer time control unit. (C) Schematic diagram illustrating UV-NMR setup (D) Illumination fiber and reflection dip probe inside the NMR. [Figures A & B reproduced from ref 352. Copyright 2016 American Chemical Society. Figures C & D reproduced from ref 345. Copyright 2018 Wiley-VCH Verlag GmbH & Co. KGaA.]

Figure 13.

(A) Schematic representation of an in situ EC-NMR spectroscopy setup with the working electrode being in the NMR detection region (inset illustrates NMR tube with working electrode (WE), counter electrode (CE) and reference electrode (RE), along with a Nafion^™ membrane providing a divided cell. (B) Schematic representation of an in situ EC-NMR spectroscopy setup with the working electrode being outside of the NMR detection region (inset illustrates NMR tube with working electrode (WE), counter electrode (CE) and reference electrode (RE). [Figure A reproduced from ref 339. Copyright 2017 American Chemical Society. Figure B reproduced from ref 340 Copyright 2019 Elsevier B.V.]

In order to profile heterogenous reaction mixtures, other methods must be employed. In situ Raman³⁴⁶ or in situ FT-IR spectroscopy^347,348 can be used to monitor reaction mixtures which are simultaneously irradiated. This approach has also been demonstrated to capture kinetic data, although these techniques provide significantly less structural information and require calibration curves to extract quantitative information. These methods do however benefit from being able to study heterogenous reactions as forced convection (stirring) can be applied. Ex situ techniques, such as collection of reaction aliquots and characterization of those via offline HPLC or NMR spectroscopy, are also useful for studying heterogenous reactions, although species produced only under photolysis or electrolysis or unstable/volatile species may not be observed, thus may not be representative of the components of the reaction mixture. Online Flow-NMR techniques are a way to handle heterogenous mixtures, with the benefit of being able to externalize the reaction vessel relative to the NMR magnet, while continuously pumping a sample from that mixture into the spectrometer through an NMR flow tube within a standard NMR probe, before returning it to the reaction vessel. This enables mixing, irradiation, addition of reagents and temperature control. Online flow-NMR has been used in the context of studying photochemical,^{349,350,351,352,353,354} as well as electrochemical³⁵⁵ transformations.

UV-Vis spectroscopy is another useful process analytical technology tool for collecting reaction time-course data;³⁵⁶ modest structural information can limit the usefulness of this technique, although examples of its application to studying photochemical reactions are widely reported.^357,358,359 Spectroelectrochemistry^{67,360,361,362,363,364} merges a spectroscopic technique (e.g. IR spectroscopy or UV-Vis absorption) with electrochemistry to spectroscopically characterize species generated by a redox event at a transparent electrode (e.g. indium-tin oxides, ITO) or a mesh electrode (e.g. Pt mesh). This enables the characterization of radical intermediates towards understanding their structure as well as their lifetime. Electrochemistry-mass spectrometry (EC-MS) is another analytical tool that has provided useful insight into products of photochemical³⁶⁵ and redox events.³⁶⁶ This method is useful for elucidating mechanistic aspect of electrosynthetic transformations, as well as mimicking oxidative metabolism^367,368,369 and studying corrosion processes.

EPR spectroscopy is another great method of characterizing radicals. If the radical species of interest can be generated with high enough concentration in a steady state approach, the sensitivity of the detection method may enable direct characterization of the radical despite the radical having a short lifetime. If this is not the case, radical species can be trapped using radical trapping agents (e.g. DMPO = 5,5-dimethyl-1-pyrroline-N-oxide) and BMPO = 5-tert-butoxycarbonyl 5-methyl-1-pyrroline-N-oxide) to generate a longer-lived radical species & accumulate its concentration which can be characterized by EPR (Scheme 18).^370,371,372 Advanced techniques such as photo-electron paramagnetic resonance (photo-EPR) and electrochemical-EPR techniques³⁷³ can enable the characterization of transiently formed species with unpaired electrons and has been realized as an in situ tool for probing redox chemistry. Coupled in situ NMR and EPR studies have also been used to study rates of electron transfer and electrolyte decomposition in redox flow batteries.³⁷⁴

Scheme 18.

Illustration of an EPR spin trapping experiment.

While the use of radical inhibitors like TEMPO, ABNO, BHT, or benzoquinone to inhibit product formation can be used as evidence that is consistent with a radical mechanism, it does not provide evidence for a radical mechanism. Positive evidence for a radical mechanism via indirect methods for product generation occurring via a radical intermediate include the use of radical probes (Scheme 19). Radical probes rely on a unimolecular bond formation/cleavage to occur if passing through a key radical intermediate and is reflected in the product outcome (e.g. opening of cyclopropyl ring when passing through a cyclopropyl carbinyl radical intermediate). In some cases, the desired radical reactivity may have comparable rates to the reactivity of the radical probe and thus lead to a mixture of products, which can then be used to benchmark the rate of the desired radical reactivity versus that of the radical reactivity built in the radical probe – these are radical clock experiments.^375,376,377 An example of using TEMPO to inhibit a radical pathway is illustrated below in a set of control experiments as part of a study on the 1,2-diazidation of alkenes by the Lin group (Scheme 19A). Anodic oxidation of a mixture of 4-tert-butylstyrene (19.1) and sodium azide typically results in a distribution of dimer 19.3 as well as hydroxazide 19.4 (arising from over oxidation and subsequent attack by water) as well as diazide 19.5. In contrast to these major products, reactions run in the presence of TEMPO suppressed the above mentioned products and instead provided azidooxygenation product 19.6, demonstrating TEMPO’s ability to inhibit the typical carbon centered radical reactivity.³⁷⁸ Subsequent report by Lin group with optimized conditions for this reaction led to an azidooxygenation of alkene method using NaN₃ and TEMPO under constant potential electrolysis, such as the conversion of 4-tert-butylstyrene (19.1) to product 19.6.³⁷⁹ The use of a radical probe such as vinylcyclopropyl derivative 19.7 affords product 19.8 which provides supporting evidence for the intermediacy of radical intermediate 19.8 which undergoes rapid ring opening to form 19.9 (Scheme 19B). The azidooxygenation of substrate 19.10 postulated to proceed via intermediate 19.11 provides for a competition reaction between radical annihilation with TEMPO to furnish product 19.12 and intramolecular 5-exo-trig cyclization to product 19.13. Experimentally, the dominant pathway leads to product 19.12. These results suggest that the radical coupling between the intermediate 19.12 and TEMPO^• occurs at a rate between 10⁶ and 10¹¹ s⁻¹. The use of radical probes is also quite prevalent in photoredox catalysis to support the intermediacy of radical intermediates.^380,381,382

Scheme 19.

(A) Illustration of using stoichiometric TEMPO to inhibit a radical reaction. (B) Illustration of a radical probes and clocks to support a mechanism proceeding via a radical intermediate and estimate rate constants in a mechanistic study.

3.10. High Throughput Experimentation (HTE)

High throughput experimentation (HTE) is a powerful approach for both reaction discovery and optimization to do more with less material in a faster timescale.³⁸³ Both reaction discovery and optimization benefit from the exploration of combinations of reaction variables (e.g. ligands, catalysts, reagents, solvents) including relative stoichiometries (e.g. metal-ligand ratios, ratios of two coupling partners, solvent ratios, catalyst loading). While chemical biology, including protein engineering, has used HTE via arrayed plate-based setups (e.g. 96-well plate), only in the past decade or so has synthetic chemistry emerged in such miniaturized formats for reaction discovery and optimization through the development of HTE workflows. Pharmaceutical and agrochemical companies now routinely leverage arrays of 8 mm × 30 mm glass vial inserts in 24-well 4 rows × 6 column array) or 96-well (8 rows × 12 column array) metal microtiter plates in which reactions can be carried out on ~100 μL volume which translates to 10 μmol scale for 0.1 M limiting substrate concentration. These microtiter plates have the standard SBS footprint and vial spacing (well positions) established by the former Society for Biomedical Sciences (SBS), now the Society for Laboratory Automation and Screening (SLAS),³⁸⁴ which enables interfacing with standard multi-channel pipettors or liquid handling robots.³⁸⁵ The use of pre-plated libraries of solids (e.g. ligands, catalysts, reagents like acids/bases) enable incorporation of screening such parameters within the HTE workflow, whereby stock solutions of the substrate and/or additional reagents/catalysts can be rapidly dosed into these pre-plated libraries to enable efficient HTE.

While a broad range of thermally mediated synthetic transformations can easily be explored (e.g. metal catalyzed cross-couplings), slightly more elaborate equipment is necessary to enable the interfacing of these setups with gases to enable HTE to carry out hydrogenations, hydroformylations, carbonylations, etc.^386,387 With the emergence of photoredox catalysis in the mid 2010’s, it became clear that having a method to introduce light into the reactions in an HTE setup would be beneficial for reaction discovery and optimization (Figure 14). DiRocco reported³⁸⁸ a method of interfacing such 24-well and 96-well plates with blue LED arrays and demonstrated its applicability in the developing a photoredox late-stage methylation of heterocycles (Minisci reaction) for pharmaceutically relevant targets. The light is introduced from below the reaction vial through circular openings in bottom of the metal microtiter plate using an array of LEDs (one LED per reaction well). Commercialized setups now offer such microtiter plate as well as a broad range of wavelength (365 nm and 450 nm being the most used, although longer wavelength applications are emerging) for the LED arrays, as well as the ability to control the light intensity. Recently, Kalyani, Lehnherr, and Lin reported³⁸⁹ equipment (HTe⁻chem) that enables electrochemistry to be performed within such microtiter 24-well plate (Figure 15). The HTe⁻chem was demonstrated to enable screening of various currents or potentials (depending if operated in constant current or constant potential mode), total charge, electrode materials, in addition to more common reaction parameters such as solvent, concentration, temperature, regent combinations (including electrolyte choice), etc. Since the HTe⁻chem setup utilizes the footprint and well spacing of standard 24-well microtiter plates, its incorporation into HTE workflows was seamless, including the ability to introduce light using LED arrays analogous to photoredox setup for HTE, thus enabling electrophotochemistry HTE screens. Reaction mixing for reactions in 24-well plates can accomplished using rotary magnetic stirring, larger 96-well plates typically require the use of tumble stirrers.³⁹⁰ Larger arrays of reactions have been achieved in 384- and 1536-well plate formats for nanomolar scale screening although to date this has been limited to thermal or photochemical transformations.^391,392

Figure 14.

(Top left) photograph of HTE photoredox setup for 24-well (not shown) or 96-well plate screening (bottom left) photoredox methylation of lepidine (right) HTE screening results (relative conversion) for 6 different solvents and 12 different photocatalysts. [Left figure reproduced from ref 388. Copyright 2014 Wiley-VCH Verlag GmbH & Co. KGaA.]. [Right figure reproduced from ref 386. Copyright 2017 American Chemical Society.].

Figure 15.

(A) Design and assembly of the HTe⁻chem (B) photograph of the fully assembled HTE HTe⁻chem setup with the constant potential top plate alongside a US quarter for scale (C) cross section of the HTe⁻chem (D) Reductive allyl silane synthesis and (E) assay yield data obtained from exploring 4 different current densities and 6 different cathode materials in the HTe⁻chem. [Figures reproduced from ref 389. Copyright 2021 American Chemical Society].

Setups for preparative lab scale commonly encountered in synthetic methodology publications (~1 mmol scale) vary greatly from lab to lab in both electrochemistry and photochemistry. For example, photochemistry is routinely run using Kessil lamp setups with or without fans for air cooling in which the vial to lamp distance can greatly influence reaction temperature and photon flux,³⁹³ while non-standardized electrochemical setups can have vastly different cell geometries, electrode dimensions, shapes, and inter-distance spacings, ultimately bring about challenges in the ease of uptake of these synthetic methods. With the advance of HTE equipment for both photo and electrochemistry, the advance of standardized reactors for larger scale (ca. 0.1 mol to 4 mol scale, 1 mL to 40 mL reaction volumes) have also emerged as useful tools for validation of HTE leads by carrying out preparative synthesis, including substrate scope. These standardized reactors have greatly facilitated the ease in reproducing results from one lab to another by controlling the critical parameters mentioned above in the equipment setup. A few notable setups include the Penn PhD m1/m2 photoreactors,^394,395 EvoluChem^™ (by HepatoChem),³⁹⁶ TAK-120 photoreactors (air or liquid cooled),³⁹⁷ while Kessil offers the PR160 Rig to enable reproducible positioning of lamps and air-cooling fans. In terms of electrochemistry, the most widely used setup is IKA’s ElectraSyn 2.0^23,313,398 which has made entry into electrochemistry facile as well as providing a standardized reaction setup for ease of reproducibility. The Electrasyn 2.0 can be interface with either a single reaction holder or a carousel for up to 6 parallel reactions, or through the use of their e-Hive accessory, up to 24 reactions can be run in parallel, although certain limitations exist, including a non-standard footprint / vial spacing that render it challenging to interface with standardized HTE workflows. We also note important contributions by Yudin in developing a 16-well parallel electrochemical setup for parallel electrosynthesis on ~1 mmol scale.³⁹⁹ Parallel reactor setups were also latter reported by Toshiki & Atsushi (5 reactions, ~1 mmol scale)⁴⁰⁰, and Waldvogel (8 reactions, ~1 mmol scale),⁴⁰¹ as well as others.⁴⁰² Beeler⁴⁰³ and Stephenson⁴⁰⁴ individually reported microfluidic based screening platforms for screening photochemical reactions.

3.11. Common Redox-activatable Radical Precursors

The generation of radicals on organic substrates is commonly accomplished via either an electron transfer event or atom transfer reaction (e.g. HAT),^{405,406,407,408,409} although other mechanisms such as halogen atom transfer (XAT)^{410,411,412,413,414,415,416,417} or ET/EnT mediated strain release mechanisms exist⁴¹⁸ (Scheme 20).

Scheme 20.

Illustration of oxidative and reductive PCET as well as HAT processes to generate radicals.

Certain functional groups provide synthetic handles to site-selectively generate radicals on organic molecules (Scheme 21). Various names have been proposed in the literature for these groups, such as radical precursor group (RPG) or electroauxilliaries. For example, carboxylic acids,⁴¹⁹ particularly under basic conditions, can be utilized to generate radicals via a decarboxylation process via a single electron oxidation process. The related N-hydroxyphthalimide esters^{420,421,422,423,424,425} (redox active esters) can undergo a single electron reduction to release CO₂, phthalimide and the corresponding alkyl radical. Many other groups exist, including oxalates^426,427 as activating groups for alcohols for radical generation, alkyl BF₃K⁴²⁸ salts, alkyl silicates,^{428,429,430,431,432} benzylsilanes, allylsilanes, alkyl halides (α-halo esters/ketones),^{433,434,435,436,437,438} aryl halides. Deaminative radical generation processes include the use of pyridiniums^439,440, tetraalkylammonium salts, and electron-rich imines.⁴⁴¹ The use of silanes (or trialkyltin) α to heteroatoms (e.g. N, O, and S) results in raising the HOMO energy and thus facilitate oxidative radical generation, examples include α-amino silanes, α-silyl ethers and α-silylthioethers;^442,443 the oxidation potential relative to the des-silyl analog is largest in magnitude for O as the α-heteroatom, and smallest for S (see Scheme 21 below).^443,444,445 The generation of radicals can also be accomplished via HAT,^{446,447,448,449} including those via oxidative proton coupled electron transfer or reductive PCET.^{450,451,452,453}

Scheme 21.

Common radical precursors for organic synthesis. All oxidation^{426,432,438,441,444,454,455,456,457,458,459,460,461,462,463,464,465,466,467} and reduction^{86,420,433,434,435,436,437,438,468,469,470,471,472,473,474,475,476,477,478,479,480,481} potentials provided are in V vs SCE.²⁵⁵

3.12. Summary

For a summary see Table 2.

Table 2.

Comparative summary of electrosynthesis and photoredox catalysis.

Feature	Electrosynthesis	Photoredox Catalysis
underlying principle	redox chemistry	redox chemistry
number of electrons in redox event	1e or 2e are common (>2e possible), the use of a redox mediator can enable control over this number	typically 1e (two sequential 1e transfer events are postulated in only a limited number of examples)
generation of radical	Direct electrolysis (DE): redox event at electrode interface, within electrochemical double layer (localized) Mediated electrolysis (ME): redox event with redox mediator (electrocatalyst) can do redox within bulk	redox event via interaction with photocatalyst (excited or ground state), substrate-catalyst distance ≤ 20 Å,482 delocalized throughout solution but only within the photon-accessible regions of the solution (Beer-Lambert law)483
concentration of radicals	DE: high, localized at electrode interface/electrochemical double layer ME: low, delocalized throughout the bulk of the solution	low, localized but only within the photon-accessible regions of the solution unless generating persistent radical or proceeding through a radical chain mechanism which enables diffusion/propagation into the bulk solution
productivity throughput (space-time yield)	limited by current density, flow electrochemistry is often best suited for maximizing space-time yield; electron flux (current) is coupled to potential (Ohm’s law)	limited by photon flux absorbed by photocatalyst, photo-flow best suited for maximizing space-time yield; photon flux is not coupled to photocatalyst redox potential
efficiency range of redox potential accessible	faradaic efficiency (current efficiency) can be adjusted in a continuous manner via external control, limited by solvent/electrolyte compatibility (electrochemical window);	quantum yield can be adjusted in discrete manner (different photocatalysts), redox potential limited by photocatalyst identity (i.e. may be unable to synthesize a catalyst with the desired redox potentials);
independent control over oxidation and reduction potentials	yes (oxidation and reduction occur at different electrodes)	no (oxidation and reduction occur with the same photocatalyst)
can oxidation and reduction events be separated	oxidation occurs at anode, reduction occurs at cathode, electrode separation distance spatially separates these events. A divided cell can provide additional physical separation of the two redox events (e.g. using a porous frit). Tailored membranes can also restrict permeability based on chemical nature of the ion (ion-selective membranes).	oxidation and reduction event both occur at the photocatalyst (one in the excited state and one in the ground state after the initial redox event from the excited state – spatially separation is likely limited by diffusion distance travelled between these two events
net oxidative transformation	requires terminal oxidant (e.g. reduction of H+ from protic solvent to H2 gas) for sacrificial reduction	requires terminal oxidant (e.g. air, persulfate salts, or reduction of H+ from protic solvent to H2 gas using co-catalyst such as cobaloximes)
net reductive transformation	requires sacrificial electrode (e.g. Zn anode) or terminal reductant (e.g. Et3N)	requires terminal reductant (e.g. Et3N)
redox neutral transformation	challenging (lifetime of radical intermediate typically not long enough to travel from one electrode to the other) – requires use of a cell with small inter-electrode spacing (<100 μm) or alternating potential/current electrolysis	facile, usually better suited for photoredox catalysis than for electrosynthesis
radical-radical coupling	achievable via DE to have a high local concentration of radicals	requires the use of a persistent radical

4. SYNTHETIC COMPARISONS BETWEEN PHOTOREDOX CATALYSIS AND ELECTROCHEMISTRY METHODOLOGIES

4.1. Introduction

The second half of this review aims to detail several key synthetic transformations shared by both photochemistry and electrochemistry, with a particular focus on the key disconnections and intermediates associated with the respective strategies. For the photoredox examples chosen, we explicitly limited these reactions to ones that proceed via ET, and omit EnT-mediated reactions, although relevant references are included. The classification of reactions as net reductive, net oxidative, or net redox-neutral is denoted in the synthetic schemes using orange circles marked with +e+e, −e−e, and ±e, respectively. The list of transformations included in these sections are inclusive to the overlap of photoredox and electrochemistry, and we hope that these comparisons will illuminate the subtle limitations that are associated with synthetic translations between the two methods.

4.2. Decarboxylation

Synthetic methods that rely on redox triggered decarboxylation event are pillars in both photoredox⁴⁸⁴ and electrochemical chemistries.⁴⁸⁵ In the context of electrochemistry, as mentioned in an earlier section, the choice of electrode material or reaction conditions, or the use of a redox mediator can aid in selectively achieving either a 1e oxidation (Kolbe process; graphite anode, low current densities) or a 2e oxidation (Hofer-Moest process, Pt or glassy carbon anode, high current densities) to access the corresponding radical vs cationic decarboxylated intermediates, respectively. In contrast photoredox is typically limited to single electron transfer events, thus the 1e oxidation chemistry underpins most methods reported to date. The following sections highlight some of these powerful transformations to form carbon–carbon bonds as well as carbon–heteroatom bonds.

4.2.1. Decarboxylative Etherification

Alkoxy aryl ethers and dialkyl ethers are common motifs in bioactive molecules⁴⁸⁶, with the Williamson ether synthesis used to access primary alkyl ethers from activated alkyl halides and alcohols. However, accessing hindered variants of these structures can be difficult as unproductive elimination byproducts predominate from S_N1 intermediates. To overcome this challenge, alternative functional handles alongside one- or two-electron redox activation pathways have been explored for decarboxylative etherification (Schemes 22 and 23).

Scheme 22.

A representative substrate scope for decarboxylative etherification methods via electrochemical and photoredox methods.

Scheme 23.

(A) Anodic oxidation produces the key alkyl carbocation for ether formation. (B) The putative metallaphotoredox mechanism for decarboxylative etherification by Hu. (C) The putative tandem photoredox and organocatalytic mechanism for decarboxylative etherification by Nagao and Ohmiya.

Baran, Blackmond and co-workers provide an electrochemical approach to this problem in their report of a modern-day Hofer–Moest reaction, in which dialkylethers are synthesized via two-electron anodic oxidation of carboxylic acids under galvanostatic electrolysis.⁴⁸⁷ The first oxidation of the carboxylate initiates decarboxylation and yields the alkyl radical, which then undergoes a second oxidation to reveal the key alkyl carbocation intermediate (Scheme 23A). Optimizing this process involved overcoming radical byproduct or elimination pathways, which were solved by using DCM as the reaction solvent. Furthermore, unproductive hydration and cathodic DCM reduction were overcome by the addition of molecular sieves and a sacrificial oxidant (AgPF₆). This method is applicable to a broad range of tertiary, secondary and primary acids; partner alcohol generality and the use of water as a nucleophile is also observed. Yields range from low to excellent and are dependent on the choice of oxidant (AgClO₄ vs. AgPF₆). Additionally, these reactions are scalable, with respective gram-scale etherification and hydroxylation of tertiary acids obtained in good yield.

Hu and co-workers report a tandem photoredox and copper catalyzed decarboxylative C(sp³)–O cross coupling between alkyl N-hydroxyphthalimide (NHPI) esters and phenols in the presence of Et₃N (Scheme 22).⁴⁸⁸ The key intermediate in this transformation is an alkyl radical formed from single electron reduction of the NHPI ester by reduced photocatalyst and subsequent radical fragmentation. A photocatalyst screen revealed that the more reducing heteroleptic iridium photocatalyst Ir[(dtbbpy)(ppy)₂]PF₆ (11.5) [dtbbpy = 4,4′-di-tert-butyl-2,2′-bipyridine; ppy = 2-phenylpyridine] was necessary for initiating NHPI esters (E_1/2^red ≤ −1.26 V vs. SCE in MeCN) as the more oxidizing catalyst 11.6 was less efficient in effecting the transformation. (Scheme 23B). Furthermore, a Cu^I species is necessary as yields drop when starting with Cu^II. Stern-Volmer studies revealed that photoexcited 11.5 oxidizes a Cu^I-Et₃N complex (23.1), which undergo ligand exchange with the phenol before trapping the alkyl radical. The resultant Cu^III alkyl aryloxide (23.2) then undergoes facile reductive elimination to furnish the desired product. The phenol scope is general, with good electronic tolerance observed when coupled to cyclohexyl bromide. Secondary and primary alkyl NHPI esters were well tolerated, with moderate to excellent yields obtained. Tertiary NHPI esters were limited to non-planarizable radicals (e.g. 1-phenylcyclopropane-1-NHPI ester (22.9) as low yields (< 30%) were observed for NHPI esters derived from pivalic acid and 1-methylcyclohexanoic acid. An organophotoredox variant of this transformation was recently reported by Nagao, Ohmiya and co-workers, wherein the decarboxylative coupling of NHPI esters and aliphatic alcohols is accomplished using a N-aryl phenothiazine derivative (22.20), without the prior Cu co-catalyst requirement⁴⁸⁹. Photoexcited 22.20 (23.2) initiates the reductive decarboxylation of the NHPI ester, forming an alkyl radical (23.3) that can recombine with the cation radical of 22 (23.4). Alternatively, the alkyl radical can be further oxidized to the alkyl carbocation (23.5) — this pathway is supported by mechanistic studies involving alkyl migration that forms the more stable carbocation — which is then trapped by 22.20 to form an alkyl sulfonium intermediate 23.6. Nucleophilic displacement by an alcohol then reveals the desired unsymmetrical dialkyl ether 23.7. This method tolerates a wide range of tertiary and secondary NHPI esters, as well as numerous functionalized primary and secondary alcohols, with good chemoselectivity for the primary O-substitution over secondary O-attack. Nagao, Ohmiya and coworkers followed up this work by coupling hindered ethers and NHPI esters across an alkene, thus broadening the potential disconnections available for unsymmetrical ether synthesis.⁴⁹⁰

4.3. Minisci Reaction with Heterocycles

Photoredox and electrochemical methods have been used to form alkyl radicals employed in the Minisci reaction, with the former strategy receiving the majority of attention. Phipps and co-workers have recently reviewed both approaches⁴⁹¹; thus, our survey of this topic will only briefly compare and contrast arene trifluoromethylation as the prototypical example. Readers interested in Minisci-type photoredox and electrochemical strategies for heteroarene alkylation^{492,493,494,495,496,497}, hydroxymethylation^498,499,500, carbamoylation^501,502, and asymmetric alkylation^{503,504,505,506}, as well as new photoelectrochemical approaches^507,508,509 are encouraged to explore the listed references.

4.3.1. Arene C–H Trifluoromethylation

The trifluoromethyl group is a privileged motif in drug discovery as its incorporation into small molecules improves their metabolic stability and can promote desirable conformational changes for better target binding.^510,511 (Hetero)arene trifluoromethylation typically proceeds by the formation of trifluoromethyl radical (^•CF₃), which can be generated by single-electron oxidation or reduction (Scheme 24). In 1993, Mallouk and co-workers reported the first example of a photochemical arene trifluoromethylation using superstoichiometric TiO₂ photooxidant and silver trifluoroacetate as the CF₃ source.⁵¹² The mechanism of the transformation proceeds via single electron oxidation of trifluoroacetate promotes decarboxylation and subsequent formation of ^•CF₃, which then traps an arene and forms the C–CF₃ bond. Consecutive oxidation and deprotonation then reveal the trifluoromethylated product. While a novel mechanism at the time, a small scope (8 substrates) and moderate-to-low yields highlight the limitations of this method. In 2011, MacMillan and co-workers improved on Mallouk’s initial report, in which a wide range of hetero(arenes) are efficiently trifluoromethylated in good-to-excellent yield using trifluoromethanesulfonyl chloride (TfCl).⁴⁷⁵ This transformation forms ^•CF₃ from TfCl via single electron reduction from a photoexcited Ru^II catalyst (Ru(phen)₃, 11.2), and releases equivalents of SO₂ and chloride byproducts. Monotrifluoromethylation was observed, with bis-trifluoromethylation only becoming competitive when higher amounts of TfCl were used. Observed regioselectivities trended with the most-electron rich C–H position, as moderate-to-low regioselectivities were observed for substrates without significant electronic bias. MacMillan and co-workers highlight the generality of their method through late-stage functionalization of several biologically active molecules, most notably Lipitor, in which its three trifluoromethylated regioisomers were individually isolated using supercritical fluid chromatography. While effective source of ^•CF₃, TfCl is prohibitively expensive to use on scale, motivating Stephenson and co-workers to use the combination of trifluoroacetic anhydride (TFAA) and pyridine N-oxides alongside Ru(bpy)₃(PF₆)₂.⁵¹³ Mixing these reagents forms a donor-acceptor adduct which then undergoes single electron reduction to reveal ^•CF₃ and single equivalents of CO₂ and pyridine byproducts. The yields for this transformation are lower (vs. MacMillan’s precedent) with bis-trifluoromethylation being problematic for several substrates, but this transformation was efficiently scaled on batch (0.12 mol) and flow (0.12 and 0.60 mol). Further mechanistic insight revealed that direct photoactivation of an EDA complex generates ^•CF₃, thus enabling arene trifluoromethylation.⁵¹⁴ The efficacy of the EDA complex was dependent on arene identity, as less electron-rich arenes gave minimal trifluoromethylation product in the absence of photocatalyst. The measured quantum yield of 0.87 suggests that presumptive chain propagation processes are not dominant. Finally, Stephenson and co-workers demonstrated the trifluoromethylation of N-Boc pyrrole on a kilogram scale using a flow system, obtaining the desired product 24.16 in 50% yield and 81% purity (0.95 kg) after 48 h.

Scheme 24.

A representative substrate scope for arene trifluoromethylation via electrochemical and photoredox methods.

Electrochemical approaches to arene trifluoromethylation have mainly focused on zinc trifluoromethylsulfinate (ZnTFMS) as the ^•CF₃ source. Blackmond, Baran and co-workers first reported the use of direct electrolysis (25 mA constant current with 1.62 F•mol⁻¹ passed; carbon cloth anode; carbon auxiliary cathode; potential drift from +0.7 to +1.3 V; Et₄NClO₄ electrolyte) to oxidize ZnTFMS and access requisite ^•CF₃ for heteroarene trifluromethylation in a divided cell.⁵¹⁵ Yields for this transformation were generally higher than their tert-butyl hydroperoxide(TBHP)-initiated method, and regioselectivity was observed for substrates with strong electronic bias. Reaction progress kinetic analysis reveals that ZnTFMS is consumed slower under the electrooxidative conditions relative to TBHP, which in turn minimizes unproductive side reactions and enable lower ZnTFMS concentrations (1.4 equiv vs. 2.0–3.0 equiv) to be used. An alternative system was recently reported by Zeng and co-workers, in which bromide oxidation to bromine is used to convert ZnTFMS to TfBr, which then is reduced to ^•CF₃, SO₂ and bromide. ⁵¹⁶ This strategy bypasses the direct electrolysis of ZnTFMS, which in turns enables the use of an undivided cell (platinum net anode; graphite plate cathode; constant current electrolysis, j = 5 mA cm⁻²) without a supporting electrolyte.

Noting the potential of merging the two approaches, Ackermann and co-workers used an acridinium photocatalyst to oxidize Langlois reagent, which fragments to ^•CF₃ and SO₂, and an undivided hydrogen-evolving electrochemical cell to oxidize the resultant acridine, promote product formation, and regenerate the photocatalyst (Scheme 25).⁵¹⁷ Control experiments reveal that the absence of either photocatalyst or electrical potential is detrimental to product formation (<10%). This strategy enables the trifluoromethylation of electron-rich arenes, heteroarenes, and the late-stage functionalization of several bioactive molecules in moderate-to-good yields. Thus, this example demonstrates the complementarity of photoredox catalysis and electrochemistry as the deficiencies present in individual systems are overcome through their merger.

Scheme 25.

A representative scope and putative mechanism for the electrophotochemical arene trifluoromethylation.

4.4. α-Cyanation of Amines

The functionalization of pyrrolidine serves as a great example of the contrasts that can be seen in the synthetic methods based on electrochemistry and photoredox chemistry. The α-functionalization of amines in the context of photoredox and electrochemistry leverage different intermediates (Scheme 26). A wealth of photoredox methods to achieve the α-functionalization of 2° & 3°-amines are known^{518,519,520,521} and these by in large rely on the generation of α-amino radicals, either from a sequential oxidation-deprotonation or a direct HAT process or an oxidative (1e) decarboxylation event. In contrast to the net 1e oxidation events used in photoredox, the oxidation of amines under electrochemical conditions is typically challenging to stop at the 1e oxidation intermediate (α-amino radical), and thus the subsequent oxidation (net 2e oxidation) is typically observed, resulting in the generation of iminiums. The prototypical example is the Shono oxidation^522,523 which achieves an α-methyoxylation of an amine via the in situ generation of the iminium. Electrochemical iminium formation via anodic oxidation of (N-acyl) amines can be achieved via a cation pool method.^{522,523,524,525,526,527,528} The use of a redox mediator can enable for α-oxygenation of amine (protected as a carbamate) as demonstrated by Stahl.⁵²⁹ We note that reductive generation of α-amino radical from imine precursors represents an alternative approach to generated α-functionalized amines.^530,531,532 Electrochemical reductive generation of α-amino radicals from iminiums has been used to form C–C bond via reaction with acrylates^{533,534,535,536} as well as for dimerizations.^537,538

Scheme 26.

Illustration of 1e vs 2e disconnection for the α-functionalization of amines.

The α-cyanation of cyclic amines can be accomplished in numerous ways either via one electron or 2 electron redox chemistries, or via HAT processes as summarized in Scheme 26. Early electrochemical methods focus on cation pool or direct oxidation approaches.^{539,540,541,542} Onomura reported an undivided cell electrolysis method using TMSCN, MeSO₃H, and graphite carbon (GRC) electrodes at 0 °C (method A1).⁵⁴³ The acid was essential for the generation of product and was proposed to control the equilibrium between HCN and CN⁻ in addition to suppressing enamine formation from the proposed iminium intermediate. Tajima has also reported a direct oxidative cyanation of imines using constant potential electrolysis, Pt electrodes and polystyrene-supported quaternary ammonium cyanide (PS-NMe₃CN, method A2).⁵⁴⁴ Stahl leveraged a redox-active catalysts to electrochemically generate an oxammonium catalyst capable of facilitating the oxidation of amines to iminiums that serve as the key intermediate undergoing nucleophilic attack by cyanide (method A3).⁵⁴⁵ The use of a redox mediator provides for milder reaction conditions compared to the direct oxidation methods and thus enables a great functional group tolerance in the substrate scope. The closest related photoredox method is one that uses rose bengal and air, either in the presence (methods B2) or absence (method B3) of graphene oxide (GO)⁵⁴⁶ to access iminiums for nucleophilic cyanation. Emmert and Oderinde reported an Ir-catalyzed photoredox method using NaCN and air as the terminal oxidant (Method B8), again proposed to proceed via an iminium intermediate.⁵⁴⁷

Strikingly different mechanistic strategies exist for the numerous photoredox methods that are proposed to access α-amino radicals. Oxidative deborylation (method B1)⁵⁴⁸ or decarboxylation (method B4 and B5) followed by cyanation of the α-amino radical using TMSCN (method B1) or hypervalent iodine reagent cyanobenziodoxolone (CBX) in the presence of CsOBz (method B4)⁴⁸⁰ or CsHCO₃ (method B5).⁵⁴⁹ The generation of alkyl radicals via photoredox decarboxylation processes are widely known and was employed as α-cyanation strategy by Gonzalez-Gomez leveraging TsCN as the cyanation reagent (method B7).⁵⁵⁰ The direct C–H functionalization approach, bypassing the requirement for pre-functionalization of the amine can be accomplished using hydrogen abstraction strategies using an HAT catalyst (BDE of α-amino C–H bonds typically range from 89–94 kcal•mol⁻¹).⁵⁵¹ Inoue reported a method using benzophenone for HAT to generate the requisite α-amino radical from the corresponding amine with subsequent cyanation using TsCN in the absence or presence of a hindered pyridine base (methods B10 & B11, respectively).⁵⁵² Another HAT approach was reported by Kanai and Oisaki, this time making use of BINOL phosphoric acid (1,1′-binaphthyl-2,2′-diyl hydrogen phosphate), TsCN and an Ir-photocatalyst [Ir(dFCF₃ppy)₂(5,5′-dCF₃bpy)(PF₆); note that dFCF₃ppy = 2-(2,4-difluorophenyl)-5-(trifluoromethyl)pyridine, 5,5′-dCF₃bpy = 5,5′-bis(trifluoromethyl)-2,2′-bipyridine] (method B9).⁵⁵³ Other methods include the use of Pd-porphyrin catalyzed oxidative cyanation method using O₂ as the terminal oxidant (method B12),⁵⁵⁴ Rueping reported methods of using an Ir-photocatalyst (method B13; note: tbppy = 2-(4-tert-butylphenyl)-pyridine)),⁵⁵⁵ or a metal oxide photocatalyst (TiO₂ or ZnO),^556,557 or Rose Bengal (method B15)⁵⁵⁸ to access iminium intermediates for nucleophilic cyanation, similar to strategies reported by Stephenson using a Ru-photocatalyst (method B14)^94,559 or those by Che using a gold photocatalyst.⁵⁶⁰ The α-cyanation of amines presented in the synthetic scheme (Scheme 27) highlights the breadth of mechanistic approaches leveraged to achieve these products and their proposed mechanisms are respectively shown in Scheme 28.

Scheme 27.

Representative examples of electrochemical (Method A) and photoredox methods (Method B) for the α-cyanation of amines.

Scheme 28.

Selected mechanisms for amine α-cyanation discussed Scheme 27: (A) electrochemical amine oxidation to iminiums; (B) indirect electrochemical oxidation using an oxoammonium; (C) photoredox oxidation of amines to iminiums; (D,E) photoredox decarboxylation via SET from a carboxylate or PCET from carboxylic acid (F,G) direct and indirect HAT using benzophenone and phosphate derived radicals, respectively.

4.5. Dehydrogenation of N-Heterocycles

The dehydrogenation of N-heterocycles such as tetrahydroquinoline can be accomplished under oxidative conditions in the presence of a redox-active TEMPO-catalyst. Comparable yields are obtained using either electrochemical⁵⁶¹ or photochemical oxidative conditions relying on a Ni-coated TiO₂ photocatalyst.⁵⁶² Tetrahydroquinoline derivatives as well as related indoline (2,3-dihydroindole), imidazoline, 1,4-dihydropyridines can be oxidized. Interestingly, incomplete oxidation of tetrahydroisoquinoline was observed to result in mixtures of the isoquinoline and 3,4-dihydroquinoline. Partial oxidation of N-arylated tetrahydroisoquinoline using Ru(bpy)₃(PF₆)₂-photoredox and CCl₄ as the sacrificial oxidant to access iminium salts.⁵⁶³

4.6. Nickel-Catalyzed Cross-Couplings

The synthetic utility of nickel-catalyzed cross-couplings has recently grown alongside the advances in understanding the radical-based mechanisms of odd-electron Ni species. When combined with the radical-forming pathways associated with photoredox catalysis and electrochemistry, Ni catalysis enables the discovery of new reaction platforms complementary to palladium-catalyzed methods.⁵⁶⁴ Three examples — C(sp²)–N, C(sp²)–S, and reductive C(sp²)–C(sp³) cross-couplings — are presented.

4.6.1. C(sp²)–N Bond Cross-Coupling

The Buchwald-Hartwig amination is the gold standard for arene C–N cross couplings, with applications ranging from medicinal chemistry to materials research.⁵⁶⁵ However, because of the high costs associated with Pd and the specialized ligands involved, there is a demand for alternative, low-cost methods. One important solution is the development of Ni-catalyzed methods that use photoredox and electrochemical strategies to overcome redox barriers. A tandem photoredox- and nickel-catalyzed method (termed Ni metallaphotoredox hereafter) was reported by MacMillan, Buchwald and co-workers, in which an Ir^III photocatalyst and Ni^II pre-catalyst were used to couple secondary and primary amines to aryl bromides and iodides in good to excellent yields under ambient conditions (Schemes 30 and 31).⁵⁶⁶ No specialized ligand was used in this transformation as the presumed ligands on the nickel center are the halide and amine nucleophile with the latter existing in equilibrium speciation states.⁵⁶⁷ This transformation was subjected to high-throughput screening by collaborators at Merck & Co., Inc., Kenilworth, NJ, USA. C–N cross-coupling with piperidine was observed for 78% of complex, drug-like aryl halides studied, highlighting its utility for high-throughput experimentation (HTE). The putative mechanism proceeds by oxidative addition of the aryl halide into a Ni⁰ species to form Ni^II oxidative addition complex 30.1 that undergoes ligand exchange with an amine to form a Ni^II aryl imido complex (30.2) (Scheme 30A). This intermediate is then oxidized to Ni^III species 30.3 by photoinduced electron transfer to excited state heteroleptic Ir^III photocatalyst Ir[dF(CF)₃ppy]₂(dtbbpy)PF₆ (11.6). This Ni^III species then undergoes facile reductive elimination to yield the desired aryl amination product. The two catalytic cycles converge with electron transfer from the reduced Ir^II photocatalyst to the Ni^I intermediate. Buchwald and co-workers then adapted this method to a flow system with Ru(bpy)₃(PF₆)₂ replacing Ir[dF(CF)₃ppy]₂(dtbbpy)PF₆ as the photocatalyst.⁵⁶⁸ Gram-scale C–N cross-couplings with (hetero)arenes were demonstrated, with 2.21 g of commercial anesthetic tetracaine synthesized in 84% yield with a 10-minute residence time. Johannes and Oderinde reported a similar transformation, albeit with dtbbpy as a supporting ligand on Ni and is limited to aniline, sulfonamide, and benzylamine nucleophiles (Scheme 30B).⁵⁶⁹ An alternative mechanism is proposed, in which reductive quenching of photoexcited Ir[dF(CF)₃ppy]₂(dtbbpy)PF₆ by aniline generates an aniline cation radical that is deprotonated to form an anilinyl radical (30.4). Trapping this open shell species at a Ni^I center forms a Ni^II imido intermediate (30.5) that is reduced to Ni^I by Ir^II before undergoing oxidative addition with the aryl halide. Facile reductive elimination from the Ni^III aryl imido complex 30.6 yields the desired arylamine. Further investigation of this mechanism by Miyake and co-workers suggest that either direct UV photoexcitation of NiIIBr₂-tris(amino) species⁵⁷⁰ or Förster-type energy transfer from Ru(bpy)₃Cl₂⁵⁶⁷ can facilitate the same transformation. More recently, MacMillan and co-workers present a revised mechanism in which aryl C–N cross-coupling proceeds via a Ni^(I/III) dark cycle and photoreduction of off-cycle Ni^II species initiates and sustains the catalytic Ni pathway (Scheme 30C).⁵⁷¹ Stern-Volmer and transient absorption spectroscopy studies show that DABCO is the primary quencher of photoexcited Ir^III, which generates a Ir^II reductant. Reduction of resting-state Ni^II species 30.7 by Ir^II initiates the Ni^I/Ni^(/III) cycle responsible for C–N coupling, as suggested by stoichiometric reductive elimination and quantum yield studies. Because Ni^II reduction is the rate-determining step, photocatalyst ligand modifications to obtain greater reductive overpotentials led to 37-fold and 10-fold increases in initial rate and quantum yield of product formation respectively. Nocera and co-worker independently provide evidence for the Ni^I/Ni^III cycle, as C–N cross-coupling is observed when a catalytic amount of Zn reductant is used in place of a photoredox catalyst, albeit for a limited substrate scope.⁵⁷² Taken together, these results suggest a complex mechanistic landscape in which modifications to catalyst, reagent and irradiation wavelength result in C–N coupling operating by different mechanisms and that a dark catalytic cycle (thermally sustained cycle, free of requiring light) may be operational with light serving to drive photoredox chemistry to bring off-cycle Ni species onto the catalytic cycle.

Scheme 30.

(A) The original mechanism proposed for nickel metallaphotoredox-catalyzed C–N cross coupling. (B) An alternate C–N cross coupling mechanism for aniline substrates proposed by Oderinde. (C) Current revised mechanism for nickel metallaphotoredox-catalyzed C–N cross coupling. Note: blue SET boxes represent a specific coupled electron transfer even between Ir^III* and organometallic intermediate 30.2.

Scheme 31.

Representative examples of electrocatalysis and photoredox catalysis for nickel-catalyzed C–N cross coupling.

The electrochemical approach to Ni-catalyzed arene C–N cross coupling was developed by Baran and co-workers using catalytic NiBr₂-dtbbpy in an undivided, galvanostatic cell.⁵⁷³ This method enables the coupling of hetero(aryl) bromides with 1°, 2°, and 3° amines in yields comparable to photoredox and palladium catalysis. This method was also scalable, with the coupled product of 4-bromobenzotrifluoride and N-Boc piperazine obtained in 66% yield. Further mechanistic investigation was carried out by Baran, Minteer, Neurock, and co-workers in which UV-Vis spectroscopy, cyclic and square wave voltammetry, and DFT computations were used to probe the elementary steps for the transformation (Scheme 31).⁵⁷⁴ A Ni^I/Ni^III pathway was found to be operative, with a Ni^I-halide species 32.1 formed via cathodic reduction from Ni^II undergoing oxidative addition with the aryl halide to form a Ni^III intermediate (32.2). This complex can substitute a halide for an amine nucleophile, setting up the Ni^III aryl imido complex (32.3) for reductive elimination to yield the desired product. However, this ligand exchange step is the minor pathway in this transformation, as 32.2 forms stable Ni^II intermediate 32.4 via facile comproportionation with 32.1 or through cathodic reduction. Ligand exchange at 32.4 is the rate-determining step and is dependent on base loading; the resultant Ni^II aryl imido complex 32.5 can then be oxidized to the key reductive elimination adduct 32.3 Thus, the overarching role of electrical current is to regenerate catalytically-active Ni^I/Ni^III intermediates. With a better understanding of mechanism, Baran, Minteer and Neurock were able to expand the nucleophile scope to amino acid esters, nucleoside analogs, and oligopeptides and the arene scope to aryl chlorides. Additionally, they demonstrate the use of flow chemistry to synthesize a precursor to the FDA-approved antidepressant vilazodone, obtaining the aminated product in 64% yield on a 100 g scale.

4.6.2. Arene C–S Cross-Coupling

The cross-coupling of aryl halides and thiols has historically been a challenge for transition metal catalysis as catalysis deactivation via the strong coordination of thiolates necessitates the use of specialized ligands, high catalyst loadings and/or high reaction temperatures for successful C–S bond formation.⁵⁷⁵ As a result, redox strategies using nickel catalysis have been developed to overcome some of these issues (Scheme 33). Oderinde, Johannes and co-workers circumvent this problem by using oxidative photoredox catalysis to generate thiyl radicals that participate in a Ni^I/Ni^III catalytic cycle to provide aryl sulfides from aryl iodides.⁵⁷⁶ Benzylthiols, thiophenols, alkyl thiols and cysteine derivatives were competent nucleophiles, with the only low-yielding substrate being the sterically-hindered tertiary thiol. The electrochemical counterpart to this method was reported by the Wang⁵⁷⁷ and Mei⁵⁷⁸ groups independently, in which cathodic reduction generates active Ni⁰ and thiolate from thiol with concomitant hydrogen evolution, while diametrical anodic oxidation provides the active thiyl radicals from the thiolate. Both undivided cell systems use LiBr, amide solvents, and nickel foam as the electrolyte, solvent, and cathode respectively, however they diverge in choice of anode and electrochemical set-up. Wang uses graphite felt (anode) under potentiostatic electrolysis, whereas Mei uses a sacrificial magnesium (anode) under a constant current. A notable side reaction pathway observed in the electrochemical set-ups is the formation of disulfides, which presumably forms via thiyl dimerization. This side product is not appreciably observed under photoredox conditions because thiyl radicals are catalytically formed.

Scheme 33.

Electrochemical and photoredox approaches to activating nickel-catalyzed aryl thiolation.

4.6.3. C(sp²)–C(sp³) Cross-Coupling

The facile and general construction of alkyl-aryl bonds via transition metal catalysis is a longstanding challenge of organic synthesis and the development of redox-centered pathways have provided important contributions towards solving this problem and streamlined its use for drug discovery.⁵⁷⁹ In particular, we highlight photoredox and electrochemical strategies involving the coupling of aryl halides with either (1) alkyl trifluoroborates (Schemes 34 and 35) or (2) alkyl halides (Schemes 36 and 37).

Scheme 34.

Representative examples of Ni-metallaphotoredox catalyzed cross-coupling of alkyl trifluoroborates and aryl halides, with respective putative mechanisms depicted.

Scheme 35.

Representative examples of electrochemically-mediated nickel-catalyzed cross-coupling of alkyl trifluoroborates and aryl halides alongside its putative mechanism.

Scheme 36.

Representative examples of nickel-metallaphotoredox catalyzed cross-electrophile coupling of alkyl and aryl halides, with respective putative mechanisms depicted.

Scheme 37.

Representative examples of electrochemical methods for nickel-catalyzed cross-electrophile coupling of alkyl and aryl halides, with respective putative mechanisms depicted.

4.6.3.1. C(sp²)–C(sp³) Couplings Between Aryl Halides and Alkyl Trifluoroborates

Palladium-catalyzed cross-couplings between aryl halides and alkyl boron nucleophiles is a classical strategy for accessing C(sp²)–C(sp³) bonds^580,581,582, with recent methods developed for enantiospecific couplings.^583,584 Despite its successes, Pd-catalyzed reactions generally require high temperatures or additives to accelerate the slow alkyl transmetalation step, which is potentially problematic for secondary alkyl boron nucleophiles due to the potential for β-hydride elimination at the palladium center. One way to alleviate this problem is to use analogous tetravalent organotrifluoroborates, which undergo cleaner transmetalation and are less susceptible to degradative oxidation relative to trivalent boron nucleophiles.^585,586 However, a more general solution is single electron transmetalation, where an alkyl radical generated via single electron oxidation of the parent alkyl trifluoroborate can add to a transition metal center to generate an odd-electron organometallic species.^587,588 Molander and coworkers report a Ni-metallaphotoredox method for generating stabilized benzyl radicals from single electron oxidation of a corresponding alkyl BF₃K species and coupling it with aryl bromides.⁵⁸⁹ A wide range of benzylic BF₃K species and aryl bromides with differing electronic properties are tolerated in this transformation, with the products obtained in moderate to excellent yield. Follow-up work by Molander and coworkers expanded the scope to include secondary alkyl trifluoroborates^590,591 — a key limitation of previously described Pd-catalyzed methods — as well as α-alkoxy-,^592,593,594 α-amino,⁵⁹⁵ α-hydroxyalkyl-,⁵⁹⁶ and α-trifluoromethyltrifluoroborates.⁵⁹⁷ Notably, the use of alkyltrifluoroborates enables selective C(sp²)–C(sp³) cross-couplings even for aryl halides containing boronic acids, boronic esters or MIDA boronates.⁵⁹⁸ The putative mechanism is as follows: The photoredox-generated open shell alkyl radical 34.5 readily enters the catalytic cycle by adding to a Ni^II-arene oxidative addition complex 34.6 to form a Ni^III intermediate 34.7 that readily undergoes reductive elimination to provide the desired C(sp²)–C(sp³) coupling product 34.8. Concomitant reduction of the resultant Ni^I complex 34.9 to Ni⁰ by an Ir^II species closes the two catalytic cycles. However, follow-up computational studies by Kozlowski and Molander reveal that an alternate mechanism may exists, where a Ni⁰-tbbpy species 34.15 intercepts an alkyl radical 34.16 to form a Ni^I species 34.17, which then participates in haloarene oxidative addition and subsequent reductive elimination to furnish the C(sp²)–C(sp³) coupled product.⁵⁹⁹ This revision likens the mechanism to aryl-alkyl Ni-catalyzed Negishi^600,601 and Kumada^602,603 couplings, where the participation of alkyl radicals is shown. This study also proposes that asymmetry at the C(sp³) center can be induced by using a sterically biased chiral bisoxazoline ligand; reversible alkyl radical fragmentation from the Ni^III intermediate leads to enantioconvergent dynamic kinetic resolution and the formation of the desired chiral species. In order to activate tertiary alkyl trifluoroborates to aryl halides, Molander and Primer switched from neutral bipyridine scaffold on Ni to the anionic 2,2,6,6-tetramethyl-3,5-heptanedionate (TMHD).⁶⁰⁴ This change enables the coupling of several tertiary alkyltrifluoroborates with electron-deficient bromoarenes; however, electron-rich bromoarenes and N-heteroaryl bromides were inefficient coupling partners. The effectiveness of this ligand switch was detailed by Gutierrez, Molander and coworkers, in which computational studies suggest that in the anionic TMHD-Ni system, aryl-alkyl coupling occurs via an outer-sphere reductive elimination (34.24), whereas inner-sphere reductive elimination is operative when the neutral tbbpy-Ni system is used.⁶⁰⁵ This distinction arises from the steric congestion at the aryl-alkyl-halo- Ni^III intermediate, where the cross-coupling barrier is at least 10 kcal•mol⁻¹ higher for acyclic tertiary alkyls. Taken together, these studies add to the growing field of work incorporating alkyl radicals into transition metal catalysis.^428,606

Electrochemical methods for the coupling of alkyltrifluoroborates and aryl halides have been relatively underdeveloped due to the difficulties in minimizing undesirable Ni-associated homocoupling side reactions, but a recent report by Liu and coworkers using convergent paired electrolysis to effect the coupling of benzyltrifluoroborates and aryl halides suggests that this strategy can mimic redox-neutral photoredox catalysis.⁶⁰⁷ Using galvanostatic electrolysis, C(sp²)–C(sp³) coupled products are obtained from electronically distinct aryl bromides and benzyltrifluoroborates in moderate to excellent yields, with the compatibility of aryl chlorides and vinyl bromides as coupling partners displayed. Notably, one advantage of this electrochemical method is its scalability, as the coupling of benzyltrifluoroborate and methyl 4-bromobenzoate can be scaled (up to 3.0 g) with minimal yield drop (93% to 86%). A key distinction of this transformation is that mechanistic studies of cathodic reduction suggest that only Ni^II/Ni^I reduction is operative, which rules out the involvement of a Ni⁰ species as proposed by the Kozlowski and Molander mechanism. Thus, the putative mechanism involves a Ni^I/Ni^III cycle, where cathodic reduction of a Ni^II-tbbpy intermediate 35.7 forms a Ni^I species 35.8 that readily undergoes oxidative addition with an aryl halide to form an aryl-bishalo Ni intermediate 35.9. Further cathodic reduction of 35.9 and halide extrusion leads to formation of the corresponding Ni^II complex 35.10, which intercepts the benzyl radical — generated from anodic oxidation of the benzyl trifluoroborate — to form the aryl-alkyl-halo Ni^III intermediate 35.11. Reductive elimination furnishes the desired C(sp²)–C(sp³) coupled product and completes the catalytic cycle. Despite their success with benzyl trifluoroborates, Liu and coworkers were unable to use other alkyl trifluoroborates, which is a current limitation, but future developments in this field should enable greater generality of both coupling partners.

4.6.3.2. C(sp²)–C(sp³) Cross-Electrophile Couplings Between Aryl and Alkyl Halides

Transition-metal catalyzed cross-electrophile couplings (XECs) between aryl and alkyl halides typically involves the use of stoichiometric metal reductants (e.g. Zn, Mn), with odd-electron organometallic species and radical intermediates implicated in the transformation.⁶⁰⁸ Thus, replacing these chemical reductants with photoredox- or electrochemical- generated electrons offer new XEC strategies (Schemes 36 and 37). Lei, Lu, and co-workers report a metallaphotoredox XEC between aryl and alkyl bromides using triethylamine as the terminal reductant, and obtained moderate to good yields for the desired products, albeit with limited substrate generality.⁶⁰⁹ The mechanism proposed is similar to the seminal XEC report by Weix and co-workers⁶¹⁰ with Ir^III photocatalyst 11.5 facilitating Ni^I/Ni⁰ reduction via the Ir^III/Ir^II cycle. A more general metallaphotoredox approach was reported by MacMillan and co-workers in which Ir^III photocatalyst 11.6 and NiCl₂•dtbbpy are used to effect C(sp²)–C(sp³) XEC between alkyl and aryl bromides in good to excellent yields.⁶¹¹ The putative mechanism operates by a Ni⁰ complex 36.10 that undergoes oxidative addition with the aryl halide to form Ni^II species 36.11, which then intercepts an alkyl radical formed in situ to yield the Ni^III complex 36.12. This alkyl radical is formed via halogen abstraction by a silyl radical 36.13 originating from tris(trimethylsilyl)silane (TTMSS); bromine radical generated from the bromide oxidation by photoexcited 11.6 participates in H-atom abstraction from TTMSS to form 36.13. Reductive elimination from 36.12 yields the desired C(sp²)–C(sp³) XEC product, and a Ni^I intermediate that closes the nickel and photoredox cycles by oxidizing Ir^II. Notably, five-membered heterocycles are compatible electrophiles, which have historically been difficult for palladium-catalyzed cross-coupling reactions. This strategy was also applicable to activated alkyl halides such as α-chloro carbonyls⁶¹² and bromodifluoromethane.⁶¹³ More recently, MacMillan and co-workers reported the XEC of aryl chlorides and alkyl chlorides through photoredox-mediated generation of a polarity-matched aza-silyl radical 36.18 to mediate effective chlorine atom abstraction from unactivated alkyl chlorides.⁶¹⁴ The scope of alkyl chlorides and aryl chlorides is broad, and good functional group tolerance is observed. Additionally, the late-stage functionalization of several pharmaceuticals is shown, with desired C(sp²)– C(sp³) coupling obtained in the presence of triazoles, amides, sulfones, and carbamates — functional groups common in medicinal chemistry settings.

The electrochemical approach to XEC⁶¹⁵ was first detailed by Périchon and co-workers, which couples activated alkyl halides (e.g. α-chloro carbonyls) and aryl bromides/iodides) using superstoichiometric Ni(bpy)₂Br₂ under constant current electrolysis in an undivided cell.⁶¹⁶ Two-electron reduction of Ni^II to Ni⁰ is observed and this species participates in oxidative addition with the aryl halide to an aryl-Ni^II intermediate that can intercept an α-carbonyl radical originating from cathodic reduction of the parent α-chloro carbonyl. This Ni^III species rapidly undergoes reductive elimination to furnish the desired C(sp²)–C(sp³) coupled product. Slow addition of the alkyl halide was necessary for circumventing unproductive alkyl halide homocoupling. The racemization of chiral methyl 2-chloropropionate suggests a radical pathway for the formation of the α-carbonyl radical and using a substrate with chiral auxiliary enables the diastereo- and enantioselective C(sp²)–C(sp³) couplings.⁶¹⁷ Hansen and co-workers extended the method to include unactivated alkyl halides, with the main modifications being the use of 4,4′-dimethoxy-2–2′-bipyridine (dmbpy) as the supporting ligand on Ni, higher constant current (10 mA; 2.0 F•mol⁻¹), and higher temperatures (65 °C) (Scheme 37A).⁶¹⁸ This XEC method is scalable up to 6.5 mmol, with a constant current of 2.0 F•mol⁻¹ and 10 mol% of NiCl₂•dmbpy. The reaction is sensitive to the rate of Ni^II reduction, as the use of high currents leads to low yield, poor selectivity, and low mass balance. Pyridine-amidine and 2,6-bis(amidine)pyridine (37.10) ligands were also used as they enabled higher yields for certain substrate classes (e.g. heteroaryl bromides) relative to dmbpy. Sevov and co-workers improved further on this system by introducing a redox shuttle to mitigate unproductive overcharge electron transfer that leads to catalyst degradation and undesirable protodehalogenated and homocoupling arene byproducts (Scheme 37B).⁶¹⁹ The reaction was performed under constant current conditions (3 mA; 2.5 F•mol⁻¹) in an undivided cell, with a tridentate bis-(pyridylamino)isoindoline[(BPyI), 37.12]-Ni species and a Ni(BPyI)₂ redox mediator found to be the most effective co-catalyst system. The overcharge protection afforded by Ni(BPyI)₂ enables XEC for redox sensitive groups such as sulfones and nitriles and challenging secondary alkyl halides at ambient temperatures and in good yields; without the redox mediator, yields are typically < 20%. Furthermore, the redox mediator enabled this transformation to be scaled in batch (75 mmol) with a high 400 mA current, providing the XEC product in 85% yield after 12 h. However, a potential downside may be a decrease in charge efficiency, as degenerate shuttling requires approximately an additional 0.5 equivalents of e (2.5 F•mol⁻¹).

The methods discussed thus far require sacrificial anodes that produce stochiometric metal waste, leading to reproducibility issues that limit its application on larger scales. Hansen, Weix and co-workers offer a workaround by using diisopropylamine as the terminal reductant, albeit in a divided cell run at a constant current (25 mA; 2.0 F•mol⁻¹), with substrates and catalyst segregated in the cathodic chamber and the reductant isolated in the anodic chamber.⁶²⁰ A dual ligand system — terpyridine (tpy) and bipyridine (bpy) — were used for Ni in this method, with varying ratios of each species influencing product yield. Qualitative analysis suggests that substrates with fast alkyl halide activation benefit from a lower tpy:bpy loading whereas high levels of aryl homocoupling can be circumvented using a higher tpy:bpy ratio.

Reisman and co-workers demonstrated C(sp²)–C(sp³) XEC can be rendered enantioselective, albeit through Ni-catalyzed reductive alkenylation between benzyl halides and vinyl bromides.⁶²¹ A chiral indanyl- substituted bis(oxazoline) (37.13) catalyst enables moderate to excellent yields with good to excellent ee under constant current electrolysis (10 mA; 2.0 F•mol⁻¹) in an undivided cell. This transformation could be scaled up on a gram scale by increasing the current to 100 mA with only minor losses in yield and enantioselectivity for a XEC between (E)-1-(2-bromovinyl)-4-methoxybenzene and (1-chloroethyl)benzene (83% yield, 91% ee). While the electrochemical and photoredox XECs may appear similar, the mechanisms are distinct because of the net electron flow involved in each respective transformation. In the electrochemical mechanism, a minimum input of 2 electrons via cathodic reduction is necessary to reduce a Ni^II pre-catalyst to generate a catalytically-active Ni species whereas in photoredox catalysis, a one-electron mechanism is invoked for generating Ni⁰ from Ni^I, with net neutral electron flow. More recently, Li and coworkers report a dehydroxylative method for alkyl-aryl XEC that proceeds through an anodic Appel reaction to yield an alkyl bromide intermediate that readily engages in the electrochemically-mediated Ni-catalyzed XEC with aryl bromides in accordance with the previously-discussed mechanism.⁶²²

4.6.4. Arene C–P Cross-Coupling

C(sp³)–P^V and C(sp²)–P^V bonds are important synthetic motifs that are found in pharmaceuticals^{623,624,625,626}, agrochemicals, organic materials⁶²⁷, ligands for asymmetric synthesis,⁶²⁸ and as organocatalysts^{629,630,631,632,633}. Precursors to the synthesis of these functional motifs via redox pathways involve the single electron oxidation of diaryl and dialkyl phosphine oxides, as well as organophosphites to generate phosphinoyl radicals after deprotonation. The formation of phosphinoyl radicals via photochemical pathways have been previously studied⁶³⁴ and their generation via photoredox or electrochemical methods opens up new reactivity pathways for these reactive intermediates. For this review, we will specifically highlight nickel-catalyzed phosphorylation of aryl halides via redox strategies (Schemes 38 and 39), but readers should consult the following reviews for convergent and divergent phosphorylation methods between photoredox catalysis^635,636 and electrochemistry⁶³⁷.

Scheme 38.

Photoredox and electrochemical arene C–P cross-coupling methods.

Scheme 39.

Proposed mechanism for photochemical and electrochemical arene C–P cross-couplings.

In 2015, Lu, Xiao and co-workers report a metallaphotoredox method using Ni(cod)₂ and Ru(bpy)₃Cl₂ to couple aryl iodides with H-diarylphosphine oxides.⁶³⁸ The arene scope is tolerant of electronic changes and compatible with heterocycles such as 5-methoxyindole and 2-iodopyridine. The putative mechanism is as follows (Scheme 39A): Ru(bpy)₃²⁺ photoexcitation and subsequent oxidation of a trivalent phosphinic acid 39.1 (the preferred tautomer relative to the alternative pentavalent H-diarylphosphine oxide 39.2) forms a phosphine centered cation radical that yields a phosphinoyl radical 39.3 upon deprotonation. Concomitant oxidative addition of the aryl iodide with Ni⁰ leads to an nickelarene intermediate 39.4 that intercepts the phosphinoyl radical to form a Ni^III complex 39.5, which then undergoes reductive elimination to yield the desired triarylphosphine oxide. Regeneration of active Ni⁰ from Ni^I via oxidation of a Ru^I species back to ground state Ru^II closes the catalytic cycles. The main limitation of this work is its reliance on H-diarylphosphine oxides, as H-dicyclohexylphosphine oxide and ethyl H-phenylphosphinate were incompatible coupling partners. This is rationalized by the preference of electron-rich secondary phosphine oxides to exist in its pentavalent form, which negates the possibility of single electron oxidation by photoexcited Ru(bpy)₃²⁺.⁶³⁹ Yu and co-workers improve on this precedent by extending the method to aryl and vinyl pseudohalides, as well as expanding the nucleophile scope to include H-diaryl and H-dialkyl phosphonates.⁶⁴⁰ The reaction scope is broad for alkenyl tosylates with moderate to excellent yields observed; however, the range of compatible aryl tosylates is rather limited but examples of C–P bond formation with an aryl mesylate and an aryl sulfamate are shown. The mechanism of this transformation is similar to the one described by Lu, Xiao and coworkers, however, Yu notes that a side pathway in which the phosphinoyl radical adds to Ni⁰ before arene oxidative addition with a Ni^I intermediate 39.6 cannot be discounted (Scheme 39B).

The electrochemical counterpart to this transformation was first reported by Léonel and co-workers, in which the nickel-catalyzed coupling of aryl bromides with H-dialkylphosphites is accomplished under galvanostatic conditions (i = 200 mA).⁶⁴¹ This strategy enables the use of a Ni^II catalyst, which is reduced to Ni⁰ to facilitate oxidative addition with the aryl halide. A wide range of aryl bromides are compatible with this transformation, and good tolerance is observed for arene electronics, albeit with reduced yields observed when ortho-substitution or carbonyl functional groups are present. A smaller scope of compatible H-dialkylphosphites is presented, but high yields are observed, except when a loss in conversion is observed with bulky isopropyl groups. Léonel and co-workers follow up on this work by demonstrating the synthesis of aryl and vinyl phosphinates when using alkyl H-phenylphosphinates as the coupling partner.⁶⁴² Cui, Xiang and co-workers report a similar transformation coupling aryl bromides with H-dialkyl phosphites, except that non-sacrificial RVC electrodes are used with a ten-fold reduction in current (i = 10 mA).⁶⁴³ This change enables cleaner reactions with previously problematic electron-rich substrates and eliminates the need of a sacrificial anode. Additionally, the synthesis of alkyl-diarylphosphinates and triarylphosphine oxides from alkyl H-arylphosphinate and H-diarylphosphine oxides is shown respectively. The putative mechanisms proposed by Xiang and Léonel diverge on active oxidation states of nickel and on the formation of the phosphinoyl radical. In Léonel’s example, a Ni^I species 39.7 —formed via cathodic reduction of an arylnickel^II intermediate 39.8 — intercepts the trivalent H-dimethylphosphite before undergoing deprotonation to arrive at an aryl-nickel-dimethylphosphonate ate complex 39.9 (Scheme 39C). Anodic oxidation, followed by reductive elimination, yields the product and closes the catalytic cycle; thus, the possibility of a phosphinoyl radical is not considered. By contrast, Cui, Xiang and coworkers propose a mechanism identical to aforementioned photoredox conditions, wherein the active catalytic cycle is a Ni⁰/Ni^II/Ni^III system, with 1 and 2 e reduction of respective Ni^I (39.10) and Ni^II (39.11) intermediates regenerating active Ni⁰ (Scheme 39D). Additionally, two-step anodic oxidation and deprotonation purportedly generates active phosphinoyl radical that joins the catalytic cycle through addition to either a Ni^II or Ni⁰ intermediate. More recently, Rueping and coworkers provide a route to unsymmetrical triarylphosphines via sequential paired electrolysis.⁶⁴⁴ Their method couples aryl halides and H-diphenylphosphine oxide in moderate to excellent yields, with H-dialkylphosphites also viable phosphorus partners.

4.7. Synthesis of Sulfones, Sulfonamides and Sulfuryl Fluorides

Sulfur^VI motifs such as sulfones and sulfonamides are important functional groups in medicinal chemistry and agrochemistry⁶⁴⁵, and have been used as bioisosteres in drug design to overcome issues related to metabolic stability and binding affinity.⁶⁴⁶ Additionally, sulfonyl fluorides are an emergent class of biocompatible electrophiles for click chemistry⁶⁴⁷ and are important functional groups for probing the activity of oxygen-, nitrogen- and sulfur-based nucleophiles of amino acid residues within proteins to enable the mapping of enzyme binding sites and protein–protein interactions.^648,649,650 Photoredox catalysis and electrochemistry offer similar and complementary pathways towards these structural motifs, with divergences observed in reaction mechanism or bond disconnection. For this review, we omit a discussion of vinyl sulfone synthesis via oxidative decarboxylation of cinnamic acids, as this topic was recently covered by Verschueren and De Borggraeve.²⁸ Additionally, readers should consult a minireview by Wu and coworkers on photocatalyzed methods involving the redox-induced trapping of SO₂ with alkyl and aryl radicals.⁶⁵¹ The use of electrochemistry can also enable for the selective oxidation of thiols to sulfinic esters (R-SO-OR¹) without over-oxidizing to the corresponding sulfonate ester (R-SO₂-OR¹).⁶⁵² Both electrochemistry⁶⁶¹ and photoredox catalysis^{653,654,655,656,657,658,659} methods to oxidize thiols have been reported to access symmetrical disulfides, and recent advances have also provided methods for accessing unsymmetrical disulfides.^660,662

4.7.1. Oxidation of Thioethers to Sulfones and Sulfoxides

Oxidation of thioethers has been realized using electrochemistry to reach either the corresponding sulfoxide (R-SO-R¹) or further oxidized to the sulfone (R-SO₂-R¹). Noël used electrochemical microflow cell with Fe electrodes in MeCN (conditions A1 & A2, Scheme 40),⁶⁶¹ while Xu reported a batch method using Pt electrodes in 1/1 (v/v) AcOH/HFIP (conditions A3 & A4, Scheme 40).⁶⁶² Both methods rely on proton reduction at the cathode as the sacrificial reduction. The electrochemical generation of H₂O₂ from O₂ and H⁺ to turnover chloroperoxidase for the enantioselective generation of (R)-methylphenylsulfoxide (>98.5% ee) from thioanisole has been reported by Liese as part of an electroenzymatic method using a carbon felt cathode in a divided cell.⁶⁶³ In the context of photoredox catalysis, the use of polyoxometalates as photocatalyst for oxidation prove to be useful once again, this time a decavanadate (TPPV10 = (Ph₄P)₄H₂[V₁₀O₂₈]) enabled oxidation of thioethers to the corresponding sulfoxide or sulfone with high levels of selectivity simply by using a different reaction solvent mixture – methylethylketone (MEK) enables access to sulfones while MEK/water mixtures enables access to sulfoxides.⁶⁶⁴ The water suppresses sulfone formation presumably preventing MEK-derived peroxide formation or decomposing MEK-derived peroxides faster than they can react with sulfoxides (conditions B1 and B2, Scheme 40). Photoredox using a uranyl photocatalyst (UO₂(OAc)₂•2H₂O) can achieve the same overall transformations (conditions B3 and B4, Scheme 40).⁶⁶⁵ The quantum yield for uranyl photocatalyzed oxidation of 4-Me-C₆H₄-S-n-Bu to its corresponding sulfoxide and sulfone were both determined to be >1 (ϕ = 7.6 and 8.2, respectively), suggesting a chain mechanism was operational. Pd-porphyrin (Pd-F₁₀TPP) photocatalyzed selective oxidation of sulfides to sulfoxides was reported by Che (method B5).⁵⁵⁴ The use of less common electrodes such as CoFe layered double hydroxide electrodes has also been demonstrated to be useful for the oxidation of sulfides to sulfoxide via electrochemical means and successfully minimizing the formation of related sulfone impurities.⁶⁶⁶ X-ray spectroscopy revealed that the CoFe-layered double hydroxide electrode transformed into amorphous CoFe-oxyhydroxide under the reaction conditions as the conversion evolved, yet the catalytic properties were demonstrated sustainable for 10 cycles.

Scheme 40.

Selective oxidation of thioethers to sulfoxides or sulfones.

4.7.2. Synthesis of Vinyl Sulfones

Vinyl sulfones are common motifs in medicinal chemistry due to their synthetic versatility^667,668, use as cysteine-selective inhibitors of proteases⁶⁶⁹ and phosphatases⁶⁷⁰, and emerging application as a molecular tag for the omic sciences.^671,672 While classic routes towards their synthesis have been established through aldehyde condensation or transition metal-catalyzed methods, accessing vinyl sulfones via redox pathways establishes a useful C–S bond disconnection between alkenes and sulfinates or sulfonyl hydrazides (Scheme 41). Photoredox methods are centered on the single electron oxidation of S^IV aryl and alkyl sulfinates, which generates a sulfonyl radical primed for addition to an alkene partner. König and co-workers use photoexcited Eosin Y to generate an aryl sulfonyl radical 42.1, which readily adds to a styrene partner at the least sterically-hindered carbon to form intermediate 42.2 before HAT to a stoichiometric radical acceptor (typically nitrobenzene) delivers the desired vinyl sulfone (Scheme 42).⁶⁷³ Trapping of species 42.2 by TEMPO provided evidence for this mechanistic pathway. The preliminary König report was limited to aryl sulfinates, but their follow-up manuscript expanded the method to include both linear, branched, and cyclic alkyl sulfinates.⁶⁷⁴ This observation is especially interesting as SO₂ extrusion is observed in synthetic applications of alkyl sulfinates that involve chemical oxidation.^{675,676,677,678} However, attempts to expand the alkene scope beyond styrenyl cores provided difficult. König and co-workers also updated their understanding of the mechanism, in which transient absorption spectroscopy showed that the triplet excited state of Eosin Y undergoes oxidative quenching with nitrobenzene (as opposed to the earlier hypothesis of a reductive Eosin Y quench with sulfinate), which then forms the sulfinate-oxidizing Eosin Y cation radical.

Scheme 41.

Representative examples of vinyl sulfone synthesis using alkenes via photoredox and electrochemical methods.

Scheme 42.

Putative mechanisms for vinyl sulfone synthesis via (A) photoredox catalysis and (B) electrochemistry.

The electrochemical counterpart of this method was reported by Yuan and co-workers, where aryl sulfinates are coupled with styrenes in an undivided cell equipped with a graphite anode-nickel cathode pair and N-tetrabutylammonium iodide as a supporting electrolyte and a redox mediator.⁶⁷⁹ The reaction mechanism is similar to photoredox conditions with a few differences: anodic oxidation of iodide to I₂ reacts with the sulfinate to form a sulfonyl iodide which fragments to the reactive aryl sulfonyl radical. Intercepting this intermediate with an alkene, followed by iodine radical, forms 42.3, which undergoes deprotonation-elimination to yield the desired product and an equivalent of hydriodic acid that is reduced at the anode to both evolve H₂ and regenerate iodide. An analogous electrochemical method using S^VI sulfonyl hydrazides as an alternate sulfur coupling partner was reported by Terenťev and co-workers.⁶⁸⁰

An interesting divergence between photoredox and electrochemical methods arises when terminal alkynes are used as the coupling partner (Scheme 43). Lei and co-workers report an Eosin Y-photocatalyzed method for the synthesis of α-vinyl sulfones, where aryl sulfonyl radicals generated from the parent sulfinates add to terminal alkynes with Markovnikov selectivity (Scheme 43A).⁶⁸¹ A wide range of aromatic alkynes provide desired product in good to excellent yields, but diminished yields were observed for aliphatic alkynes. The putative mechanism proceeds via reductive quenching of excited state Eosin Y by in situ-generated sulfinate 43.12, which forms the key sulfonyl radical intermediate 43.13. Eosin Y radical anion then reduces the terminal alkyne to the alkyne radical anion, which can undergo sulfonyl radical trapping and protonation sequence to arrive at the desired product. Alternatively, the same product can also be formed via alkyne trapping of the sulfonyl radical (43.14) followed by a reduction–protonation sequence. However, the electrochemical coupling of aromatic alkynes and sulfonyl hydrazides under potentiostatic conditions results in alkynyl sulfones (Scheme 43B).⁶⁸² The divergence in product formation is rationalized by the redox activity of iodine, as the absence of N-tetrabutylammonium iodide is detrimental. The anodic oxidation of iodide to iodine leads to the formation of the key sulfonyl radical intermediate, which has two potential reaction pathways. The first pathway proceeds via anti-Markovnikov addition of the sulfonyl radical to the alkyne, followed by iodine radical trapping and base-promoted hydriodic acid elimination to reveal the sulfonyl alkyne. Alternatively, sulfonyl radical addition to in situ-formed alkynyl iodide followed by iodide radical extrusion also leads to the desired product. For both pathways, cathodic proton reduction closes the redox cycle. Mechanistic studies suggest that both reaction pathways are likely operative, with O₂ accelerating the formation of sulfonyl alkyne.

Scheme 43.

Representative examples of vinyl sulfone synthesis using alkynes via photoredox and electrochemical methods, with corresponding putative mechanisms (A) and (B).

4.7.3. Synthesis of β-Keto or Hydroxy Sulfones

The synthetic versatility of β-keto sulfones,⁶⁸³ especially as an auxiliary group⁶⁸⁴ for the synthesis of C–C bonds makes it a useful motif for total synthesis.⁶⁸⁵ As a result, photoredox and electrochemical strategies for β-keto sulfone synthesis with alkynes have been developed (Scheme 44). Photoredox methods for synthesizing this functional moiety have centered coupling alkenes or alkynes with catalytically-formed sulfonyl radicals under oxidative conditions. Cai and coworkers demonstrate that the reductive quenching of a stoichiometric iodide source by Ru(bpy)₃²⁺ enables the synthesis of β-keto sulfones using a wide range of sulfonyl hydrazides and aryl alkynes.⁶⁸⁶ Trapping the alkyne partner with catalytically generated iodine radical forms an unstable vinyl radical that reacts with oxygen to form a short-lived vinyl hydroperoxide that is readily reduced with excess iodide to the vinyl enolate, which then tautomerizes to the desired product. In the same year, Yang, Wang and coworkers report a similar synthesis of β-keto sulfones using styrenes and sulfinic acids as the reaction partners under oxidative conditions with Eosin Y as the photocatalyst.⁶⁸⁷ tert-Butyl hydroperoxide fragmentation by oxidative quenching of excited state Eosin Y forms tert-butoxyl radical, which undergoes HAT with sulfinic acid to form the alkene-trapping sulfonyl radical. Oxidation of this intermediate by Eosin Y cation radical generates a benzylic cation that is trapped by either by hydroxide or water to yield the benzyl alcohol. This hypothesis is supported by the observation that when an α-substituted styrene is used, the reaction stops at the tertiary alcohol. Downstream oxidation of this α-functionalized benzyl alcohol furnishes the aryl ketone. An electrochemical route for the synthesis of aryl β-keto sulfones from aryl methyl ketones or aryl alkynes was reported by Yavari and Shaabanzadeh, with a terminal oxidant necessary for competent reactivity with the latter substrate.⁶⁸⁸ When aryl methyl ketones are used, trapping of oxidatively formed sulfonyl radical by the enol tautomer yields a benzylic radical that is later oxidized to the desired ketone by catalytic iodine formed under galvanostatic conditions. If aryl alkynes are used, the oxidation of a vinyl sulfone sp²-centered carbon radical by tert-butyl hydroperoxide leads to the desired product in a manner similar to the mechanism proposed by Yang, Wang and coworkers.⁶⁸⁷

Scheme 44.

Representative examples of β-keto sulfone synthesis via photoredox and electrochemical methods.

The synthesis of β-hydroxy sulfones — the reduced variant of the parent ketone — can also be accessed via photoredox and electrochemical pathways (Scheme 45). Reiser and coworkers demonstrate the photoredox-catalyzed synthesis of β-hydroxy sulfones arising from styrene, sulfonyl chlorides and water as the reaction partners.⁶⁸⁹ Oxidative quenching of photoexcited 11.4 by sulfonyl chlorides forms a sulfonyl radical that traps a partner styrene. Oxidation of the resultant benzylic radical by an Ir^IV species closes the photoredox cycle and generates a benzylic carbocation that is then trapped by water — isotopic labeling with H₂¹⁸O supports this hypothesis. This reaction is broadly applicable to a range of styrenes and sulfonyl chloride partners, however a major limitation of this method is the lack of reactivity with aliphatic alkenes. The electrochemical counterpart to this method was reported by Chen, Chang and coworkers in which sodium sulfinates were used instead of sulfonyl chlorides.⁶⁹⁰ As is common with the earlier examples, iodide is used as the redox mediator for this transformation, which leads to broad compatibility with a wide range of styrene coupling partners. Except for this key difference, the reaction mechanism mirrors Reiser’s reported transformation.

Scheme 45.

Representative examples of hydroxy sulfone synthesis via photoredox and electrochemical methods.

4.7.4. Arene Sulfonylation

Aryl sulfones are an important component of numerous pharmaceuticals and agrochemicals⁶⁹¹, and new redox-mediated strategies towards the C(sp²)–SO₂R bond disconnection are welcome additions to a growing field of synthetic methods. Photoredox methods have largely centered on improving the Ni-catalyzed C–S coupling of (hetero)aryl halides and sulfinates, beyond the limitations of thermally-activated precedents.⁶⁹² Rueping and co-workers reported the first photoredox example using iridium photocatalyst 46.16, where a broad range of (hetero)aryl halides were coupled to aryl sulfinates in moderate to excellent yield.⁶⁹³ Additional examples of sulfinate coupling to aryl iodides and chlorides, as well as vinyl bromides was demonstrated. Within a similar timeframe, two other similar strategies using Ru(bpy)₃²⁺ were independently reported by 1) Manolikakes and coworkers,⁶⁹⁴ and 2) Molander, Gutierrez, and coworkers.⁶⁹⁵ The former example focuses on expanding the scope of compatible aryl iodides with aryl and alkyl sulfinates whereas the latter strategy builds on the Rueping work and provides computational analysis of the reaction mechanism. The mechanism is as follows (Scheme 46A): the formation of a sulfonyl radical 46.17 by reductive quenching of photoexcited catalyst by a sulfinate salt is intercepted by a Ni⁰ species to form a Ni^I–sulfinate species (46.18) that readily undergoes oxidative addition with an aryl halide to yield a Ni^III intermediate (46.19). Reductive elimination of the two coupling partners furnishes the desired product and a Ni^I species (46.20) that turned over by reductively quenched photocatalyst to complete both catalytic cycles. Interestingly, Molander and Gutierrez note the presence of an aryl sulfide side product, which they hypothesize forms via a pathway involving stepwise Ni^III-sulfonyl bond dissociation, light-promoted reduction of the sulfonyl radical, and recombination with off-cycle Ni^II aryl halide intermediate. A photocatalyst-free method has also been reported, with Zhang, Yan and coworkers demonstrating that irradiating EDA complexes that form between aryl halide and sulfinate with 365 nm light can induce the formation of desired aryl sulfone.⁶⁹⁶ This strategy works well for electron-deficient aryl bromides and iodides, however significantly reduced reactivity observed when electron-rich arenes are used, which is consistent with electronic restraints observed for photochemical reactions involving EDA complexes.⁶⁹⁷ Photoredox methods are not limited to aryl halides as a collaborative effort between the Willis, Dixon, Paton, Schofield, and Smith groups resulted in the oxidative C–H sulfonylation of anilines using iridium photocatalyst 11.6 and potassium persulfate as the terminal oxidant.⁶⁹⁸ A wide range of electron-rich disubstituted anilines are sulfonylated in moderate to excellent yield, with observed site-selectivities mirroring arene electronics, although steric effects can induce greater para-selectivity. Coupled with a general alkyl and aryl sulfinate scope, this method can be used for late-stage C–H sulfonylation of multiple drug candidates — an important strategy for diversifying known biomolecules for the discovery of new therapeutic leads. The proposed mechanism suggests that two independent photocatalyst cycles are operative; oxidative quenching of 11.6 by persulfate generates an oxidizing Ir^IV intermediate 46.21. Reductive quenching of two equivalents of this Ir species respective oxidizes the aniline to the aniline cation radical 46.22 and the sulfinate to the sulfonyl radical. Radical coupling of these two oxidized intermediates then furnishes the desired product. Additionally, the photoredox-catalyzed, in situ formation of aryl sulfinates from (hetero)aryl halides and thiourea dioxide enables the formation of (hetero)aryl sulfones and sulfonamides in two steps.⁶⁹⁹

Scheme 46.

Representative examples of photoredox catalyzed methods for the synthesis of aryl sulfones.

Electrochemical methods predominantly focus on C–S bond formations involving oxidative (hetero)arene C–H sulfonylation with either S^IV or S^VI reagents (Scheme 47). Lei, Huang and coworkers report a galvanostatic method using aryl sulfonyl hydrazides and hetero(arenes) as coupling partners in an undivided cell.⁷⁰⁰ A broad scope of functionalized benzofurans were successfully sulfonylated, with C2 selectivity observed; other arenes and N-heterocycles are also amenable to sulfonylation using this strategy (Scheme 47A). Oxidative conversion of the sulfonyl hydrazide generates the sulfonyl radical, which adds to the (hetero)arene to form a stabilized carbon radical. Subsequent rearomatization via stepwise oxidation-deprotonation yields the (hetero)aryl sulfone. Other methods for arene C–H sulfonylation use more easily-accessible aryl and alkylate sulfinates as coupling partners. A majority of the early methods for phenol sulfonylation were developed by Nematollahi and coworkers, who used potentiostatic electrolysis to sulfonylate quinone-based substrates.^701,702,703 Waldvogel and coworkers offer a galvanostatic alternative for mequinol and guaiacol derivatives, with moderate yields observed for an appreciable arene and sulfinate scope.⁷⁰⁴ A key advantage of this method is its scalability, as quadrupling the reaction scale from 5.0 mmol to 20 mmol gave the desired product with minimal change in the product yield. This work was quickly followed up with an expansion of the substrate scope to include a large scope of electron-rich arenes, especially aniline derivatives.⁷⁰⁵ A similar strategy is independently disclosed by Li, Song and co-workers, with its focus entirely on N,N-disubstituted anilines; this method is closely related to the photoredox arene sulfonylation strategy from the Willis, Dixon, Paton, Schofield, and Smith groups (Scheme 47B).⁷⁰⁶ Additionally, Oh and coworkers expand the heteroarene scope to include 2H-indazoles with highly-selective C3 sulfonylation observed.⁷⁰⁷

Scheme 47.

Representative examples of electrochemical methods for the synthesis of aryl sulfones.

4.7.5. Sulfonamide Synthesis

The frequency of sulfonamide use in numerous pharmaceuticals and its favorable pharmacological properties are well-documented in medicinal chemistry.^{708,709,710,711} Furthermore, sulfonamides are classic carboxylic acid and carboxamide bioisosteres with the added benefit of having a tunable pK_a for the sulfonamide N–H through substituent design.^712,713 Traditional methods of sulfonamide synthesis involve reacting sulfonyl chlorides with a partner amine⁷¹⁴, with transition metal-catalyzed methods enabling greater flexibility over reaction partners for the construction of (hetero)arylsulfonamides.^715,716 Despite these advances, photoredox and electrochemical methods have the potential to improve existing methods or to create new C–S and S–N bond disconnections for sulfonamide synthesis (Scheme 48). One example of the former strategy is shown by Zeng, Little, and co-workers, where the oxidative amination of sodium sulfinates in the presence of catalytic iodide enables the synthesis of sulfonamides in moderate to good yield.⁷¹⁷ While chemical oxidation methods exist for the same transformation^{718,719,720,721,722}, this galvanostatic method uses less net oxidant than the previous strategies that rely on stoichiometric peroxide or iodide. Mechanistic studies suggest that reaction pathways involving the formation of sulfonyl iodide or N-iodoamine (48.14) are viable, with the former mirroring classic sulfonamide syntheses whereas the sulfinate displacement of the iodide from the latter intermediate would furnish the desired product (Scheme 48A). A more interesting use of electrochemistry for sulfonamide synthesis is reported by Noël and co-workers, who use an electrochemical flow cell to oxidatively couple thiols with amines under potentiostatic conditions.^277a A broad scope of thiol and amine partners was demonstrated with moderate to excellent yields. Notably, the lower oxidation potentials of both thiols and amines allows for the inclusion of oxidation-sensitive functionalities such as alcohols, alkenes, alkynes, and arenes in the product structure. Mechanistic studies suggest that concomitant oxidation of amine and thiol form the corresponding amine cation radical and disulfide respectively, which then readily form a sulfenamide intermediate (48.15). Treatment of an isolable sulfenamide to the reaction conditions furnishes the desired sulfonamide, thus demonstrating its role in the transformation. Radical trapping experiments yield products that hint at the formation of aminium radical intermediates, thus supporting the putative mechanism.

Scheme 48.

Representative examples of electrochemical methods for the two-component synthesis of sulfonamides with corresponding mechanisms depicted.

More recently, Waldvogel and coworkers report an electrochemical, three-component coupling of electron-rich alkoxyarenes, alkylamines, and SO₂ to yield sulfonamides in low to good yields when using BDD electrodes under galvanostatic conditions (Scheme 49).⁷²³ Regioselectivity for arene sulfoamidation is substrate-dependent and occurs at most electron-rich C(sp²)–H site for the highly substituted arenes. Additionally, both secondary and primary amines are competent reaction partners, but reaction conversions can be low when using the latter substrate class. This transformation can be scaled up from 0.6 mmol to 8.0 mmol with a slight improvement in yield when using a divided H-cell. The putative mechanism of the reaction is as follows: anodic oxidation of the arene generates an arene cation radical, which is trapped by an amidosulfinate intermediate (49.5)—a Lewis pair adduct originating from SO₂ and amine. Subsequent stepwise oxidation and deprotonation furnish the desired product.

Scheme 49.

The electrochemical, three-component synthesis of sulfonamides with the corresponding mechanism depicted.

Given that the electrochemical strategies require multiple oxidation steps — a current limitation of photoredox catalysis—other bond disconnections must be considered. One such method is the sulfonamide synthesis reported by Gouverneur and coworkers, which focuses instead on the C–S bond disconnection between sulfamoyl chlorides and alkene coupling partners (Scheme 50).⁷²⁴ Broad compatibility of sulfamoyl chlorides and electron-deficient alkenes with the reaction conditions is demonstrated; interestingly, using an alkyne coupling partner provides the (Z)-vinyl sulfonamide with high selectivity (9:1 Z:E). However, a major limitation of this transformation is the lack of reactivity when unactivated or electron-rich alkenes are used — an opportunity for further reaction development. A putative mechanism is as follows: tris-(trimethylsilyl)silane (TTMSS) reductively quenches photoexcited Eosin Y to form a Si-centered radical (50.5) after subsequent deprotonation. Intermediate 50.5 then forms the sulfamoyl radical 50.6 from the parent sulfamoyl chloride via halogen atom transfer; 50.6 then adds to the alkene with Giese-type regioselectivity to form the stabilized radical 50.7. While a reduction-protonation sequence involving Eosin Y radical anion or radical chain propagation with TTMSS are both viable pathways for converting 50.7 to the desired coupled product, radical trapping and deuterium labeling studies suggest that the latter mechanism dominates. It is also worthwhile to note the report by MacMillan and coworkers on a photosensitized Ni-catalyzed method for C–N coupling between aryl halides and sulfonamides.⁷²⁵ While general compatibility between the two general reaction partners is observed, this strategy’s reliance on energy-transfer sensitization instead of photoinduced redox changes precludes further discussion of this transformation.

Scheme 50.

The photoredox-catalyzed synthesis of sulfonamides with the corresponding mechanism depicted.

4.7.6. Sulfonyl Fluoride Synthesis

Developing new methods for the synthesis of sulfonyl fluorides is an important goal due to their emerging importance of in organic synthesis and chemical biology. Current strategies rely primarily on chloride/fluoride exchange on reactive sulfonyl chlorides^726,727,728 or transition metal-catalyzed strategies^729,730 that require atom-inefficient amounts of electrophilic fluorine reagents. Therefore, applying redox strategies to this synthetic challenge can enable new disconnections for sulfonyl fluoride synthesis (Scheme 51). A key example is the electrochemically-mediated synthesis of sulfonyl fluorides reported by Noël and coworkers, where thiols and disulfides are oxidatively coupled with potassium fluorides under galvanostatic conditions (Scheme 51A).⁷³¹ Whereas stoichiometric chemical methods for the synthesis of sulfonyl fluorides from disulfides require excess amounts of electrophilic fluorine (>6 equiv. of Selectfluor)⁷³², the Noël method uses a biphasic system to form in situ HF-pyridine, which diffuses into acetonitrile to maintain equilibrium amounts of nucleophilic fluoride in the organic layer.

Scheme 51.

Representative examples of photoredox and electrochemical methods for the two-component synthesis of sulfonyl fluorides with corresponding mechanisms depicted.

A wide range of aryl and alkyl thiols are compatible with this transformation, with moderate to excellent yields observed. In several cases, the instability of the sulfonyl fluoride requires extraneous trapping by phenol to yield the phenyl sulfonate. Mechanistic studies suggest that the disulfide is oxidized to the sulfur cation radical, which then traps fluoride to yield a short-lived sulfenyl fluoride (51.14) that is further oxidized to the sulfonyl fluoride at the anode; no conversion to the desired product is observed when electrophilic fluorine sources are used. Kinetic experiments suggest that extended reaction times due to mass transfer limitations are prominent in batch electrochemical experiments, which can be overcome by using an electrochemical microflow reactor with small interelectrode gaps; this switch enables the synthesis of benzenesulfonyl fluoride from thiophenol in 5 minutes.

While an analogous photoredox strategy remains to be developed, a complementary route for the synthesis of aliphatic sulfonyl fluorides is attainted through the coupling of alkyl radicals and ethene sulfonyl fluoride (ESF), a commercially available precursor.⁷³³ Liao and coworkers report a method to that couples alkyl radicals — formed via photoredox-induced decarboxylation of redox-active N-hydroxyphthalimide esters — with ESF.⁷³⁴ An extensive range of primary, secondary and tertiary NHPI esters were successfully used, with good to excellent yields observed. In particular, carboxylic acid moieties in natural products and pharmaceuticals are functional handles for efficient conversion to the corresponding sulfonyl fluoride. Interestingly, the mild reaction conditions enable isolation of the parent sulfonyl fluorides with minimal loss of fidelity. The putative mechanism for this transformation involves reductive quenching of Eosin Y by Hantzsch ester (HE) to form Eosin Y radical anion which induces the decarboxylation of the NHPI ester (Scheme 51B). Subsequent trapping of the resultant alkyl radical 51.15 by ESF, followed by HAT to the ESF-alkyl adduct 51.16 from a HE radical or an amine base furnishes the aliphatic sulfonyl fluoride.

4.8. Alkene Mono- and Difunctionalizations

The difunctionalization of alkenes has been an area of intense research both in the context of electrolysis and photocatalysis.^209,735,736 Many approaches have relied on the addition of a radical to an alkene, followed by oxidation of the newly generated radical intermediate to enable a radical-polar crossover mechanism and subsequent nucleophilic attack of the cationic species. Alternatively, the initial radical intermediate can be trapped by transition metal catalysts (e.g., Cu or Ni) followed by a more traditional cross-coupling approach to form the 2^nd bond of the difunctionalization via a reductive elimination process. Homo-difunctionalizations using electrochemistry have been reported, including diazidation,^378,737,738 diamination,⁷³⁹ dichlorination,^740,741,742 difluorination,⁷⁴³ and dihydroxylation.⁷⁴⁴ Photoredox diaminations are also known.^745,746,747 Vicinal heterofunctionalization of alkenes have also been extensively studies and subject to reviews,^104,748 including those relying on dual catalytic systems involving both a photocatalyst and a transition metal (e.g., Ni or Cu). Asymmetric electrochemical cyanophosphinoylation and cyanosulfonylation of vinylarenes have been reported,⁷⁴⁹ and bear similarity to the photoredox asymmetric cyanofluoroalkylation of alkenes,⁷⁵⁰ and cyanotrifluoromethylation of alkenes,^751,752 as well as the thermal enantioselective copper-catalyzed cyanotrifluoromethylation of alkenes.⁷⁵³ In these examples of alkene difunctionalizations these methods do not yet have a photochemical or electrochemical counterpart.

Alternatively, similar radical-polar crossover mechanisms for alkene difunctionalization can be accomplished without transition-metal co-catalysts. Lin and coworkers report a recent example of using an electroreduction approach to first reduce alkyl halides to alkyl radicals, which after coupling to alkenes in an anti-Markovnikov fashion, can be reduced again to form a benzyl carbanion which readily traps an available electrophile—DMF, MeCN and CO₂ respectively, to yield carboformylation, hydroalkylation, and carbocarboxylation products.⁷⁵⁴ This approach is conceptually similar to analogous photoredox methods, in which substrate activation by a photoredox catalyst generates a reactive intermediate that can then trap alkenes to afford the benzyl radical, followed by consecutive one-electron reduction and electrophile trapping. Comparable hydroformylation^755,756, hydroalkylation^{454n,757,758,759,760}, carboalkylation⁷⁶¹, hydrocarboxylation⁷⁶², and carbocarboxylation⁷⁶³ products are obtained, with key divergences being the coupling partners as well as product regioselectivity.

4.8.1. Vicinal Dichlorination of Alkenes

Vicinal dichlorination of alkenes has been realized using several electrochemical and photoredox methods (Scheme 52). Lin reported⁷⁴⁰ a method relying on stoichiometric MgCl₂ (3 equiv) as the chloride source in the presence of Mn(OTf)₂ which was proposed to generate a Mn^II chloride salt which upon anodic oxidation forms the chlorinating Mn^III chloride reagent. Morandi and Waldvogel reported⁷⁴¹ a related approach in which they merged shuttle catalysis and paired electrolysis to achieve the 1,2-dichlorination of alkenes using either 1,2-dichloroethane or 1,1,1,2-tetrachloroethane as the chlorine source. These chlorinated ethane derivatives can be reduced to generate chloride and the corresponding alkene in situ, while the opposite electrode (anode) oxidizes the chloride (or a Mn^II chloride salt analogous to the Lin chemistry above) to generate the chlorinating reagent. Sequential paired electrolysis provides method of halogenating alkenes without the use of more toxic, hazardous Cl₂ or Br₂ reagents and was also demonstrated to enable 1,2-dibromination of alkenes using 1,2-dibromoethane instead of 1,2-dichloroethane. Photochemical 1,2-dichlorination of alkene using white LEDs was reported by Wan⁷⁴² using stoichioimetric CuCl₂ for aryl substituted alkenes, while alkyl substituted alkenes could be dichlorinated using catalytic CuCl₂ in the presence of HCl and air (as the terminal oxidant). This chemistry relies on photoexcitiaton of CuCl₂ (or L_nCuCl₃⁻ species when exogenous chloride is present such as in HCl)^128,764 to enable a ligand-to-metal charge transfer (LMCT) and subsequent generation of chlorine radical and CuCl.

Scheme 52.

Vicinal dichlorination of alkenes.

4.8.2. Chloro-trifluoromethylation

The vicinal difunctionalization of alkenes involving trifluoromethylation⁷⁶⁵ has been extensively explored (Scheme 53).^766,767 Chlorotrifluoromethylation of olefins using electrochemistry was reported by Lin⁸⁵ using a manganese acetate as a pre-catalyst, stoichiometric MgCl₂ as the source of chloride and sodium trifluoromethylsulfinate as the CF₃ source. The reaction was proposed to operate via anodically coupled approach in which oxidation of the trifluoromethylsulfinate generates the CF₃ radical followed by addition to the alkene to generate intermediate 53.1. Concurrently, Mn^II is oxidized to Mn^III, generating a Mn^III–Cl persistent radical able to chlorinate intermediate 53.1. Han reported a redox neutral approach based on Ru-photoredox and trifluoromethanesulfonyl chloride.⁷⁶⁸ Reduction of CF₃SO₂Cl generates the CF₃ radical and subsequent reaction with the alkene affords radical intermediate 53.2 which is oxidized to the corresponding cation (53.3) and trapped by chloride. The scope of the photoredox method appears to perform better with alkenes lacking aryl substituents whereas the electrochemical approach performs well with either aliphatic or aryl functionalized olefins. Additionally, the photoredox method is limited to terminal olefins whereas internal alkenes can be functionalized using the electrochemical strategy.

Scheme 53.

Chlorotrifluoromethylation of alkenes.

4.8.3. Aminotrifluoromethylation

Vicinal amino-trifluoromethylation of alkenes can be accomplished via anodically coupled electrolysis⁷⁶⁹ and redox-neutral photoredox catalytic methods (Scheme 54).^770,771 Oxidative generation of CF₃ radical from sodium triflinate, addition of the radical to the styrene and subsequent oxidation of the benzylic radical enables benzylic cation generation, which is trapped by MeCN solvent in a Ritter-type amination to generate the product. In contrast a reductive generation of the CF₃ radical is utilized in the photoredox method, ultimately arriving at the analogous benzylic radical that is oxidized by the photocatalyst and analogous subsequent steps to the electrochemical method to produce the vicinal amino-trifluoromethylated product.

Scheme 54.

Aminotrifluoromethylation of styrenes.

4.8.4. Hydroxytrifluoromethylation

Leveraging the same mechanistic manifolds as the aminotrifluoromethylation of alkenes in Section 4.8.2, the vicinal oxytrifluoromethylation of alkenes can be accomplished via electrochemistry⁷⁷² as well as photoredox (Scheme 55).⁷⁷³ The benzylic carbocation is directly trapped by water to afford the benzylic alcohol with a beta-CF₃ group for styrene derivatives.

Scheme 55.

Olefin hydroxytrifluoromethylation.

4.8.5. Hydrofunctionalization of Alkenes

Hydrofunctionalization of alkenes have been realized to introduce a functional group and a hydrogen atom across the alkene.⁷⁷⁴ For example the addition of an azide to an alkene has been realized in a photoredox hydroazidation,⁷⁷⁵ while no electrochemical method has yet been reported.

The asymmetric synthesis of benzylic nitriles has been achieved electrochemically via a hydrocyanation of alkenes⁷⁷⁶ and via photoredox using NHPI esters (Scheme 56).⁷⁷⁷ In each case the catalyst leverages a chiral box ligand bound to Cu which is postulated to trap a benzylic radical, the copper catalyst also requires oxidation (either prior or after trapping the radical) to ultimately generate a R–Cu^III–CN intermediate for facile reductive elimination and formation of the C–CN bond. The photoredox process is redox neutral with the reduction event being photoredox-induced NHPI-decarboxylation to generate the benzylic radical. In contrast, the electrochemical process operates via anodically coupled processes where the 2^nd oxidation event oxidizes the Co^II to Co^III, enabling reaction with the silane to form a Co^III-hydride capable of HAT to the alkene. A closely related photoredox mediated asymmetric carbocyanation⁷⁷⁸ of styrene has also been reported using NHPI esters to deliver a carbon centered radical to the alkene followed by a Cu–bis-oxazole catalyzed asymmetric cyanation.

Scheme 56.

Olefin hydrocyanation.

4.8.6. Olefin Hydroxyfunctionalization

Alkene hydration by electrochemical and photoredox methods proceeds via the alkene cation radical, albeit with interesting divergences in hydroxylation regioselectivity (Schemes 57 and 58). Aiwen Lei and coworkers report two methods for photoredox-catalyzed anti-Markovnikov alkene oxidation wherein co-catalyst choice dictates the final product oxidation state (Scheme 57).^779,780 Single electron oxidation of the alkene generates the olefin cation radical, which is preferentially hydroxylated at the terminal position to yield 57.12. When a cobaloxime species (57.13) in used, a terminal aldehyde is obtained from styrenyl derivatives via hydrogen gas evolution that involves stepwise reduction and protonation steps — the possibility of PCET is not suggested but is plausible. When diphenyl disulfide is used, HAT from thiophenol to 57.12 results in the terminal alcohol.

Scheme 57.

Photoredox-catalyzed olefin oxidation and hydration with corresponding mechanisms.

Scheme 58.

Electrochemical alkyne carbohydroxylation with corresponding mechanism.

An interesting divergence in hydration regioselectivity is observed in the electrochemically-mediated alkene carbohydroxylation reported by Li, Xu and co-workers, with terminal alkenylation and olefination by potassium organotrifluoroborate precursors observed alongside hydration at the internal carbon site (Scheme 58).⁷⁸¹ Subjecting the alkynyltrifluoroborate to similar photoredox conditions only results in terminal olefin oxidation, thus suggesting that water outcompetes carbon nucleophile trapping. This outcome is likely due to the unique electrode surface effects; the build-up of anionic organotrifluoroborate at the positively charged anode surface, which then reacts efficiently with the olefin radical cation. Subsequent anodic oxidation of the resultant alkyl radical (58.11) results in a stabilized tertiary carbocation (58.12) that readily undergoes hydration to furnish the observed carbohydroxylation product.

4.9. Reductive Coupling of Ammonium Salts with CO₂

Reductive coupling of trialkylbenzylammonium salts with CO₂ can provide access to carboxylic acids (Scheme 59). Electrochemically driven direct anodic reduction of trimethylbenzylammonium bromide salts at a carbon cloth anode in DMF under CO₂ atmosphere under constant cell potential of −4.5 V can provide benzylic carboxylic acids (Scheme 59).⁷⁸² The byproduct of the anodic reaction releases Me₃N, which acts as a terminal reductant, thus the reaction did not require the use of a sacrificial anode. The choice of counter-anion in the electrochemical method influences the yield, while the use of the Cl and BF₄ salt results in ~20% decreased yield of phenylacetic acid, only 25% yield is obtained with the iodide salt (no mention of the outcome with triflate salts). The photoredox catalyzed method⁷⁸³ employs benzyltrialkylammonium triflate salts as starting materials in the DMF in the presence of a mixtures of cesium and sodium carbonate bases (2 and 1 equivalents, respectively) and affords comparable yields and scope, both methods also tolerating heterocycles such as thiophene and furan derivatives although devoid of nitrogen heterocycles or amines. Benzyl halides are also suitable precursors for an electrochemical reductive coupling with CO₂ to access arylcarboxylic acids.^784,785,786

Scheme 59.

Reductive coupling of CO₂ with trialkylbenzylammonium salts to access benzylcarboxylic acids.

4.10. Hindered Primary Amine Synthesis

Recently the Rovis group in collaboration with Merck & Co., Inc., Kenilworth, NJ, USA reported three synthetic methods to access hindered primary and secondary amines via a radical-radical coupling between cyanoheteroarenes and α-amino radicals derived from either iminiums or oximes (Scheme 60).^86,787,788 These methods enable the synthesis of primary amines with a fully substituted α-carbon center with broad functional group tolerance, including the incorporation of heterocycles and various heteroatom containing groups.

Scheme 60.

Synthesis of hindered amines from cyanoheterocycles and iminiums chlorides (or oximes).

In comparing over scope of the greater than 60 hindered amines accessed via the three synthetic methods, complementarity in terms of yield is clearly observed. Whenever one method has short comings in terms of yield, one or both of the other methods prevail to afford useful yields of the desired amine. Reflecting on the scope, the electron rich cyanoarenes perform better using the oxime photochemistry, whereas electron deficient cyanoarenes are better suited for electrochemical reductive coupling with iminiums. Beyond cyanopyridyl substrates, azaindole performed significantly better in the photochemistry from the oximes than the electrochemical coupling method. In contrast, pyrazine, pyrimidines, and purine derived products were better suited for synthesis via electrolysis.

In terms of the electronics on the α-amino-benzyl radical coupling partner, differences are also observed between methods. Analysis of the Hammett series of electronically varied oxime substrates indicates a rather flat response in terms of yield whereas electron-rich iminiums (e.g. 4-MeO- and 4-Me-substituted substrates) clearly perform better than electron-poor iminiums (e.g. 4-CF₃- and 4-Cl-substituted substrates) regardless of using photochemistry or electrochemistry. The use of an ortho-methyl substituent on the phenyl ring of the iminium substrate was demonstrated to improve coupling yields in the case of iminium substrates (photo- or electrochemical methods) as a result of a conformational change that raises the energy of the LUMO. This substitution pattern on the oxime substrates had the negative consequence of dramatically increasing the T₁ to S₀ energy (ca. 74 kcal•mol⁻¹) for the Z-oxime to be outside the range that could be photosensitized by the photocatalyst utilized (ca. 56 kcal•mol⁻¹ for PC1), explaining why incomplete consumption of the oxime was observed in those transformations.⁷⁸⁹

Despite sharing similarities in the mechanistic pathway, the differences in the three methods are explained by the subtle changes in the conditions. First, the electrolytic method where the substrate undergoes the reduction event at the electrode results in a high local concentration of reduced substrate (α-amino radical) at the electrode, whereas photochemistry has significantly lower concentrations of these species. As a consequence, dimerization of the α-amino radical to generate 1,2-diamine impurities is suppressed under photochemical methods compared to the electrolysis method. While the photochemical methods rely on the photocatalyst for the driving force of the reduction process of the substrate (e.g. cyanoarene), the electrolysis does not have a fixed reduction potential – the electrode is adjusted to a more negative potential until it finds something to reduce in order to maintain constant current.⁷⁹⁰ This is not the case for the photocatalysis where thermodynamically neutral or endothermic processes may be unfavorable to the point of not being able to activate that substrate towards reduction and coupling (back electron transfer from the substrate to the catalysts may outcompete radical-radical coupling). Finally, the putative iminium generated from the oxime starting material is the iminium benzoate salt, whereas in the case of starting from the iminium substrate directly, it is the iminium chloride salt. Mechanistically, the identity of the counteranion imparts subtle differences in the downstream coupling chemistry, particularly due to the difference in the reduction potential of these two iminium salts. It is well known that the reduction potential for PCET events can be modulated via the strength of the acid (i.e. different pK_a) according to Bordwell’s equation.^451,791 This likely explains the differences in the cyanoarene electronic preferences when comparing oxime vs iminium photocatalytic methods presented herein keeping in mind that the acid for these PCET is the iminium salt (benzoate vs chloride).

While iminium substrates can be readily accessed from arylnitriles in a single step via addition of organometallic reagents (e.g. alkyllithiums) followed by salt formation using anhydrous HCl, these conditions are usually incompatible with functional groups prone to react with strong nucleophiles/bases (e.g. esters). This is where the oximes substrates provide unique access to the necessary requisite starting material bearing those functional groups or heterocycles (e.g. benzofuran). Additionally, the synthesis of primary amines with α-CF₃ groups is again uniquely suited for the oxime route in contrast those relying on iminium substrates. Similarly, substrates where the iminium is hydrolytically unstable (strongly electron deficient bearing substrates), or those that are challenging to crystallize during the HCl salt formation (α-cyclopropyl or heterocycle bearing-derivatives), or where the requisite arylnitrile staring material is not available are better suited for the oxime chemistry by utilizing readily available requisite ketones, generating the oxime substrate under mild conditions and avoiding the above stability/crystallization issues.

These products generated from the methods in Scheme 60 are high utility building blocks for medicinal chemists and this synthetic method enables efficient and modular exploration of chemical space. The starting materials are readily available and can be stored long term, ready to be utilized to access libraries via a permutation approach to explore chemical space to provide bi-directional building blocks.⁷⁹² In fact, a recent report demonstrated the use of the above reaction for parallel synthesis of a library of hindered amines using the high throughput experimentation electrochemistry equipment (HTe⁻chem) described in Section 3.10.³⁸⁹ With the advances in high throughput experimentation for parallel synthesis and direct to biology workflows⁷⁹³ that utilize reaction mixtures coming from solvents like DMSO directly into bioassays, these synthetic methods may accelerate the exploration of chemical space to test biological hypotheses to solve important medical and agrochemical challenges.

An alternate photoredox method for accessing hindered primary amines was reported by Gilmore, in which they describe three examples of a three-component coupling between 4-cyanopyridine, ammonia and a (hetero)arylketone (Scheme 61).⁷⁸⁸ The reaction uses Hantzsch ester (2.2. equiv) as the terminal reductant, stoichiometric TFA in 60 °C MeCN and Ru(bpy)₃Cl₂•6H₂O as the photocatalyst. While it remains unclear how broad the scope is for this transformation, is does look promising as the (hetero)arylketones are structurally varied — specifically, 3-acetylpyridine, 2-acetylfuran, and 4-fluoroacetophenone each provide their corresponding hindered amine in good to excellent yield (72%, 80%, and 99%, respectively). The reaction is proposed to proceed via in situ formation of an iminium, with its 1e reduction is enabled by photoredox catalysis to generated the transient α-amino radical for coupling with 4-cyanopyridine.

Scheme 61.

Reductive arylations of (hetero)aryl ketones to generate primary amines with α-tri-substituted centers and its proposed mechanism.

4.11. Oxidative Arene Functionalization

Oxidative arene functionalization occurs either by oxidation of a redox-active mediator or by direct oxidation of the arene or one of its electron-rich substituents. Photoredox and electrochemical methods for intramolecular dehydrogenative lactonization and lactamization of arene C–H bonds, which occur by the former mechanism, have been recently covered²⁸ and are not discussed further. This section will instead cover examples involving arene oxidation.

4.11.1. Arene C–H Amination

Anodic oxidation of aromatics has rich history^794,795 but practical applications were limited due to unproductive oxidation of either coupling partner or of the product. One such example is aryl C–H amination of electron-rich arenes with N-centered nucleophiles, in which both coupling partners are susceptible to overoxidation. Yoshida and co-workers approached this problem by demonstrating the electrochemical coupling of electron-rich arenes and pyridine under constant current electrolysis (Scheme 62A).⁷⁹⁶ The key intermediate is an oxidatively-generated arene cation radical, which traps pyridine to yield an arylpyridinium intermediate that is deprotected to the aniline after a secondary Zincke reaction. Good to excellent yields were observed (65 to 99%) for a range of electron-rich arenes, with site-selectivity ranging from excellent para-amination selectivity relative to the most electron-rich substituent to slight para:ortho selectivity (1.3:1 to 2.3:1) relative to the methoxy group. A follow-up publication showing N-aryl imidazole synthesis via arene cation radical trapping with N-methylsulfonateimidazoles followed by piperidine deprotection (Scheme 62B).⁷⁹⁷ A key limitation of this method is preferential amination of benzylic C–H bonds. Arene amination with primary amines was also discovered later, but is limited to heterocyclic, N-protected primary alkylamines bearing β or γ N/O-functionality; these reveal the arylamine when deprotected with ethylenediamine (Scheme 62C).⁷⁹⁸ In all three methods, the reactions were run in a LiClO₄/MeCN or Bu₄NBF₄/MeCN solution (0.1 to 0.3 M) under a constant current (8.0 mA, 2.5 F•mol⁻¹) in an H-type divided cell equipped with a carbon felt anode and a platinum plate cathode. A photoredox complement to Yoshida’s work was developed by Nicewicz and co-workers, in which electron-rich arenes were aminated with azoles and ammonium carbamate using a highly oxidizing 9-mesityl-3,6-di-tert-butyl-10-phenylacridinium tetrafluoroborate (Mes-3,6-dtb-Ph-Acr, 11.8, PC-1) photoredox catalyst and TEMPO as a co-catalyst under an oxygen atmosphere (Scheme 62D).⁷⁹⁹ N-arylazole and aniline yields were generally moderate to excellent (26 to 99%) for a greater range of electron-rich arenes and azoles, with no benzylic amination observed. Aminated products were either obtained as single regioisomers or with moderate to excellent para:ortho site-selectivity. The reaction proceeds by PET from the arene to photoexcited PC-1, generating the key arene cation radical which is then trapped by the nucleophile. Co-catalyst TEMPO or molecular oxygen act as the oxidants in the transformation, and presumably turn over photocatalyst cycle. A follow-up work by Nicewicz and co-workers expand the amine scope to primary amines using PC-2, with amino acids, linear and branched amines, hindered amines, benzylamines and complex amines tolerated (Scheme 62E).⁸⁰⁰

Scheme 62.

Representative examples of arene C–H amination via electrochemical and photoredox methods.

4.11.2. Arene C–H Cyanation

The direct C–H cyanation of hetero(arenes) enables facile access to the aryl cyano group, which is a versatile synthon typically used in functional group interconversion (FGI) to access aryl carbonyl, imine and heterocycle scaffolds. Several redox-centered methods for benzonitrile synthesis, have been developed (Scheme 63) with Nicewicz and co-workers reporting the cyanation of electron-rich aromatics using an acridinium photoredox catalyst (11.8).⁸⁰¹ This reaction occurs via the formation of a key arene cation radical intermediate, with minimal oxidation of the cyanide detected under reaction conditions. Simple and complex (hetero)aromatics are functionalized with moderate to excellent para:ortho selectivity relative to the most electron-rich substituent. The key to successful cyanation is the use of trimethylsilyl cyanide, as it afforded the slow release of cyanide which would otherwise be competitively oxidized if present in excess. An electrochemical counterpart was reported by Gooßen, Tschulik and co-workers, where sodium cyanide is used to trap arene cation radicals formed via anodic oxidation.⁸⁰² A relatively diverse substrate scope is reported, with lower para:ortho selectivity observed for substrates similar to the photoredox method. Platinum electrodes were used under constant current (20 mA), and two-electron anodic oxidation was coupled to cathodic hydrogen evolution. A key observation in this transformation is the necessary passivation of the platinum electrodes by cyanide, which the authors hypothesize leads to greater substrate scope diversity.

Scheme 63.

Representative examples of arene C–H cyanation via electrochemical and photoredox methods.

4.11.3. Arene C–¹⁸F Fluorination

The direct radiofluorination of aryl C–H bonds enables the development of ¹⁸F-labeled small molecules and their application towards positron emission tomography. However, a limitation is the requirement for short reaction times, as t_1/2(¹⁸F) is 109.8 min. Thus, redox-centered methods for arene C–H ¹⁸F-fluorination must account for ¹⁸F lifetime limitations (Scheme 64). Sadeghi and co-workers attempted the radiofluorination of an analog of the nonsteroidal anti-inflammatory drug (NSAID) celecoxib via anodic oxidation of the heteroaromatic ring.⁸⁰³ The electrolysis was performed under pulsating potentiostatic conditions (working phase of 2.7 V vs Ag/Ag⁺ for 4 s, then recovery phase pulse of 0.3 V vs Ag/Ag⁺ for 1 s) with platinum electrodes and Bu₄NClO₄ as the electrolyte. The radiofluorination was carried out in MeCN under carrier-added conditions (i.e. ¹⁸F reagent has residual ¹⁹F) with Et₄N[¹⁸F]•4H[¹⁸F], and afforded the ¹⁸F-labeled arene in 70 minutes (0.8–2.0 radiochemical yield [RCY, decay-corrected]). This radiofluorinated celecoxib analog was shown to have good metabolic stability and demonstrated promising pharmacokinetics for future PET studies. However, its low molar activity (3 Ci•mmol⁻¹) prevents its use as an imaging agent, a problem that could be resolved through the use of no-carrier added ¹⁸F sources. A photoredox-catalyzed arene C–H radiofluorination method was reported by Nicewicz, Li and coworkers, which builds upon their arene C–H functionalization strategy with highly oxidizing acridinium photoredox catalysts.⁸⁰⁴ RCYs for this reaction ranged from 4.9 ± 0.5 to 50 ± 11% as simple and complex electron-rich (hetero)arenes are radiofluorinated with no-carrier added [¹⁸]tetrabutylammonium fluoride ([¹⁸F]TBAF) with high para-selectivity relative to the most electron-rich substituent. The molar activity obtained for radiofluorinated diphenyl ether is 1.37 Ci/μmol (yield: 38.2 ± 10% RCY), which suggests that imaging agents for positron emission tomography can be developed. The utility of this method was demonstrated with the synthesis of [¹⁸F]DOPA, and the application of radiolabeled NSAID [¹⁸F]fenoprofen and tyrosine analog 64.5 to the imaging of inflammation and cancer tumors respectively in mouse models.

Scheme 64.

Representative examples of arene C–H radiofluorination via electrochemical and photoredox methods.

4.11.4. Thiolation/Heterocycle Formation

The synthesis of benzothiazoles from benzothioamides via redox methods proceeds by a sulfur-centered radical (thioamidyl) through oxidative mechanisms (Scheme 65). The electrochemical strategy reported by Song and Xu uses indirect electrolysis with catalytic TEMPO as the main redox agent in an undivided cell under constant current (10 mA; RVC anode, Pt plate cathode; Bu₄NBF₄ electrolyte; MeOH/MeCN (1:1) solvent).⁸⁰⁵ A wide range of functionalities are tolerated with this method, which directly contrasts with a previous method using harsher direct electrolysis conditions.⁸⁰⁶ Yields obtained are moderate to excellent for most substrates, with high to exquisite regioselectivity observed. An oxoammonium intermediate formed via the electrochemical oxidation of TEMPO traps the benzothiazole at sulfur to form a weak S–O bond. This species is deprotonated and undergoes rapid S–O bond homolysis (BDE ~ 12.5 kcal•mol⁻¹) to form the thioamidyl radical, which rapidly cyclizes to the azacyclohexadienyl radical. DFT computations suggest that the regioselectivity observed arises from the kinetics of radical cyclization and the overall thermodynamic favorability of the azacyclohexadienyl radical regioisomer. Rearomatization via proton and electron loss furnishes the desired benzothiazole. A photoredox counterpart to this reaction was developed by Wu and Lei, in which a two-catalyst system — Ru(bpy)₃(PF₆)₂ and cobaloxime 65.14 — were employed, with moderate to quantitative yields and excellent regioselectivity observed for a diverse substrate scope.⁸⁰⁷ Experimental studies of the reaction mechanism established that deprotonation of benzothioamides was necessary to generate a thioamide anion species that is readily oxidized by photoexcited Ru(bpy)₃²⁺ to the thioamidyl radical which subsequently cyclizes. Reduced Ru(bpy)₃⁺ can transfer an electron to the Co^III-species 65.14, which forms a Co^II intermediate capable of oxidizing the azacyclohexadienyl radical, which rearomatizes by deprotonation to the desired benzothioamide. The Co^I species then intercepts two protons in a stepwise manner to generate H₂ and regenerate 65.14.

Scheme 65.

Representative examples of intramolecular arene C–H thiolation via electrochemical and photoredox methods.

4.11.5. Intramolecular Oxidative Biaryl Couplings

The synthesis of polycyclic aromatic hydrocarbons (PAHs) and graphene nanoribbons, including small molecule models of graphene and nanotubes, often leverage oxidative cyclodehydrogenation reactions (e.g. Scholl-oxidation).^{808,809,810,811,812} These reactions convert ortho-arylene precursors to larger aromatic compounds via a net dehydrogenative biaryl coupling using stoichiometric oxidants (e.g. DDQ).⁸¹³ Non-photochemical conditions relying on the use of stoichiometric oxidants (e.g. DDQ) can render the reaction purification challenging.^814,815 Thus the use of catalytic DDQ which can be regenerated electrochemically provides benefits towards addressing the above problem as was reported by Hilt in the oxidative biaryl coupling shown in Scheme 66.²²⁰ Since the reduction of DDQ to generate the corresponding dihydroquinone (DDH) is a net 2e/2H⁺ reduction event, a source of protons is required. Brønsted acid, such as MeSO₃H or TFA, not only provide the necessary protons but also shift the redox potentials associated with the cycling between DDQ and DDH, as is typical of quinone redox chemistry.⁸¹⁶ The Mallory reaction uses light to transform ortho-arylene compounds to their dehydrogenative biaryl coupled analog via the use of light and oxidants such as iodine or oxygen.⁸¹⁷ The reaction is proposed to proceed via a photoinduced 6π-electrocyclization with subsequent oxidative aromatization via hydrogen abstraction.^817,818 For example photochemical conditions B1 in Scheme 66 were leveraged to access various triphenylenes.⁸¹⁹ The Katz-modified Mallory reaction leverages propylene oxide as an additive to scavenge the HI byproduct, thus suppressing acid-mediated rearrangements/side-products.⁸²⁰ The application of these conditions (method B2 in Scheme 66) were demonstrated in the synthesis of 2-methyltriphenylene.⁸²¹

Scheme 66.

Intramolecular oxidative biaryl couplings.

Electrochemical cross-dehydrogenation C–C couplings are now widely reported. Oxidative homo- and hetero-coupling of phenols^822,823 has been extensively studies using electrochemistry, particularly by Waldvogel.^822,824,825 the use of a BDD anode and HFIP as the solvent enabled for homocoupling of phenols to access 2,2’-biphenols⁸²⁶ as well as 4,4’-biphenols (Schemes 67 and 68).⁸²⁷ The use of graphite electrodes and fluorinated additives such as TFA was found to also provide for useful conditions to oxidatively dimerize phenols via electrolysis (Scheme 67, method A2). A templating strategy of pre-forming a tetraborate salt containing the phenol enabled anodic oxidation of these salts to the biphenol including phenols lacking a para-substituent relative to the hydroxyl group (Scheme 67, method A4).⁸²⁸ Demonstration of oxidative dimerization of phenols in flow using glassy carbon anode and stainless steel cathode (j = 60 mA•cm⁻², Q = 0.8F) under supporting-electrolyte-free in conditions using HFIP with 5 vol % pyridine at 0 °C achieved 59% yield of 3,3′,5,5′-tetramethyl-2,2′-biphenol with a productivity of 9.60 g/h (Scheme 67, method A3).⁸²⁹ Kozlowski reported a photocatalyzed method based on acridinium photocatalysts achieving both homo- and hetero-cross couplings (Schemes 67 and 68).⁸³⁰ Both methods achieve similar products, and are proposed to proceed via a similar reaction mechanism, specifically via a radical−neutral coupling in which a 1e oxidation of the phenol generates a phenoxyl radical intermediate followed by reaction with an unoxidized (neutral) phenol. In the context of electrochemistry, the anode facilitates the oxidation, while the photochemical method relies on an acridinium photocatalyst [(Mes-Me-Acr(BF₄)], a biphenyl derivative (4,4’-di-tert-butylbiphenyl) as a redox mediator, and oxygen (from air) as the terminal oxidant, as shown in Scheme 66. The synthesis of unsymmetrical biphenols can be accessed using similar photochemical and electrochemical⁸³¹ conditions, with the photochemical methods usually providing improved yields.

Scheme 67.

Oxidative homo-coupling of phenols.

Scheme 68.

Oxidative cross-coupling of phenols.

Müllen, Gu, and Ma recently reported an electrochemical synthesis and deposition of polycyclic aromatic hydrocarbon films on ITO electrodes for optoelectronic applications (Scheme 69).⁸³² While thermal conditions typically rely on stoichiometric use of DDQ as the oxidant usually in solvent mixtures of chlorinated solvents and TFA, the electrochemical method could be carried out directly at the electrode or mediated by 5 mol% of DDQ in the presence of TFA in CH₂Cl₂ solutions. Morin has accessed related PAH structures using a photochemical cyclodehydrochlorination reaction⁸³³ with the benefit of being able to obtain preparative amounts of the products in contrasts to the electrodeposited films (Scheme 69).

Scheme 69.

(Left) Electrochemical synthesis of polycyclic aromatic hydrocarbons as films on ITO electrodes. (Right) Photochemical cyclodehydrochlorination to PAH derivatives.

4.12. C(sp²)–F Activation

4.12.1. Arene Hydrodefluorination

The strategic inclusion of fluorine atoms within aromatic scaffolds of pharmaceuticals is a common practice in drug discovery because it potentially enhances drug potency and improves the metabolic stability of electron-rich phenyl rings.⁸³⁴ However, because site-selective aryl fluorination is challenging, conventional syntheses of fluorinated pharmaceuticals start with regio-defined fluorinated precursors.^835,836 An alternative strategy is site-selective hydrodefluorination of perfluorinated arenes — which are readily synthesized through the well-established LaMar process involving F₂ gas or through electrochemical fluorination⁸³⁷ — to access partially fluorinated aromatic scaffolds. Weaver and co-workers report a method for photoredox-mediated aromatic hydrodefluorination using the reducing photocatalyst Ir(ppy)₃ and sacrificial amine (Scheme 70).⁸³⁸ This strategy proceeds by reductive quenching of photoexcited Ir(ppy)₃ by a donor amine to form an Ir^II species that then reduces the perfluorinated (hetero)arene to a perfluoro(hetero)aryl radical anion 70.10. Fluoride extrusion, followed by HAT to the resulting aryl radical 70.11 reveals the desired product. HDF regioselectivity is largely dictated by the electronic stability of the resultant radical anion; computational studies of the arene σ* SOMO show that hydrodefluorination site-selectivity correlates with the arene sites containing the greatest electron density and the longest C–F bonds.⁸³⁹ Di- and tri-hydrodefluorination is observed, albeit limited to electron-deficient substrates. Since this initial report, Weaver and co-workers have expanded the scope of trapping agent for the perfluoro(hetero)aryl radical to alkenes⁸⁴⁰, (hetero)arenes⁸⁴¹, alkynes⁸⁴², nitroalkanes⁸⁴³, oxazolones⁸⁴⁴, and prenyl and allyl electrophiles⁸⁴⁵. In several examples^840,823, stepwise carbo- and hydrodefluorination were used to quickly construct functionalized difluoroaryl scaffolds. More recently, Chu and coworkers show that fluoroarene radicals generated via photoredox catalysis can be used in palladium catalysis, with a net cross-electrophile coupling with aryl bromides and triflates.⁸⁴⁶ This transformation highlights the potential for new metallaphotoredox couplings for radical species generated via photoreduction.

Scheme 70.

Photoredox-catalyzed hydrodefluorination of perfluorinated arenes, with the corresponding mechanism.

While strategic hydrodefluorination is widely employed in photoredox catalysis, far fewer electrochemical methods have been reported (Scheme 71). Drakesmith reported the reductive hydrodefluorination of pentafluorobenzoic acid under acidic conditions.⁸⁴⁷ Cathodic reduction with a potential of −1.20 V vs SCE resulted in excellent conversion to 2,3,5,6-tetrafluorobenzoic acid (71.1, 66%), with further reduction of product to 2,3,5,6-tetrafluorobenzyl alcohol (71.2) and unproductive reduction of substrate to pentafluorobenzyl alcohol (71.3) observed (20% and 6% respectively). Increasing the negative potential up to −1.30 V led to full substrate conversion, albeit with increased amounts of 71.2 (from 20% up to 48%) and 71.3 (from 6% up to 24%). Despite this example, reports of perfluorinated arene hydrodefluorination via electrochemical methods are sparse. On the other hand, electrochemical reductions of less fluorinated arenes are more common. Vajtner and Kariv-Miller report the potentiostatic hydrodefluorination of 1,3-difluorobenzene and fluorobenzene using tetraalkylammonium salts as the electron mediator at the Hg cathode surface.⁸⁴⁸ Using N,N-dimethylpyrrolidinium tetrafluoroborate ((DMP)BF₄), the direct electrolysis of 1,3-difluorobenzene in diglyme-H₂O afforded 71.4 in 85% yield; reactions at higher current densities led to competitive double dehydrofluorination of 1,3-difluorobenzene to 71.5. Treating fluorobenzene to similar electroreduction conditions (j = 1.25 mA•cm⁻¹) afforded benzene in 76% yield. This concept was improved on by Huang and co-workers, who use sodium borohydride as a sacrificial reductant to accelerate arene hydrodefluorination under galvanostatic conditions.⁸⁴⁹ Using Pt electrodes in an undivided cell containing 0.2 M Bu₄NBF₄ solution (20 mA), a range of electron-rich and electron-neutral fluoroarenes were efficiently hydrodefluorinated (yields 70–99%) whereas full defluorination was observed for di- and trifluorinated arenes. Deuterium labeling studies suggest that the solvent or tetraalkylammonium electrolyte counterion is the proton donor in this reaction and that direct HAT from borohydride to the fluoroarene anion radical is a minor reaction pathway.

Scheme 71.

Electrochemical hydrodefluorination of arenes with the corresponding mechanism.

The putative mechanism for hydrodefluorination is an ECEC process: single electron reduction of fluoroarene forms arene radical anion, from which fluoride expulsion occurs (71.12). Facile reduction of 71.12 to 71.13 then occurs, followed by protonation to the desired product. The second hydrodefluorination event is likely slower than first ECEC process as suggested by the need for either a higher overpotential or current density for multiple defluorinations.

4.12.2. Defluorinative Carboxylation of gem-Difluoroalkenes with CO₂

Redox methods for C−F bond carboxylation of gem-difluoroalkenes can be achieved with high selectivity for the Z- product (Scheme 72). Wu and Zhou reported an electrochemical method relying on a Pt cathode and sacrificial Ni anode in DMF containing Bu₄NI as electrolyte in the presence of 1 atmosphere of CO₂.⁸⁵⁰ The mechanism was proposed to follow an ECEC mechanism in which the gem-difluoroalkene was reduced to the radical anion, followed by reaction with CO₂ and a subsequent reduction and loss of fluoride to generate the Z-carboxylated alkene product. The analogous photoredox transformation has been achieved using an Ir-photocatalyst in the presence of a Pd co-catalyst using Pd(PPh₃)₄ as its pre-catalyst.⁸⁵¹ The mechanism initially mirrors that of the electrochemical pathway in that the gem-difluoroalkene is reduced to its radical anion by the reduced formed of the photocatalyst (obtained via reductive quenching by Hünig’s base) but then the mechanism is proposed to diverge. Loss of fluoride and interception of the fluorovinyl radical 72.1 by Pd⁰ is proposed to afford a vinyl-Pd^I species which bind CO₂ and enables C–C bond formation via a migratory insertion elimination process, SET from the reduced form of the photocatalyst to the Pd^I regenerates Pd⁰. Feng and co-workers propose that reversible addition of radical 72.1 to Pd⁰ is responsible for the interconversion between E- and Z-isomers, as the more kinetically labile form of intermediate 72.2 participates in the carboxylation step. However, it is also conceivable that the E → Z isomerization of these α-fluoroacrylic acids can occur via EnT sensitization by the photocatalyst.⁸⁵²

Scheme 72.

Defluorinative carboxylation of gem-difluoroalkenes with CO₂.

4.13. Aryltrifluoromethyl C–F Activation

The aryl difluoromethyl substituent is an important bioisostere⁸⁵³ as it imparts a lipophilicity increase relative to a methyl analog and also demonstrates hydrogen bonding ability similar to an O–H group.⁸⁵⁴ Furthermore, benzylic difluoroalkyl motifs are gaining interest due to improved metabolic stability⁸⁵⁵ and the difluoroethyl moiety is an effective bioisostere for aryl methoxy substituents.⁸⁵⁶ An attractive route to these pharmacophores involves the reduction of benzotrifluorides, which forms the radical anion (73.5) leading to fluoride extrusion to reveal the aryldifluoromethyl radical (73.6), which can either undergo further reduction/fluoride extrusion or participate in further functionalization. The electrochemical reduction of benzotrifluorides is stepwise, with the potentials for aryl-CF₃, -CHF₂, and -CH₂F groups existing within a small potential window, with complete reduction to the methyl usually observed.^857,858,859 Attempts at interrupting the defluorination at the RCHF₂ or RCH₂F moiety exist, but are limited. Périchon and co-workers demonstrated that the electroreductive coupling of benzotrifluoride and 4-fluorobenzotrifluoride with carbonyl species occurs in moderate to good yield, with only the monodefluorinated product observed under constant current electrolysis in an undivided cell (2.2 F•mol⁻¹).⁸⁶⁰ While an important proof-of-concept, the electrophile scope is limited to solvents (acetone and DMF) or dissolved CO₂, as successful coupling requires the generation of a RC₆H₅CF₂⁻ (R = H or F) anion (73.7). Bordeau and co-workers explored the electroreductive silylative defluorination of m-bis(trifuoromethyl)benzene (m-BTFMB) and observed the defluorinative mono- and di-silylation of one CF₃ group.⁸⁶¹ Defluorination selectivity is dependent on the amount of current passed (optimal current > 2.0 F•mol⁻¹) and the difference in reduction potentials between the trifluoro and the difluorosilyl moieties. Small differences in E_red (< 70 mV) led to unselective product distribution, whereas co-solvent-enabled ΔE_red values > 150 mV led to high yields of 73.8 and 73.9 from benzotrifluoride and m-BTFMB respectively (undivided cell; 2.4 F•mol⁻¹). Difluorosilylated m-trifluoromethylphenol (73.11) and aniline (73.12) were also obtained in excellent yields with minimal disilylation. Thus, these methods highlight the predominance of two stepwise, one-electron reduction pathways in benzotrifluoride defluorinative functionalization (Scheme 74A)

Scheme 74.

A comparison of (A) electrochemical and (B) photoredox mechanisms for the defluorinative functionalization of benzotrifluorides.

While the selective functionalization of aryl-CF₃ groups has been a challenge through electrolysis, photoredox catalysis offers a complementary CF₃ activation mode that enables successful monodefluorinative functionalization (Schemes 74B and 75). König and co-workers reported the first example of a photoredox-catalyzed benzotrifluoride defluoroalkylation, in which electron-deficient benzotrifluorides are coupled to N-aryl methacrylamides with assistance from an in situ generated Lewis acid to yield oxindole products in moderate to excellent yield.⁸⁶² This Lewis acid is formed from protonated 2,2,6,6-tetramethylpiperidine (TMP) and pinacolborane, and is key to this transformation as its exclusion inhibits desired reactivity. Jui and co-workers build upon this work with a procedure for benzotrifluoride defluoroalkylation catalyzed by organic photoreductant N-phenylphenothiazine (11.11, PTH) and cyclohexanethiol, in which electron-deficient benzotrifluorides are coupled to unactivated alkenes in moderate to excellent yields.⁸⁶³ Instead of overreduction, catalytic single electron transfer from an excited state PTH forms the arene radical anion 74.1, which rapidly undergoes defluorination to form arene radical 74.2. This electrophilic species can trap an alkene to form 74.3, which reacts with a thiol cocatalyst (74.4) to furnish desired product. The photocatalyst and thiol catalytic cycles are turned over by the concomitant oxidation of net reductant sodium formate by oxidized PTH and HAT from oxidized formate to thiyl 74.5. Alternatively, radical 74.2 can undergo HAT with a thiol co-catalyst 74.3 to yield the hydrodefluorination product (74.6). Jui and co-workers follow up this initial report with an expansion of the substrate scope to unactivated benzotrifluorides, which is enabled by phenoxazine 11.12 and conducting the reaction at elevated temperatures (100 °C).⁸⁶⁴ This method was applied to the facile syntheses of benzylic difluoroalkyl motifs found in bioactive difluoroalkylaromatic molecules (yields ≥ 63%, 1–2 steps); prior literature routes usually require ≥ 3 steps with expensive fluorinating agents and suffer from low yields. In the same paper, Jui and co-workers also demonstrate the synthesis of aryl difluoromethanes in moderate to good yield through the use of cesium formate as the H-atom source; only monodefluorination is observed in this hydrodefluorination (HDF) method. Gouverneur, Noël, and co-workers expand on this HDF strategy by targeting electron-poor trifluoromethyl (hetero)arenes, which would furnish electron-poor difluoromethyl (hetero)aryl cores prevalent in pharmacophores.⁸⁶⁵ This transformation is performed at room temperature, with yields ranging from moderate to good; more electron-deficient arenes proved slightly more problematic as bis-defluorination was observed. An isophthalonitrile-based organic photoredox catalyst (4-DPA-IPN) was used alongside a 4-hydroxythiophenol (4-HTP) co-catalyst, in which thiol oxidation by photoexcited 4-DPA-IPN yields its reduced counterpart, the species implicated in the arene reduction; this mechanism was supported by Stern-Volmer quenching and radical trapping studies. This method was also applied to continuous-flow conditions, with the HDF of 4-(trifluoromethyl)benzonitrile performed on a 14.6 mmol scale in 69% yield.

Scheme 75.

Photoredox-catalyzed defluorinative functionalization of benzotrifluorides with the corresponding mechanism.

4.14. Birch Reduction

The two-electron reduction of aromatics to cyclohexadienes (Birch reduction) is traditionally carried out with sodium or lithium metal in ammonia (E°= − 3.29 V (Li), −2.95 V (Na) vs. SCE), and proceeds by a key radical anion intermediate.⁸⁶⁶ Despite its synthetic utility, the necessity of super stoichiometric alkali metal and ammonia limits the scalability of the Birch reduction for industrial applications. Thus, milder electrolysis and photoredox-centered methods offer new replacements for metal reductions (Scheme 76). Baran, Minteer, Neurock, and co-workers report an electrochemical alternative that uses a constant current (10 mA) undivided cell with a sacrificial Mg (anode) and galvanized steel wire (cathode) at room temperature or sacrificial aluminum (anode) and zinc (cathode) at −78 °C.⁸⁶⁷ The key to obtaining reproducible yields was the use of a phosphoramide additive (tris(pyrrolidino)phosphoramide, TPPA) and 1,3-dimethylurea (DMU) as the proton source. TPPA was especially crucial in minimizing electrode passivation by unproductive Li deposition and THF electrolysis. Computational and experimental studies suggest that two-electron reduction occurring at the cathode is favored over a Li⁰ pathway. The scalability of this transformation was demonstrated with TBS-protected p-cresol in batch and flow (>10 g) with minimal loss in reaction efficiency. Because the Birch reduction is a two-electron process, two-photon systems for photoredox catalysis have been developed to harness either a tandem EnT-ET excitation pathway or two consecutive photoredox cycles (see Section 5.2 for a discussion of two-photon photoredox catalysis). The former mechanism was invoked in the Birch-type reduction of hetero(arenes) reported by König and co-workers, in which Dexter energy transfer between a polyarene and a photoexcited Ir^III chromophore generates a triplet polyarene that can be reduced by a separate Ir^II species that is generated via amine oxidation by photoexcited Ir^III.⁸⁶⁸ The resultant arene radical anion then undergoes two-step HAT and protonation to yield the reduced arene. A wide range of poly(hetero)aromatic substrates were competent substrates for reduction, with anthracenes and phenanthrenes reduced to the respective dihydro products. The photoreduction of naphthalenes formed both the dihydro- and tetrahydro products, with their respective ratios dependent on reaction times and substitution. The reduction selectivities of azo derivatives (e.g. acridine, quinoline) mirror the patterns observed for the carbocycle variants. More recently, a photoredox-catalyzed Birch reduction method operative via two consecutive PET steps was reported by Miyake and co-workers, in which benzo[ghi]perylene monoimides (BPI) were used as photocatalysts.⁸⁶⁹ While the scope of compatible (hetero)arenes is similar to the electrochemical precedent, yields were generally lower, reaction times are much longer (4–6 days) and multiple additions of photocatalyst (3–5 additions after 24 h) were required to obtain synthetically useful yields. Superstoichiometric amounts of hydroxide are required to generate a photocatalyst-hydroxide complex, which presumably eliminates hydroxyl radical upon irradiation (405 nm) to generate BPI radical anion (BPI^•−). Irradiation of the BPI intermediate leads to excited-state BPI^•− (BPI^•−*), which is capable of reducing (hetero)arenes (E°_comp= −2.43 V to −4.28 V vs SCE). Mechanistically, this process merges the energy of two-photons to generate a highly reducing catalytic species.

Scheme 76.

A comparison of electrochemical and photoredox methods for Birch reduction.

4.15. Aliphatic C–H Oxidation

Regioselective functionalization of alkyl C–H bonds is a fundamental goal of organic synthesis as it offers new disconnection patterns for introducing molecular complexity within aliphatic architectures. One approach is the development of redox-activatable catalysts to oxidize strong C–H bonds, with photoredox and electrochemical methods being key to generating high-energy catalytic intermediates (Scheme 77). In 1983, Masui reported⁸⁷⁰ the use of N-hydroxyphthalimide and superstoichiometric pyridine in acetonitrile for anodic oxidation of weak C–H bonds (e.g. benzylic and allylic) using NaClO₄ electrolyte and glassy carbon electrodes under constant potential electrolysis. A range of substrates were demonstrated including the conversion of cyclohexene to cyclohex-2-en-1-one in 44% yield, with additional examples reported in a 1985 publication.⁸⁷¹ In 2016, Baran and co-workers reported the electrochemical oxidation of allylic C–H bonds using a redox-active N-hydroxytetrachlorophthalimide (Cl₄NHPI) under a constant current (10 mA•mol⁻¹) in an undivided cell with pyridine, tert-butyl hydroperoxide, and acetone as the base, terminal oxidant and solvent respectively.⁸⁷² This transformation is applicable to (a)cyclic alkenes, monoterpenes, diterpenes, triterpenes, sesquiterpenes and steroids, providing enones from allylic substrates. Deprotonation and subsequent electrochemical oxidation of Cl₄NHPI generates a N-hydroxylphthalimide radical capable of generating a stable allylic radical via HAT. Trapping of this species by electrochemically generated tert-butyl hydroperoxyl radical leads to its collapse to the enone upon elimination of tert-butanol. Cathodic reduction of protonated pyridine liberates the base and H₂ gas, effectively turning over the catalytic cycle. This transformation was also adapted to the process-scale (up to 100 g) allylic oxidation of steroids and terpenes using graphite electrodes. A follow-up manuscript by Baran and co-workers on the aerobic oxidation of unactivated C–H bonds used a redox-active quinuclidine as the HAT reagent alongside an RVC anode and a nickel foam cathode under galvanostatic conditions (25 mA•mol⁻¹) in MeCN.²³² Secondary C–H bonds are oxidized to the ketone, with high selectivities for activated 2° C–H bonds and significantly lower selectivities for electronically indistinguishable 2° C–H bonds. Tertiary C–H bonds are oxidized to the corresponding alcohols. The mechanism for this transformation is similar, with anodic oxidation of quinuclidine necessary to generate catalytically-active quinuclidine cation radical capable of HAT. More recently, Baran, Neurock and coworkers report N-ammonium ylides as a new class of tunable redox mediators for aliphatic C–H oxidation, with substrate-specific formation of the corresponding alcohol, carbonyl species, or mixture of both products. These ylides enable new or improved regioselective oxidations of several steroid, cyclohexane and decalin frameworks; for the most part the oxidations observed in this systems mirror established electrochemical methods or other chemical oxidants.⁸⁷³

Scheme 77.

A comparison of electrochemical and photoredox methods for aliphatic C–H oxidation.

The photoredox counterpart for this transformation was independently reported by the Noël group⁸⁷⁴ and Schultz and co-workers at Merck & Co., Inc., Kenilworth, NJ, USA (Scheme 77).⁸⁷⁵ Both research groups use a decatungstate (DT) photooxidant (1 to 5 mol%, 365 nm LED irradiation) to initiate HAT at an electron-rich alkyl C–H bond with oxidative trapping of the resultant radical with either molecular oxygen or peroxide. Notably, Noël’s reactions were run under continuous flow conditions. Site-selectivity is substrate-specific for 2° C–H bonds in Noël’s work, with the oxidation occurring at the most sterically-accessible electron-rich C–H bonds for a range of substrates. Similar trends are observed in Schultz’s work with aliphatic amines; protonation of free amines deactivates its a and (in some cases) β positions such that oxidation is observed at either the β or γ sites δ. Mechanistic studies using in situ LED-NMR show the formation of 3-hydroperoxypyrrolidine from pyrrolidine, which Schultz and co-workers suggest is the intermediate that funnels to the ketone. Finally, both Schultz and Noël demonstrate the amenability of the method for scale up, with the former obtaining N-Boc pyrrolidin-3-one (77.5) in 46% yield on a 5 g scale and the latter obtaining artemisitone-9 (77.11) in 59% yield on a 5 mmol scale. The photocatalytic strategy can be adapted to a metal–organic framework wherein the integration of a copper photosensitizer and an iron-centered oxidation site enables the aerobic oxidation of benzylic C–H bonds to a ketone product.⁸⁷⁶ Efforts towards the merger of the two catalytic strategies are relatively limited, but a photo-electrochemical method from Sayama and coworkers enables the oxidation of cyclohexane to cyclohexanol and cyclohexanone (KA oil) under aerobic conditions using a WO₃ photoanode and simulated solar light (10 mW•cm⁻²).⁸⁷⁷ The method provides with high partial oxidation selectivity (99%) and high current utilization ratio (76%) at room temperature and atmospheric pressure of air achieving photon to current efficiencies at 365 and 420 nm of 57% and 24%, respectively.

4.15.1. Benzylic Etherification

In contrast to C–H oxygenation, the etherification of benzylic C–H bonds typically proceeds via direct oxidation of the aromatic substructure, either through SET to generate a radical cation (photoredox), or two stepwise SET to form a benzyl carbocation (electrochemistry) (Scheme 78). Benzylic C–H bonds are heavily acidified upon single-electron oxidation⁸⁷⁸, thus the formation of a benzylic C-centered radical is a common intermediate between the two methods. Sharma and coworkers summarize recent progress in the photochemical and electrochemical C–H functionalization of benzylic C–H bonds, and readers are encouraged to refer to this reference for more information.⁸⁷⁹ To highlight the key divergences exist between these two systems, the outcomes of benzylic etherification are compared. Yoon and co-workers demonstrate that a photoredox-generated electron-rich benzylic radical undergoes further oxidation by a Cu^II species to form a benzylic carbocation that is then trapped by a partner alcohol to furnish the benzyl ether after facile deprotonation.⁸⁸⁰ The substrate scope is strictly limited to oxyarenes because the formation of a putative quinone methide intermediate is necessary to stabilize the benzylic carbocation. Despite this requirement, exquisite site-selectivity is afforded and trends with the predicted stability of the quinone methide intermediate; this enables highly selective functionalization of p-alkoxy-activated benzylic C–H bonds even when weaker benzylic C−H bonds are present. Additionally, the alcohol scope is impressive with a range of functionalities well-tolerated, notably serine, hexose and pentose derivatives, and terpene alcohols. In complex substrates with preexisting stereochemical bias, high diastereoselectivity of C–O bond formation is observed. Lei and co-workers report an electrochemical counterpart to benzylic etherification, in which direct arene electrolysis under mild basic conditions forms the requisite benzylic carbocation that is trapped by a partner alcohol⁸⁸¹. Using a constant current (10 mA), indane is successfully coupled to a range of alcohols, albeit lacking the sensitive functionality tolerated in Yoon’s examples. This is likely due to potential overoxidation given that the highly oxidizing potentials are required. While this method can be applied to arenes with multiple alkyl substituents, it cannot tolerate oxyarenes, which presumably dearomatize and dimerize under direct anodic electrolysis.⁸⁸²

Scheme 78.

A comparison of electrochemical and photoredox methods for benzylic etherification.

4.15.2. Aliphatic C–H Fluorination

The direct fluorination of aliphatic C–H bonds is an important synthetic tool because hydrogen-to-fluorine substitution has the ability to impart desirable potency, conformation, metabolism and membrane permeability effects onto pharmaceutical targets^834,856 and enable the synthesis of radiotracers using ¹⁸F for biological and disease mechanisms through PET imaging.⁸⁸³ Letcka and co-workers reported the use of UVB (280–315 nm) activated 1,2,4,5-tetracyanobenzene (79.10) to catalyze the fluorination of aliphatic⁸⁸⁴ and benzylic⁸⁸⁵ C–H bonds using Selectfluor as the electrophilic fluorine source. While mechanism data is only presented for benzylic systems, Letcka proposes that fluorination occurs via the formation of radical cations rather than HAT from a photoactivated intermediate. Britton and co-workers demonstrate the use of a HAT mechanism, where a UVA photoactivated DT abstracts a hydrogen atom from an electron-rich C–H bond; the carbon radical is then fluorinated through fluorine transfer from N-fluorobenzenesulfonimide (NFSI).⁸⁸⁶ Sorensen and co-workers present a visible-light alternative using a photoactivated uranyl cation operating by the same mechanism (HAT), albeit with abbreviated substrate tolerance.⁸⁸⁷ In the examples presented, simple and complex aliphatic C–H bonds are fluorinated with preference for 3° C–H bonds and sterically-accessible electron-rich C–H bonds in examples containing 2° C–H bonds. Britton and co-workers are able to leverage this selectivity using their DT system to enable the ¹⁸F-fluorination of 3° C–H bonds in branched aliphatic amino acids and peptides using [¹⁸F]NFSI as the radiofluorine source; radiolabeled amino acids were to image glioma xenografts through in vivo PET imaging.^888,889 An electrochemical counterpart was reported by Baran and co-workers, in which unactivated 3° and 2° C–H bonds are selectively fluorinated using Selectfluor as the fluorine source and electrolyte, in addition to using sodium nitrate as the initial redox mediator under galvanostatic electrolysis (3 mA, 0.25–3.0 F•mol⁻¹).⁸⁹⁰ Site-selectivities are similar to those obtained under photocatalytic conditions, and the di/tri-fluorination of unsubstituted adamantanes was observed. The transformation was amenable to large scale 3° C–H fluorination of a protected amino acid (100 g), which was isolated in 78% yield. Mechanistic studies suggest that the reaction proceeds by a radical mechanism due to the observation of > 100% current efficiency. This suggests that radical propagation is occurring, with the amine cation radical of defluorinated Selectfluor acting as an initiator.

More recently, radical-polar crossover methods in photoredox catalysis are opening new polarity-reversed disconnections for aliphatic C–H fluorination by enabling the formation and trapping of a carbocation by nucleophilic fluoride (Scheme 80). Independently-published methods from the Doyle⁸⁹¹ and Musacchio⁸⁹² groups demonstrate the mono- and difluorination of benzylic C–H bonds, with a photoredox-activated chemical oxidant generating a benzyl radical via HAT; single-electron reduction and generation of a radical precursor—tert-butyl peroxybenzoate to an O-centered radical for Musacchio and N–acyloxyphthalimide to methyl radical for Doyle. Subsequent oxidation of the radical by the photoredox catalyst furnishes the carbocation required for fluoride trapping. Substrate scope is broad for both methods, with yields ranging from low to excellent. Musacchio and coworkers demonstrate a sizeable scope for benzylic difluorination, with low to moderate yields obtained. Allylic and aliphatic C–H fluorination are more efficient using Doyle’s method, but yields currently remain low. Other heteroatom-centered nucleophiles are amenable to this transformation, as well as arenes, which follow Friedel-Crafts reactivity patterns.

Scheme 80.

Representative examples of photoredox-catalyzed alkyl fluorination using nucleophilic fluoride.

4.15.3. Nitrogen-centered 1,5-Hydrogen Atom Transfer

Photochemical and electrochemical methods have been used to initiate the intramolecular 1,5-hydrogen atom transfer (1,5-HAT) mechanism to generate reactive C-centered radicals from alkyl C–H bonds to N-centered aminyl or amidyl radicals (Scheme 81). In 2016, Rovis⁸⁹³ and Knowles⁸⁹⁴ independently reported the generation of amidyl radicals via oxidation-initiated photoredox catalysis. Rovis and co-workers propose that their major reaction pathway is the direct oxidation of deprotonated alkyl trifluoroacetamide by a photoexcited iridium catalyst which reveals the trifluoroacetamidyl radical, a hypothesis supported with Stern-Volmer luminescence quenching studies. On the other hand, Knowles and co-workers propose that their system requires a concerted PCET mechanism in which oxidation of a N-aryl amide-phosphate, hydrogen-bonded complex by an excited state iridium photocatalyst furnishes the desired N-aryl amidyl radical; Stern-Volmer luminescence quenching and NMR studies support their hypothesis. The resultant C-centered radical then participates in Giese-type reactions with electron-deficient olefins, with closure of the catalytic cycle accomplished via two-step SET from reduced Ir^II and protonation of the resulting anion. Both the Rovis and Knowles studies describe broad substrate scopes with good functional group tolerance and show high selectivity for 1,5-HAT over 1,6-HAT. Rovis and co-workers use this regioselectivity preference to perform a stepwise, double C–H functionalization of an alkyl trifluoroacetamide, in which the 1,5-position relative to the N–H bond is alkylated before 1,6-alkylation. Knowles and co-workers show that multiple alkyl N-aryl amides and an alkyl sulfonamide are competent substrates, but observe significantly diminished yields when an alkyl tert-butyl carbamate is used. Additionally, Knowles and co-workers demonstrate intermolecular C–H activation, with alkylation of cyclohexane, tetrahydrofuran, and N-Boc pyrrolidine (at the 2-position for the latter two substrates) observed.

Scheme 81.

A comparison of electrochemical and photoredox methods for alkyl C–H functionalization via nitrogen-centered 1,5-hydrogen atom transfer.

The electrochemical approach to amidyl-based 1,5-HAT initiation proceeds via halogen-mediated formation of an N-halo intermediate or via a PCET mechanism initiated by base-promoted electrolysis. However, this strategy diverges from the photoredox examples as the synthetic pathways discussed are electrochemical alternatives to the Hoffmann-Loffler-Freytag (HLF) reaction. ⁸⁹⁵ Shono and co-workers report the synthesis of N-tosyl pyrrolidine that proceeds via bromide-mediated electrolysis.⁸⁹⁶ Constant current anodic oxidation of potassium bromide or iodide (j = 50 mA•cm⁻¹) in either a refluxing water-cyclohexane mixture or in refluxing methanol provides the desired N-tosyl pyrrolidines selectively. The mechanism of this transformation proceeds via the formation of the N-halo tosylamine. Homolytic cleavage of the N–I bond reveals an N-centered radical, from which 1,5-HAT, C–I bond formation and subsequent ring closure furnish the N-tosyl pyrrolidine via a mechanism reminiscent of the HLF reaction. Alternatively, Lei and co-workers show that galvanostatic electrolysis can initiate an acetate-mediated PCET process to generate the requisite N-centered radical for the HLF reaction.⁸⁹⁷ While a stepwise deprotonation-oxidation mechanism may be operative if solvent-derived hexafluoroisopropoxide is formed, control studies suggest that the acetate-based PCET pathway is operative. Additionally, electrolysis serves an additional purpose — anodic oxidation of the resultant C-centered radical forms the requisite carbocation that leads to nucleophilic trapping of the tosylamine — due to the absence of halide. Lastly, a range of sulfonylamines and benzamides can be used in this transformation, thus highlighting its N-protecting group versatility. Stahl and co-workers show that the strategic use of photochemistry can facilitate the photochemical cleavage of weak nitrogen-halogen bonds and enable the use of iodide as a redox mediator.⁸⁹⁸ Iodide has a narrower redox window for mediator regeneration, which enables greater method compatibility for substrates containing electron-rich functional groups. Additionally, this method can also be used to generate N-centered imidate-based radicals for the synthesis of oxazolines and 1,2-amino alcohols.

4.15.4. Aminoxyl-mediated Alcohol Oxidation

The oxidation of alcohols to aldehydes, ketones and carboxylic acids is a key transformation in organic synthesis, and the convergence of photoredox catalysis and electrocatalysis on the use of organic aminoxyl species (Schemes 82–84).⁸⁹⁹ The low redox potentials required to oxidize aminoxyls to the catalytically-active oxoammonium (0.506 V. vs. SCE) leads to selective carbonyl formation at with low overpotentials⁹⁰⁰, thereby minimizing undesirable oxidative pathways and allowing a broader range of functional groups to be used concurrently alongside the alcohol of interest (Scheme 82A). There are two broad reactivity patterns for alcohol oxidation with oxoammoniums: under basic conditions, deprotonation and N–O adduct formation at the nitrogen first occurs before intramolecular hydride transfer yields the carbonyl and hydroxylamine products. Under acidic conditions, a bimolecular hydride transfer occurs instead (Scheme 82B). These two differing pathways have important implications for site-selectivity, as the oxidation selectivity between secondary and primary alcohols can be mediated with pH changes. Additionally, comproportionation-1e oxidation of the oxammonium and the hydroxylamine form of the electrocatalyst to afford two molecules of the nitroxyl via a base mediated process has also been postulated.⁹⁰¹

Scheme 82.

(A) The redox pathways between the hydroxylamine, nitroxyl and oxoammonium states of aminoxyl oxidants. (B) The pH-dependent divergence in mechanism for oxoammonium-based alcohol oxidation.

Scheme 84.

Representative putative mechanisms for the oxoammonium-based oxidation via (A) electrochemical and (B) photoredox pathways.

The first example of nitroxyl-mediated electrooxidation was reported by Semmelhack and coworkers, in which alcohols are selectively oxidized to aldehydes and ketones using catalytic amounts of TEMPO (Scheme 83).⁹⁰² The direct conversion of aldehydes to nitriles can also be accomplished, with TEMPOnium-mediated oxidation of an imine intermediate leading to the desired product.^903,904 Extension of this methodology to the synthesis of carboxylic acids was first achieved on biomass-type substrates under basic conditions from the parent alcohol^905,906 (Anelli-type oxidation), but more recent advances by Stahl and coworkers using 4-acetamido-TEMPO (ACT), which upon electrooxidation forms the corresponding oxoammonium to facilitate Pinnick-type oxidation of aldehydes to the corresponding acid in addition to Anelli-type oxidations.⁹⁰⁷ Systematic evaluation of electrocatalytic alcohol oxidation with monocyclic and bicyclic nitroxyl radicals has also been explored, with mechanistic data demonstrating that the favorable oxidation potentials of cheap monocyclic nitroxyls (notably ACT) increase their electrocatalytic efficiency relative to more expensive bicyclic nitroxyls (Scheme 84A).⁹⁰⁸ This result highlights the difference in reactivity between chemically-mediated oxidation (e.g. bleach) in which catalytic activity for bicyclic nitroxyl appears to be superior to their monocyclic variants due to reduced steric hindrance around the active nitroxyl/oxoammonium group.⁹⁰⁹

Scheme 83.

A comparison of photoredox and electrochemical methods for oxoammonium-based alcohol and aldehyde oxidation.

Photoredox catalysis can also be used to mediate the aminoxyl/oxoammonium cycle, albeit with a stoichiometric chemical oxidant (Schemes 83 and 84B). Leadbeater and coworkers report the synthesis of amides⁹¹⁰, aldehydes and ketones⁹¹¹, nitriles⁹¹², and carboxylic acids⁹¹³ from the parent alcohols and/or aldehydes with Ru(bpy)₃(PF₆)₂ as the photoredox catalyst, ACT as the nitroxyl co-catalyst, and persulfate salts as the stoichiometric oxidant. All of the aforementioned synthetic methods employ a variant of this strategy and a general mechanism is as follows: the photoexcited Ru chromophore reduces persulfate to sulfate anion and sulfate radical anion, and forms a Ru^III intermediate that oxidizes the parent nitroxyl to the key oxoammonium catalyst, hence closing the photoredox cycle. The resulting hydroxylamine can undergo HAT with the persulfate radical anion to regenerate ACT and close the nitroxyl redox cycle.

4.16. Hole Catalysis

4.16.1. SET-Triggered [4+2] and [2+2] Cycloadditions

Radical chain reactions can be initiated by light (photoinduced catalysis) or electrochemical means. Photoinduced catalysis refers to “photochemical reaction generates an active species that participates in thermal catalytic reactions. The quantum yield may exceed unity and the overall free energy of the catalyzed reaction must be negative.”⁹¹⁴ Electrocatalytic reactions are chain processes where the electrochemical transformation only requires a catalytic amount of current, relative to the amount of starting material consumed. The chain mechanism in either the photoinduced catalysis or electrocatalytic reactions requires that the intermediate and/or product that is photochemically or electrochemically generated can activate the starting material, thus propagating the chain process. Several examples are shown below in SET-triggered cycloadditions.⁹¹⁵

The Diels-Alder reaction, [4+2] cycloaddition, enables the construction of 6 membered rings from a diene and a dienophile alkene, with redox-triggered methods enabling C–C bond formation between species of differing ground state electronic compatibilities (Scheme 85). Chiba and coworkers reported⁹¹⁶ an anodic SET-triggered cycloaddition variant of the classic Diels-Alder, providing an umpolung approach to electronically mismatched coupling partners. The olefin geometry on the anethole has a minor impact on the diastereoselective outcome of the reaction. trans-Styrene provides cleanly the trans product, whereas the cis-anethole results in 1: >10 cis/trans ratio. A photoinitiated method⁹¹⁷ using TiO₂ and 365 nm light provides comparable results and a slight broader scope under otherwise nearly identical solvent/electrolyte conditions, illustrating the similarities because the chemistry relies on “hole-catalysis” via a chain mechanism. The Ru-photocatalyzed variant disclosed by Yoon and coworkers disclosed enables the same transformation with a broader substrate scope (method B1).^918,919,920

Scheme 85.

A comparison of photoredox and electrochemical methods for redox-triggered [4+2] cycloadditions.

Anion radical chain [2+2] cycloadditions of tethered enones were first reported by Krische and Bauld using chemical reductants^{921,922,923,924}, and they later reported an electrochemical variant by Krische and Bauld in 2002 using electrolysis in a divided cell to provide mixtures of products, including observation of a [4+2]-cycloaddition side product (Scheme 86).⁹²⁵ This preliminary study serves as inspiration for the photoredox variant developed by Yoon and coworkers in 2008, where significantly improved [2+2] cycloaddition selectivity and diastereoselectivity are observed (relative to the electrochemical method).⁹²⁶

Scheme 86.

A comparison of photoredox and electrochemical methods for redox-triggered [2+2] cycloadditions.

4.16.2. Redox Triggered [3+2] Cycloadditions

Cyclopropylamines provide a synthetic handle for redox triggered intermolecular [3+2] cycloaddition with olefins by either electrochemical⁹²⁷ or photoredox methods.³⁸² The oxidation of the lone pair, provides a radical exocyclic and alpha to the cyclopropyl ring, which enables for ring opening to relieve ring strain via formation of a distonic radical cation⁹²⁸ in which the primary carbon centered-radical can attack an olefin, and after cyclization, ultimately leads to the formation of a five membered ring. The radical cation 5-membered intermediate can either undergo back electron transfer from the reduced photocatalysts (redox neutral process) or alternatively can propagate a chain process via oxidation of the starting material cyclopropylamine. The proposed radical chain process was supported by the measurement of quantum yields (ϕ) > 1 (ϕ = 1.44 to 1.68).⁹²⁹ In the context of the electrochemical methods, the chain process enables for the use of catalytic amounts of total charge and indeed this was verified experimentally (0.34 equiv. of charge is required).⁹²⁷ Scheme 87 illustrates the ability to access functionalized cyclopentylamine derivatives using styrenes or acrylamide as olefin partners for intramolecular reaction with cyclopropylamines. The diastereoselectivities are typically low, but may still be useful for the synthetic needs of medicinal chemists. Products containing 5,5-fused rings can be obtained if the cyclopropylamine is a 2-azabicyclo[3.1.0]hexane (a 3,5-fused system). Booker-Milburn and Aggarwal recently reported⁹³⁰ a related diastereoselective photoredox-catalyzed [3+2] cycloaddition of N-sulfonyl cyclopropylamines with electron-deficient olefins to access trans-cyclopentanes bearing a sulfonamide.

Scheme 87.

Intermolecular [3+2] cycloaddition of cyclopropylamines with olefins.

4.16.3. Redox Triggered Newman-Kwart Rearrangement

The conversion of a phenol to a thiophenol can be accomplished in a multi-step manner via the Newman-Kwart rearrangement.^931,932 Traditionally Newman-Kwart rearrangement leverages high temperature (200–300 °C) to overcome the high energy barrier required to convert an O-aryl thiocarbamate (88.1) to a S-aryl carbamate (88.2) via spirocyclic compound 88.3 (Scheme 88) which can lead to low yields due to undesired side-reactions. Recently, oxidatively triggered O- to S-rearrangement via intermediate 88.4 followed a reduction step to obtain the desired product can enable the redox neutral transformation at room temperature with high yields. An electrochemical approach using CCE, carbon anode in HFIP containing Bu₄NClO₄ was reported by Francke in 2018,²⁸⁰ who also subsequently reported a detailed mechanistic study.⁹³³ HFIP was critical to the success of the reaction, as other solvents (e.g. TFE, MeOH, CH₃CN or CH₂Cl₂) give poor results. This can in part be understood due to HFIP’s high anodic stability and low pK_a which enables it to participate in sacrificial proton reduction without interfering in oxidative processes.⁹³⁴ The adaptation of these batch conditions to electrolyte-free flow electrochemical conditions were successfully demonstrated with productivity of > 2 g•h⁻¹. Noteworthy is the use of catalytic amounts of charge (Q = 0.3 F•mol⁻¹) to obtain 95% yield of 4-methoxy-thiophenolcarbamate, supporting a radical chain process. The activation barriers, as calculated by DFT, do not sufficiently explain the observed substrate-specific reactivity outcomes for the electrochemical Newman-Kwart rearrangement, and the full understanding also requires consideration of the thermodynamically favorable equilibrium forming an off-cycle dimer (88.5). The hydrogen-bonding from HFIP to the key transition state 88.6 was also postulated to both decrease the activation barrier of the rearrangement and improve the thermodynamic driving force for the final reduction step to generate 88.2. Nicewicz reported the use of a 2,4,6-tri(p-tolyl)pyrylium tetrafluoroborate photocatalyzed method in 2015 for the Newman-Kwart rearrangement⁹³⁵ and a subsequent detailed mechanistic study.⁹³⁶ The use of chemical oxidant, namely cerium ammonium nitrate⁹³⁷ or persulfate⁹³⁸ has also been demonstrated to affect such rearrangements. A key difference between the electrochemical and photochemical Newman-Kwart rearrangement is related to the back-electron transfer to either 88.5 or 88.7, either events resulting in termination of the chain process. While turnover of the photocatalysts necessitates a reduction event from PC⁻, the electrochemical system does not suffer from this restriction. This is highlighted by the increased concentration resulting in lower efficiency only in the photochemical and not the electrochemical variant of the Newman-Kwart rearrangement.

Scheme 88.

Redox triggered Newman-Kwart rearrangement.

4.17. Polymer Chemistry

4.17.1. RAFT Polymerizations

Reversible addition–fragmentation chain transfer (RAFT) polymerizations are radical-based living polymerizations that operate via degenerative chain transfer processes involving xanthate, dithiocarbamate, dithioester, or trithiocarbonate-based chain transfer agents (CTA).^939,940 Original developments of this strategy centered on the use of free radical initiators (e.g. azobisisobutyronitrile; AIBN) to initiate the RAFT process and while photoinitiated RAFT was initially demonstrated with thiocarbonylthio compounds⁹⁴¹, a lack of end-group fidelity due to UV-light photolysis necessitated new developments in photocontrolled RAFT methodologies (Scheme 89). Boyer and co-workers reported a photoredox-controlled RAFT polymerization strategy, wherein PET via oxidative quenching of photoexcited fac-Ir(ppy)₃ by thiocarbonylthio-capped species enables an off-cycle RAFT process. Upon the removal of light stimulus, concomitant reduction of the Ir^IV catalyst to Ir^III and oxidation of the thiocarbonylthiolate group results in efficient end-capping of the growing polymer (a process now known as PET-RAFT).⁹⁴² Stern-Volmer analysis confirmed that thiocarbonylthiolate compounds quench the excited state of fac-Ir(ppy)₃, although with differing efficiencies. The dithiobenzoate 4-cyano-4(phenylcarbonothioylthio)pentanoic acid (89.1) is quenched very rapidly relative to trithiocarbonates 2-(n-butyltrithiocarbonate)-propionic acid (89.2) and benzylsulfanyl-thiocarbonylthiosulfanyl propionic acid (89.3), as well as xanthate 89.4. Initiators 89.1, 89.2, and 89.3 were used for PET-RAFT polymerization of conjugated monomers, with optimal monomer-initiator compatibility determined empirically. Most PET-RAFT polymerizations were accomplished using ≥ 5 ppm of photocatalyst (relative to monomer), and excellent control over polymer weight and dispersity (Ð < 1.21) was observed. Higher light intensities (4.8 W) led to faster polymer kinetics, but most polymerizations on smaller scale could be accomplished with a 1 W blue LED. More importantly, polymerization is solely controlled by light, with light on-off studies demonstrating that conversion only occurs during the irradiation phase. PET-RAFT also enables the living polymerization of high molecular weight polymers, as shown by the synthesis of poly(methylacrylate) with conversions (≥ 93%) with low dispersity⁹⁴³ (Ð = 1.08–1.09) were demonstrated for M_n ranging from 1.8 kDa to 2.18 MDa (with 1 ppm of photocatalyst).

Scheme 89.

Representative examples of PET-RAFT and putative mechanism.

While 89.1, 89.2, and 89.3 were ideal initiators and CTAs for conjugated monomers, they were less efficient in initiating the polymerization of unconjugated monomers (e.g. vinyl acetate). However, xanthate 89.4 enables PET-RAFT of unconjugated monomers, albeit with reduced monomer conversion (65–81%) and requiring slightly higher catalyst loadings (5–10 ppm). Nevertheless, good agreement between theoretical and experimental molecular weights is observed, and the polymers obtained have low dispersities (Ð < 1.4).

A feature of RAFT polymerization is the ability to synthesize block copolymers, thus chain-end fidelity was studied. Polymer chains subjected to PET-RAFT typically retained chain end fidelity for 5 cycles, with decreases starting at the 6^th cycle. This observation enabled the application of PET-RAFT towards the controlled synthesis of ultrahigh molecular weight (M_n > 300 kDa) triblock copolymers using a range of conjugated polymer macroinitiators (Ð < 1.30). Another important advance of PET-RAFT is its efficacy in the presence of oxygen as oxygen-mediated deactivation of radical pathways is a problem associated with traditional radical polymerization methods. While an inhibitory period was observed (3–4 h), the polymerization of methyl acrylate (MA) and methyl methacrylate (MMA) in non-degassed reaction solution proceeded with very similar kinetics to the degassed solution. Additionally, no substantial differences between polymer dispersity was observed, thus highlighting robustness of PET-RAFT. These observations enabled the synthesis of di- and tri-block polymers in degassed solution. PET-RAFT has since grown rapidly and has been expanded to include a range of photocatalysts^{944,945,946,947} and applications.^948,949,950

The electrochemical analog to PET-RAFT (namely, eRAFT) by comparison, is largely underdeveloped. Johannsmann and co-workers first demonstrated that using a trithiocarbonate CTA in ammonium persulfate-mediated polymerization of N-isopropylacrylamide improves the homogeneity of the resultant hydrogel, thus suggesting greater control over intermolecular crosslinking (Scheme 90).⁹⁵¹ However, this preliminary study lacked thorough mechanistic investigations on the role of initiators in eRAFT. This inspired Matyjaszewski and co-workers to use electrochemically-mediated activated radical initiation to trigger eRAFT polymerization.⁹⁵² A limitation of traditional RAFT polymerization is the irreversible nature of radical mediators, which necessitates their continuous initiation in order to sustain polymerization amid inevitable chain termination. Noting this, Matyjaszewski and co-workers reduced benzoyl peroxide (BPO) and diazonium salt 90.1 to initiate RAFT polymerization. While BPO activation enabled the potentiostatic polymerization of MMA, the process was inefficient due to the overlap in reduction potentials for BPO and CTA agent used (90.2). This led to the use of easily-reducible diazonium 90.1, which has minimal overlap with 90.2 (−0.1 V vs. SCE, ~ 1 V more positive than 90.2). Potentiostatic conditions proved problematic with 90.1 due to undesirable electrografting of aryl radicals on the electrode surface, thus a switch to galvanostatic conditions was adopted. This change enables the eRAFT with n-butyl acrylate (BA) at low applied currents (−50 to −200 μA), and provides controlled polymer growth with good conversion (58–80%) and low dispersities (Ð < 1.5). Lower applied current currents led to slower but more controlled polymer growth. Block co-polymers of acrylates were also synthesized using eRAFT, with molecular weights and dispersities similar to traditional RAFT polymerization, thus demonstrating the chain-end fidelity of polymers obtained via eRAFT. Attempts at bypassing the use of electrochemically-initiated radicals through the use of electrochemical mediator to activate CTA agents have been shown with mixed success. Matyjaszewski and co-workers identified meso-tetraphenylporphyrin as a potential mediator, with the polyacrylates obtained with low dispersities and good experimental molecular weight agreement with theoretical values. However, these polymerizations are slow and gradual decomposition of meso-tetraphenylporphyrin is observed.⁹⁵³ Yan and co-workers identified a coenzyme-mediated system, wherein electrochemically-switching between polymerization-active nicotinamide adenine dinucleotide (NADH) (90.3) and polymerization-inactive NAD⁺ (90.4) enables temporal control over eRAFT.⁹⁵⁴ Using CTA agent 90.5, the controlled growth of polyMMA (Ð = 1.07, ~1.2% divergence from M_{n, theo}) is obtained under potentiostatic conditions (E_app = −0.65 V) with high monomer conversion observed after 6 hours. Intermittent electrochemical potential switching between −0.65 and −0.40 V showed polymer growth during the former whereas a stop in polymerization is observed when the lower reducing potential is applied. This eRAFT method can be applied to a range of conjugated and unconjugated monomers, with high monomer conversions, low dispersities (Ð ≤ 1.21) and good molecular weight agreement (< 23% disparity) for high molecular weight polymer (up to 42 kDa) observed. This method can also be used to synthesize amphiphilic co-block polymers, which form self-assembled bowl-shaped vesicles in water.

Scheme 90.

Representative examples of eRAFT and respective putative mechanisms.

4.17.2. Atom Transfer Radical Polymerization

Atom transfer radical polymerization (ATRP) is a synthetic strategy for the precise construction of well-defined architectures polymers through high levels of control over polymer molecular weights and molecular weight distribution (Ð < 1.5). Its success depends on maintaining a dynamic equilibrium between propagating radicals and dormant macromolecular alkyl halides through halide transfer between the organic species and a transition metal catalyst, with controlled polymer chain growth occurring when the concentration of active propagating species is kept low. In the case of copper-based catalysts, stochiometric reductants can be used to regenerate active Cu^IBr complexes from Cu^IIBr₂ species via electron transfer processes, which enables external control over polymerization rates and minimizes homopolymerization of block copolymers⁹⁵⁵. Matyjaszewski and co-workers reported the first example of electrochemical ATRP (eATRP), a method that enables dynamically modulation of the equilibrium between Cu^IBr/Me₆TREN (Me₆TREN = tris[2-(dimethylamino)ethyl]amine) and Cu^IIBr₂/Me₆TREN speciation (Scheme 91).⁹⁵⁶ ATRP of methyl acrylate with an ethyl 2-bromopropionate initiator carried out with a constant potential (E_c) of −0.69 V vs. Ag⁺/Ag — the E_1/2 for the Cu catalyst couple — in a divided cell shows approximately 80% conversion within 2 h, with linear, first-order kinetic behavior and excellent correlation between experimental and theoretical weight-average molecular weights (M_W,exp and M_W,theo respectively) observed. Additionally, constant decreases in Ð (Ð_min = 1.06) and a narrow, monomodal distribution of polymeric species were noted with increasing monomer conversion — features indicative of a living polymerization. The electrochemical potential is then used as a dynamic polymerization “on-off” switch via repetitive stepping of E_c between −0.69 and −0.40 V; at the former potential, Cu^I speciation is favored leading to polymerization whereas in the latter situation, the Cu^II state predominates, resulting in polymerization deactivation. Throughout the on-off cycling process, strong correlation between M_W,exp and M_W,theo, low Ð values, and the consistent growth of a high molecular weight polymer were observed, thus confirming the dynamic nature of eATRP. Matyjaszewski and co-workers also successfully applied this strategy to the controlled polymerization of the acidic monomer methacrylic acid (MAA) under acid, aqueous conditions, which is a historical limitation of ATRP⁹⁵⁷. The inhibitive irreversible chain-end PMAA cyclization involving a carboxylate and a tertiary alkyl bromide was initially observed, but three changes — using Cl as chain-end halogen, lowering the pH to 0.9, and using an applied potential of −0.18 V for rate acceleration — enables the controlled synthesis of PMAA with high monomer conversion and low Ð. Electrochemical cycling was also performed by cycling E_app between −0.2 and 0.8 V vs SCE; negligible conversion was observed for the off-period whereas steady growth of a high M_W polymer during the on-period was detected. Additional details regarding the growth and application of eATRP are summarized by Matyjaszewski and co-workers in a recent review.⁹⁵⁸

Scheme 91.

Representative examples of eATRP and putative mechanism.

While eATRP relies on redox modulation of Cu^I/Cu^II speciation, initial attempts at photoredox-controlled ATRP used transition-metal based photocatalysts that operate via reductive⁹⁵⁹ or oxidative^960,961 quenching of the excited state chromophore (Scheme 92). These methods pioneered the use of light as a tool for controlling living radical polymerizations, and the work from Hawker and co-workers being especially notable for producing polymers with low dispersities (Ð < 1.50) and with good control over its molecular weight. However, recent methodologies have shifted towards the use of organic photocatalysts to initiate and sustain polymerization (O-ATRP). Fors, Hawker and co-workers report the metal-free, light-mediated polymerization of methyl methacrylate using the chromophore PTH (11.1) and the ATRP initiator ethyl α-bromophenylacetate (EBPA) with good agreement between M_W,exp and M_W,theo observed and low Ð values (Ð < 1.35) obtained.⁹⁶² The O-ATRP process only occurs upon irradiation as light “on-off” studies show no conversion during the dark phases. More importantly, linear increases in M_W vs. conversion are observed despite multiple light “on-off” cycles, and chain-end fidelity is maintained when the light stimulus is removed. Success of this method depends on the highly reducing nature of excited state PTH (E_red = −2.10 V vs. SCE) and less oxidizing PTH cation radical (PTH^•+, E_ox = 0.68 V vs. SCE) as using fac-Ir(ppy)₃ — a transition-metal photocatalyst with lower reducing ability (E_red = −1.73 V vs. SCE) and a higher Ir^IV/Ir^III oxidation potential (E_ox = 0.77 V vs. SCE) — results in uncontrolled polymerization (Ð = 3.69) of dimethylaminoethyl methacrylate due to side reactions arising from competitive amine oxidation. Lastly, the resultant homopolymer from O-ATRP can be used to form multiple block copolymers with acrylates or styrene in high molecular weight (M_W > 20 kDa) with good dispersity (Ð = 1.06 – 1.31). Miyake and co-workers improve on this methodology by developing diaryl dihydrophenazine (DDP) photoreductants (e.g. 92.1) that enables the use of visible light for initiating O-ATRP, with Ð improvements observed for polymerizations of similar scale, with a slight loss in polymerization control (Ð = 1.54) occurring during the synthesis of a high M_W polymer (M_n = 85.5 kDa).⁹⁶³ Computational analysis suggests that efficient reduction from excited state DDP species requires SOMO electron localization on one aryl species rather on both rings. This prediction is confirmed by the development of 2-naphthyl and 1-naphthyl DDP species — photoreductants with spatially separated excited-state SOMOs — that enable the synthesis of PMMA with dispersities that rival metal-based ATRP catalysts (Ð = 1.03–1.08). Further catalyst development from the Miyake led to the development of tailored phenoxazine species (e.g. 11.12)⁹⁶⁴ capable of excited-state reduction for use in organic ATRP⁹⁶⁵ as well as for synthetic applications.⁵⁶⁷

Scheme 92.

Representative examples of PET-ATRP and O-ATRP, with the putative mechanism provided.

4.17.3. Living-Type Cationic Polymerizations.

Cationic polymerization is a widely-used strategy for chain growth polymerization by which an initiator generates a cationic charge on a monomer, which then transfers the charge to another monomer in a chainwise fashion to form a polymer (chain growth). While initially developed using discrete Brønsted and Lewis acids, electrochemical^966,967 and photochemical^{968,969,970,971,972} methods have been used to initiate cationic polymerization, with recent photoinitiated strategies involving activated olefins demonstrate the characteristics of living-type polymerizations (Scheme 93).^973,974 However, stimuli-mediated control over cationic polymerization was not demonstrated until a report by Fors and coworkers involving a dithiocarbamate CTA (93.1) and an oxidizing 2,4,6-p-methoxyphenylpyrylium tetrafluoroborate (93.2) photocatalyst.⁹⁷⁵ This photoredox process enables the high conversion, living-type polymerization of isobutyl vinyl ether (IBVE), with low dispersities (Ð = 1.19 to 1.37) and good agreement between the experimental and theoretical number-average molecular weights (M_n,exp and M_n,theo respectively). Temporal control was obtained using light on-off studies, with high conversions only observed in the light-on periods, and initial polymerization rates were found to be linearly dependent on light intensity. Multiple vinyl ether monomers were polymerized with good M_n,exp and M_n,theo agreement and low Ð values, and chain-end fidelity was demonstrated via the successful formation of a block copolymer of ethyl vinyl ether and IBVE with narrow dispersity. The putative mechanism is as follows: PET from the CTA to the photoexcited 93.2 generates a dithiocarbamate radical and the polymerization-initiating oxocarbenium ion (Scheme 94A). During the light-off phase, the photoredox cycle closes with electron transfer from reduced photocatalyst to dithiocarbamate radical, which forms the anion necessary to cap polymer chain growth. Further mechanistic insights into this system revealed the importance of photocatalyst and CTA to successful photocontrolled living-type cationic polymerization, as respective photoinitiation and uncontrolled polymerization are observed with either the substitution or exclusion of CTA 93.1 and pyrylium 93.2.⁹⁷⁶

Scheme 93.

A comparison of electrochemical and photoredox methods for cationic polymerization.

Scheme 94.

A comparison of putative mechanisms for (A) photoredox and (B) electrochemical cationic polymerizations.

The electrochemically-controlled polymerization of vinyl ethers was accomplished by Lin, Fors, and coworkers, in which electrooxidation mediates the activation of dithiocarbamate CTA responsible for initiating vinyl ether polymerization.⁹⁷⁷ Under constant potential conditions (divided cell; E_a = 325 mV vs. Fc⁺/Fc), the cationic polymerization of IBVE was observed, but bimodal molecular weight distributions and broad Ð values persist. This uncontrolled polymerization was attributed to unproductive polymer plating at the electrodes, thus a redox mediator TEMPO was used to control homogenous CTA electrooxidation. Using these conditions, a polymer with low Ð and matching M_n,exp and M_n,theo values was obtained; this latter observation indicates a controlled cationic polymerization is operative. Furthermore, polymers with lower Ð values and higher conversions were obtained when run under galvanostatic conditions (1 mA) relative to the potential of the TEMPO redox couple. Temporal control over polymer growth was obtained by using an alternating sequence of an oxidizing current (1 mA) followed by a reducing potential (E_c = −875 mV vs Fc/Fc⁺); high chain growth was only observed during the oxidizing current phase, with minimal to no background growth observed when the reducing potential was applied. Various vinyl ether and styrenyl monomers were polymerized with good M_n,exp and M_n,theo agreement and low Ð values, and two distinct vinyl ether monomers were used to form a diblock copolymer with narrow dispersity. The putative mechanism is as follows: electrochemical oxidation of TEMPO leads to an oxoammonium that traps the CTA and forms a polymerization-initiating oxocarbenium ion, a dithiocarbamate radical, and TEMPO after fragmentation (Scheme 94B). Applying a reducing potential then reduces the dithiocarbamate radical, which in turn caps the propagating polymer chain. A similar strategy was independently reported by Yan and co-workers, where instead of TEMPO the 2e cycling between 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and its dianion (DDQ²⁻) was used to mediate the electrochemically-controlled, living-type, cationic polymerization of vinyl ethers and styrenes.⁹⁷⁸ Cathodic oxidation of DDQ²⁻ to DDQ under a constant potential (E_a = +1.20 V) initiates SET from the CTA-capped polymer and subsequent cationic RAFT polymerization. The resultant semiquinone DDQ radical anion can also participate in SET with the CTA-capped polymer to initiate the cationic polymerization process. High monomer conversions (> 90%) to polymers with low dispersities (Ð > 1.25) and good M_n,exp and M_n,theo agreement were observed, and the synthesis of a vinyl ether–styrene co-block polymer was demonstrated.

4.17.4. Activating Olefin Metathesis

Olefin metathesis (OM) is a fundamental organic transformation with broad application across scientific disciplines. Advancements in catalyst design and rigorous mechanistic studies have resulted in the development of efficient catalysts — Mo and W imido alkylidenes⁹⁷⁹ and Ru-NHC complexes⁹⁸⁰ — for a broad range of substrates. However, because alkenes and OM-catalysts are redox-active species, substrate SET via photoredox- or electrochemically-induced oxidation can initiate OM (Scheme 95).

Scheme 95.

A comparison of electrochemical and photoredox methods for substrate-activated olefin metathesis.

4.17.4.1. Substrate Activation

The electrochemical oxidation of electron-rich enol ether species and application towards intermolecular OM was shown by Chiba and coworkers, in which 4-methoxybut-3-enylbenzene (95.1) was anodically oxidized via potentiostatic electrolysis (1.0 F•mol⁻¹) and coupled to 1-hexene (95.2) to yield 3-butenylbenzene (95.3) in 78% yield.⁹⁸¹ Alkyl enol ethers were also tolerated as 1-methoxy-tridec-1-ene (95.4) was converted to tridec-1-ene (95.5) easily (76% yield). The mechanism of this transformation proceeds by the oxidation of the enol ether, followed by intermolecular C–C bond formation with a partner alkene to generate the less sterically-hindered four-membered radical cation ring, which fragments to yield the metathesis product and a new enol ether cation radical — this intermediate can initiate another metathesis event by intermolecular ET from the parent enol ether (Scheme 95A). This concept was applied to OM-polymerization by Boydston and coworkers, in which photoredox-catalyzed oxidation of various enol ethers were used to initiate the ring-opening metathesis polymerization (ROMP) of norbornene.⁹⁸² Polymerizations in DCM initiated by methyl vinyl ether oxidation demonstrated dispersity (Ð) values between 1.3 and 1.7 while also showing a consistent correlation between the M_n,exp and M_n,theo values respectively, with the former being higher than expected for observed monomer/initiator ratios and % conversions. A gradual increase in M_n was observed with increasing monomer conversion, which is suggestive of a chain growth ROMP mechanism, however the lack of precise linearity suggests that this process is not a controlled living ROMP that is characteristic of fast-initiating Ru-based metathesis catalysts (Scheme 95B). This strategy was also applied to the ROMP of endo-dicyclopentadiene (DCPD) to form linear polydicyclopentadiene (polyPCPD).⁹⁸³ This transformation is unattainable with metal-based catalysts due to their propensity to activate the cyclopentane towards polymer cross-linking. While monomer conversion was low (endo-DCPD: 20%, M_n = 5.1 kDa; exo-DCPD: 20%, M_n = 10.8 kDa), the polymer was obtained with low dispersity (Ð = 1.5 and 1.4 respectively). and high purity. Mechanism studies involving endo- and exo-DCPD and their dihydro-analogs suggest that the low conversion observed for DCPD arises from unproductive quenching pathways of the alkene rather than steric impedance.

4.17.4.2. Catalyst Activation

The electrochemical activation of molybdenum and tungsten chlorides towards OM was explored by Petit and coworkers, in which they demonstrated that the reduction of WCl₆ in the presence of DCM generates the requisite metallocarbene initiator.^984,985 The electrolysis is performed in an undivided cell (Pt anode; Al cathode) under a constant potential (E_c = −0.9 V vs. SCE), with the generation of reduced WCl₆⁻ crucial for the formation of Cl₄W=CH₂ (96.1); supporting electrolyte was deleterious towards reactivity. Cross metathesis involving equimolar concentration of 1- and 2- pentene proceeded with 93% selectivity and a 70.5 h⁻¹ turnover rate for the alkene monomers, providing propene and 3-heptene in highest yield (15.7% for both) for a distribution of OM products. The catalyst was also sufficiently stable to undergo two additional reloadings of the olefin, albeit with lower 2-pentene conversion. MoCl₅ catalysts were also studied but demonstrated lower turnover rates and selectivity. More recently, Bielawski and co-workers report a method for potentiostatic control over Ru-based olefin metathesis with a modified Hoveyda–Grubbs catalyst containing a redox-active quinone built into NHC ligand (96.2).⁹⁸⁶ Electrochemical reduction of the quinone to its radical anion deactivates the catalyst towards olefin metathesis by stabilizing the ruthenacyclobutane resting state of the catalytic cycle and thus suppressing retro-[2+2] cycloaddition step. This strategy was applied to the ring closing metathesis (96.3) and ROMP (96.4), with approximately a seven-fold decrease in relative reaction rates upon single electron reduction

A more general method for catalyst oxidation-initiated OM was demonstrated using photoredox catalysis, wherein bis-NHC-Ru complex (97.1) and 2,4,6-triphenylpyrylium tetrafluoroborate (11.9) were used to spatiotemporally control olefin metathesis (Scheme 97).⁹⁸⁷ Coordinatively saturated 97.1 is inactive, but oxidation by photoexcited 11.9 induces the dissociation of a carbene cation radical, thus forming a catalytically-active, 14-e Ru species (97.2). Ring closing and cross metathesis reactions proceeded smoothly (46–90% yields), and ROMP was demonstrated for cyclooctadiene, norbonadiene, dicyclopentadiene, and a range of norbornene derivatives. Light on-off studies with diethyl diallylmalonate show maximal reactivity only in the presence of light, whereas the dark phase only provided minimal yields (0–3%). Additionally, the macroscopic patterning of poly(dicyclopentadiene) and microscopic patterning of poly(norbornadiene) were accomplished with photomasks, thus demonstrating that photoredox catalysis enables high spatiotemporal control over Ru-controlled OM.

Scheme 97.

A photoredox method for catalyst-activated olefin metathesis. Macroscopic patterning picture reproduced from ref 987. Copyright 2019 American Chemical Society.

4.17.5. Lignin Degradation.

Lignin is a key component of lignocellulosic biomass (20–35% by weight; > 40% by energy content) and is the only biopolymer to have a high percentage of aromatic monomers within its structure.⁹⁸⁸ Thus, lignin depolymerization offers an opportunity to harness renewable sources of organic feedstocks. An efficient method for converting biomass to aromatic commodity chemicals involves depolymerization of the β-O-4 linkage in lignin (Scheme 98). The two major strategies in Scheme 98 show that controlling site-selectivity of alcohol oxidation within the β-O-4 linkage to the corresponding ketone or carboxylic acid is key as it enables access to differing monomeric fragmentation outcomes.

Scheme 98.

General oxidative strategies for lignin depolymerization.

Photochemical approaches towards this goal focus on exploiting the β-O-4 cleavage of oxidized lignin and its corresponding model systems (Scheme 99). This transformation proceeds first by oxidation of 1-phenylethanol groups in its backbone to the 1-phenylethanone moiety through stoichiometric aminoxyl oxidants⁹⁸⁹, catalytic palladium^990,991,992, or electrochemistry.⁹⁹³ This carbonyl is crucial for reactivity as proton-assisted single electron reduction forms an α-hydroxyl radical intermediate which readily fragments to the corresponding ketone and phenol after H-atom transfer. Yields for β-O-4 cleavage within lignin model systems are typically good (most > 65%) and its application to native lignin yields approximately 43 wt% of oligomeric units and up to 55% of low molecular weight species.⁹⁹³ There are exceptions to this approach, which include inducing an O-4’ cleavage in lignin model systems through an arene cation radical intermediate⁹⁹⁴ or a PCET strategy to directly cleave β-O-4 linkages in native lignin without necessitating substrate oxidation.⁹⁹⁵

Scheme 99.

Representative photoredox strategies for oxidative lignin depolymerization.

An electrochemical strategy towards lignin depolymerization was developed by Stahl and co-workers using bulk electrolysis by first oxidizing the 1° alcohols of lignin model systems to either the aldehyde or the carboxylic acid, which can undergo a retro-aldol C–C bond cleavage of the β-O-4 linkage (Scheme 100). ⁹⁹⁶ This transformation was carried out using TEMPO and/or 4-acetamido-TEMPO (100.1) as the catalytic oxidant and a constant potential (0.80 V) undivided cell in basic solution (pH 10 to 12.5). In lignin model systems without β-O-4 cleavage, high yields were observed for the oxidation of 1° and 2° alcohols to the carboxylic acid and ketone respectively. Running the electrolysis at lower pH (9.2) results in full oxidation of 1° alcohol with minimal β-O-4 cleavage. However, the basic conditions used for electrolysis were not translatable towards lignin depolymerization as only low amounts of lignin monomers were obtained (≤ 8 wt%) relative to the mass of initial lignin, with monomer oligomerization and oxidative degradation products observed. Thus, Stahl and co-workers developed a two-step basic electrochemical oxidation/acid-promoted depolymerization sequence, where higher amounts of lignin monomers were obtained (29 wt% with H₂O/formic acid) from the depolymerization of oxidized lignin. Syringyl (100.4–100.6) and guaiacyl-based (100.7–100.9) species were comprised the majority of the monomers, with the resultant aldehydes indicative of β-O-4 fragmentation whereas the observation of diketone and carboxylic acid monomers suggests alternative cleavage mechanisms. The cleavage of C(sp²)–C(sp³) σ-bonds in lignin has also recently been accomplished via a coupling a dye-sensitized photoelectrochemical cell system with a hydrogen atom transfer (HAT) mediator, namely 4-ACT.⁹⁹⁷

Scheme 100.

Representative photoredox strategies for oxidative lignin depolymerization.

4.18. Deprotection via Redox Chemistries

Not only can electrochemistry facilitate key bond forming steps towards building complex molecules but it can also be useful for protecting group manipulations, such as removal of protecting groups (e.g. Ts, PMB, Bz on oxygen or nitrogen),^998,999 as well as their installation,^1000,1001 as well as cleavage of C–C bonds.¹⁰⁰² Electrochemical removal of numerous other protecting groups such as benzyl groups, benzyloxycarbonyl groups, dithioketals,¹⁰⁰³ and ester hydrolysis, are known.^998,999 Oxidative dealkylation of amines has been reported both by electrochemical¹⁰⁰⁴ and photochemical^1005,1006 methods, as well as a related reductive dealkylation of amides,¹⁰⁰⁷ and sulfonamides.¹⁰⁰⁸

4.18.1. Removal of PMB Groups.

Chemical removal of PMB groups proceed primarily through harsh oxidative strategies (e.g. DDQ is used as a stoichiometric oxidant) and redox-mediated strategies improve on this process by enabling the use of milder oxidants (Schemes 101 and 102). Weinreb reported a preparative scale direct electrochemical oxidative method for PMB group deprotection (Scheme 101, method A1) using divided cell.¹⁰⁰⁹ Steckhan reported the use of tris(4-bromophenyl)amine as a redox mediator for the oxidative removal of PMB groups for two substrates (Scheme 101, method A2) using a divided cell.¹⁰¹⁰ Zheng and Little reported a novel triarylimidazole as a redox mediator for the electrochemical oxidative PMB group removal but focused on obtaining the yield of the aldehyde byproduct and not on that of the alcohol.¹⁰¹¹ Brown has reported an electrochemical deprotection in flow (Scheme 101, method A3) using an undivided cell.¹⁰¹² Stephenson reported an Ir-photoredox catalyzed deprotection of PMB groups using BrCCl₃ as the terminal oxidant (Scheme 101, method B1).¹⁰¹³ Cheng reported the use of eosin Y as a photoredox catalyst for the oxidative cleavage of PMB ethers to reveal alcohols using a mixture of H₂O₂ and NaHSO₄ as the terminal oxidant (Scheme 101, method B2).⁹³ The same transformation was reported by Woo using an acridinium photocatalyst and (NH₄)₂S₂O₈ and air the terminal oxidants (Scheme 101, method B3).¹⁰¹⁴ Most of these methods provide comparable yields and afford high selectivity for deprotection of PMB ethers in the presence of other protecting groups (alcohols protected with THP and TBS groups, or amines protected with a Piv, Boc, or Ts group). The electrochemical anodic oxidation methods for PMB removal rely on a net 2 electron oxidation,^1011,1015 whereas the photoredox methods leverage 1e oxidation followed by a subsequent HAT event to arrive at the same benzylic cation prone to hydrolysis. The application of these anodic oxidation for the removal of para-methoxyphenyl (PMP) groups from the anomeric alcohol of mono-, di- and tri-saccharides has been reported by d'Alarcao.¹⁰¹⁶ A closely related method for the deprotection of 4-methoxythioethers is also known using electrochemistry.¹⁰¹⁷ Kappe reported a photochemical generation of 4-methoxybenzyl bromide for telescoped PMB group installation on amines, the method relies on halogenation of toluene using BrCCl₃, 365 nm irradiation, and benzophenone as an HAT catalyst.¹⁰¹⁸

Scheme 101.

Oxidative deprotection of PMB groups.

Scheme 102.

Proposed mechanisms related to oxidative deprotection of PMB groups.

4.18.2. Desulfonylation of Tosyl Protected Amines.

Reductive cleavage of a tosyl (Ts) protecting group on aliphatic amines, aromatic amines, and alcohols is known, typically in aprotic solvents such as DMF or MeCN and the presence of an alkylammonium electrolyte. The ease of reductive cleavage for S–O and S–N bond in tosyl-protected species is as follows: Ts–O–Ar > Ts–O–Alkyl, Ts–NH–Ar > Ts–NH–Alkyl > Ts–NH–CH(Alkyl)–CO₂H (in descending order).¹⁰¹⁹ Electrochemical methods of desulfonylation of tosylprotected amines has been known for decades. Horner and Neuman reported electrochemical conditions in 1965 relying on a Hg pool cathode.^1020,1021 Constant current electrolysis using a divided cell and a lead cathode was reported by Iwasaki and Matsumoto in 1973.¹⁰²² While the literature has numerous reports of related conditions utilizing a Hg pool cathode^{1023,1024,1025,1026,1027,1028,1029,1030,1031,1032}, select examples using RVC exist which are more practical and greener alternatives (Scheme 103, methods A1 & A2),¹⁰³³ and method A3).¹⁰³⁴ Silvestri reported constant potential electrolysis using compact graphite cathode in a divided cell (Nafion^™ 324 cation exchange membrane) in batch mode, as well as a related continuous batch recirculation mode using a filter press two-compartment microflow cell to effect detosylation of tetratosylcyclen to cyclen reaching as high as 80% yield with 55% faradaic efficiency.¹⁰³⁵ The use of redox mediators such as pyrene and naphthalene¹⁰³⁶ can provide conditions that operate at less reducing potentials. More recently the use of Pt as a cathode and naphthalene as a redox mediator (catalytically generating naphthalide in situ) was demonstrated to provide milder conditions (method A4).¹⁰³⁷ Naphthalenesulfonamides are a milder alternative to tosylsulfonamide protecting groups as they can be deprotected with lower reducing potentials (typically by about 200–400 mV).¹⁰³⁸ Monteiro realized that p-toluenesulfonyl groups attached to the nitrogen of tryptophan- and histidine side-chain residues of amino acids have reduction potentials that are less negative than those linked to the nitrogen of an aliphatic amine. This enables the development of potential-selective deprotection of p-toluenesulfonyl protected tryptophan- and histidine side-chain residues in the presence of the p-toluenesulfonyl protected α-amino group in good yields using an divided cell with Et₃N•HCl as the proton source and Et₄NCl electrolyte in acetonitrile.¹⁰³⁹ Liu and Xiao reported a photochemical methods for Ts deprotection of tosylamines relying on Hantzsch ester as the terminal reductant (Scheme 103, method B1).¹⁰⁴⁰ Song and Wang reported an Ir-photocatalyzed tosyl deprotection of N-heterocycles that has selectivity for the N-aryl over N-alkyl Ts-group as shown by monodeprotection of bis-N-Ts-tryptoline (Scheme 103, conditions B2).¹⁰⁴¹ As already described in the sequential 2e reduction section, Nicewicz reported the photocatalyzed method based on oxidizing an amine using an acridinium photocatalyst to generate a persistent radical anion derived from the acridinium catalyst, which upon photoexcitation produces a highly potent reductant capable of reductively cleaving the Ts–N bond of Ts-protected amines (Scheme 103, method B3).¹⁰⁴² The use of hydride reagents as the terminal reductant was also demonstrated in the context of photoredox catalysis for the Ts deprotection.^{1043,1044,1045}

Scheme 103.

Representative methods for amine desulfonylation via electrochemical and photoredox pathways.

4.19. Formylation of Aryl Halides

The formylation of aryl halides to synthesize benzaldehyde derivatives can be done via electrolysis in the present of DMF as a formylating agent (Scheme 104, methods A1–A4).¹⁰⁴⁶ The stainless steel cathode is pretreated by freshly electrodepositing Zn, Cd, or even tin which facilitate the subsequent electrolytic formylation reaction carried out on that cathode, while a sacrificial anode, such as Mg, balances the redox chemistry. A Pd catalyzed electrochemical formylation of aryl halides was reported by Carelli.¹⁰⁴⁷ Mariano and Wang reported a nickel and organic dye co-catalyzed formylation of aryl halides, aryl triflates and, vinyl triflates using diethoxyacetic acid as a formyl equivalent via a decarobylxation process (Scheme 104, method B1).¹⁰⁴⁸ Doyle reported a related approach using 1,3-dioxolane as a formyl equivalent leveraging HAT and Ni-catalysis (Scheme 104, method B2).¹⁰⁴⁹ Fu reported a photoredox decarboxylation of glyoxylic acid in the presence of aryl halides and a Pd catalyst to achieve their formylation (Scheme 104, method B3).¹⁰⁵⁰ Analogous to the formylation method by Mariano and Wang described above, the same groups reported a hydroformylation of styrenes.^755a

Scheme 104.

Formylation of aryl halides to access benzaldehydes and their derivatives.

4.20. Olefin Aziridination and Cyclopropanation

4.20.1. Olefin Aziridination

In 2001 the Yudin group reported an electrochemical olefin aziridination using N-aminophthalimide under constant potential electrolysis in a divided cell (Scheme 105, method A1).^1051,1052 It was proposed that the anodic oxidation of N-aminophthalimide generates the corresponding nitrene intermediate based on the observation that the aziridination of cis-2-hexen-1-ol is stereospecific, yielding exclusive formation of the cis-aziridine (no yield was provided). Interestingly, the choice of the anode material was critical – no aziridine product was observed when the optimal Pt anode was replaced by a graphite anode – perhaps hinting at analogies to electrode material impacting 1e vs 2e oxidation process as observed in electrochemical decarboxylations (i.e. Kolbe vs Hofer-Moest electrolysis). Zeng and Little reported an olefin aziridination using N-aminophthalimide and tetrabutylammonium iodide as a redox mediator (Scheme 105, method A2), although control experiments support ambient laboratory light contributing to the success of the reaction.¹⁰⁵³ The lack of stereoretention in the aziridination, namely that both cis-stilbene and trans-stilbene afford the cis-aziridine product, suggests the reaction proceeds via a stepwise process, and rules out the involvement of a singlet nitrene. Reactions in the presence of TEMPO as a radical inhibitor, or the use of I₂ in the absence of light and electrolysis afforded low yield (5–11%) of the desired azridine product, suggesting a radical pathway as well as ambient laboratory light providing a beneficial role for the reaction outcome. Cheng reported the aziridination of olefins using a partially fluorinated sulfonamide reagent under constant potential electrolysis (Scheme 105, method A3)¹⁰⁵⁴ and Xu reported a photoredox approach to olefin aziridination using an Ir-photocatalyst and an N-protected-1-aminopyridinium reagent for a redox neutral approach (Scheme 105, method B1).¹⁰⁵⁵ Reduction of the N-protected-1-aminopyridinium reagent was proposed to release the N-protected amino radical able to add to alkenes and the subsequent intermediate was oxidized by the photocatalyst to generate a carbocation, enabling C–N bond formation to generate the aziridine. The associated mechanisms in the methods described above are shown in Scheme 106.

Scheme 105.

Olefin aziridination.

Scheme 106.

Proposed mechanisms associated with olefin aziridinations shown in Scheme 105.

4.20.2. Olefin Cyclopropanation

The cyclopropanation of alkenes via electrochemistry¹⁰⁵⁶ or photoredox catalysis¹⁰⁵⁷ have similarities in retrosynthetic disconnection (i.e. one and two carbon synthons for the cyclopropane), but the methods have stark differences. The two general electrochemical strategies for cyclopropane synthesis are (1) direct substrate electrolysis (Scheme 107) and (2) indirect electrolysis of redox-active species (Scheme 108). The following methods for substrate activation primarily involve cathodic reduction as oxidative methods are still underdeveloped but a few exceptions exist.^1058,1059 A classic electrochemical method of synthesizing cyclopropanes is cathodic reduction of either 1,3-dibromoalkanes or 1,3-di(methanesulfonate)alkanes to yield 1,3-difunctionalized alkanes. Electrolysis has proven useful for the reduction of alkyl halides and the formation of organometallic reagents in situ.^{1060,1061,1062,1063} While the use of Zn dust to reduce 1,3-dibromopropane to afford cyclopropane in 56% yield was reported in 1882,¹⁰⁶⁴ its electrochemical analog was reported 85 years later by Rifi in 1967.¹⁰⁶⁵ The method involves potentiostatic (E_c = −2.0 ± 0.1 V vs SCE), two-electron reduction of 3-bromopropyltriethylammonium bromide, which forms a highly reactive carbanion that undergoes intramolecular substitution at the alkylammonium to eject triethylamine and form cyclopropane (yield not reported). Similar conditions were used to reduce 1,3-dibromo-1,3-dimethylcyclobutane and 1,3-dibromo-2,2-di(bromomethyl)propane to the corresponding 1,3-dimethylbicyclo[1.1.0]butane and spiro[2.2]pentane in 55% and 50% yield respectively. Reduction of 1,3-dibromopropane under similar conditions furnishes cyclopropane as a product, but attempts at quantifying the yield proved difficult. Further elaboration of this concept was reported by Shono in which galvanostatic reduction of 1,3-dimethanesulfonates using a divided cell provides a range of cyclobutanes in moderate yields (50–75%).¹⁰⁶⁶ The key to obtaining these high yields was the slow addition of substrate to the cathodic chamber, which minimizes undesirable substrate decomposition (presumably to favor intramolecular cyclization over bimolecular oligomerization). Another strategy for electrolytic substrate activation is to generate stabilized carbenes (e.g. dihalocarbene);¹⁰⁶⁷ this was accomplished on a preparative scale by Fritz and Kornrumpf,^{1068,1069,1070} as well as Baizer and Chruma.¹⁰⁷¹ A route to gem-dichlorocyclopropanes following a similar strategy have been reported by Petrosyan and coworkers using CCl₄ and alkenes in chloroform containing tetraalkylammonium electrolyte in a divided cell using a lead cathode.¹⁰⁷² A synthetically useful electrochemical analog to the Simmons-Smith reaction was first shown by Périchon and coworkers, who report the synthesis of cyclopropanes via dihalomethane reduction in the presence of alkenes within an undivided cell.¹⁰⁷³ The results suggest in situ formation of a zinc carbenoid (CH₂ZnI₂), an intermediate observed in the Simmons-Smith reaction. This leads to two reported conditions, with the difference being whether exogenous ZnBr₂ was absent or present prior to electrolysis, respectively, to accelerate the formation of reactive zinc carbenoid.

Scheme 107.

Electrochemical methods for cyclopropane synthesis via substrate reduction.

Scheme 108.

Mediator-centered electrochemical methods for cyclopropane synthesis

Electroreductive formation of stabilized carbanions is another effective strategy for olefin cyclopropanation.¹⁰⁷⁴ Le Menn and Sarrazin show that galvanostatic electrolysis of dibromomalonate and dichloromalonate in the presence of Michael acceptors enables the synthesis of substituted cyclopropanes in good yield (≥ 70%); solvent choice is crucial as unproductive protonation of halocarbanions can be a problem.¹⁰⁷⁵ Expansion of this strategy to phosphonate-stabilized carbanions was carried out by Feasson and coworkers, where galvanostatic reduction of tetraethyl dichloromethylbis(phosphonate) generates a stabilized carbanion that adds to (meth)acrylate, (meth)acrylonitrile, and methyl vinyl ketone in moderate to good yields.¹⁰⁷⁶ This method is extended to the galvanostatic reduction of diethyl α,α-dichlorobenzylphosphonate in the presence of Michael acceptors yields α-aryl, β-substituted cyclopropylphosphonates, although low diastereoselectivity is observed.¹⁰⁷⁷ A different activation strategy is the formation of carbonyl-stabilized carbanions, which Petrosyan and coworkers demonstrate in an electrochemical Perkin-type reaction between 1,3-dicarbonyl compounds and 1,2-dihaloalkanes to form substituted cyclopropanes.¹⁰⁷⁸ While yields were moderate to low under direct substrate electrolysis, using an electrogenerated azobenzene base significantly improves reaction yields (e.g. from 12% to 80%).

This success of redox-active reagents is translated to other cyclopropane syntheses, and is notable in the galvanostatic cyclopropanation of Michael acceptors with stabilized 1,1-dichloroalkanes reported by Paugam and coworkers, in which an electrogenerated low-valent copper species catalyzes the reaction (Scheme 108A).^{1079,1080,1081} The electroreduction of CuBr (i₁ = 0.3 A) forms redox-active Cu⁰ species (108.9) in situ, which undergoes oxidative addition into the substrate C–Cl bond and subsequent reduction (i₂ = 0.1 A) to form a discrete copper carbenoid species (108.10) analogous to Cu⁰ cyclopropanation methods first reported by Saegusa.^{1082,1083,1084,1085} A nickel-catalyzed variant was also disclosed by Paugam and coworkers during the development of their copper-catalyzed method.¹⁰⁸⁶ Additionally, a tandem intramolecular radical [2+1] cycloaddition facilitated by electroreductive formation of Ni^I was demonstrated by Ozaki and coworkers, providing bicyclic [3.1.0] derivatives in moderate yields.¹⁰⁸⁷

Another distinguishing factor of cyclopropanation strategies for redox mediator-centered electrolysis is the reliance on the electrochemical oxidation of redox mediators, in contrast to the methods involving direct substrate reduction. These transformations follow McCoy-type cyclopropanation, as in situ halogenation of stabilized carbanions enables base-catalyzed condensation with Michael acceptors (Scheme 108B). White demonstrated the first example of this via the electrooxidative cyclization of tetramethyl-propane-1,1,3,3-tetracarboxylate with sodium iodide as a mediator to form tetramethyl-cyclopropane-1,1,2,2-tetracarboxylate (108.4) in 40% yield.¹⁰⁸⁸ Cathodic reduction of the O–H proton of ethanol generates H₂ and ethoxide enabling deprotonation of acidic protons from the substrate to form stabilized carbanion 108.11. This anion traps iodine — generated via anodic oxidation of iodide — to furnish an alkyl iodide (108.12). A second deprotonation event of intermediate 108.12 forms a carbanion (108.13) that readily cyclizes to product 108.4 by a S_N2-type ring closure. The yields and scope of tetramethyl-propane-1,1,3,3-tetracarboxylates was improved on by Elinson and coworkers,¹⁰⁸⁹ and Okimoto and coworkers expand this transformation to the cyclization of 1,3-diaroylpropanes.¹⁰⁹⁰ This strategy can also be applied to the cyclotrimerization of dimethylmalonate¹⁰⁹¹ and ethylcyanoacetate¹⁰⁹² through a repeating stepwise deprotonation-halogenation-halogen elimination sequence culminating in cyclopropane synthesis. Applying halide redox mediators to the coupling of malonic acid derivatives and Michael acceptors eliminates the need for direct reduction of substrate as the transformation proceeds mechanistically similar to McCoy-type cyclopropanation. This strategy has been extensively covered by Elinson and coworkers.^{1093,1094,1095,1096,1097,1098,1099,1100,1101} Variations of this method have been applied to the spiro-coupling of barbituric acid derivatives with benzylidenemalononitriles and benzylidenecyanoacetates.¹¹⁰² Lastly, redox-mediated electrosynthesis of functionalized cyclopropanes via three-component coupling of aromatic aldehyde, malononitrile, and dimethylmalonate has been shown by Elinson and coworkers.¹¹⁰³ Knoevenagel condensation of aldehyde onto malononitrile forms an alkylidenemalononitrile that then participates in the McCoy-type cyclopropanation sequence with dimethylmalonate as outlined previously. This method is also compatible with barbituric acid derivatives as the coupling partner to form spirocyclopropylbarbiturates.¹¹⁰⁴

The first disclosure of a photoredox-catalyzed alkene cyclopropanation using 1,1-dihaloreagents was reported by Guo in 2015 using dibromomalonates (R1, Scheme 109) as the one-carbon synthon and activated styrenes as the reaction partner.¹¹⁰⁵ Double single electron reduction and single halogen extrusion of the dibromomalonate by photoactivated Ru(bpy)₃²⁺ purportedly yields a stabilized carbanion that undergoes Michael addition and subsequent bromide extrusion to reveal the cyclopropane ring. Interestingly, stereoconvergence is observed in this transformation, as only the trans-product 109.1 is observed when using either Z- and E- styrene isomers. A more general photoredox method for stereoconvergent cyclopropanation was reported by Suero in 2017 using diiodomethane (R2, Scheme 109).¹¹⁰⁶ A range of internal (1,2-disubstituted and 1,2,3-trisubstituted) alkenes are compatible, but terminal alkenes (e.g. 4-methoxystyrene or 1,1-diphenylethylene) provided low yields of cyclopropane or open-chain alkyl iodides. The scope was later extended to also include Michael acceptors (e.g. α,β-unsaturated aldehydes and ketones) but ester derivatives are not tolerated.¹¹⁰⁷ The postulated mechanism (Scheme 109A) for both methods proceeds via reductive quenching of the Ru^II photocatalyst to Ru^I, followed by reduction of diiodomethane (E_red = −1.44 V vs SCE) to turn over the photocatalyst and generate iodomethyl radical (109.13), which can add to the alkene. The resulting radical intermediate (109.14) is sufficiently long-lived to allow equilibration between rotamers, thus leading to ring closure to the trans-product and concomitant release of I^•. Expanding on the versatility of the di-iodomethyl reagents, Charette and coworkers report the use of 1,1-diiiodo-pinacol boronate (R3, Scheme 109) in the photoredox-catalyzed cyclopropanation of styrenes using 350 nm light and xanthone as the photocatalyst to afford borocyclopropanes.¹¹⁰⁸ The reaction performed well with unsubstituted styrenes or α-substituted styrenes, but fewer examples of α,β-disubstituted styrenes (e.g. β-methylstyrene) were reported. Overall, this transformation is useful as the boryl group provides a functionalization handle for further diversification of the cyclopropane via cross-coupling or oxidation strategies.

Scheme 109.

Photoredox methods for olefin cyclopropanation via 1,1-difunctionalized carbon synthons.

Complementary one-carbon synthons can be obtained by replacing one halogen in prototypical 1,1 dihalo reagents with a redox-active precursor, as shown by Molander, Gutierrez and coworkers, where a photoredox method for olefin cyclopropanation proceeds via redox-neutral radical polar crossover, (Scheme 109B).⁷⁶¹ The method relies on benchtop stable triethylammonium bis(catecholato)iodomethylsilicate reagent (R4, Scheme 109), which is synthesized in two steps from chloromethyltrimethoxysilane. Using organophotocatalyst 4CzIPN (11.10), a wide range of substituted alkenes are tolerated with impressive stereoconvergence in cases when a starting mixture of E/Z isomers are used. Later developments of chloromethylsilicates¹¹⁰⁹ (R5, Scheme 109) and bromomethylsilicates¹¹¹⁰ (R6, Scheme 109) variants enabling greater generality in substrate scope. The mechanism here diverges from Suero’s method, as the reductive quenching of photoexcited Ru(bpy)₃²⁺ is used to generate halomethyl radical (109.15) from the silicate, which adds to the alkene to form a stabilized radical (109.16). SET from the resultant Ru^I species to the alkyl radical leads to a radical-polar crossover event to turn over the photocatalyst and generate an alkyl carbanion (109.17), which displaces the iodide via S_N2-type ring closure.

Diazo compounds are a widely-used one-carbon synthon in transition-metal catalyzed cyclopropanations,^1111,1112 and early reports by Pérez-Prieto and Stiriba have shown that benzophenones can act as triplet sensitizers to generate triplet carbenes from diazo precursors.^1113,1114 A different activation mechanism was accomplished by Ferreira and Sarabia, in which a chromium photocatalyst is used to generate styrenyl radical cations (109.18) via single electron oxidation to enable the cyclopropanation of styrenes with ethyl diazoacetate (R7, Scheme 109), α-alkyl diazo esters (R8, Scheme 109) and diazo arylketones (R9, Scheme 109).¹¹¹⁵ An alternate mechanism for the involvement of ethyl diazoacetate in photoredox-catalyzed cyclopropanation was reported by Li in 2018 using catalytic I₂ as an activating agent to form ethyl 1,1-diiodoacetate (R10, Scheme 109) in situ that participates in the photoredox reaction.¹¹¹⁶

A mechanistically-distinct radical addition-polar cyclization cascade (Scheme 110) was reported by Aggarwal, Noble and coworkers, where 4CzIPN-catalyzed decarboxylation of carboxylic acids generates a reactive alkyl radical (110.9) that combines with an alkene to form a stabilized carbon-centered radical intermediate (110.10).¹¹¹⁷ This reaction is distinct from Molander’s example in that the halide nucleofuge is installed in the alkene (as a homoallyl chloride) rather than in the one-carbon synthon. Despite requiring an alkenyl Bpin or ester substituent to stabilize formation of tertiary carbanion 110.11, the scope of the transformation is quite general, and the chloride nucleofuge can be substituted for a tosylate. Expansion of this strategy to incorporate other radical precursors and generalize the substrate scope was accomplished by Molander and Kelly,^1118,1119 as well as Li, Jin and Fang.¹¹²⁰ Lastly, visible light activation of aryldiazoacetates¹¹²¹ and 2,2-diiodoacetates¹¹²² enable the cyclopropanation of styrenes, but a discussion of their mechanisms is outside the scope of this review.

Scheme 110.

Photoredox methods for olefin cyclopropanation via the merger of radical precursors with alkenes containing a built-in electrophile.

4.21. Ring Expansions

4.21.1. Semi-pinacol Rearrangement for Ring Expansion from Vinyl Alcohols.

Simple ring expansion from vinyl alcohols has been realized via electrochemical^{1123,1124,1125} and photochemical¹¹²⁶ methods. Below we describe related method that achieve functionalization of the alkene as well as ring expansion, such as trifluoromethylation or sulfonylation, from allylic alcohols.

4.21.2. Functionalization-Ring Expansion of Allylic Alcohols via Semi-Pinacol Rearrangements

4.21.2.1. Trifluoromethylative Ring Expansion

Semi-pinacol ring expansion-trifluoromethylation has been realized using electrochemistry using allylic alcohols (Scheme 111, method A1¹¹²⁷ and method A3)¹¹²⁸ or their silylated derivatives (Scheme 111, method A2).¹¹²⁹ Two closely related photoredox catalytic methods have also been reported starting from the alcohols which are in situ converted to the silyl ether (Scheme 111, method B1)¹¹³⁰ or simply used as is (Scheme 111, method B2).¹¹³¹ The photoredox approaches use a redox neutral strategy to a reductively generate of the trifluoromethyl radical, followed by its addition to an alkene, subsequent oxidation of the transient radical to the corresponding cation (radical-polar crossover) and finally ring expansion via a 1,2-alkylshift to afford the desired product. This is in contrast to the electrochemical method where two sequential oxidative events are necessary, specifically anodic oxidation of Langlois’ reagent (CF₃SO₂Na) enables trifluoromethyl radical generation after SO₂ extrusion, with the rest of the mechanism being analogous to the photoredox cycle where a subsequent oxidation of the radical intermediate is required for the radical-polar crossover and 1,2-alkylshift to achieve the ring expansion.

Scheme 111.

Trifluoromethylative semi-pinacol ring expansion of allylic alcohols.

4.21.2.2. Sulfonylative Ring Expansions

Analogous to the ring expansion-trifluoromethylation presented in the previous section, other functional groups besides a trifluoromethyl group can be introduced via this approach, such as sulfones. Electrochemical sulfonylative semi-pinacol ring expansion via an oxidation approach can be accomplished using sodium p-toluene sulfonate under constant current electrolysis (Scheme 112, method A1).¹¹²⁷ Kim demonstrated the use of p-toluenesulfonyl hydrazide in a sulfonylation/semipinacol rearrangement sequences of alkenylcyclobutanols using electrolysis relying on NaI as both the electrolyte and redox mediator (Scheme 112, Method A2).¹¹³² A related semi-pinacol rearrangement method which installs a phenylselium instead of an arylsulfone group via electrolysis enables the cyclopentanone-selenium products to undergo a subsequent Dowd–Beckwith-type ring-expansion to access the corresponding one-carbon ring-expanded ketones.¹¹³³ In contrast to sequential anodic electrolysis approach of method A1, a photoredox neutral approach using photocatalysis was reported in which TsCl is reduced to generate the requisite sulfonyl radical (Scheme 112, method B1)¹¹³⁴ or three-component coupling leveraging oxidative approach (Scheme 112, method B2).¹¹³⁵

Scheme 112.

Sulfonylative semi-pinacol ring expansion of allylic alcohols.

Related arylative ring expansion processes have been reported using aryl diazoniums.¹¹³⁶ Related ring opening chemistries from cycloketone oxime derivatives are numerous using photoredox chemistries but underexplored using electrochemical means.¹¹³⁷ Electrochemical ring opening of epoxides using mixtures of chloroform and carbon tetrachloride to obtain chlorohydrins are known. Ring opening arylation of aziridines and epoxides using a Ni/photoredox cross-electrophile coupling strategy has been reported by Doyle.^1138,1139 Opening of aziridines using photoredox to install an azide, halides, ethers, alkyl or dihydropyridyl groups has also been reported.^{1140,1141,1142} The generation of radicals derived from epoxides and aziridines for their addition to alkenes and acrylates has been reported.¹¹⁴³

5. EMERGING TOPICS AND OPPORTUNITIES

5.1. Redox Neutral Electrochemistry

5.1.1. Microfluidic Electrochemistry for Redox-Neutral Reactions.

While redox neutral processes are common in photoredox chemistry, for the most part, they have been elusive in the electrochemical literature in the context of organic synthesis. This is in part due to the lifetime of radicals and the location at which they are generated. In photoredox catalysis, the photocatalyst can act both as an oxidant and a reductant (one role in the excited state and the other role in the ground state). Thus, oxidation and reduction can effectively occur in the same location in the reaction mixture. In contrast, electrochemical transformations (in the absence of a redox mediator) are localized, namely oxidation events at the anode and the reduction events at the cathode. Thus, a redox neutral transformation would require intermediates generated at one electrode to live long enough for migration to the other electrode for the opposite redox event to occur. Typical batch electrolysis setups have an interelectrode separation distance that is simply too large (mm to cm distances) to enable migration of electrochemically generated species from one electrode to another on the timescale compatible with the lifetimes of organic radicals used in synthesis. Equation 34 illustrates the problem, namely that the characteristic time, t, is governed by the inter-electrode distance (d), and the molecular diffusivity (D).^{124,267,1144,1145}

$$t=\frac{d^2}{2D}$$ (34)

The problem of short radical liftetimes relative to the long duration require to migrate between electrode pairs in traditional bulk electrolysis setups is further exasperated due to mixing inefficiencies in batch settings. In contrast the use of flow chemistry can both enable efficient mixing and also provide a small electrode spacing (e.g. 25 μm) that together redox neutral electrochemical processes can be realized. Buchwald and Jensen¹¹⁴⁶ recently demonstrated the use of microfluidic electrochemistry to achieve five different redox neutral transformations previously demonstrated using photoredox (Schemes 113 and 114). A 25 μm interelectrode distance provides a short enough spacing to enable diffusion of persistent radicals derived from electron deficient cyanobenzenes from the cathode to the anode. The diffusion time is on the subsecond timescale, which is substantially shorter than the lifetime of the radical. Scheme 113 illustrates electrochemical redox neutral decarboxylative arylation (Scheme 113, top), α-amino-arylation (Scheme 113, middle), and deborylative arylation (Scheme 113, bottom), all of which proceed via convergent paired electrolysis. The reactions are complimentary to their redox neutral photoredox counterparts.^{457,1147,1148,1149,1150} The use of HAT catalysts or redox mediators can also be incorporated into redox neutral transformations. Scheme 114 (top) illustrates an allylic arylation using a thiol as an HAT catalyst, while the bottom of Scheme 114 illustrates a Minisci-type reaction using a redox mediator to facilitate the oxidation of the key pyridinium intermediate. Photoredox counterparts to these reactions operate similarly. Specifically, the allylic arylation utilizes the same thiol HAT catalyst,¹¹⁵¹ while the Minisci-type reaction uses a Brønsted acid co-catalyst.^491,495,1152 Redox neutral convergent electrolysis C–O couplings catalyzed by Ni/dtbbpy were also accomplished using this microfluidic electrochemical method, contrasting to MacMillan’s photochemical report which was proposed to operate via energy transfer.¹¹⁵³

Scheme 113.

Redox neutral transformations: (top) decarboxylative arylation, (middle) α-amino-arylation, (bottom) deborylative arylation. (Note: SET events are depicted by arrows touching an electrode).

Scheme 114.

Redox neutral transformations: (top) allylic arylation using a thiol HAT catalyst, (bottom) Minisci reaction.

5.1.2. Alternating Polarity Electrolysis.

The use of alternating current electrolysis is not a new concept^{1154,1155,1156} however, it is an underutilized method in the context of organic synthesis for redox neutral transformations (Figure 16).^1157,1158 Alternating polarity electrolysis relies on alternating the polarity of the electrode (e.g. from an oxidizing to a reducing potential) to accomplish both an oxidation and a reduction event at the same electrode. Under the term of alternating polarity electrolysis, we can sub-classify this concept into alternating current and alternating potential electrolysis (ACE or APE, respectively). A quiet time where no potential (no current) is applied to the electrode can be used in between switching the polarity of the electrode. Figure 16A illustrates the alternating current profile of a single electrode as a function of time for a “square wave” ACE (a sinusoidal function for ACE has also been used for synthesis). APE is analogous to ACE, with the only difference being that the reaction is operated at a constant potential (instead of constant current) when a potential is applied across the electrodes during the non-quiet periods (Figure 16B). In ACE, the amplitude of the wave is defined by the peak current (i_p) and is alternated between +i_p and −i_p. Analogously, APE relies on alternating between peak voltages +U_p and −U_p. The duration of the applied current (or applied potential) is characterized by time t₁ prior to switching polarity. In some examples, it may be beneficial to introduce a quiet period of duration t₂, in which no potential (no current) is applied to the electrode in between the periods of applying opposing current (or opposing potential) (Figures 15C and 15D). This quiet period is introduced to enable the newly generated radical intermediate enough time to react with the substrate (as well as enable diffusion of key reactants, intermediates, products, or electrolyte ions away from the electrode). If no quiet period is present, the reversal of the electrode polarity may result in imparting the reverse redox event on the intermediate that was generated in the prior pulse of opposite polarity (e.g. a radical generated from a reduction event of a starting material may be reversibly re-oxidized to the initial starting material). If the quiet period is too long, the transiently generated radical intermediate may not live long enough to undergo the opposing redox process to form product. Thus, careful attention must be devoted to optimizing both t₁ and the duration of the quiet period (t₂) for the successful outcome of redox neutral transformations via ACE or APE. Diffusion models¹¹⁵⁹ and electron transfer¹¹⁶⁰ models for describing alternating current electrolysis have been developed.

Figure 16.

Alternating current electrolysis (A) and alternating potential electrolysis (B) without a quiet time or with quiet times (C and D respectively).

The trifluoromethylation of heterocycles (pyrroles, furans and thiophenes) and electron rich benzene derivatives has been realized using APE through a sequential paired electrolysis mechanism (Scheme 115).¹⁹⁸ The reduction of CF₃SOCl generates the CF₃ radical along with SO₂ and Cl⁻. Addition of the CF₃ radical to the (hetero)arene provides a key intermediate that undergoes subsequent oxidation and loss of proton (net re-aromatization) to generate the desired trifluoromethylated (hetero)arene product. MacMillan reported the use the analogous redox neutral photocatalytic trifluoromethylation of (hetero)arenes using CF₃SOCl.^468o

Scheme 115.

Trifluoromethylation via alternating potential electrolysis (method A) compared to a redox neutral photocatalytic method (method B). Reaction mechanism associated with APE is illustrated on the bottom. (Note: SET events are depicted by arrows touching an electrode).

Pulsed potential electrolysis has also been recently used in the context of optimizing the electrohydrodimerization of acrylonitrile to synthesize adiponitrile, a precursor to Nylon 6,6.¹¹⁶¹ The conversion of acrylonitrile to adiponitrile, which has been used on metric ton scale, is a net reductive process, and is traditionally carried out under continuous electrolysis conditions. The pulsed potential was found beneficial towards suppressing undesired side reactions.

Other synthetic examples of using ACE includes the synthesis of mixed disulfides via sulfur-sulfur bond metathesis from symmetrical disulfide starting materials.¹¹⁶² Alternating current electrolysis can also be used in transition-metal catalysis as recently showcased with several examples of Ni-catalyzed cross-couplings,¹¹⁶³ including amination (C–N coupling), etherification (C–O coupling), and esterification of aromatic bromides. Selected examples using this alternating current electrolysis provided higher yields and selectivity compared to those with direct current electrolysis. The improvements were attributed to the alternating current facilitating turnover limiting steps (either oxidative addition or reductive elimination steps) while not having to rely on intermediates generated at one electrode, which may be short lived, having to migrate to the opposite electrode to achieve productive chemistry. Alternating current electrolysis has also been used for the synthesis of phenol from benzene with high selectivity and higher current efficiency than direct current (DC) electrolysis. These results were in part due to generating reactive oxygen-containing species (e.g. HO^•) both during the oxidation (via oxidation of water) and reduction (via reduction of O₂) segments of the AC electrolysis. Inversion of product selectivity¹¹⁶⁴ in benzylic C–H oxidation processes have also been demonstrated when comparing direct current vs alternating current electrolysis, such as in the oxidation of 4-methylanisole (Scheme 116).¹¹⁶⁵ Very recently Kawamata and Baran also demonstrated the application of alternating current electrolysis for the reduction of carbonyls such as those found in imides, aldehydes, thioesters, and α,β-unsaturated esters. Improved chemoselectivity between different carbonyls was demonstrated using alternating current electrolysis relative to direct current electrolysis.¹¹⁶⁶ The electrochemical synthesis of various metal-NHC complexes¹¹⁶⁷ based on Cu, Pd, Au, Ni, and Fe has also been realized^{1168,1169,1170,1171,1172}. Alternating polarity electrolysis has been used to minimize the reliance on mass transport of intermediates generated at opposite electrodes towards product formation of metal-NHC complexes, such as Cu^I-NHC from Cu electrodes and IMes•HCl in MeCN.¹¹⁷³ Optimization of the switching frequency could suppress the build-up of metal dendrites that cause short-circuiting.

Scheme 116.

Product selectivity effect dependent on using direct vs alternating current electrolysis.

5.1.3. Bipolar Electrodes

Related to alternating current electrolysis and alternating potential electrolysis used to conduct redox neutral transformations at a single electrode, the use of bipolar electrodes (BPE) can achieve redox neutral transformations.^{1174,1175,1176,1177} “A bipolar electrode is an electrically conductive material that promotes electrochemical reactions at its extremities (poles) even in the absence of a direct ohmic contact.” ¹¹⁷⁸ The use of bipolar electrodes can be viewed as a wireless technique in which a potential is applied across a set of driving (feeder) electrodes interfaced with the electrolyte solution that contains the bipolar electrode, The bipolar electrode facilitates oxidation and reduction at its opposite anodic and cathodic poles. A key point is that the poles of a bipolar electrode are oriented in the opposite polarity of the driving electrodes. This is denoted in Scheme 117 below in which the driving cathode induced the closest extremity of the BPE to become the anodic pole (performing oxidation of an analyte in solution denoted by the blue arrow). The red arrow denotes the reduction process occurring at the cathodic pole of the BPE facing towards the anode driving electrode in the right-hand side of Scheme 117. The potential drop over a BPE (ΔU_BPE) is given by equation 35, where ΔU_total is the potential drop between the driving electrode, l_BPE is the length of the BPE, and l_channel is the interelectrode spacing between the driving electrodes.³²⁰

$$\Delta U_{BPE}=\Delta U_{total}(\frac{l_{BPE}}{l_{channel}})$$ (35)

Scheme 117.

A comparison of the experimental set-ups for open bipolar electrolysis (A) and conventional electrolysis (B). An approximately linear gradient electric field is present in the bulk of the solution between bipolar electrodes due to the low concentration of supporting electrolyte (C), while in conventional electrolysis electric fields are localized at the electrode surface (~exponential decay over tens of Angstroms) as a high concentration of supporting electrolyte is used (D). (E) An example of a closed, split bipolar electrode setup. Note: O, O', R, and R' represent oxidized and reduced species occurring at either the anodic pole of the BPE (facing the cathode driving electrode), or the cathodic pole of the BPE (facing the anode driving electrode).

Several key differences are present in BPE electrochemistry (Scheme 117A) compared to a conventional electrolysis setup (Scheme 117B) that enable the redox chemistry to occur at the BPE and not the driving electrodes.¹¹⁷⁹ The supporting electrolyte concentration is lower in BPE electrochemistry compared to conventional electrochemistry which results in a high electric field in the bulk of the solution (Scheme 117C) in contrast to the conventional electrochemistry where no significant electric field is present in the bulk (Scheme 117D) as it is localized to the electrode-solution interface. Finally, the potential on the electrode is a gradient on a BPE, in contrast to being uniform in a conventional electrolysis setup. The BPE material is usually selected to have a significantly lower kinetic barrier (i.e. lower overpotential) than the driving electrodes when used in an open BPE setup. Alternatively, multi-compartment setup (i.e. a closed BPE setup) can be utilized in which an insulating wall separates the two driving electrodes. ¹¹⁸⁰

Bipolar electrochemistry can simplify micro- and nanofabrication of materials such as directional growth of Cu microwires, asymmetric modification of materials, generation of compositional gradients, as well as applications in sensing technologies.¹¹⁷⁸ To date BPE has been demonstrated to be suitable for the rapid screening of electrocatalysts for the oxygen reduction reaction and has been applied for the concomitant H₂ and O₂ evolution from aqueous media at the same electrode. Despite these advances, bipolar electrochemistry has not yet made significant impact on organic synthesis. Of the few impactful synthetic examples relevant to organic synthesis using BPE, the synthesis of propylene oxide from propylene gas and sodium bromide electrolyte solution has been reported in flow using a packed bed reactor.¹¹⁸¹ Despite the low current efficiency (15 to 55%) due to competing processes such as bromate formation, relatively high space time yields of 10 to 100 kg•m⁻³•h⁻¹ were achieved near ambient pressures. BPE have made impact in enabling parallel screening of electrocatalysts¹¹⁸² and will likely continue to bring new impactful directions in the future. A challenge in using BPE for electroorganic synthesis is that in situ monitoring of the current is challenging.³²⁰ A noteworthy synthetic application of bipolar electrodes, particularly split bipolar electrodes (s-PBE), is the C(sp³)–H fluorination of triphenylmethane in a U-shaped cell.¹¹⁸³ In contrast to bipolar electrodes, a split bipolar electrode employs an insulator shielding wall in the middle of the BPE, which augments the potential drop around the split electrodes and enables monitoring of the electrical current (Scheme 117E). The reaction is postulated to proceed via a net 2e benzylic oxidation leading to the trityl cation, enabling subsequent nucleophilic fluorination from the fluoride provided by the CsF electrolyte.

5.2. Two Photon-Mediated Photoredox Catalysis

In most photoredox catalytic cycles, the one-photon excitation of a ground state chromophore is typically invoked for the formation of its excited state counterpart. In terms of common excitation wavelengths, irradiation with 365 nm, 390 nm, and 450 nm light leads to respective theoretical upper limits of 3.4, 3.2, and 2.8 eV for electron transfer, although practical values end up lower due to vibrational relaxation and nonradiative pathways.¹¹⁸⁴ One approach for overcoming this barrier is to use the energy of two photons in a single catalytic cycle, which is best illustrated in the development of challenging aryl halide reductions (Scheme 118), in which the energy of two photon is required to access a reducing excited state chromophore. It is important to note that photoredox-induced aryl reductions have been used as a benchmark,¹¹⁸⁵ and recent developments in ligand design have led to the bis-cyclometalated iridium photocatalysts with electron-rich beta-diketiminate ancillary ligands, which are potent one-photon photoreductants and accomplish the proto-dehalogenation of bromo-, chloro-, and fluoroarenes, as well as alkyl bromides.¹¹⁸⁶ Photoexcitation of polysulfide anions (S₄²⁻) have also been demonstrated to enable single electron reduction of haloarenes to generate aryl radicals for protodehalogenation, borylation and (hetero)biaryl cross-couplings.¹¹⁸⁷ However, for the purposes of this review, this section will focus mainly two-photon strategies.

Scheme 118.

The common mechanism for aryl radical formation (left) and relative reduction potentials for aryl halides (right). Potentials are from reference 438.

One strategy is to access the excited state of a radical anion species, which would then serve as a more potent reductant than the ground state counterpart. König and co-workers demonstrate this concept with a perylene diimide derivative (PDI, 115.1) to accomplish aryl halide reduction via a consecutive PET (conPET).¹¹⁸⁸ Reductive quenching of photoexcited 119.1 by a sacrificial amine forms a PDI radical anion (119.2), which is photoexcited with blue light to reveal a potent single-electron reductant (119.3) capable of reducing electron-deficient aryl iodides, bromides, and chlorides (Scheme 119). Furthermore, König and co-workers show that the aryl radical intermediate is an effective trap for pyrroles, furnishing the C–C bond forming product at the 2-position of the pyrrole. A follow-up manuscript from the König group uses the redox-dependent absorption of rhodamine 6G (Rh-6G, 119.6) species to enable two-photon, chromoselective reduction of polyhalogenated arenes.¹¹⁸⁹ Green-light excitation of ground state 119.6 — which can also be excited with blue light — and subsequent reductive quenching yields Rh-6G radical anion (119.7), which reduces electron deficient aryl halides (E_red ≤ −1.0 V vs. SCE). However, blue light irradiation of 119.7 results in the formation of excited state 119.8, which capable of reducing more electron-rich aryl halides (E_red ≤ −2.4 V vs. SCE). The utility of this method was highlighted by chemoselective reduction of polybrominated arenes, wherein monoarylation was observed in the presence of green light whereas diarylated product is obtained when blue light is used.

Scheme 119.

Representative examples of conPET and chromoselective reductions for aryl halides.

Two-photon chromophore excitation can also be applied to transition-metal photoredox catalysts (Scheme 120). Wenger and co-workers demonstrate the formation of a hydrated electron (120.3) in the presence of a sacrificial reductant when a water-soluble tris-sulfonylated Ir(ppy)₃ derivative (120.4), is subjected to two laser pulses — first at 430 nm, then at 532 nm — to generate the long-lived excited-state triplet of 120.4 and to promote 120.3 production.¹¹⁹⁰ This method efficiently applied to the dehalogenation of chloroacetate, monodefluorination of 4-(trifluoromethyl)benzoate and debenzylation of benzyltrimethylammonium cation. Polyzos and co-workers show that the non-innocence of the tbbpy ligand on the Ir^III photocatalyst (Ir-1, 11.5) leads to its dearomatization in the presence of HAT-capable reductants and results in the formation of an Ir^III chromophore (Ir-2, 120.9) with a greater excited state oxidation potential (E(PC⁺/PC*) −1.70 to −3.0 V vs. SCE) than excited state 11.5 (−0.96 V vs. SCE).¹¹⁹¹ This enables the reductive dehalogenation of aryl halides and the reductive formal hydrogenation of 1,1-diaryl olefins and α- or β-substituted styrenes, with the latter method also enabling the anti-Markovnikov alkene hydrofunctionalization with ketones.¹¹⁹²

Scheme 120.

Representative examples of two-photon excitation of a chromophore to access highly reducing photoredox organometallic catalysts.

Lastly, this two-photon absorption strategy can also be applied to the excitation of neutral radical organic chromophore, as shown by Nicewicz and co-workers (Scheme 121).¹⁰⁴² Reductive quenching of excited state acridinium (121.9) by a sacrificial tertiary amine leads to a stable acridine radical (121.10) that can be photoexcited with 390 nm light to access two excited states — a lower energy doublet and a higher energy twisted intramolecular charge-transfer (121.11) with respective oxidation potentials of −2.91 and −3.36 V vs. SCE. This highly-reducing photoexcited acridine is capable of electron-rich aryl bromide and chloride protodehalogenation, as well as reductive detosylation of N-aryl and N-alkyl tosylamines — a notable deprotection strategy that is historically limited to strong acids, dissolving metal, and low-valent transition metal reductions (electrochemical strategies exist, see section 4.18.2). Overall, these methods demonstrate the growing interest in multiphoton excitations for accessing highly reducing species for photoredox catalysis and may yet reveal new highly oxidizing chromophores.

Scheme 121.

Representative examples of two-photon excitation of an organic chromophore to access highly reducing photoredox catalysts.

5.3. Electrophotochemistry – Combining the Best of Both Worlds

Combining aspects of photoredox and electrochemistry dates back decades – in fact electrophotochemistry has been investigated since the 1970s. The field is experiencing a resurgence of interest, especially within the context of organic synthesis, with several recent minireviews/highlights^{1193,1194,1195} providing an overview. It is important to clearly distinguish electrophotochemistry (EPC) from photoelectrochemistry (PEC).^29,1196,1197 Photoelectrochemistry — sometimes referred to as interfacial photoelectrochemistry (iPEC)¹¹⁹³ — refers to light-induced sensitization of a semiconductor electrode material (e.g. photoanode) to generate a photocurrent which promotes a chemical transformation.¹¹⁹⁸ In contrast, electrophotochemistry — sometimes referred to as electrochemically mediated photoredoxcatalysis (e-PRC)¹¹⁹³ — refers to the use of electrochemistry to generate an intermediate via a redox event, which is then photoexcited. This photoexcited intermediate is usually a catalyst which experiences highly potent redox properties (e.g. photoexcited radical anion of 9,10-dicyanoanthracene is highly reducing, E_ox* = −3.2 V vs SCE; photoexcited dicationic trisaminocyclopropeniums can be highly oxidizing, E_red* = +3.3 V vs SCE). We also note a third category exists in which the electrochemistry and photochemistry have separate, discrete roles, termed decoupled photoelectrochemistry (dPEC), but few examples of synthetic transformations via this strategy have been disclosed.^{898,1193,1199} Additionally, electrophotochemistry has the potential to make photochemical reactions greener by replacing sacrificial reductants or oxidants used in photoredox reactions. The redox event at an electrode can be used for photocatalyst turnover, which when coupled to desirable half-reactions such as hydrogen evolution, can minimize waste production.

A more synthetic-focused reason for using electrophotochemistry is its ability to generate highly reductive/oxidative species under mild conditions (Schemes 122A and 122B). Lambert and Nuckolls demonstrated that cyclopropenium perchlorate photocatalyst 122.1 could be oxidized to its dicationic form and upon its photoexcitation would generate a highly oxidizing catalyst (ca. +3.3 V vs SCE) enabling oxidative C–H functionalization of unactivated arenes for C–N bond formation (Scheme 122A).¹²⁰⁰ Lambert and Huang also report a electrophotochemical cation radical accelerated S_NAr^994a (CRA-S_NAr) of unactivated fluorobenzenes with nitrogen and oxygen nucleophiles, which is enabled by pairing a DDQ photocatalyst with CPE.¹²⁰¹ This method is best compared to analogous photooxidatively-mediated CRA-S_NAr reported by Nicewicz¹²⁰² and Zhou¹²⁰³, where highly oxidizing xanthylium and acridiniums are used to facilitate similar transformations. Wickens and coworkers also demonstrate that PTH (11.11) can be electrochemically oxidized to its corresponding cation radical, which is sufficiently oxidizing to generate arene cation radicals from benzene, toluene, chlorobenzene, xylenes, and mesitylene for arene C–H amination with pyrazoles.¹²⁰⁴ Lambert recently demonstrated an electrophotochemical C–H heterofunctionalization approach using DDQ as the catalyst and blue LEDs in an undivided cell electrolysis setting.¹²⁰⁵ The use of water, alcohols, or carboxylic acids as a nucleophile provided direct access to phenols, arylethers, and aryl esters, respectively, via C–O bond formation. Further extension with nitrogen nucleophiles was demonstrated with benzamide, ethyl carbamate, urea, acetamide, and sulfonamide derivatives, via C–N bond formation.

Scheme 122.

Oxidative and reductive electrophotochemistry along with selected examples of catalysts.

Electrophotochemistry can also be used to generate highly reductive catalysts (Scheme 122B). One example is from the Lambert and Lin labs, where CPE is used to reduce 9,10-dicyanoanthracene (122.2) to its radical anion, which is then photoexcited to generate a highly reducing catalyst (ca. −3.20 V vs SCE) to enable reduction of unactivated aryl chlorides and bromides, and the subsequent trapping of the resultant aryl radical with boron, tin and heteroaryl electrophiles.¹²⁰⁶ The electrophotochemical reduction of aryl chlorides was also independently reported by Wickens and coworkers, where a highly reducing catalyst (ca. −3.3 V vs SCE) is formed via photoirradiation of an electrochemically-reduced N-aryl naphthalene imide (122.3) radical anion.^248h

5.4. Emerging Alternatives to Blue-light Activated Photoredox

There is a growing interest in using low-energy light as improved reaction media penetration can potentially enable efficient photoredox reactions on scale and allow for biological applications that do not suffer from phototoxicity associated with high-energy light.^1207,1208 However, the challenge with this approach is that most widely-used photoredox catalysts require near-UV (365 nm = 78.3 kcal•mol⁻¹, 390 nm = 73.3 kcal•mol⁻¹) and blue (450 nm = 63.5 kcal•mol⁻¹) light for activation.^1209,1210

5.4.1. Triplet Fusion Upconversion.

Triplet fusion upconversion (TFU) is a strategy that converts low-energy photons to higher energy photons through triplet donor (sensitizers) and acceptor (annihilator) molecules¹²¹¹ (Scheme 123). Two long-lived triplet sensitizers (³S) formed through stepwise ¹MLCT excitation and ISC, or by direct ³MLCT, transfer their energies to two discrete annihilators (¹A) to form two long-lived triplet annihilators (³A). Triplet annihilation between two ³A* species generates a higher energy singlet exciton on one annihilator (¹A*) and a quenched partner (¹A), with the restriction that E(¹A*) < 2 x E(³A*). The excited singlet ¹A* can then either emit a high energy photon via fluorescence or participate in single-electron redox transfer as a photoredox catalyst. Congreve, Rovis, Campos and co-workers recently reported near-infrared (NIR) photoredox catalysis using Pd- and Pt-based sensitizers and organic annihilators (Scheme 124).¹²¹² Using palladium^II octabutoxyphthalocyanine (124.1) as the sensitizer with furanyldiketopyrrolopyrrole (124.2) as an annihilator¹²¹³ enables upconversion of NIR photons (730 nm, 38 kcal•mol⁻¹) to orange region (λ_em,max ~ 550 nm) whereas using the sensitizer platinum^II tetraphenyltetranaphthoporphyrin (124.3)^1214,1215 coupled with the annihilator, tetrakis(tert-butyl)perylene (124.4) enables NIR-to-blue photon upconversion (λ_em,max ~ 460 nm). The former system successfully enables Eosin Y-mediated hydrodehalogenation and reductive cyclization, as well as Rose Bengal-catalyzed amine oxidation¹²¹⁶ and Eosin Y catalyzed¹²¹⁷ radical cyclization. The TFU system with 124.3 and 124.4 were successfully used to excite Ru(bpy)₃²⁺ for an intramolecular [2+2] reaction⁹²⁶, and additional experiments demonstrate that the two-component system is capable of photoredox catalysis. More importantly, this TFU system demonstrates the enhanced material penetrance of NIR light, as the photo-ATRP of MMA¹²¹⁸ was demonstrated in the presence of several visible light-absorbing barriers; only NIR irradiation generated a freestanding gel of crosslinker-doped MMA (5% ethylene glycol dimethacrylate).

Scheme 123.

Representative comparisons of energy for UV, blue and NIR light (left) and a general schematic for triplet fusion upconversion (right).

Scheme 124.

Triplet fusion upconversion for photoredox catalysis.

TFU has also been successfully applied to aqueous systems (Scheme 125), as demonstrated by Wenger and co-workers in their green light (532 nm)-mediated monodehalogenation of trichloroacetate using Ru(bpy)₃²⁺ as a sensitizer and the water-soluble annihilator anthracene-9-propionate (125.2).¹²¹⁹ Interestingly, this reaction proceeds in air-saturated water despite the facile quenching of triplet sensitizer or annihilator by oxygen gas to form singlet oxygen. This observation is rationalized by the low O₂ solubility in water (~0.27 mM), which is tenfold lower than in common organic solvents.¹²²⁰ Wenger and co-workers build on this work by reporting methods for blue (420 nm)-to-near UV upconversion λ_em,max ~320 nm) and photoreduction using sulfonylated Ir^III catalyst 125.3 as the sensitizer and the annihilators 1,5-naphthalenedisulfonate (125.4) and naproxen (125.5).¹²²¹ The latter method was applied towards the reductive debromination of 4-bromo-2-chloro-5-fluorobenzoate and debenzylation of benzyltrimethylammoniums in water, owing to the highly reducing nature of photoexcited singlet naproxen (−2.7 V vs. SCE). With these examples, the future of TFU for photoredox catalysis is bright, with sensitizer and annihilator development driving advances in this rapidly growing field.

Scheme 125.

Triplet fusion upconversion in aqueous systems.

5.4.2. Photoredox Catalysis with DR/NIR-absorbing Chromophores.

An alternative strategy is to use deep red (DR; λ = 660 nm) and NIR-light absorbing chromophores to generate excited-state species capable of electron transfer (Scheme 126). Turro and co-workers report dihydrogen formation using a DR-excited dirhodium^II photosensitizer; this catalyst performs two step-wise DR-mediated oxidations to generate a doubly reduced Rh₂ species (126.1) capable of converting two protons into dihydrogen.¹²²² More recently, Rovis, Joe, and co-workers report the development of DR and NIR-photoredox catalysis using Os^II chromophores (126.2–126.4).¹²²³ The versatility afforded by these photoredox catalysts is observed in successful redox-based photopolymerizations, redox-initiated synthesis, and metallaphotoredox transformations. Additionally, the excited and ground state redox potentials of these photocatalysts can be modulated through modifications to the terpyridine, azine, and phenanthroline ligand scaffolds, thus enabling their rational design. Lastly, NIR photoredox catalysis enables mole scale arene trifluoromethylation using a batch reactor. This observation is notable given that arene trifluoromethylation yields drop when using blue light and Ru(bpy)₃²⁺, whereas using NIR with an Os chromophore (126.4) leads to a consistent yield increase for scale-comparative transformations. A concurrent report by Gianetti and co-workers show that a helical carbenium ion (126.8) operates as a DR organic photoredox catalyst.¹²²⁴ These recent reports are encouraging signs for future development of photoredox reactions using DR and NIR light to mediate electron-transfer mechanisms for organic synthesis.

Scheme 126.

Representative examples of photoredox catalysis with DR/NIR-absorbing chromophores.

5.5. Singlet Fission.

Singlet fission is in effect the reverse process of triplet-triplet fusion upconversion. Singlet fission is the process of using one photon to generate a singlet which then spontaneously generates two triplets. The energetics require that the energy gap between the S₁ and S_o state are greater than twice the energy gap between the T₁ and S_o state. While singlet fission1225,1226,1227,1228,1229,1230,1231,1232 continues to be of interest within the solar cell community due to the promise of improving photon-to-current conversion efficiencies beyond the 30% Shockley–Queisser limit, applications in synthetic photocatalysis are limited. Intramolecular singlet fission (iSF) whereby two chromophores are covalently linked to enable the generation of two triplets on two chromophores in close proximity has been demonstrated, for example in pentacene dimers.¹²²⁵ A key example is from Steigerwald, Sfeir, Campos, and coworkers, where a bridged pentacene dimer undergoes near perfect iSF in ~ 220 ps to yield two long-lived pentacene triplets (270 ns).¹²³³ The mechanism for iSF is highly dependent on the linker length and identity, as iSF can lead to the formation of the triplet pair directly from the photoexcited pentacene or it may require access to charge-transfer states (Scheme 127A).¹²³⁴ A discussion of the photophysical considerations is outside the scope of this review. We envision that iSF can be leveraged to generate two separate electron hole/donor pairs, and thus may enable new ways to carry out doubly reductive (or doubly oxidative) transformations using a single photocatalyst, akin to common electrochemical reactions occurring at a single electrode (Schemes 127B and C). A photocatalytic process relying on singlet fission could enable new transformation or selectivities not attainable via electrochemistry, potentially even utilizing a combination of redox and energy transfer (triplet-sensitization) processes (Schemes 127D and E).

Scheme 127.

(A) The mechanism for intramolecular singlet fission for bridged pentacene dimers. (B–D): Potential outcomes when leveraging two triplets from singlet fission for (B) a doubly oxidative quenching cycle, (C) a doubly reductive quenching cycle (2e redox events), (D) double energy transfer (EnT) cycle, (E) a consecutive ET-EnT cycle (the analogous process where the EnT precedes the ET step can also be envisioned).

5.6. Machine Learning/QSAR.

The use of machine learning coupled with automation tools for the discovery and optimization of chemical reactions is an attractive direction.^1235,1236 Predictive models for the classification of excited states of heteroleptic Ir^III-photocatalysts based have recently been developed.^1237,1238 While thermodynamic based predictors like redox potential can be used to rationalized outcomes of reactions using various photocatalysts, the kinetic components related to quenching of the excited state photocatalyst by various substrates is also a critical factor. To being to address this, predictive models recently have been developed.¹²³⁹ Applications of quantitative structure activity relationship (QSAR) models using electroanalytical parameters are emerging and may impart new machine learning approaches to developing new transformations as well as understanding trends and limits of existing synthetic methods.^{1240,1241,1242} Design of experiments (DoE) techniques are routinely applied in industrial applications for the optimization of reactions. Examples of using DoE techniques in the context of optimizing electrochemical reactions have been reported to successfully optimize factors such as stir rate, inter-electrode spacing, concentration of reactants, total charge, and current density.¹²⁴³ Machine learning algorithms have been used to build predictive models for optimization of membranes,¹²⁴⁴ cathode materials,¹²⁴⁵ as well as electrolyte composition.¹²⁴⁶ Progress towards being able to predict the outcome (reaction yield) of electro-synthetic experiments using machine learning algorithms based on multiple electrochemical parameters (electro-descriptors) such as onset potential, Tafel slope, and effective voltage were demonstrated in the context of a variety of transformations ranging from phosphorylation of tetrahydroquinolines, aziridination of alkenes, TEMPO-mediated dehydrogenation of N-Heterocycles.¹²⁴⁷ Machine learning algorithms have also been demonstrated successful in the context of optimizing of the dimerization of acrylonitrile to form adiponitrile via alternating current electrolysis.¹¹⁶¹ In this case the duration of the pulse as well as the current density and the presence/absence of a quiet period were critical parameters and were optimized via artificial intelligence to minimize side reactions and maximize yield. Advances in predictive models related to photoredox chemistry such as excited state energies, redox properties and Stern-Volmer quenching rates have emerged with an aim to discovering and understanding reactions.^1239,1248

6. Concluding Remarks and Outlook

This review provides a detailed comparison between electrochemistry and photochemistry, focusing primarily on the fundamental aspects pertinent to both methods. While we present key synthetic transformations shared by both photochemistry and electrochemistry, there is a much larger volume of chemical space in which there is a lack of corresponding overlap between either photoredox or electrochemistry. We believe that this empty space signals opportunities for the discovery and development of complementary synthetic methods — each with their own advantages and limitations — and further contributions of unexpected discoveries (e.g. side reactions/unexpected reactions, new reaction concepts, novel catalysts, improved functional group tolerance).

The wealth of synthetic methods presented in this review not only highlights the creativity and utility of redox chemistries (i.e. electrochemistry and photoredox catalysis) but also supports their kinship. Subtle limitations may arise when trying to translate a photoredox method into an electrosynthetic method (and vice versa) and detailed mechanistic studies should help improve synthetic translations between the two strategies. For example, the generation of intermediates at the electrodes after the first redox event may be prone to undergo a second redox event (i.e. net doubly oxidative process as in the Hofer-Moest decarboxylation to the carbocation instead of the alkyl radical as observed in Kolbe electrolysis). The choice of electrode material and/or the current density can aid in tuning the reaction between the 2e pathway (Hofer-Moest is favored by the use of graphite anode and high current densities) or the 1e process (Kolbe electrolysis is favored by the use of Pt anode and lower current densities in the decarboxylation example above). Additionally, redox mediators can be used to suppress 2e redox chemistry and the effect of the electrode material on the redox outcome of the substrate. Likewise, consecutive electron transfers via emerging photoredox strategies can help translate electrochemical reactions that redox-neutral photoredox methods struggle with.

The traditional limitation of electrochemical synthetic methods to net-reductive and net-oxidative transformations is due to technological limitations imposed by electrochemical cell designs and available operating modes. In particular, the large inter-electrode distance (>0.5 cm) prevents transiently generated radical intermediates from efficient migration from one electrode to the other to achieve a redox neutral transformation. Thus, recent advances in electrochemical microflow cell designs and the re-emergence of alternating potential/current electrolysis provide two useful pathways forward to achieve redox neutral reactions which have been typically better suited for photoredox catalysis. The APE/ACE approach has the benefit of not being restricted to homogenous solution required for the electrochemical microflow cell. Continuous processing via adaptation of APE/ACE into a CSTR will enable the processing of heterogenous/slurry mixtures in net redox neutral processes (avoiding clogging issues with heterogeneous reactions that plague flow cells). An exciting path forward is the integration of electrochemistry and photochemistry — namely, electrophotochemistry — in which an electrochemically-generated persistent intermediate is photoexcited to enable access to highly potent oxidants and reductants to bypass the use of direct electrolysis with extreme potentials. We expect new electrocatalysts with tuned radical lifetimes and redox potentials (pre- and post-photoexcitation) will accelerate discoveries in this area of research. We believe that major advances await in both redox-neutral electrochemistry and electrophotochemistry are areas and new developments in these fields will result in the discovery of new and improved synthetic transformations. Engineering innovations are also key to success for both fields. Improved cell design to modulate and control light input reproducibly and improvements membrane technologies are necessary. The ability to screen and monitor electrochemical and electrophotochemistry reactions in a high-throughput fashion is necessary and currently lags behind photochemical solutions.³⁹¹

While at first sight one may postulate that photocatalysis and electrochemistry would differ in activation methods, given that electrochemistry involves only the ground state potential energy surface, whereas photochemistry also involves both the ground and excited state potential energy surfaces. However, this is not necessarily correct. While the photocatalyst may operate on the excited potential energy surface (PES), the redox event with substrates/reagents results in oxidized/reduced forms of the substrate/reagent still on the ground state energy surface. Only in photochemical examples where no photocatalyst is used and direct excitation of the substrate/reagent leads to the desired redox process via an excited state or excited EDA complex will the substrate be on the excited state PES. The use of energy transfer in photocatalysis enables for tandem processes in which both an EnT catalytic cycle and a photoredox cycle may operate,¹²⁴⁹ something that is not achievable using electrochemistry alone – yet nothing precludes a user from combining photosensitization and electrochemistry. EnT can be useful not only for alkene isomerization,^1250,1251 photoderacemization processes,¹²⁵² rearrangements or 4n p-cycloadditions/electrocyclizations (e.g. [2+2]-cycloadditions) but also for fragmentations reactions such as σ-bond cleavage (e.g. N–O bond cleavage of oximes),^787,1137 as well as accessing spin selective transformations (triplet vs singlet reactivity such as in nitrene chemistry¹²⁵³ and reductive elimination from transition metal complexes.^1153,1254 Additionally, the electron flux (current) is coupled to potential (Ohm’s law) for electrochemistry, while the photon flux is not coupled to photocatalyst redox potential in photoredox catalysis. However, because the redox window accessible for a photocatalyst is limited by the input energy of an absorption wavelength, limitations will surface if one uses higher energy photons (shorter wavelength) than conventionally-used irradiation sources (e.g. hν < 365 nm). Specifically, organic substrates start to become competitive absorbers of light relative to the photocatalyst, which may lead to decreased efficiency and undesirable side reactions.

Perhaps one of the most significant differences in the comparison is that reduction (at cathode) and oxidation (at anode) are spatially separated in electrochemistry, unless performing alternating current/potential electrolysis in which both redox events occur at the same electrode. This contrasts with photochemistry where both redox events occur at the photocatalyst, thus occur spatially close, namely not significantly further than the distance the photocatalyst can diffuse during the lifetime between the first and the second (and opposite) redox event associated with the photocatalyst’s catalytic cycle. The other major difference being that multielectron redox events are more easily achieved via electrochemistry although we have highlighted several examples of consecutive SET events via photochemistry. Additionally, the use of high-powered light sources (e.g. lasers) may enable the concentration of excited states to be high enough to render ternary reaction events (two excited photocatalyst being able to simultaneously transfer an electron each to the substrate to achieve a multi-electron transfer event).

More trivial differences are related to reaction mixture composition; including the common use of electrolytes in electrochemistry to reduce the resistance of the reaction mixture to facilitate conductivity between the two electrodes; whereas no electrolyte is needed in photochemistry. Electrochemical reactions can also proceed in the absence of an electrolyte when the solution resistance between the two electrodes is low enough (e.g. very small electrode separation or the reagents used in the reaction mixture can provide the needed mixtures of low resistance). Green chemistry aspects unique to electrochemistry revolve about the amount of electrolyte used, often stoichiometric or super-stoichiometric relative to the limiting reagent. Towards addressing this challenge, solutions have either focused on recycling¹²⁵⁵ of the electrolyte or minimizing/eliminating it altogether via leveraging flow electrolysis where the electrode separation distance is small enough that solution resistance in the absence of electrolyte is negligible.

While the focus has been on the pathway leading to the desired product and metrics such as yield and efficiency (e.g. the Faradaic efficiency in electrochemistry and the quantum yield in photochemistry), what happens in the non-productive pathways and how do those compare between electrochemistry and photochemistry? In electrochemistry, the non-productive consumption of electricity includes redox events of species not associated with productive pathway but also with non-Faradaic current consumption (charging of the double layer) and external energy loss due to electrical resistance in the setup (leading to Joule heating). In photochemistry, photons can be wasted due to the photocatalyst not absorbing the photon, or absorbing the photon to reach an excited state but the excited state of the photocatalyst returning to the ground state via (a) internal conversion (photon to thermal heat generation) or (b) emission of light, either via fluorescence or phosphorescence depending on the nature of the excited state (e.g. S₁ vs T₁). Undesired redox events may also consume photonic energy via the photocatalysts oxidizing or reducing a reagent/intermediate in a non-productive manner. Energy loss associated with the light source (e.g. low efficiency in electrical to light energy conversion can also result in low energy efficiency of the setup and significant heat generation at the light source.

Twenty years into the 21^st century and it is undeniable that we are experiencing a renaissance in both electrochemistry and photochemistry. Many challenges lie ahead of us, not only in the synthetic realm but also global environmental challenges such as climate change, energy crisis and pollution. Research in photocatalysis and electrochemistry are starting to yield innovations as solutions to the aforementioned problems. For example, converting greenhouse gases such as CO₂ into valuable feedstock chemicals^1256,1257 via CO₂ fixation¹²⁵⁸ methods is a first step in shifting away from commodities based on fossil fuels, ¹²⁵⁹ and the use of water splitting¹²⁶⁰ is a key step towards greener fuel sources (e.g. water powered fuel cells replacing fossil fuel combustion engines). Both hydrogen evolution reaction^1261,1262 and oxygen evolution reactions¹²⁶³ are subjects of years of intensive research.¹²⁶⁴ Additionally, the merger of photo- and electrochemistry in the context of photoactive electrodes (photoelectrochemistry) also plays a role in solar fuel research.¹²⁶⁵ Furthermore, energy conversion technologies, including those related to solar and wind energy conversion to electrical energy, energy storage technologies (fuels & batteries, including redox flow batteries) continue to be a challenge of which both photo- and electrochemistry are crucial in providing solutions.^{1266,1267,1268,1269} Additionally, both photo- and electrochemistry have long played an important role in water treatment/remediation via the oxidation of organic pollutants in water,^{1270,1271,1272,1273} and more recently in the desalination of water.^1274,1275 This need is most urgently felt in the remediation of per- and polyfluoroalkyl substances (PFAS) — termed “forever chemicals” due to their persistence in the environment and their inertness towards breaking down in the environment — as their presence poses significant adverse health effects (e.g. cancer, immunotoxicity, metabolic diseases, and neurodevelopmental disorders). One promising solution is the electrochemical oxidation of PFAS,¹²⁷⁶ and this breakthrough is likely linked to the recent popularization of BDD electrodes, which have excellent resistance to fouling under high current density conditions. While non-exhaustive, we hope that these topics clearly solidify the need for continued research in both photoredox and electrochemical methods to address pressing needs of global significance.

Scheme 29.

Dehydrogenation/aromatization of N-heterocycles via electrochemical or photoredox methods.

Scheme 32.

The putative mechanism for electrochemically-mediated nickel-catalyzed C–N cross coupling.

Scheme 73.

Electrochemical defluorinative functionalization of benzotrifluorides with the corresponding mechanism.

Scheme 79.

A comparison of electrochemical and photoredox methods for aliphatic C–H fluorination with electrophilic fluorine sources.

Scheme 96.

A comparison of electrochemical methods for catalyst-activated olefin metathesis.

ABBREVIATIONS

1,5-HAT

1,5-hydrogen atom transfer

18-C-6

18-crown-6, CAS 17455–13–9

4CzIPN

1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene, CAS 1416881–52–1

4-DPA-IPN

2,4,5,6-tetrakis(diphenylamino)isophthalonitrile, CAS 1846598–27–3

4-HTP

4-hydroxythiophenol

5,5′-dCF₃bpy

5,5′-bis(trifluoromethyl)-2,2′-bipyridine

A

acceptor molecule

ABNO

9-azabicyclo[3.3.1]nonane N-oxyl

AC

alternating current

Ac

acetyl

ACE

alternating current electrolysis

AcOH

acetic acid

Acr

acridinium

ACT

4-acetamido-TEMPO

Ad

adamantly

AIBN

azobisisobutyronitrile

APE

alternating potential electrolysis

Ar

aryl

ATRP

atom transfer radical polymerization

BA

n-butyl acrylate

B(Ar^F)₄

Tetrakis(3,5-bis(trifluoromethyl)phenyl)borate

BDE

bond dissociation energy

BDD

boron-doped diamond

BHT

butylated hydroxytoluene; 2,6-di-tert-butyl-4-methylphenol

BMPO

5-tert-butoxycarbonyl 5-methyl-1-pyrroline-N-oxide

Bn

benzyl

BNAH

1-benzyl-1,4-dihydronicotinamide

Boc

tert-butyloxycarbonyl

BPE

bipolar electrode

BPI

benzo[ghi]perylene monoimides

bpm

2,2′-bipyrimidine

BPO

benzoyl peroxide

bpy

2,2′-bipyridine

BPyI

bis(pyridylamino)isoindoline

bpz

2,2′-bipyrazine

BrCCl₃

bromotrichloromethane

n-Bu

n-butyl

Bz

benzoyl

cat

catalyst

CBX

cyanobenziodoxolone

cbz

carboxybenzyl

CCE

constant current electrolysis

CCl₄

carbon tetrachloride

CE

counter electrode

CF₃

trifluoromethyl

CFL

compact fluorescent light

Cl₄NHPI

N-hydroxytetrachlorophthalimide

Co(dmgH)₂(p-Me₂NPy)Cl

chloro[(4-dimethylamino)pyridine]bis(dimethylglyoximato)cobalt(III), CAS 483979–48-2

Co(dmgH)₂pyCl

chloro(pyridine)bis(dimethylglyoximato)cobalt(III), CAS 23295–32–1

conPET

consecutive photoinduced electron transfer

CPE

constant potential electrolysis

CRA-S_NAr

cation radical accelerated S_NAr

Cr(Ph₂phen)₃(BF₄)₃

chromium(III) tris(4,7-diphenyl-1,10-phenanthroline-κN¹,κN¹⁰)-, (OC-6–11)-, tetrafluoroborate (1:3), CAS 1808257–86–4

CsOBz

cesium benzoate

CSTR

continuous stirred tank reactor

CTA

chain transfer agent

CV

cyclic voltammetry

Cy

cyclohexyl

Cy₂NMe

N,N-dicyclohexylmethylamine

CySH

cycohexylthiol

D

donor molecule

DBU

1,8-Diazabicyclo[5.4.0]undec-7-ene, CAS 6674–22-2

DC

direct current

DCE

1,2-dichloroethane

DCM

dichloromethane

DCPD

endo-dicyclopentadiene

DDP

diaryl dihydrophenazine

DDQ

2,3-dichloro-5,6-dicyano-1,4-benzoquinone

DDH

2,3-dichloro-5,6-dicyano-p-hydroquinone

DE

direct electrolysis

DET

double electron transfer

dF(CF₃)ppy

2-(2,4-difluorophenyl)-5-trifluoromethylpyridine

DFT

density functional theory

diglyme

diethylene glycol dimethyl ether

DIPEA

N,N-diisopropylethylamine

DMA

dimethylacetamide

DME

dimethoxyethane

DMF

dimethylformamide

DMPO

5,5-dimethyl-1-pyrroline-N-oxide

DMSO

dimethylsulfoxide

dPEC

decoupled photoelectrochemistry

DoE

design of experiments

dmbpy

4–4′-dimethoxy-2–2′-bipyridine

DMF

dimethylformamide

(DMP)BF₄

N,N-dimethylpyrrolidinium tetrafluoroborate

DMU

1,3-dimethylurea

dr

diastereomeric ratio

DR

deep red (e.g., λ = 660 nm)

DT

decatungstate

DTBP

di-tert-butylperoxide

dtbbpy

4,4′-di-tert-butyl-2,2′-bipyridine

e

electron

eATRP

electrochemical atom transfer radical polymerization

EBPA

ethyl α-bromophenylacetate

EC

electrochemistry

EDA

electron donor-acceptor

EDL

electric double layer

ee

enantiomeric excess

EnT

energy transfer

Eosin Y

2′,4′,5′,7′-tetrabromofluorescein

EY-Na₂

Eosin Y disodium, CAS 17372–87-1

E _pa

anodic peak potential

E _pc

cathodic peak potential

EPC

electrophotochemistry

EPR

electron paramagnetic resonance

er

enantiomeric ratio

ESF

ethylene sulfonyl fluoride

ET

electron transfer

Et

ethyl

Et₃N

triethylamine

EtOH

ethanol

e-PRC

electrochemically mediated photoredox catalysis

eV

electron volt

fac

facial

Fc

ferrocene

Fc⁺

ferrocenium

Fppy

2-(2,4-difluorophenyl)pyridine

FT

Fourier transform

ΔGPET

Gibbs free energy of photoinduced electron transfer

GO

graphene oxide

GLC

glassy carbon

glyme

1,2-dimethoxyethane

GRC

graphite carbon

H⁺

hydrogen ion

H₂O₂

hydrogen peroxide

HAT

hydrogen atom transfer

HDF

hydrodefluorination

HE

Hantzsch ester

HER

hydrogen evolution reaction

HFIP

hexafluoroisopropanol

HLF

Hoffmann-Loffler-Freytag

HOMO

highest occupied molecular orbital

HPLC

high-performance liquid chromatography

HTE

high-throughput experimentation

i-Pr

isopropyl

iPEC

interfacial photoelectrochemistry

IBVE

isobutyl vinyl ether

IR

infrared

i _p,a

peak anodic current

i _p,c

peak cathodic current

i-Pr₂NEt

N,N-diisopropylethylamine

i-Pr₂NH

N,N-diisopropylamine

i-PrOH

isopropanol

ISC

intersystem crossing

Ir[dF(CF₃)ppy]₂(dtbbpy)PF₆

[4,4′-bis(1,1-dimethylethyl)-2,2′-bipyridine-N1,N1′]bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C]Iridium(III) hexafluorophosphate, CAS 870987–63-6

[Ir(dFCF₃ppy)₂-(5,5′-dCF₃bpy)]PF₆

[5,5′-Bis(trifluoromethyl)-2,2′-bipyridine-κN,κN]bis[3,5-difluoro-2-[5- (trifluoromethyl)-2-pyridinyl-κN]phenyl]Iridium(III) hexafluorophosphate, CAS 1973375–72-2

Ir(dF(Me)ppy)₂(dtbbpy)PF₆

[bis[2-(2,4-difluorophenyl)-5-methylpyridine-N,C₂₀]-4,40-di-tert-butyl-2,20-bipyridine iridium(III)] hexafluorophosphate, CAS 1335047–34-1

Ir[p-F(t-Bu)-ppy]₃

tris-(4-(tert-butyl)-2-(5-fluoro-phenyl)-pyridine)-iridium(III)], CAS 1311386–93-2

Ir(ppy)₃

tris[2-phenylpyridinato-C²,N]iridium(III), CAS 94928–86-6

Ir(ppy)₂(dtbbpy)PF₆

[4,4′-bis(1,1-dimethylethyl)-2,2′-bipyridine-N1,N1′]bis[2-(2-pyridinyl-N)phenyl-C]iridium(III) hexafluorophosphate, CAS 676525–77-2

[Ir(tbppy)₂(bpy)]PF₆

[(2-(4-tert-butylphenyl)-pyridine)₂(2,2'-bipyridine)]iridium(III) hexafluorophosphate, CAS 1352428–78–4

iSF

intramolecular singlet fission

ITO

indium tin oxide

KA oil

ketone-alcohol oil

LED

light emitting diode

LMCT

ligand to metal charge transfer

LUMO

lowest unoccupied molecular orbital

MA

methyl acrylate

ME

mediated electrolysis

Me

methyl

MeCN

acetonitrile

Me₆TREN

tris[2-(dimethylamino)ethyl]amine, CAS 33527–91-2

MEK

methylethylketone

MeOH

methanol

(Mes-2,7-dMe-Ph-Acr)BF₄

9-mesityl-2,7-dimethyl-10-phenylacridinium tetrafluoroborate, CAS 1621020–00-5

(Mes-3,6-dtb-Ph-Acr)BF₄

9-mesityl-3,6-di-tert-butyl-10-phenylacridinium tetrafluoroborate, CAS 1810004–87-5

(Mes-3,6-dtb-Ph-Acr)ClO₄

9-mesityl-3,6-di-tert-butyl-10-phenylacridinium perchlorate

(Mes-Me-Acr)BF₄

9-Mesityl-10-methylacridinium tetrafluoroborate, CAS 1442433–71-7

(Mes-Me-Acr)ClO₄

9-Mesityl-10-methylacridinium perchlorate, CAS 674783–97-2

(Mes-Ph-Acr)BF₄

9-Mesityl-10-phenylacridinium tetrafluoroborate, CAS 1621019–96-2

MeSO₃H

methanesulfonic acid

MIDA

N-methyliminodiacetic acid

MLCT

metal to ligand charge transfer

MMA

methyl methacrylate

M _n,exp

experimental number-average molecular weights

M _n,theo

theoretical number-average molecular weights (determined by computational methods)

MS

mass spectrometry

MTES

methyl(triethyl)ammonium sulfate (MeNEt₃)(OSO₂OMe)

M _W,exp

experimental weight-average molecular weights

M _W,theo

theoretical weight-average molecular weights (determined by computational methods)

NADH

1,4-dihydronicotinamide adenine dinucleotide

NBu₄

tetra-n-butylammonium

NEt₄

tetraethylammonium

NFSI

N-fluorobenzenesulfonimide

NHC

N-heterocyclic carbene

NHPI

N-hydroxyphthalimide

NIR

near infrared

NMe₄

tetramethylammonium

NMR

nuclear magnetic resonance

NSAID

nonsteroidal anti-inflammatory drug

OAc

acetate

O₂CCF₃

trifluoroacetate

OER

oxygen evolution reaction

OM

olefin metathesis

P

product

PAHs

polycyclic aromatic hydrocarbons

PC

photocatalyst

PC*

electronically excited photocatalyst

PCET

proton-coupled electron transfer

PEC

photoelectrochemistry

PES

potential energy surface

PET

photoinduced electron transfer

PFAS

per- and polyfluorinated alkyl substances

PFR

plug flow reactor

PG

protecting group

Ph

phenyl

phen

1,10-phenanthroline

Phenox O-PC^™ A0202

3,7-Di(4-biphenyl) 1-naphthalene-10-phenoxazine, CAS 1987900–95-7

Phth

phthalimide

Piv

pivaloyl

PMB

para-methoxybenzyl

PMP

para-methoxyphenyl

PMMA

poly(methyl methylacrylate)

PNO

pyridine-N-oxide

polyPCPD polydicyclopentadiene

(p-OMeTPP)BF₄ 2,4,6-Tris(4-methoxyphenyl)pyrylium tetrafluoroborate, CAS 580–34-7

PPh₃

triphenylphosphine

ppy

2-phenylpyridine

PS-NMe₃CN

polystyrene-supported quaternary ammonium cyanide

PTH

10-phenylphenothiazine, CAS 7152–42-3

py

pyridine

QSAR

quantitative structure-activity relationship

R

rest

RAFT

reversible addition-fragmentation chain transfer

RCY

radiochemical yield

RE

reference electrode

RFTA

riboflavin tetraacetate

RPG

radical precursor group

RPK

reaction progress kinetics

ROMP

ring-opening metathesis polymerization

rr

regiosiomeric ratio

Ru(bpy)₃Cl₂•6H₂O

tris(2,2′-bipyridyl)dichlororuthenium(II) hexahydrate, CAS 50525–27-4

Ru(bpy)₃(PF₆)₂

tris(2,2′-bipyridine)ruthenium(II) hexafluorophosphate, CAS 60804–74–2

Ru(bpz)₃(BArF)₂

tris(2,2′-bipyrazine)ruthenium(II)tetrakis[3,5-bis(trifluoromethyl)phenyl]borate, CAS 1350432–81–3

Ru(bpz)₃(PF₆)₂

tris(2,2′-bipyrazine)ruthenium(II) hexafluorophosphate, CAS 80907–56–8

Ru(bpz)₃Cl₂

tris(1,10-phenanthroline)ruthenium(II) dichloride, CAS 23570–43–6

Ru(phen)₃(PF₆)₂

tris(1,10-phenanthroline)ruthenium(II) hexafluorophosphate, CAS 60804–75–3

RVC

reticulated vitreous carbon

SBS

Society for Biometrical Sciences

SCE

saturated calomel electrode

Selectfluor

1-Chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate, CAS 140681–55–6

SET

single electron transfer

SLAS

Society for Laboratory Automation and Screening

SOMO

singly occupied molecular orbital

SPE

solid polymer electrode

STY

space-time yield

TBAF

tetra-n-butylammonium fluoride

t-Bu

tert-butyl

TBHP

tert-butyl hydroperoxide

tbppy

2-(4-tert-butylphenyl)-pyridine

TBS

tert-butyldimethylsilyl

TEMPO

2,2,6,6-tetramethylpiperidin-1-yl)oxyl

TFA

trifluoroacetic acid

TFAA

trifluoroacetic anhydride

TfCl

trifluoromethanesulfonyl chloride

TFU

triplet fusion upconversion

THF

tetrahydrofuran

tmc

tetramethylcyclam, 1,4,8,11-tetramethyl-1,4,8,11-tetraazacyclotetradecane

TMG

1,1,3,3-tetramethylguanidine

TMHD

2,2,6,6-tetramethyl-3,5-heptanedionate

TMP

2,2,6,6-tetramethylpiperidine

TMS

trimethylsilyl

TMPA

tris(2-pyridylmethyl)amine, CAS 16858–01-8

ToF-SIMS

time-of-flight secondary ion mass spectrometry

Tol

toluene

TPPA

tris(pyrrolidino)phosphoramide

TPPBF₄

2,4,6-Triphenylpyrylium tetrafluoroborate, CAS 448–61–3

TPPV₁₀

tetrakis(tetraphenylphosphonium) dihydrogen decavanadate, (Ph₄P)₄H₂[V₁₀O₂₈], CAS 138521–25–2

tpy

2,2′:6′,2′′-terpyridine

TREN

tris(2-aminoethyl)amine, CAS 4097–89–6

Ts

toluenesulfonyl, tosyl

TTA

triplet-triplet annihilation

TTMSS

tris(trimethylsilyl)silane

UV

ultraviolet

Vis

visible

v/v

volume per volume

WE

working electrode

XAT

halogen atom transfer

XEC

cross-electrophile coupling

ZnTFMS

zinc trifluoromethylsulfinate

Symbols

|

undivided cell

‖

divided cell

Ð

dispersity

E^o

standard potential

E _0,0

excited state energy of an electronically excited fluorophore in its lowest energy vibrational state

E1/2

half-wave potential

E_a

anode potential

E_c

cathode potential

E_e

thermodynamically required cell potential

E_ox

oxidation potential

E_p/2

half-peak potential

E _p,a

peak anodic potential

E _p,c

peak cathodic potential

E _red

reduction potential

ε

molar extinction coefficient

η

overpotential

F

Faraday constant (23.061 kcal•V⁻¹•mol⁻¹ or 96485 C•mol⁻¹)

ϕ

quantum yield

i

current

i _p,a

anodic peak current

i_p,c

cathodic peak current

j

current density

l _BPE

length of bipolar electrode

l _channel

length of channel between driving electrodes

λ

wavelength (photochemistry)

λ

reorganization energy (electron transfer)

Q

total charge

R

ideal gas constant (8.31447 J•mol⁻¹•K⁻¹)

τ

lifetime

U _cell

cell potential

ν

scan rate

$\dot{V}$

volumetric flow rate

V _r

reactor volume

Biographies

Nicholas E. S. Tay was born in Johor Bahru, Malaysia in 1992 and immigrated to the United States of America in 2008. He attended Messiah College, obtaining a B.S. in Chemistry with Departmental Honors in 2014, after carrying out research on microelectrode development for zinc selenide surfaces with Professor Alison R. Noble. He also conducted synthetic organic research in the lab of Professor Steve Buchwald at the Massachusetts Institute of Technology in the summer of 2013. Nicholas began graduate studies at the University of North Carolina at Chapel Hill in 2014, where he joined the lab of Professor David A. Nicewicz and developed new methodologies for organic-photoredox-catalyzed C–H and C–O functionalizations of (hetero)arenes as a National Science Foundation Graduate Research Fellow. He completed his PhD in 2019 and then began his postdoctoral studies with Professor Tomislav Rovis at Columbia University. His research in the Rovis group has focused on the development of new chemical tools for deep red and near-infrared photoredox catalysts, with a particular focus on applications for process chemistry and chemical biology.

Dan Lehnherr received his BSc degree from the University of Victoria (Canada), where he carried out undergraduate research on photochemistry topics in the laboratory of Prof. Peter Wan. He obtained his PhD from the University of Alberta under the mentorship of Prof. Rik R. Tykwinski (Chemistry) and Prof. Frank A. Hegmann (Physics) developing conjugated organic materials for optoelectronic applications (e.g. photodetectors, thin film transistors) and dimeric pentacenes as a platform for investigating intramolecular singlet fission for solar cell technologies. He was an NSERC Postdoctoral Fellow at Harvard University with Prof. Eric N. Jacobsen focusing on organocatalysis and reaction mechanism elucidation where he developed dimeric thiourea catalysts for cooperative anion-binding catalysis. Subsequently he carried out postdoctoral research at Cornell University with Prof. William R. Dichtel developing synthetic methods to foldamers and nanographenes and studying their properties. Since 2016 he has been in the Catalysis Group within Process Research and Development at Merck & Co., Inc., Kenilworth, NJ, USA.

Tomislav Rovis was born in Zagreb in the former Yugoslavia but was largely raised in Southern Ontario, Canada. Following his undergraduate studies at the University of Toronto, he earned his Ph.D. degree at the same institution in 1998 under the direction of Professor Mark Lautens. From 1998–2000, he was an NSERC postdoctoral fellow at Harvard University with Professor David A. Evans. In 2000, he began his independent career at Colorado State University and was promoted in 2005 to Associate Professor and in 2008 to Professor and John K. Stille Chair in Chemistry. His group’s accomplishments have been recognized by a number of awards including an NSF CAREER and a Roche Excellence in Chemistry award. He has been named a GlaxoSmithKline Scholar, Amgen Young Investigator, Eli Lilly Grantee, Alfred P. Sloan Fellow, Monfort Professor at Colorado State University, Fellow of the American Association for the Advancement of Science, Katritzky Young Investigator in Heterocyclic Chemistry, and an Arthur C. Cope Scholar. In 2016, he moved to Columbia University where he is currently the Samuel Latham Mitchill Professor of Chemistry.