English

• 1. Introduction

  In 1830, Michael Faraday discovered organic electrochemistry [1], following on from the pioneering work on general electrochemistry in 1800 by Alessandro Volta with the discovery of the first electrochemical cell (the voltaic pile) [2]. Electrochemistry is an excellent example of “advancement of an ancient technology” [3]. Organic electrosynthesis uses electric current as the main driving energy in organic synthesis. It has been acknowledged as a mild but effective synthetic methodology because of its inherent advantages [4,5]. It has since developed to meet a wide range of needs in metallurgy, chemical synthesis, and energy storage [6]. The distinctive properties of electrochemical systems are responsible for the success of electrochemistry in these various contexts. The main benefit of using an external applied potential is that it makes possible to force reactions away from thermodynamic equilibria. Hence, it opens up reaction pathways and access to chemical intermediates that would be challenging to use under other circumstances. Furthermore, the electrochemical systems frequently provide moderate reaction conditions with the possibility of scalability which support the commercial synthesis of bulk compounds [7]. In this technique, a simple use of the electron as a “traceless” reagent can reduce the risk and expense of synthetic protocols as well as reduce waste production [8-10]. Numerous recent reviews have already been published to introduce beginners to the fundamentals of organic electrosynthesis due to its popularity. These reviews cover basic principles and methods like “constant-current/potential electrolysis,” “(un)divided cell”, “indirect electrolysis”, and “mediated electrolysis” [11-13]. That is why, we have excluded some topics from this review or only briefly mentioned.

  In the past, organic electrosynthesis was considered “outdated” for use in organic synthesis and was a specialised field of study carried out nearly solely by experts in electrochemistry. After being long neglected in organic synthesis, organic electrosynthesis has noticed a renaissance in academia during the last few decades. The primary explanations for why electrochemistry has been underappreciated by organic chemists are as follows: (i) Its disconnection from organic synthesis when taught to chemists and chemical engineers in undergraduate and graduate courses (primarily as a branch of analytical and physical chemistry) rather than being integrated into lectures on organic chemistry and demonstrated in supplementary laboratory classes. (ii) The prohibitive cost of some electrode material. (iii) The failure of synthetic chemistry laboratories to provide resources for cell assembly. (iv) The limited number of intriguing and general electrochemical reactions that have been reported in the literatures [14,15].

  To summarise, these issues have contributed greatly to electrosynthesis being considered “outside” of standard synthetic organic chemistry and have made it difficult for many organic chemists to set up and optimise electrochemical reactions.

  Despite these difficulties, exploring these narrow domains and branching out into new study topics outside of a particular specialisation has become a growing theme for innovation as a result of the search for synthetic approaches that are better, simpler, and less expensive [16,17]. Technological developments such as in-line analytical equipment [18] and flow and batch reactors [19] have also made a significant contribution to the uptake of electrosynthesis. The field of electro-organic conversions presents a broad outlook for future developments, as more and more organic chemists become aware of its advantages. However, there are some new areas that must consider adhering to “green chemistry” principles, which,to date, are not always taken into account [20].

  Electrode material has also advanced in efficiency [21] and aided in the designing of electrodes. It is evidenced by the availability of boron-doped diamond electrodes which provide a broad potential window for electrochemical reactions [22]. This has led to an exponential surge in study for organic electrochemistry over the last 40 years or so as a way to find new types of chemical transformations, or to substitute thermal processes or chemical reagents [23]. As a result, standardized electrolysis cells are being receiving far greater credit for their merit as a tool in organic synthesis. The following features unequivocally demonstrate the potential of electro-organic synthesis as a technology [24]: (ⅰ) Access appropriate reagents are not readily available. (ⅱ) Electricity can be used to accelerate complex catalytic cycles. (ⅲ) Redox reactions with unfavourable kinetics can be carried out with ease. (ⅳ) The reactivity can be precisely monitored. (ⅴ) High selectivity/no runaway reactions are feasible.

  This review article will discuss a variety of electrochemical processes, approaches and tools, making it an invaluable resource for synthetic chemists, particularly novices in this field. It demonstrates preparative electrochemical setups such as power supply, potential behavior, electrode materials, solvents, electrolytes, cell designs. It will also highlight electrolytic modes (direct, indirect, paired, and alternating electrode), cyclic voltammetry, applications of anodic and cathodic organic transformations and the use of electro-auxiliaries. These points are made more interesting by practical examples. In order to further improve the sustainability and efficiency of synthetic processes, the manuscript also examines how electrochemistry can be integrated with other technologies, such as continuous chemical flow system and photochemistry. Notably, this research deals with the industrial uses of electrosynthesis, which are usually not discussed in earlier studies.

  2. Basic concepts of organic electrochemistry

  Typical components of an organic electrosynthesis system are given in the Table 1. Fig. 1a gives conventional setup of batch electrolysis with all the typical components. Fig. 1b demonstrates various categories of organic chemical reactions such as anodic oxidation, cathodic reduction and paired electrolysis, which utilizes the benefits of the first two procedures [25].

  Table 1

  

  Table 1.  Typical components of organic electrochemical cells.

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  Typical components	Features
  Electric power supply	It supplies either direct current (DC) or alternating current (AC)
  Anode	It is connected to the power supply's positive pole and oxidation occurs at this electrode
  Cathode	It is linked to the power supply's negative pole and reduction occurs at this electrode
  Reaction vessel	It is usually a pot-shaped or H-type cell with a separator if needed
  Reaction solution	It usually consists of substrates and solvents along with electrolytes and other additives if required
  Reference electrode	This additional electrode is needed for complex conversions that need accurate control over the cell potential

  Figure 1

  

  Figure 1.  Basic principles of organic electrosynthesis. (a) Conventional setup for a batch electrochemical cell. (b) Typical categories of organic electrochemical reactions. Reproduced with permission [25]. Copyright 2022, Elsevier.

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  Depending on the experimental setup, electrochemical reactions of organic compounds can occur through many routes, however, in every case, the transfer of electrons converts the starting molecule (RX) into a reactive intermediate and then into the target product (Scheme S1 in Supporting information) [26].

  2.1 Practical electrochemical reaction setting

  Best practice is to keep the initial reaction settings as simple as possible. Typically, anode is made up of platinum or graphite and cathode is made of platinum or stainless steel in initial settings. The reaction mode should be galvanostatic (50 mA, 1–2 F/mol). The concentration of substrate should be 0.05–0.5 mol/L. Usually 0.1 mol/L of tetrabutylammonium tetrafluoroborate (TBABF₄) is taken as an electrolyte. Monitoring of the electrochemical reaction is continuously done using LCMS, TLC, etc. If a batch electrochemical cell setup is applied then the 5 mm of electrode distance, 20 mL of solvent, 0.5 mol/L of solvent, 0.2 mmol of electrolyte, 0.5 mol/L of substrate are used. The reaction time is usually 39 min and electric current is 1.2 F/mol. The electrode size is 10 × 50 mm² with submerged area approximately 10 × 10 mm² (Fig. 2) [27].

  Figure 2

  

  Figure 2.  Initial reaction setting.

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  If there is no current flowing, there can be a connection problem or insufficient electrolyte. Before adding electrolyte, make sure all connection are secure. Add more electrolyte if needed. Reaction time can be shortened or prolonged by current regulation. High current densities can break graphite electrodes and cause heating, affecting reaction outcome. It can be beneficial to increase electrode surface area and current simultaneously.

  The initial potential for a chemical reaction typically ranges from 5 V to 2 V, with variations depending on the electrode spacing (usually 5 mm). To increase resistance, less electrolyte may be used, while high potentials may require additional electrolyte or current reduction. Expanding electrode surface area or adding additives can also boost counter reactions.

  Galvanostatic settings are easier to set up under batch conditions and more reproducible due to direct regulation of electron equivalents. Potentiostatic techniques yield better results when reactions have poor selectivity or no conversion. Both conditions are more reproducible with continuous flow [28].

  Electrochemical processes demand identical electrode positioning, precise setup, temperature and reagent concentration and purity. Accurate and consistent results are guaranteed by interlaboratory reproducibility, which can be assured by reported setups with thorough descriptions.

  Electrode cleaning significantly influences reproducibility, with different materials requiring different approaches. Metal electrodes can be polished using sandpaper such as P1200. Copper electrodes can be cleaned with HCl and acetone. Metal-coated electrodes can be cleaned and wiped down. Platinum electrodes can be cleaned by flame cleaning and glassy carbon electrodes can be polished. The performance of the electrode material affects reaction stability. Stainless steel or Pt as the cathode and glassy carbon or Pt as the anode are examples of mechanically stable electrode materials that can be useful. A glassy carbon electrode can be a useful option [29].

  Analysing the resulting materials will allow for further optimisation of the reaction, similar to what happens in a conventional chemical reaction. The reaction can be performed for a longer period, or the current can be raised to speed up the reaction if there is still starting material available. If undesirable side products are present, increasing electrode surface area, decreasing current, adding more electrolyte, or using a divided cell can improve Faradaic efficiency. CV should be performed to identify issues if the redox system fails to function.

  In Table 2, we have summarised parameter adjustments for electrochemical processes. Supporting information section concerns troubleshooting as we cover common issues that emerge in electrochemical reactions [11].

  Table 2

  

  Table 2.  Brief summary of parameter adjustments for electrochemical processes.

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  Galvanostatic mode (Constant current)	↑ ↓ Electrolyte concentration, surface area, stirring	↓ ↑ Potential and resistance	Constant reaction rate
  	↑ ↓ Electrode gap	↑ ↓ Potential and resistance	Constant reaction rate
  Potentiostatic mode (Constant potential)	↑ ↓ Electrolyte concentration, surface area, stirring	↑ ↓ Current density and reaction rate
  	↑ ↓ Electrode gap	↑ ↑ Current density and reaction rate

  2.2 Preparative electrochemical aspects

  In order to facilitate an electrochemical reaction, the following section attempts to give some general information on the preparative elements of synthetic electro-conversion. Basic concepts are briefly explained and then taken into account whilst selecting a suitable cell design. The most typical cell configurations, preparative challenges, and feasible solutions are described [30].

  Two settings of electrolysis are available for preparative electrochemical conversions (Fig. 3): (ⅰ) Galvanostatic mode, which involves applying a constant current density; (ⅱ) Potentiostatic mode, which involves keeping a constant potential at the working electrode during the electrolysis.

  Figure 3

  

  Figure 3.  Modes of operation for organic electrosynthesis (a) galvanostatic and (b) potentiostatic mode.

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  Further details on these two electrochemical conversion modes are provided, along with explanations on some essential components such as the power supply, electrode materials, supporting electrolytes, and solvents used in the electro-organic synthesis.

  2.2.1   Power supply

  Power is typically supplied through a potentiostat or a battery to overcome electrochemical cell resistance. Potentiostatic or galvanostatic studies (Fig. 3) are used in electroorganic conversion, with galvanostatic reaction mode offering easy setups and scalable reactions. Only two electrode configurations with simple DC devices for rapid and reliable reactions are needed. Exact equivalents of electrons are also known (F/mol). However, in this case, the voltage range is not regulated. Commercially available modern electrical devices that offer a consistent current in the range of 10⁻³–2 A are available.

  Potentiostats and bench-top power supplies can be used to adjust current or voltage in electrochemical analytical techniques like cyclic voltammetry. Researchers are interested in controlling the potential drop at the interface between working electrode’s surface and the solution without introducing another electrode to the solution [31]. Concurrently potentiostats enable the use of a reference electrode, allowing for exact control of the voltage at the working electrode [32]. The working electrode potential can be controlled or measured by using the three-electrode setup. Then, we can examine the fundamental significance of the potential control using Eq. 1.

  $ \mathrm{Sub}_{\mathrm{Red}} \rightleftarrows \mathrm{Sub}_{\mathrm{Ox}}+\mathrm{ne}^{-} $

  (1)

  Sub_Red and Sub_Ox depict a species' reduced and oxidized forms, respectively.

  A bench-top power supply is frequently sufficient for electrochemical syntheses without the need for a reference electrode, and suitable equipment (such as Tenma 72-10480) can be bought for less than £100. A multichannel power supply or an RS232 adaptor for a computer connection are examples of potential modifications [11].

  By regulating the current density and the amount of power transferred, the yield and selectivity of the product can be increased. As applied potential and current density have connections, altering the current density results in a potential change. The starting substrate concentration should be taken into consideration while choosing the current density. The current density should be low while the substrate concentration is low, and vice versa. Eq. 2 makes easy to compute the electrolysis time and amount of electricity passed [31].

  $ \text { current }(\text {A}) \times \text { time }(\text {s})=\text { electricity}(\text {C}) $

  (2)

  On the basis of potential behavior, there are following types of electrosynthesis techniques (Fig. 4): (ⅰ) direct current (DC) electrolysis (Fig. 4a), (ⅱ) alternating current (AC) electrolysis (Fig. 4b), (ⅲ) rapid alternating polarity (rAP) electrolysis (Fig. 4c), and (ⅳ) pulsed electrolysis (Fig. 4d).

  Figure 4

  

  Figure 4.  Potential behavior in existing electrosynthesis techniques. (a) DC (direct current); (b) AC (alternating current); (c) rAP (rapid alternating polarity) and (d) pulsed electrolysis. Reproduced with permission [42]. Copyright 2024, ACS Publications.

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  DC electrolysis uses a single cathode-anode pair with or without a reference electrode. In this approach, electrons move in a single direction and electrode polarity remains unaltered. It has traditionally been used to carry out electrochemical reactions [12]. On the other hand, despite its many applications in daily life, the use of AC in synthetic electrochemistry has received little attention. This may be due to the historical belief that adopting a waveform of that kind would not yield distinctive reactivity or selectivity, as well as the lack of easily accessible instrumentation to lower the engineering barrier to widespread adoption. AC electrosynthesis, a lesser-used approach, uses a sinusoidal waveform of electricity [33-36]. A stirring-free batch reactor is made possible by the use of alternating current, in which uniform electrolysis is produced across the reactor volume by a periodic change in electrode polarity. A simple method for expanding electrosynthesis from parallel screening tests to large-scale preparative electrolysis is suggested by the AC-derived design [35]. For example, AC-mediated Kolbe synthesis [37].

  rAP, which changes an electrode's polarity in milliseconds, is a significant advancement in this field. A square potential waveform is formed when the polarity is reversed at a specific frequency in rAP. Therefore, alternating voltage (V₊₁ at t_POS and V₋₁ at t_NEG) is experienced by a specific electrode during the reaction rather than a resting phase. This technique of current flow, recently incorporated in the extensively used potentiostat, ElectraSyn2.0, offers access to unique reactivity and selectivity in organic synthesis that are very difficult or now unable to obtain by any known approach (chemical or electrochemical). Opening up new possibilities in contemporary synthetic electrochemistry is rAP's exceptional chemoselectivity and ease of use [38]. It is a modified form of AC electrolysis that achieves selective reductions (birch reduction and imide reduction) [39,40].

  Through the application of electrical pulses to the reaction solution, pulsed electrosynthesis produces an active phase (polarization of the electrode) and a resting phase (zeropotential), which enhances mass movement by renewing reactants across the electrode surface. While the resting phase (t_R) in this process is not directly involved in the production of the product, the electrochemical reaction does occur during the active phase (t_A). By charging and discharging the electrochemical double layer electrical double layer (EDL), it was also clear that this method was effective in facilitating the periodic renewal of the diffusion layer to raise the local concentration of reactants. Some of these innovative findings include the adiponitrile synthesis mediated by pulsed electrolysis (using artificial intelligence to generate controlled electricity pulses) [41].

  2.2.2   Electrodes

  One of the most crucial aspects of electrolysis is the electrode material selection because it serves as both an electrocatalyst and an interface for electron transfer with the substrate molecule. A proper electrode material must be carefully chosen because the proposed electrolytic reaction will not progress if an inappropriate electrode material is used [31]. The electric field distribution in the electrochemical cell is influenced by the electrode design, with a homogenous field produced by concentric or coplanar electrode arrangements. Current density and selectivity are influenced by the electric field distribution, with rough electrode surfaces increasing currents at their peaks [43]. The selection of the electrode in terms of surface area, reusability, and components are some of the most crucial elements in an electrochemical organic synthesis design. The availability of non-standardised electrodes, such as aluminium foil, including the wide variety of semiconducting materials available commercially, is a major obstacle in the field of electrochemistry. The outcome of the reaction is greatly impacted by the electrode material selection because the transmission of electrons occurs at electrode surface/reaction solution interface. It should be noted that a “reference electrode” is usually be inserted, however, for preparatory constant potential tests one is not require. Voltammetric measurements are performed using solid electrodes of various shapes (e.g., disks, wires, plates) and sizes (e.g., a few square centimeters for plate electrodes, a few micrometres to a few centimetres in disk diameter). The most common method of making solid electrodes for voltammetric measurements is to enclose the electrode material in a nonconductive glass or inert polymeric sheath, such as Teflon, poly-etheretherketone (PEEK), or poly-chlorotrifluoroethylene (Kel-F). The exposed electrode material is often shaped like a disk (Figs. 5a and b). The typical disk diameters that are sold commercially fall between 1 µm and 1 cm. Spot welding is typically used to join metal plate electrodes to lead wire, which is then enclosed in a nonconductive sheath made of inert polymeric material or glass (Fig. 5c) [31].

  Figure 5

  

  Figure 5.  Different shaped working electrodes. Reproduced with permission [31]. Copyright 2014, Wiley.

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  Electrochemical processes involve simple electron transfers from electrodes to substrates. Three potential results exist in electro-organic syntheses including the use of conventional inert electrode, selectivity achieved by varying electrode voltage, and electro-conversion at the electrode surface [22]. The majority of organic electrosynthesis reactions are conducted on electrodes materials such as graphite [44] or Pt [45] that are intended to be inert under operating conditions (Fig. 6a) [24]. The electrocatalytic technique is crucial for selectively addressing complex compounds, as the actual catalytic function of the applied electrode is often overlooked. Electrocatalytically active species, or immobilised redox-active reagents, are present on the surface of an active electrode (Fig. 6b) [24]. In ideal conditions, an in situ electrochemical regeneration layer that is both compact and electrically conductive is developed [46].

  Figure 6

  

  Figure 6.  Different operation modes of electrodes in electrosynthetic applications. (a) Inert electrode, (b) active electrode, (c) high surface electrode; and (d) sacrificial electrode. Reproduced with permission [24]. Copyright 2020, Royal Society Chemistry.

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  Active electrodes with a redox active layer function as a filter, reducing potential impact and simplifying experimental setups. These electrodes operate at constant current in undivided cells and basic flow cells, but rarely in electro-reductions such as fluorinations and nickel-based anodes for oxidation processes in alkaline medium. A high surface area electrode is illustrated in Fig. 6c [24]. It is an area-structured electrode which could be graphite felt, meshes, RVC foam, and Ni foam, etc. Fig. 6d depicts the sacrificial cathode that is consumed in the electrolysis process [24]. Examples of sacrificial electrode materials includes zinc, aluminium and magnesium, etc.

  Redox-active species in electro-organic synthesis act as mediators and reagents, preventing over-potentials and allowing milder potentials [47]. However, this strategy may lead to increased expenses and waste production. The electrocatalytic properties of electrodes are crucial for yield, selectivity, and stability. These organic conversions are frequently assisted by the intermediates generated by the electrocatalytic conversion of solvent molecules (water and others) [48]. The use of inexpensive materials as electrodes in electro-organic synthesis is obviously a cost-effective solution to this problem. Stainless steel, nickel and cobalt alloys, platinum, graphite, silver, nickel, copper, and other conducting carbons are a few popular electrode materials used in electro-organic synthesis. Inert electrodes are preferred for novel organic synthesis principles.

  In addition to the dense electrode material, porous forms are also utilised. The preferred material for higher electrochemical potentials appears to be doped diamond [49]. Factors such as counter reaction costs, availability, and chemical and electrochemical inertness should be considered when choosing electrode materials [11]. A detailed study of most commonly used electrodes is given below.

  Platinum is an expensive electrode. It is a gold standard catalyst due to its exceptional hydrogen evolution and oxygen reduction catalytic activity [50]. Because platinum has a high level of stability and resistance to corrosion, organic chemists frequently use Pt electrodes in processes to produce superoxide, which attacks organic molecules at electron deficient carbon centres. Pt has been employed primarily as a cathode to increase the cathodic reaction rate in organic synthesis electrochemical reactors. It has also been used to produce a variety of oxygenated hydrocarbons by electrooxidizing organic molecules at the anode. Occasionally, Pt is used as both anode and cathode because of these benefits, which include Shono oxidation, dehalogenation, and inter- and intra-cyclisation processes. Pt exhibits inherent oxygen reduction electrocatalytic activity, which makes it an excellent electrocatalytic material for proton abstraction and oxygen insertion to and from both aromatic and aliphatic molecules. This furthermore suggests that in order to maximise yield and selectivity, one should constantly be aware of the electrode's electrocatalytic properties when aiming to perform targeted organic conversions.

  Carbon electrodes remains the mainstay of electro-organic synthesis, despite the development and establishment of numerous other electrode materials. These carbon systems include glassy carbon reticulated vitreous carbon (RVC) and several forms of graphite. Conductive carbon electrodes are commonly used in a variety of electrochemical processes. The first commercial product to use carbon directly as an anode was the dry cell. Electrochemical energy conversion reactions using carbon materials are extensively researched, however, it has only recently been applied as an electrode in the field of electro-organic synthesis [51]. Carbon in the form of graphite electrode, is a porous material. However, routine cleaning of graphite electrode is very important. It can be used as an anode as well as a cathode. Glassy carbon electrodes are similar to graphite but these are non-porous materials. Reticulated vitreous carbon (RVC) is similar to graphite but contains very high surface area [11]. On the carbon anode, the majority of electrochemical C–C activation reactions operate via a radical cation mechanism. The reason why the carbon surface is more active as an anode in producing carbocations and radicals is that it can stabilise carbon radicals and carbocations and is thus more commonly used in electrochemical oxidation processes, particularly in conversions involving aromatic alcohol, amines, and thiol derivatives. Nevertheless, the behaviour of carbon materials limits their application in abrasive environments, leading to more moderate conditions being employed in which numerous electrochemical C–C activation reactions on carbon materials were carried out [52]. RVC (reticulated vitreous carbon) has been employed as an anode in a number of processes because of its high surface area and appropriate potential zero charge (PZC) [53]. A carbon anode is the preferred medium for C–C bond production via C–C and C–H activation reactions due to its considerable abundance. For carbon-based electrodes, however, the electrochemical stability window is negligible. A small, unexpected error while selecting the potential window for carbon electrodes could have a negative impact and result in a number of undesirable side effects, including the self-corrosion of carbon. Moreover, selectivity shifts toward superoxide generation in non-aqueous protic and aprotic solvents, and carbon-based electrodes are weak at catalysing the complete reduction of O₂ as a cathode. They also tend to generate hydrogen peroxide to a higher extent in aqueous solution. This suggests that, while bearing in mind the electrochemical stability window, carbon can likewise be utilised in oxygen insertion reactions in place of costly Pt. Carbon electrodes may be the only viable sustainable option going forward that does not exhaust essential metals or resources due to poor durability of other electrodes which may experience corrosion or fouling.

  Proton reduction electrocatalytic activity of nickel (Ni) is next to that of the Pt electrode. It is suitable as a sacrificial anode. Both pure metal and its derivatives have been utilised as cathode materials in alkaline water electrolysers [54]. Although Ni has demonstrated proton reduction catalytic activity comparable to that of Pt, its rapid rate of dissolution and consequently low stability prohibit its application in extremely acidic conditions such as H₂SO₄, HCl, HClO₄ [55]. Simultaneously, it was discovered that a mild organic acid, i.e., pivalic acid, was a great catholyte (i.e., an electrolyte in the cathode compartment) for a nickel electrode. Moreover, nickel has been utilised in the direct methanol fuel cell because it has demonstrated strong electrocatalytic activity towards alcohol oxidation in basic solutions [56]. A plethora of investigations to demonstrate the capability of nickel in proton abstraction processes (both aryl and alkyl) has been anticipated to emerge in the near future. However, it cannot be used in place of Pt in severe acidic environments due to its weak stability.

  The polymorph of carbon known as boron-doped diamond (BDD) is extremely resistant to corrosion and highly abrasive. It is resistant to harsh electrochemical and chemical conditions. Despite its extreme scarcity and high expense, it has been extensively employed as an electrode in contemporary electrochemistry to capitalise on its intriguing electrocatalytic properties [57]. Diamond was discovered to be especially effective in alcohol oxidation, where it demonstrated better kinetics than any other material. The incorporation of boron to the diamond adjusts its electrocatalytic activity and maintains diverse chemical intermediates [58]. In addition to demonstrating a strong interest in electrochemical sensors and the elimination of pollution, BDD is also very resistant to corrosion in severe anodic conditions and can tolerate high hydroxyl radical concentrations [59,60]. Because of its strong resistance to corrosion, it is often used in electrochemical oxidation reactions for the elimination of pollutants. Unfortunately, until now, this extremely corrosion-resistant material that can tolerate harsh anodic environments and high hydroxyl radical concentrations has not been widely used in targeted and focused organic transformations powered by electrochemical potential. Due to its remarkable stability and extraordinarily elevated hydrogen and oxygen overpotentials, this electrode has also found application in electro-organic reactions where the hydrogen evolution reaction (HER), oxygen evolution reaction (OER), and oxygen reduction reaction (ORR) exhibit notable toxic effects. As a result, it might be a good substitute for a lot of electrodes that have high levels of HER, OER, and ORR activity, which reduces the rate and yield of the desired organic reaction. Since this electrode offers the widest stable electrochemical potential window in aqueous media compared to other materials, it is anticipated that it can soon be used to perform other kinds of organic conversions. BDD functions effectively as both a cathode and anode to activate C–O bonds in CO₂, phenols, and the C-terminal of peptides [21,61]. This implies that the oxidation of aliphatic, aryl, allyl alcohols, carbonyls, esters, and amides can be driven by this electrode material in both reductive and oxidative pathways. In the near future, this electrode is expected to be widely utilised for a variety of organic transformations involving C–O bonds as well as reactions where HER, OER, and ORR are unfavourable.

  Stainless steel (SS) is an alloy material composed of iron (Fe), nickel, chromium, as well as other elements, developed to prevent corrosion of Fe, which accounts for 65%-95% of the composition. It is inexpensive but it is not suitable as anode because it can get rusty [11]. SS has been applied to a number of electro-organic processes [62-66]. Unfortunately, the application of SS electro-organic transformation is extremely restricted, even though it is a corrosion-resistant material in neutral and basic solution. Because of its oxygen electrocatalytic capabilities, it is anticipated that this material will be used often in electro-organic transformations where oxygen intermediates play important roles [11,67].

  The active alkaline earth and certain d and p-block metals, such as Mg, Zn, and Al, have a high oxidation potential, which makes them useful as sacrificial electrodes in a variety of applications, particularly in corrosion prevention and some recent electro-organic syntheses [68]. These metals are employed as sacrificial electrodes in cathodic protection processes by electrochemically connecting with another material that has to be protected against corrosion (electrochemical oxidation). The cathodic protection of stainless steel using magnesium, in which magnesium serves as a sacrificial anode, is a good example of this context. Instead of anodic metal leaching, ORR and HER now occur at the reductive cathode where previously corrodible (oxidizable) stainless steel would have generally occurred. This prevents corrosion on pipelines made of stainless steel.

  Electrochemical reduction reactions can also be carried out using the same technique, which involves pairing these highly active metals with another metal whose surface enables the desired reduction to take place [69]. Unfortunately, the employment of these sacrificial anodes in synthetic organic conversions under an applied electrochemical potential is discouraged by the high processing cost of alkaline media, alkaline-earth metals, and the development of paired electrolysis. Sacrificial anodes function only as a localised source of electrons and electrochemical potential, which is strong enough to power several organic transformations. Unfortunately, it is difficult to stabilise the voltage that these sacrificial anodes exert at the working electrode due to inadequate control over their rate of dissolution. As a result, the desired reaction rate and yield will be significantly affected. Thus, rather than using catalysts in the form of foams or powder, the use of smooth foils or stripes made of these metals is suggested. Additionally, following a considerable amount of reaction time, the solution has a high concentration of the cation generated by the dissolving of these sacrificial anodes, which hinders and slows down additional dissolution. As a result, the voltage of these sacrificial anodes at the working electrode, which is responsible for catalysing the necessary reduction, would gradually decrease. Therefore, it is proposed that this approach is only valid for fast reactions. A large electrolyte volume cell can be used as a solution to this problem. This allows the user to lengthen the time for which the sacrificial anode exerts a similar voltage at the working electrode. However, in order to lower the reactant, a highly concentrated solution must be used, which will affect the reaction yield.

  To precisely measure the voltage delivered to the working electrode, a reference electrode (RE) can be employed in addition to the working and counter electrodes. Here, the power supply regulates the voltage between the working and reference electrodes, which are typically much closer together and have lower resistance than the working and counter electrodes. The reference electrode measures the potential at the working electrode precisely by using a well-defined redox process (e.g., Ag/AgCl) without intervening in the reaction process. There are various kinds of reference electrodes availableElectrode potential measurement in aqueous solutions is a well-established approach [70]. The primary reference electrode is the standard hydrogen electrode (SHE), which has a zero potential at all temperatures. A saturated calomel electrode (SCE) (Fig. 7a) and a silver–silver chloride (Ag/AgCl) electrode (Fig. 7b) are the most commonly used reference electrodes for practical studies. The technique for determining electrode potential in non-aqueous solutions is still undefined. There is no primary reference electrode, like the SHE for non-aqueous electrolytes, and no reference electrode as reliable as the aqueous Ag/AgCl electrode, which is the most significant issue. However, steps are being taken to improve the scenario. There are two types of reference electrodes that are utilized in non-aqueous systems. An example is an aqueous reference electrode, which is typically a SCE or aqueous Ag/AgCl electrode. However, because the non-aqueous solution has been polluted with both water and the electrolyte (often KCl), it is not advisable to dip the aqueous reference electrode directly into it. The reference electrode should be in a different compartment to avoid this, and the working electrode and reference electrode compartments should be connected by a salt bridge. The salt bridge is dipped into the non-aqueous solution at its tip, which is packed with the non-aqueous electrolytes. An important consideration when using such aqueous reference electrodes is the liquid junction potential between the aqueous and non-aqueous solutions. For this reason, the IUPAC Commission on Electrochemistry suggested that the electrode potential be reported as values referring to the apparent standard potential of the system and that the Fc⁺/Fc couple be measured in the same system. In the alternative approach, the reference electrode's internal solvent is the same solvent as the solution being studied. The most widely used reference electrode in non-aqueous solutions is the Ag/Ag⁺ electrode, which works with a wide range of solvents (Fig. 7c). Despite being commercially accessible, the reference electrodes presented in this section can also be constructed in the laboratory [31]. Interconverting potentials, however, requires caution because a number of factors including solvent and electrolyte material might influence them [71]. The performance of cyclic voltammetry and reproducibility in constant potential reactions depend on the use of a reference electrode. It is necessary to use a potentiostat because standard bench-top power supplies often struggle to control the potential against a reference electrode [11].

  Figure 7

  

  Figure 7.  Examples of reference electrodes: (a) saturated colomel electrode (SCE); (b) Ag/AgCl electrode; (c) Ag/Ag⁺ electrode. Reproduced with permission [31]. Copyright 2014, Wiley.

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  The auxiliary electrode, also known as the counter electrode, is an electrode used in a three-electrode electrochemical cell for voltammetry that allows electrical current to flow between the working and auxiliary electrodes. Thus, when the working electrode is acting as an anode, the auxiliary electrode acts as a cathode, and vice versa. Because of its great stability, platinum (such as Pt wire or Pt plate) is an excellent material for the auxiliary electrode [32]. To ensure that it does not impede the total reaction rate, the counter reaction must be as optimal as possible; selecting a counter electrode that will increase the counter reaction time is vital. This can be accomplished by selecting the appropriate material and increasing the surface area (the surface area of the counter electrode should always be at least as large as the surface area of the working electrode). A sacrificial anode composed of readily oxidised material for reductions can accelerate the counter reaction by generating metal cations. This requires that those metal cations must be tolerated by the desired reaction. Nickel, zinc, and copper are a few examples. There is also a chance for additional sacrificial reactions or oxygen generation. Additionally, it is necessary to encourage the reduction if an oxidation is the desired reaction. The majority of the time, the counter reaction is the generation of hydrogen; the amount of potential required depends on the substance. Adding acids or using protic solvents can help to encourage it [11].

  2.2.3   Solvents

  The choice of a solvent is crucial for electron transport from electrode to substrates. Factors like dielectric constant, dipole moment, accessible potential window and solubility of electrolytes and substrates influence the selection of a solvent [72]. Numerous studies have been conducted regarding the possible range of solvent/electrolyte combinations [72-74]. Solvents and electrolytes can control an electrochemical cell by reducing resistance and increasing conductivity [74]. Key characteristics of electrochemical solvents include their capacity to dissolve ionic salts, polarity, oxidation/reduction ability, acidity/basicity and electrophilic/nucleophilic behavior [75-77]. The solvent window, influenced by the electrolyte species, concentration and other factors determines the stability of the solvent against oxidation and reduction. However, a solvent with a low degradation potential can be utilised if the reaction is carried out inside the window. For example, a reaction carried out at 1.0 V can employ a solvent that degrades at 1.5 V.

  In an oxidation reaction, the solvents oxidative degradation is crucial to avoid competition. Protic solvents, which provide protons for hydrogen reduction, can be useful oxidation solvents. Additional proton sources like acids can encourage counter reactions. In practice, substrate will be consumed first with lower potential than solvent degradation [11]. Few frequently used solvents in different electrochemical reactions are given in the Table 3 [31,32].

  Table 3

  

  Table 3.  Some frequently used solvents in electrochemical reactions.

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  Solvent	Dielectric constant (ε)
  Electrochemical oxidation reaction
  1,2-Dimethoxyethane	3
  Dichloromethane	9
  Propylene carbonate (PC)	64
  Nitromethane	37
  Electrochemical reduction reaction
  Tetrahydro-furan (THF)	7
  Benzonitrile	26
  Hexamethylphosphoramide (HMPA)	30
  N,N-Dimethylformamide (DMF)	37
  Dimethylsulfoxide (DMSO)	47
  Redox reactions due to its high upper and lower potential
  Acetonitrile	38

  Electrochemical solvents are classified into two types: (ⅰ) protic solvents and (ⅱ) aprotic solvents. Further details on types of solvents and environmental impact of solvents are given in Supporting information.

  2.2.4   Electrolytes

  Electrolytes are essential for maintaining charge neutrality in electrochemical cells. Organic solvents are non-conductive, so a supporting electrolyte is needed to maintain low cell resistance. Electrolytes can range from polar solvents to ionic liquids, but must be soluble and form solvent-separated ion pairs for low resistance. During the reaction, electrolytes also help in changing the electrodes surface [13]. The electrolyte's solubility, redox potential window, and ease of separation all play a role in its selection [72].

  Electrolyte recovery and reuse are crucial for the application of green chemistry principles. An electrolyte that is more readily dissolve in water should be readily extracted from the reaction mixture after the reaction. Ionic liquids, made up of ion pairs and are salts in a liquid state at low temperatures, have been developed to increase electrolyte reusability [73,74]. Ionic liquids consist of cations such tetrabutyl ammonium (TBA), pyrrolidinium, piperidinium, and imidazolium ions, as well as anions like [PF₆^-] and [BF₄^-]. These characteristics make it possible to use ionic liquids as solvents and electrolytes. TBA ions and stable cationic entities are essential for cathodic electrolyses, with alkali metal salts being an excellent category. Large cations have minimal chelation interactions with organic substrates. Anionic electrolyte components must be resistant to oxidation. As counter ions, halides like Br⁻ and Cl⁻ can be employed, but if the potential is too high, they may oxidise. In electrochemical synthesis, BF₄⁻ and PF₆⁻ are typically employed as electrolyte counterions since ClO₄⁻ can function as a weak oxidant. However, other counterions including PF₆⁻, BF₄⁻ and ClO₄⁻ are inert in most electrochemical circumstances. Since iodide ions have been found to initiate radical reaction pathways at the anode, they are not appropriate for use as inert electrolytes [75]. Batch reactors require stoichiometric amounts of electrolyte to lower resistance, but purification and atom efficiency may be challenging. In aqueous environments, inorganic salts like KCl and NaCl can be used as supporting electrolytes, but not tetraalkylammonium salts. In practice, the supporting electrolyte concentration should ideally be higher than 0.1 mol/L [31].

  2.2.5   Choosing the appropriate cell design

  An electrochemical cell's design is primarily determined by the kind of experiment being conducted. Materials for the electrochemical cell construction could range from glass (such as Pyrex or quartz) to Teflon or nylon [76]. Nonetheless, the cost effectiveness and inertness to the electrochemical reaction must be considered when designing an electrochemical cell. It is also crucial to remember that during sensitive measurements, the material utilised for building the electrochemical cell cannot interfere. For instance, glass corrosion can occur in systems that have a high pH level or include hydrofluoride. Similarly, a plastic cell may break down in the presence of an organic solvent.

  ■ The undivided cell is achieved by maintaining a space between electrode holders and electrodes, ensuring the separation between them (Fig. 8a). The beaker-type cell could be sealed with a Teflon stopper to produce an inert atmosphere. In addition to transforming substrate A, the bulk electrolysis at the undivided cell can also influence the composition of the counter electrode material. It is crucial to make sure that, at the counter electrode, product B does not revert to substrate A, rendering the electrolysis ineffective [77].

  Figure 8

  

  Figure 8.  Cell design and schematic operating concept of (a) an undivided cell: the preferred and most simple setup; (b) a divided cell: separation of anolyte and catholyte suppress side reactions at the counter electrode; and (c) a quasi-divided cell design with two electrodes that differ greatly in surface area.

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  ■ Divided cells are more complex than the undivided cells, as seen in Fig. 8b. A porous membrane separates two cells in a two-compartment cell, requiring a separator for substrate A’s reaction at the counter electrode. This allowed for paired electrolysis, without separation issues. A conductive substance is required to split the cell compartments, allowing ion transfer across porous membranes while controlling reactant and product transportation. Ceramic frits or polymer membranes are two potential materials for the separator [24].

  ■ The characteristics of divided and undivided electrochemical cells are combined in the quasi-divided cell. A low current galvanostatic electrolysis occurs between electrodes with two distinct surface areas that often make up a quasi-divided cell [78]. Different conditions are applied to the two distinct electrodes (Fig. 8c). Such as (ⅰ) the working electrode undergoes quasi-potentiostatic electrolysis, transforming the material with the lowest redox potential throughout the process. The working electrode experiences a low current density (J = 10 mA/cm²) due to a constant current of I=10 mA. (ⅱ) The counter electrode has a large current density (J ≫ 10 mA/cm²) due to 10 mA flowing in the opposite directions and a smaller surface area. Insufficient mass transfer to the electrode and a relatively low concentration of the starting material prevent solvent electrolysis, preventing a “chemical short-cut” during cell design. Table 4 lists some of the options that need to be taken into consideration during the cell design process [79].

  Table 4

  

  Table 4.  An overview of the differences between standard divided and undivided industrial electrochemical configurations.

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  Parameters	Cell deign
  	Undivided	Divided
  Operation mode	Batch or continuous
  Electrode geometry	2D	3D
  Pair of electrodes	Single	Multiple
  Electrode movement	Static	Dynamic
  Electrode material	Noble metals, carbon, nickel, steel
  Interelectrode gap	Narrow	Capillary
  Electrode connection	Monopolar	Bipolar

  For the readers convenience, the standard notations for undivided and divided cells used in this review are shown in Fig. 9. Each reaction equation specifies the parameters along with the electrolysis modes, which include constant current electrolysis (CCE), constant potential electrolysis (CPE) and constant-voltage electrolysis (CVE).

  Figure 9

  

  Figure 9.  Notations for electrodes and typical (a) undivided and (b) divided cells in this review.

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  2.3 Alternating electrode electrolysis (AEE)

  A revolutionary approach, AEE, enables a three-component electro-photochemical reaction without the need for a catalyst or mediator. It has been shown that pulsed electrolysis and DC are less efficient than the AEE approach for this reaction. In order to conduct an electrochemical reaction in AEE, a four-electrode system (two pairs of anodes and cathodes) have been depicted in Fig. 10a. In this case, one pair of anodes and cathodes is active while the other pair is in the resting phase. In the subsequent instant, the state is reversed, and as a result, the system in a given cell always stays in an active phase (Fig. 10a). As a result, no electrode in the AEE configuration experiences polarity reversal (a cathode, for instance, is either in the cathodic phase or the resting phase). During the resting period, the EDL around the electrode pairs instantly depletes, and during the active phase, it reorganizes. Reactant diffusion around an electrode is improved and mass transfer during a reaction is enhanced while preserving a constant overall potential when counterions migrate back into the solution and to another electrode of the same polarity that is in the active phase (Fig. 10b). This enables increased current density in addition to all the other advantages of pulsed electrolysis [42]. The arrangement of electrodes and practical setup of AEE are given in Fig. S1 (Supporting information).

  Figure 10

  

  Figure 10.  Alternating electrode electrolysis (AEE). (a) Cell setup, AEE cycle (b) cell potential behaviour (combined effect of two pairs of anodes and cathodes. Reproduced with permission [42]. Copyright 2024, ACS Publications.

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  This system uses two pairs of cathode–anode in a single cell to quickly use the photoactivated short-lived intermediates while using the benefits of pulsed electrolysis without the need for a resting period. The BQ radical anion Ⅰ has been generated by first reducing 1 at the cathode. 1 is easier to reduce than the other reactants, such as acetone 3 (−2.5 V) and phenyl diazoesters 2 (−1.74 V). Under a blue LED, the carbonyl functionality of acetone 3 is attacked by the anionic oxygen of 1 to form intermediate Ⅲ, which then reacts with the singlet carbene Ⅲ produced from 2. The final product 4 was generated by further cyclization and oxidation at the anode or by benzoquinone 1 itself (Scheme 1) [42].

  Scheme 1

  

  Scheme 1.  Electrochemical production of monoketal derivative of benzoquinone 4 via alternate electrode electrolysis.

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  Extensive analyses revealed that a significant portion of carbenes split down into undesirable byproducts under other electrochemical reaction conditions, such as DC and pulsed electrolysis. AEE has several advantages, including higher current density, faster utilization of transient carbenes by electrochemically activated intermediates, higher mass transfer, and avoidance of double-reduction or reversible oxidation reactions of benzoquinone 1, leading to higher yield.

  AEE performed better under the same reaction conditions than DC and pulsed electrolysis. Moreover, it has been attempted to produce benzyl amine 6 by reducing benzonitrile 5 using AEE, but this was not practical in DC settings. In another scenario, the hydroxylation of fluorinated acetophenone 7 was successfully accomplished by the stand-alone use of AEE. In the phthalimide 9 process, AEE produced reduced product 10 in excellent yield at 11 F current consumption (Scheme 2) [42].

  Scheme 2

  

  Scheme 2.  Applications of AEE in organic electrosynthesis. (a) Benzonitrile 5 reduction. (b) Hydroxylation of fluoro-acetophenone 7 and (c) phthalimide 9 reduction reaction.

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  It may be claimed that two antiphase pulse electrolysis processes with four electrodes would provide approximately the same integral current as two big electrode pulse electrolysis processes (equal in surface area as four small electrodes). However, since capacitance is directly proportional to the active surface area of the electrodes, as given by the equation C = Aε/l (parallel plate electrodes), where “A” is the active surface area of the electrodes, “l” is the interelectrode distance, and “ε” is the medium's dielectric constant, doing so will double the system's capacitance at any given time. Therefore, more energy is needed to charge this capacitive layer, which raises the amount of energy disposed of in the nonfaradaic event.

  2.4 Scale up of preparative electrosynthesis

  Electro-organic transformations have a long reaction time due to substrate sensitivity to current densities. It hinders the widespread use in organic chemical laboratories due to ease of application and resistance to changes in reaction parameters and consumption of electricity [80]. However, only a small number of electro-organic processes such as the Baizer and Kolbe electrolysis processes are conducted at high current densities [81]. Waldvogel et al. have revealed remarkable advances for the anodic cross-coupling of phenols 12 with arenes 13, which result in the product 14 with exceptional yields of up to 70% and outstanding selectivity at a high current density of 100 mA/cm², thereby significantly reducing the electrolysis time (Scheme 3) [82].

  Scheme 3

  

  Scheme 3.  Robust anodic carbon-carbon bond production with selectivity for the cross-coupling reaction >100:1 at various current densities.

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  Mass transfer and low viscosity of HFIP-methanol mixture enhance its robustness over a two-order current density range. Galvanostatic electrolyses produce desired results without fluctuations, resulting in minimal waste. However, over-conversion of substrates necessitates rigorous workup techniques to avoid undesirable by-products. Focusing on parameter changes for smooth electro-organic conversion is crucial.

  Scaling up electrosynthetic conversions presents challenges like electrode contact corrosion and managing current density and potentials. Bipolar designs, in which electrode material acts as both the cathode and the anode, are preferred over monopolar ones using stacked, parallel, or serial electrode cells. Bipolar configuration provides a consistent distribution of potential and current density without individual contact. Paired electrosynthesis uses bipolar design and flow electrolysis for value-added products. This combination is a well-known example of a successful scale-up on an industrial scale. BASF scientists invent this process. By increasing the number of cells or scaling parameters, flow electrolysis cells offer rapid scale-up [43].

  2.5 Applications of anodic and cathodic organic transformations

  Certain applications of anodic and cathodic organic transformations are given in this section.

  2.5.1   Anodic transformations in water splitting for value-added compounds

  Future societies will undoubtedly rely on methanol or hydrogen to some extent as chemical fuel substitutes for mobility-related purposes. Currently, research is being conducted regarding electrochemical water splitting as a means of manufacturing high-purity oxygen and hydrogen. The overpotential for oxygen evolution in water splitting is still a significant problem [83]. This problem can be solved via the manufacture of high-performance oxidisers in an excellent process as an alternative to forming molecular oxygen. These potent oxidisers have the ability to catalyse additional processes and can be either periodate or persulphate [84]. In this case, organised methods are needed for the oxidisers recovery and recycling (Fig. 11).

  Figure 11

  

  Figure 11.  Synthetic applications of anodic production of high-performance oxidisers during water splitting. Reproduced with permission [24]. Copyright 2020, Royal Society of Chemistry.

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  The anodically enabled electrochemical transformations have been utilised much more than the cathodic reduction-driven ones, despite the conceptual appeal of both methods.

  2.5.2   Cathodic organic transformations

  This section provides an overview of the recently developed reductive electrosynthetic protocols in an effort to promote the development of cathodically enabled organic processes. Research on reductive transformations at the cathode is less common, even though cathodic reductions using safer, sacrificial reductants in milder conditions is clearly a desirable substitute for the conventional protocols that use potentially dangerous reductants such as H₂, low-valent metals, metal hydrides, boranes, silanes. However, there are few high-efficiency, highly selective practical preparative procedures available. The basic limitations of the cathodic processes, such as the competing proton/O₂ reduction with the expected transformations and electrode passivation under severely decreasing potentials, are partially accountable for this situation. When compared to the hydrogen evolution counter-reaction for anodic transformations, finding appropriate anodic counter-reactions is similarly a challenging task [85]. Cathodic reduction-enabled processes have gained attention due to the revival of total organic electrosynthesis and the invention of new techniques. R–X bonds are frequently subjected to electro-reductive cleavages. According to Scheme S1, the overall reaction produces a radical R^• and an anion X^- through a dissociative electron transfer. The radical is then typically reduced to the corresponding carbanion R^-. There are several uses for these cathodic cleavages in environmental, synthetic, and analytical fields [86]. For example, it has been reported that electrochemical hydrogenation has been investigated as a safer substitute for catalytic hydrogenation. This alternative technique is based on a multistep mechanism wherein an organic component is first adsorbed onto the metal surface, and then the organic molecule is electrocatalytically hydrogenated [87]. The two-electron reduction of acetophenone 15 to 1-phenylethanol 16, which has various uses in the fine chemical and pharmaceutical sectors, was studied by Sáez et al. [88,89]. With 2 F charge and 10 mA/cm² current density, the hydrogenation process utilising Pd/C 30 wt% in ethanol solutions with different loadings as cathode and a hydrogen gas diffusion anode to demonstrate a 90% selectivity. The reaction between the atomic hydrogen adsorbed on the Pd surface and the acetophenone 15 adsorbed on the carbonaceous support provides a tenable explanation of the mechanism of the electrocatalytic hydrogenation of 15, in accordance with Ménard and his coworkers [87,90,91]. Ultimately, when the Pd catalyst loading rises from 0.025 mg/cm² to 0.2 mg/cm², the current density of these processes increases as well. When acetophenone was electrocatalytically hydrogenated, only 1-phenylethanol was obtained as main product while, ethylbenzene and hydrogen were found as byproducts. A decrease in the rate of hydrogen oxidation is also brought about by the presence of 1-phenylethanol in the solution; however, this effect is not seen when ethylbenzene is the sole substance present. Thus, it appears that ethylbenzene can also be hydrogenated from 16 produced by electrocatalytic hydrogenation of 15. The benzene ring does not hydrogenate under these circumstances. The evolution of hydrogen is the competitive reaction in electrochemical hydrogenation, which often excludes the use of high current densities. To lessen the impact of current efficiency on the feasibility of the synthesis of 16, this hydrogen was oxidized in a gas diffusion electrode as an anodic reaction. The energy cost decreases along with the potential used for the synthesis. Hydrogen that supplies the gas diffusion anode needs to be supplemented with some hydrogen gas from other sources (Scheme 4). In order to facilitate an industrial scale-up of the electrochemical process, electrochemical reduction was performed in a PEMER (polymer electrolyte membrane electrochemical reactor), which has a fuel cell structure (Fig. S2 in Supporting information).

  Scheme 4

  

  Scheme 4.  Electrochemical production of 1-phenylethanol 16.

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  2.6 Paired electrolysis

  The paired electrochemical process, a method that minimizes energy and chemicals needed, generates less waste, and uses power more efficiently, is being used in industrial applications such as metal refinement and the production of chlorine and sodium hydroxide [92]. This method is based on adsorbed oxygen or hydrogen species, enabling electrocatalytic hydrogenation and electrocatalytic oxidation [93]. It is preferable to “pair” the anodic and cathodic electrode reactions, allowing for more intricate reaction routes involving oxidation and reduction [94].

  Better energy efficiency and a simpler reactor design are made possible by the paired electrosynthesis technique. Fig. 12 gives the overview of paired electrolysis. In case A, the electrode processes are independent (e.g., when creating innocent or sacrificial side products, or when forming divergent products from one or two substrates). In case B, when two electrode processes are coupled, the anode and cathode both contribute to the production of the product [95]. Paired electrosynthesis using independent electrode reactions can be categorised as either “divergent” or “convergent” based on the way that in which products are produced. The distance between electrodes when anode and cathode processes are coupled might be wide (having separate diffusion layers for each electrode) or narrow (having overlapping diffusion layers). Regarding reactor design and chemical complexity, there are potential advantages and disadvantages in each of these scenarios. Case A is widely used because it allows for some of the benefits of pairing processes to still be realised despite the minimal complexity of the chemical processes. Case B is preferable, particularly for “self-supported” reactions that do not require additional electrolyte and for very tiny gaps between the anode and cathode (refer to infra). This eliminates the need for an electrolyte separation step, reduces waste, and may provide purer products.

  Figure 12

  

  Figure 12.  Overview of paired electrosynthesis. Reproduced with permission [92]. Copyright 2021, Wiley Online Library.

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  Scheme 5 provides an illustration of paired electrosynthesis. A Substrate can be electrochemically reduced to produce its corresponding Sub^–·, which then transforms into an intermediate, Int-1. It is possible for the Int-1 to be oxidised at the anode surface during an electrochemical reaction that is conducted in an undivided cell, forming Int-2, a second intermediate that subsequently produces the product. Only electrical energy is used in this electrochemical process.

  Scheme 5

  

  Scheme 5.  Paired electrolysis of product.

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  With a broad variety of substrates and easy scale up, paired electrosynthesis can be conducted in a simple undivided cell without the need for an external supporting electrolyte. Scheme 6 suggests and illustrates two possible routes for the electrochemical arylation of C(sp²)–H using aryldiazonium salts. The product 19 was produced in 53% yield (1.82 g (10.6 mmol)) when 20 mmol (1.92 g) of 17 was mixed with 40 mmol of aryl diazonium salt 18 using a circulation pump in conjunction with an undivided cell that was fitted with graphite as anode and cathode. The electrochemical procedure may be helpful in small-scale industrial settings because the gram scale reaction time is comparable to the small scale. Consequently, the aryl diazonium salts first undergo reduction at the cathode surface, producing corresponding phenyl diazo radicals Ⅰ. After molecular N₂ is lost, pyrazin-2(1H)-one 17 and its subsequent aryl radical Ⅱ combine to form radical intermediate Ⅲ. The corresponding product 19 is then obtained by oxidising intermediate Ⅲ at the anode (pathway 1). Apart from the paired electrolysis pathway, intermediate Ⅲ also generates Ⅰ and experiences homogenous electron transfer in solution with the aryldiazonium salts, followed by the loss of a proton that results in product 19 (pathway 2). Only a catalytic amount of charge is needed because the radical chain reaction also causes the generation of phenyl diazo radicals Ⅰ [96].

  Scheme 6

  

  Scheme 6.  Gram-scale electrochemical production of 19 and its proposed mechanism.

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  Succinic acid 21 is a significant chemical raw material that finds extensive application in the industries of fine chemicals, resin, medicines, and insecticides. Succinic acid 21 has been employed extensively in the domains of organic coatings, biodegradable polymers, and polybutylene succinate (PBS) in recent years. The Supporting information discloses a method for producing sulphuric acid and succinic acid by paired electrolytic synthesis [79]. Fig. 13 shows a schematic diagram of the experimental apparatus used in this invention while, the present inventions process flow diagram is shown in Fig. S3 (Supporting information).

  Figure 13

  

  Figure 13.  Schematic representation of an experimental device. Reproduced with permission [79]. Copyright 2020, Royal Society of Chemistry.

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  The following section will provide a brief discussion and example of each of these four options using a single, selected example from the literature. There are review articles available for comprehensive details and more examples.

  2.6.1   Parallel paired electrolysis

  When two starting materials undergo transformations concurrently, it is referred to as parallel paired electrolysis. One substrate is reduced at the cathode, and one is oxidised at the anode. This results in the formation of two useful products, and this kind of electrolysis can theoretically be carried out in both divided and undivided cells (Scheme 7). Naturally, using an undivided cell will reduce the issue of separating leftover products from starting materials. On that note, a patent for a parallel paired electrolysis in an undivided flow-cell was filed by the BASF Company in 1997. Two important products were obtained annually on a multi-ton scale in well-balanced reactions, where the side products (protons and methanol) of the individual electrode reactions are necessary for the reaction at the counter electrode (Scheme 7) [97]. Their other difficulty was industrial separation, which BASF also managed to overcome. Products 23 and 25 can be utilized to produce insecticides [98].

  Scheme 7

  

  Scheme 7.  Operational design and example of practical application of parallel paired electrolysis.

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  It should be emphasised that laboratory work-up techniques such column chromatography are not appropriate on an industrial scale, which is defined as the utilisation of more than one ton of starting material per electrolysis. Additionally, various cell designs are significant [81].

  2.6.2   Divergent paired electrolysis

  Divergent paired electrolysis can only be used with starting materials that have the potential to provide both reduced and oxidised products (Scheme 8). There are very few functional groups that can permit such a transition, and it is important to keep in mind that the corresponding products may react with one another to produce additional, perhaps unintentional byproducts. For example, 5-(hydroxymethyl)furfural (HMF) 26 can be converted to biobased monomers for the manufacture of polymers. This method shows that, in a paired electrochemical cell, HMF may be effectively converted to two significant biobased polymer precursors, 2,5-bis(hydroxymethyl)furan (BHMF) 27 and 2,5-furandicarboxylic acid (FDCA) 28. The cathode catalyst for the electrocatalytic hydrogenation of 26 to 27 is self-prepared Ag/C. Moreover, the bulk HMF concentration and cathode voltage affect the selectivity and efficiency of BHMF production. Additionally, it has been demonstrated that the carbon support material in Ag/C was active for HMF reduction at cathodic potentials more negative than approximately -1.2 V, which resulted in low BHMF selectivity and hydrodimerization to BHH. The use of ACT as a homogenous electrocatalyst to promote indirect HMF oxidation at the anode is a crucial component of this methodology. It is possible to pair the half-reactions of HMF hydrogenation and oxidation in a single divided cell that is controlled by cathode potential since the selectivity of ACT-mediated HMF oxidation is independent of anode potential. High yields of BHMF 27 and FDCA 28 (85% and 98%, respectively) and a total electron efficiency of 187% are obtained in the paired cell through electrocatalytic HMF 26 conversion, which is roughly two times more efficient than in the unpaired cells. This method demonstrates the possible advantages of employing paired electrochemical cells in the manufacture of chemicals in a sustainable manner [99].

  Scheme 8

  

  Scheme 8.  Schematic representation and a practical example of the application of a divergent paired electrolysis.

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  2.6.3   Convergent paired electrolysis

  A single electron added to an electrophile (e.g. R-Hal) will produce a radical (R^•), while another single electron transfer (SET) will produce a nucleophile (R^-) from the starting material. Based on the substituents bonded to the carbon atom in the starting material or the electrolytic reaction conditions, the abstraction of electrons from a nucleophile (e.g., R^-) leads to the creation of a radical (R^•) or a carbenium ion (R⁺). Thus, when a cathodic reaction produces a nucleophile and an anodic reaction provides an electrophile, convergent paired electrolysis can be achieved (Scheme 9).

  Scheme 9

  

  Scheme 9.  Schematic representation and an example of a practical application of a convergent paired electrolysis.

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  Examples of radical-based redox-neutral cross-coupling via convergent paired electrolysis are exceedingly rare, despite the fact that electrochemistry is one of the most appealing ways to encourage SET events. This is primarily because radical species are transient and typically do not have a long enough lifetime to travel to the opposite side of the electrolysis cell. It has proven possible to produce benzylic amines 31 by direct arylation of tertiary amines 29 and benzonitrile derivatives 30 at room temperature using a metal-free, convergent paired electrolysis technique. Without the need for metals or stoichiometric oxidants, this TEMPO-mediated electrocatalytic reaction fully utilizes anodic oxidation and cathodic reduction, demonstrating its enormous potential and benefits for useful synthesis. With cathodically produced species, this convergent paired electrolysis approach offers a simple and effective way to realise cross-coupling and activation of C–H bonds (Scheme 9).

  When convergent paired electrolysis occurs, mass transfer of reactive species from the electrode surface to the bulk solution is more important than in conventional electrolysis. In scale-up experiments, this has been revealed as the key component. A three-electrode system, RVC(+)-RVC(−)-RVC(+), was employed, with the spacing between each electrode being as close as practically possible to maximise the concentration of α-amino radicals at the anode and the collision frequency of anodic and cathodic intermediates. This allowed for the gram-scale electrochemical arylation to be carried out on a 10 mmol scale, yielding a synthetically useful yield of 31 (1.52 g). 2.94 g (20 mmol) of 1-phenylpyrrolidine 29, 1.28 g (10 mmol) of 1,4-dicyanobenzene 30, ⁿBu₄NClO₄ (5.25 g, 0.1 mol/L), TEMPO (0.16 g, 1.0 mmol), 1,4-lutidine (2.4 mL, 20 mmol) and 150 mL DMA were mixed. For 0.5 h, N₂ bubbled was through the reaction mixture. After assembly, the electrode was inserted into the solution. N₂ was added to the reaction three times after it had been degassed. The mixture was electrolysed for 10 h at a continuous current of 100 mA. 150 mL of ethyl acetate was used to dissolve the combined mixture. It was filtered, concentrated under low pressure, dried over Na₂SO₄, and cleaned with H₂O (200 mL × 2). Using silica gel column chromatography, the resultant crude product was refined to produce 31 (1.52 g, 61%). It should be mentioned that a batch electrochemical setup was used to achieve this electrochemical redox-neutral radical-radial coupling in synthetically practical yields. The success of this electrolytic system may be attributed to the use of a redox-active electrocatalyst, which marks the development of homogeneous, relatively stable carbon-centred radical Ⅰ processes, as well as the persistent radical nature of the radical anion Ⅲ produced at the cathode [100].

  2.6.4   Sequential paired electrolysis

  Sequential oxidation and reduction reactions at the anode and cathode (or vice versa) yield the product in sequential paired electrolysis. A catalyst-free electrochemical decarboxylative coupling of NHP esters with N-heteroarenes was described by Lei, Shi, and coworkers in 2019 (Scheme 10) [101]. Model substrates used were 4-methylquinoline 32 and NHP ester 33. This reaction was remarkably amplified to the gram-scale in a continuous-flow setup with an attempt to decrease the reaction time. This protocol shows that the flow system had a good isolated yield and a greater faradaic efficiency [101]. 33 (4.10 g (15 mmol), 2 equiv.), ⁿBu₄NBF₄ (1.64 g (5 mmol), 0.05 mol/L), 1.94 g (11.25 mmol), 1.5 equiv. of p-TsOH, DMA (100 mL) and 32 (1.07 g (7.5 mmol), 1 equiv.) are mixed were electrolysed at room temperature for 45 h with a continuous current of 10 mA after stirring for 10 min. Saturated aqueous sodium carbonate was used to quench the reaction. EtOAc was used to extract the organic layer, which was then dried with anhydrous Na₂SO₄, filtered, and concentrated under low pressure. Using flash column chromatography on silica gel, the pure product 34 was afforded, yielding 71% of the isolated yield (1.2 g). Scheme 10 depicts the potential mechanism for the electrochemical decarboxylative cross-coupling reaction based on the aforementioned experimental findings. Prior to undergoing decarboxylation to produce the corresponding alkyl radical Ⅱ, the NHP ester 33a was able to extract one electron from the cathode to produce a radical anion Ⅱ. The protonated quinoline might then be attacked by the alkyl radical to create a new C–C bond Ⅲ. In the end, the produced radical lost a proton and an electron on the anode to produce the desired product 34a.

  Scheme 10

  

  Scheme 10.  Schematic representation and an example of a practical application of a sequential paired electrolysis.

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  2.6.5   Linear paired electrolysis – The 200% cell

  Furthermore, a brief discussion of linear paired electrolysis, a fascinating and potentially challenging method of creating product by oxidizing or reducing a starting material is given in Scheme 11.

  Scheme 11

  

  Scheme 11.  Schematic representation and an example of linear paired electrolysis via oxidation of hydroxylamines 35.

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  This is not feasible unless a mediated process is used to produce a potent reducing or oxidising agent at the anode or cathode, respectively. The introduction of a cathode material that transformed molecular oxygen into H₂O₂ under reductive conditions was a crucial step in this kind of paired electrolysis [102]. The authors then suggest that, at the electrolysis scenarios, H₂O₂ combines with tungstate (WO₄^2-) I to form pertungstate (WO₅^2-) Ⅱ, which is a useful oxidising agent. The electrochemical processes are then completed on the anode by the production of bromine from the bromide anions-containing supporting electrolyte (NaBr). Two electrons overall crossed the electrochemical cell, producing four electron oxidants (Br₂ and WO₅^2-). Thus, a current yield of up to 200% might be achieved by passing just two electrons through the solution (and with some assistance from ambient oxygen); in the example given, a current yield of 185% was observed. Prior to the untimely death of Professor Eberhard Steckhan, his successor in the Steckhan group achieved the highest current yield to date (up to 195%), which was documented in a diploma thesis [103]. Therein, it is stated that furan is indirectly oxidised by reducing oxygen to H₂O₂ at the cathode and oxidising bromide to bromine at the anode in methanol solution, both of which are accomplished by use of the phenanthrolin-dione mediator type. It is clear that there are several potential reactions in the reaction sequence depicted in Scheme 11, each of which has a relative rate of reaction. Maintaining a balance between these relative rates is crucial for the effective production of the desired product during paired electrolysis [104].

  A significantly reduced yield of 92% (ce: 184%) on a 2.5 mmol scale was obtained through larger-scale bromination for 38 (Scheme 12) [103].

  Scheme 12

  

  Scheme 12.  Bromination of cyclohexene 37 by linear paired electrolysis.

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  2.7 Direct and mediated organic electrosynthesis (electrocatalysis)

  Molecules can transmit electrons to the electrode surface via direct electrolysis (Fig. 14a), but large over-potentials can occur due to kinetic hindrance. Organic species can decrease electrode surface conductivity, leading to conductive polymer films. In the worst case scenario, an isolating film forms and the galvanostat/potentiostat responses, requiring manipulation through cell designs and electrochemical condition [105].

  Figure 14

  

  Figure 14.  A comparison of schematic principles of (a) direct and (b) indirect electrolysis.

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  An indirect electrolysis may be useful in these situations where the heterogeneous electron transfer is problematic. The drawbacks of direct electrolysis can become more obvious when electrochemistry is used to synthesize and modify complex organic compounds. Nevertheless, redox-active catalysts can be used to overcome these limitations [47]. The electron-transfer shuttle in indirect electrosynthesis moves from the heterogeneous electrode surface to the homogeneous dissolved substrates through a redox mediator that is more readily oxidised or reduced than the substrate [106]. Redox catalysts, also known as mediators, are used for this purpose in order to move electrons from the electrode to the starting material (Fig. 14b).

  The indirect electrolysis approach uses redox catalysts as homogeneous electron transfer mediators, removing kinetic inhibition and providing direct control over selection. This method boosts atom economy, reduces energy consumption and improves energy efficiency, allowing reactions to occur at less positive or negative potential. It is possible to lower the overpotential of electron transfer, leading to milder reaction conditions and greater tolerance to functional groups [47].

  The processes of indirect electrolysis, also known as electrocatalysis, can use an electrode surface directly (known as heterogenous electrocatalysis) [107] or molecular mediators as catalytic species, such as transition metal complexes or redox-active organic compounds (known as molecular or homogenous electrocatalysis). The former scenario, comprising a catalytic electrode, is traditionally defined as “electrocatalysis” [108]. Energy storage in the chemical industry is made attainable via electrocatalysis [109].

  There are a few current examples of industrial uses for electrocatalytic techniques, for example, due to its potential to alleviate CO₂-related environmental issues while employing clean energy and creating high-value products, research on the electrocatalytic CO₂ reduction reaction (eCO₂RR) has garnered a lot of attention recently. Additional criteria have been suggested for eCO₂RR research in order to apply it to the industrial setting. These include long-term stability, high product selectivity (above 90%), and high current density (over 200 mA/cm²). It is essential to systematically design and optimise the eCO₂RR system in order to meet these objectives. In eCO₂RR, potential industrial products are suggested (Fig. 15). These products, which include ethanol, carbon monoxide, formic acid, and ethylene, are in great demand on the market and have demonstrated strong product selectivity and current density in theoretical studies. The three-electrode system functions in the electrolyser and is essential to the overall setup of the eCO₂RR cell. Developing a sensible eCO₂RR cell configuration is crucial for accelerating the commercialisation of eCO₂RR, particularly with regard to the electrodes and the electrolyser. Among the several carbon dioxide reduction catalysts, carbon-based catalysts, SACs (single-atom catalysts), copper-based catalysts, and molecular catalysts have the most potential for industrial applications [110].

  Figure 15

  

  Figure 15.  Economic analysis of carbon dioxide reduction products. The prices of various products are derived from the current international market prices. eCO₂RR, electrocatalytic CO₂ reduction reaction. Reproduced with permission [110]. Copyright 2023, Wiley Online Library.

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  Numerous homogeneous ETMs, such as halides, amines, benzoquinones (DDQs), transition metals, N-oxyl radicals, and hypervalent iodine species, have been established. Redox catalysts include arylimidazoles [111], triarylamines (Ar₃N) [112], quinones [113], transition metal ions (Co^Ⅱ/^Ⅲ, Fe^Ⅱ/^Ⅲ, etc.), and many more [114]. Numerous mediators including ferrocene, hypervalent iodine reagents, and derivatives of 2,2,6,6-tetramethylpiperidinyl-1-oxyl (TEMPO) have been used in a number of anodic operations [115-117]. Halide salts, on the other hand, are usually preferred over these in industrial operations because they are simpler to utilise and can be extracted from reaction mixtures with ease [19]. The literature has comprehensive reviews on the application of redox catalysts [7]. One such example being the moderate electrochemical α-oxygenation of benzamides in an undivided cell using oxygen gas as the oxygen supply, as illustrated in Scheme 13. The ¹⁸O labelling and radical scavenger studies demonstrated the existence of a radical pathway. This is the gram-scale methodology which is free of bases and metals. N-Hydroxyphthalimide (NHPI) is a powerful electrochemical mediator that has been widely employed in the oxidation of the C(sp³)−H bonds [10,118]. N-Benzylacetamide 39 was employed as a benchmark substrate for the reaction conditions which, for optimal performance, included platinum plate (Pt) as the cathode (-), graphite plate (C) as the anode (+), NHPI as the redox mediator, 2,4,6-colidine perchlorate (0.01 mol/L) as the electrolyte, an undivided cell with acetone as the solvent, and 1 atm of O₂ at room temperature. Benzimide 40 is produced with an 89% yield using this process [119]. Scheme 13 also provides the gram scale manufacturing of corydaldine 41. The electrolyte 2,4,6-collidinium Ⅱ undergoes cathodic reduction, yielding 2,4,6-collidine Ⅰ and hydrogen gas. On the other hand, NHPI Ⅴ uses 2,4,6-collidine Ⅰ to help it lose a proton in order to produce N-O negative ions Ⅲ. After intermediate Ⅲ undergoes anodic oxidation to yield PINO radical Ⅳ, a benzylic proton is abstracted from substrate 39 to yield benzylic radical Ⅵ. Molecular O₂ can extract a benzylic hydrogen atom from this radical to form peroxy radical Ⅶ, which traps the radical to produce the intermediate hydroperoxide Ⅷ. Benzimide 40 is generated when Ⅷ is dehydrated.

  Scheme 13

  

  Scheme 13.  Gram-scale electrochemical production of benzimide 40 and its proposed mechanism.

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  2.7.1   Organo-electrocatalysis

  Organocatalysis has revitalized with remarkable success for producing novel and challenging organic transformations in the very stereo-selective manners. It seems difficult to achieve exciting organic transformations without catalytic systems, yet organocatalysis has recently demonstrated extraordinary compatibility with electrochemistry. The use of organo-mediators has several benefits and may result in the development of new organic transformations. This technique could solve a number of practical problems pertaining to organic synthesis [120]. Such mediators contribute in the transfer of electrons between the substrate and the electrode, which in turn affects the selectivity of electrosynthetic methodology. Since the supporting electrolyte and mediators are both costly and unproductive, it is extremely desirable for industrial applications to reuse and recover them in terms of different cycles [121].

  Cumulenes are organic molecules with several consecutive double bonds. Phillip J. Milner et al. discovered that these molecules can act as catalytic redox mediators for the electroreductive radical borylation of (hetero)aryl chlorides at relatively low cathodic potentials (about −1.9 V vs. Ag/AgCl) without photoirradiation. The borylation of 8 mmol of ethyl 4-chlorobenzoate (42, E_p/2 = −2.40 V vs. Fc/Fc⁺) as a model reaction using 2.0 equiv. of bis(pinacolato)diboron (B₂Pin₂) 43 as the radical trap was performed in order to examine the viability of chloroarene electroreduction employing cumulene-based mediators. 1.67 g of corresponding boronate ester 44 can be obtained in 62% yield by using 1,1,6,6-tetraphenylhexa-1,2,3,4,5-pentaene (Ph₄-5-CML) Ⅰ as the redox mediator, pyridine (py) as an additive, tetrabutylammonium hexafluorophosphate (TBAPF₆) as the electrolyte, porous carbon as the cathode, zinc as a sacrificial anode, acetonitrile (MeCN) as the solvent, and an applied cell potential of 2.5 V at room temperature. According to the suggested process, at relatively low cathodic potentials, electrogenerated Ⅱ catalyzes thermodynamically uphill SET to the haloarene substrate Ⅳ. A reactive aryl radical intermediate Ⅵ is created after the haloarene radical anion Ⅴ rapidly fragments and Ⅲ reforms. To give the required aryl boronate product 44a, this radical is trapped with a stabilized boryl radical Ⅱ’ (Scheme 14) [122]. Fig. S4 (Supporting information) demonstrates the practical setup for the gram scale organo-mediated electrochemical synthesis.

  Scheme 14

  

  Scheme 14.  Gram-scale organo-mediated electrochemical production of boronate ester 44 and its proposed mechanism.

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  There are a few recent examples of oregano-mediated large scale electrosynthesis. For example, Richard C. D. Brown et al. reported electro-reductive radical cyclisation of aryl halides in an undivided flow cell utilizing phenanthrene as a mediator (0.05-1.0 equiv.) without the need for a sacrificial anode. The practical utility of cathodic radical cyclization is increased by the fact that a dissolving metal anode is not required and that the mediator can be used in a sub-stoichiometric amount (0.05 equiv.). A commercial narrow gap, prolonged path flow electrolysis cell with a stainless steel (SS) cathode and a glassy carbon anode was used. 1-(Allyloxy)-2-iodobenzene 45 was cyclized on a 0.5 mmol scale in MeCN with Et₄NBF₄ as the supporting electrolyte (flow rate 0.25 mL/min; run period 20 min). The flow process is easy to scale up in the lab using the same reactor (Scheme 15a). The cyclization to give nitrile 46 was carried out on a 25 mmol scale generating a 71% yield. Tricyclic fused and spiro systems are obtained by applying this approach to O-, N-, and C-tethers. The primary pathway in the absence of a mediator is the cathode's 2e⁻ process of hydrogenolysis of the C-X bond. It is consistent with homogeneous electron-transfer in a reaction layer that is separated from the cathode surface, where the flux of phenanthrene- leaving the electrode is such that little aryl halide reaches the cathode, that the radical pathway predominates in the presence of a strongly reducing mediator (phenanthrene) [123].

  Scheme 15

  

  Scheme 15.  Examples of organo-mediated electrochemical production.

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  Similarly, the electroreductive carboxylation of organic carbon-halogen bonds (X = Br and Cl) facilitated by catalytic amounts of naphthalene as an organic mediator was also reported by Wang et al. Without the use of expensive transition metals, wasteful stoichiometric metal reductants, or sacrificial anodes, this transformation proceeds easily in mild circumstances with a wide range of substrates, yielding the valuable and versatile carboxylic acids in moderate to good yields. Its synthetic value is demonstrated by late-stage carboxylations of pharmacological and natural product derivatives. Mechanistic investigations verified that naphthalene played a crucial part in this reaction and that carbon-halogen bonds were activated through single-electron transfer. An undivided cell including a Pt cathode and a graphite felt anode was used for the electrocatalysis. 2.33 g of 4-bromo-1,1′-biphenyl 47, 384 mg of naphthalene, 5.56 mg of TBD, and 3.29 g of ⁿBu₄NBF₄ were introduced to an electrochemical cell fitted with a magnetic bar. A syringe was then used to add 100 mL of anhydrous DMF after the tube had been drained and back-filled under CO₂ flow three times. Using a CO₂ balloon at room temperature, the electrocatalysis was carried out for 30 h at 60 mA. Following that, 2.0 N of HCl_(aq) was used to acidify the reaction mixture. The carboxylation product 48 (67%, 1.33 g) was obtained by purifying the crude product using column chromatography (Scheme 15b) [124].

  The deuterium isotope effect is widely used, however selectively labeling chemical compounds with deuterium is still quite difficult. By using deuterium oxide (D₂O) as the cost-effective deuterium source, Qiu et al. developed a simple and efficient electrochemically driven, organic mediator-enabled deuteration of styrene 49. It is significant that this transition may work well for different electron-rich styrenes that are mediated by triphenylphosphine (TPP). The reaction produced the necessary products in good yields with outstanding D-incorporation (D-inc, up to >99%) under mild conditions without the use of transition-metal catalysts. This approach was sufficiently supported by mechanistic investigations using cyclic voltammetry tests and isotope labeling procedures. Interestingly, this technique turned out to be an effective means of deuterating biorelevant compounds at a late stage. An undivided cell including a Pb cathode and a graphite felt anode was used for the electrocatalysis. The electrochemical cell was filled with 1.60 g of 4-tert-butylstyrene 49, 524.6 mg of TPP, 10.0 g of D₂O, and 1.29 g of Et₄NI. 40 mL of anhydrous DMF was then added. At room temperature, the electrocatalysis was carried out for 24 h at a constant current of 200 mA. Column chromatography was used to purify the crude product, yielding the intended product 50 in 63% (1.04 g) (Scheme 15c) [125].

  2.7.2   Metalla-electrocatalysis

  Transition metals are attractive catalysts due to their adjustable redox potentials and versatile reactions. Conventional methods produce unwanted by-products, making a catalytic control strategy with metals more effective for achieving chemo-, region-, and stereo-selectivity. However, indirect electrolysis reduces the possibility of negative reactions while increasing the potential range. Here, we offer a practical example of the metalla-electrocatalysis process. The electro-oxidative C–H transformations in the presence of metal catalysts are characterised by better chemoselectivies with a broad tolerance of sensitive functionalities. Furthermore, the integration of metalla-electrocatalysis with flow and photochemistry will allow for safe and effective scaling up in the future and might potentially enhance reaction kinetics, timings, and yields to tackle challenges related to green chemistry and sustainability [121,126]. Many new reaction pathways were discovered as a result of the combination of transition metal catalysis with electrosynthesis, which allowed for innovative resource-economic bond functionalisations [127]. By coupling potent metal catalysts with sustainable electrosynthesis, electrochemical metal catalysis greatly increased the potential applications of electrosynthesis [128]. This approach is a desirable way to facilitate C–H and C=C functionalisation [10,121,129,130] and cross-coupling [131,132].

  For example, a nickel catalysed electrochemical reaction is given in the Scheme 16. Significant synthetic potential would be achieved in this protocol; a special SET catalytic cycle is produced by nickel catalysis which may be an appealing means to facilitate cross-coupling reactions. 3 mmol of 2-quinoxalinone 51 was reacted on a large scale with NHP ester 52 (6 mmol). A graphite felt (GF) anode and a Ni foam cathode were fitted into an undivided cell and connected to a DC controlled power source. NiCl₂·6H₂O (0.6 mmol), LiClO₄ (2.0 mmol) and 4,4′-di-tert-butyl-2,2′-bipyridine (0.6 mmol) were added to the cell. Then argon was added to the tube three times. 20.0 mL of anhydrous N,N-dimethylacetamide (DMA) and triethylamine (2.5 mL) were added using a syringe. The balloon containing argon was then inserted into the bottle and sealed with a rubber stopper. The mixture was electrolysed for 10 h at a continuous current of 40 mA after first reacting for 30 min at 60 ℃. The final product 53 was purified to provide 68% yield. Good to exceptional yields of physiologically significant 3-alkylated quinoxalinones 53a-53c were achieved by this protocol (Scheme 16b) [133].

  Scheme 16

  

  Scheme 16.  (a) Gram-scale electrochemical production of quinoxalinone 43 and its proposed mechanism. (b) Pharmacologically relevant compounds containing 3-alkylated quinoxalinones motifs 43a-43c.

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  Based on the aforementioned experimental findings and related literature reports [134], Ni(Ⅱ) is first reduced to Ni(Ⅰ) at the cathode, as shown in Scheme 16a. After undergoing a single electron transfer with NHP ester 52, the resultant Ni(Ⅰ) species yields Ni(Ⅱ) species and a cyclohexyl radical (path a). It is not completely ruled out that 52 could be directly reduced at the cathode to produce a cyclohexyl radical (path b) [135]. The cyclohexyl radical then reacts with complex Ⅰ in an addition process to produce radical cation Ⅱ, which then loses one H⁺ molecule to produce radical Ⅲ. Ultimately, radical Ⅲ experiences more oxidation and subsequently loses one Ni(Ⅱ) molecule, resulting in the desired product 53. In the meantime, a triethylamine radical cation is produced at the anode by the oxidation of NEt₃.

  Through cathodic reduction using a sacrificial anode material, electrochemical reduction demonstrates mostly unexplored promise for reductive organic syntheses [136]. How can one find an appropriate redox catalyst to carry out this kind of indirect electrolysis? Cyclic voltammetry (CV) is perhaps the easiest method to identify a good mediator (Fig. S5 in Supporting information) [13]. The guidelines mentioned in Supporting information file can help us find an appropriate mediator to help CV trigger the desired transformation:

  2.8 Electrochemical flow reactor design

  Electro-organic processes for industrial use face challenges due to poor durability and the potentiostatic method [137,138]. Potentiostatic method requires complex three-electrode configuration and prolonged reaction time. Scaling up requires careful consideration of multiple parameters and addressing volume-to-surface area ratio issues [43]. Flow electrolysis cells have been developed to overcome these issues by performing galvanostatic electrolysis efficiently without expensive electrical setups [139]. These cells can produce value-added products economically, reducing potential overoxidation and facilitating sensitive substrate conversions. Multiple flow electrolysis cells can be employed for continuous product removal [140].

  Numerous flow-electrolysis systems have been developed, however, micro-flow setups have limited electrode surface area and poor economic production. Long-channel flow cells should only be used in processes that can withstand a broad variety of current densities and do not have any opportunities for gas release (single pass conversions). Therefore, in order to maximise the electrolysis conditions and raise the overall capacity, scale-up is typically accomplished by adding more flow cells and switching between them [141]. Despite this, studies have shown that flow cells have some advantages, such as excellent surface area to volume ratios, minimal electrical resistance due to short inter-electrode gaps, and precise temperature control [142]. When residual conductivity, such as that caused by water traces is present, narrow gap electrolysis cells do not require a supporting electrolyte [140].

  An ancient technology, continuous flow chemistry has been spreading quickly throughout a number of industries, the pharmaceutical industry being the most recent to adopt it [143]. Large-scale batch reactions can have several drawbacks, such as issues with heat runaway, mixing, and mass transfer. These issues can be mitigated by switching from batch reactions to continuous flow processes, whether they are chemical, thermal, or electrochemical. Running reactions in continuous flow has the significant benefit of allowing academics to model and develop reactions in a very industry-like situation. The fact that flow cells are used in practically all industrial electrochemical processes makes flow electrochemistry research even more crucial [144].

  Flow chemistry is a method that shows great promise as a synthetic tool and provides quicker, safer, and more consistent opportunities to produce high-purity chemicals [145]. The configuration of chemical synthesis with flow chemistry is highly flexible; however, pressure regulators, mixing units, reactor/flow cells, collection units and reagent and fluid delivery systems (often pumps) are essential factors to its operation (Fig. 16) [146].

  Figure 16

  

  Figure 16.  The fundamental components of an electrochemical flow setup. Reproduced with permission [147]. Copyright 2020, Cell Press.

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  Primarily, a continuous electrochemical flow synthesis is performed by continuously pumping a reactant solution into a flow reactor (typically in a laminar flow mode). Diffusion, which is caused by a concentration gradient from the reaction progress, and migration of the charged species in a potential field, are responsible for mass transfer along electrodes [148]. There are spacers between the electrodes that range in size from mm to µm. This short distance is particularly favourable since it is proportionate to the resistance of the solvent/electrolyte mixture. Reaction parameters like temperature and pressure are regulated inside the reactor, and the product stream can be fed into a second reactor or diverted into a collection unit [149].

  Residence time, which is a function of reactor volume and flow rate (residence time = reactor volume/flow rate), determines how long reactants stay in a flow reactor. The amount of material injected, or how long the material was allowed to flow into the reactor, determines the reaction scale. Therefore, a flow synthesis that combines advancements in process improvement and optimisation can be imagined spanning the successive scaling routes of laboratory size/discovery-stage scale, pilot plant, and full-scale commercial production [150]. At all scales, a proverbial wall between the sectors is broken by a continuous flow process that retains the same fundamental operational notions throughout reaction scales. The opportunity to integrate all the phases involved in a complete synthesis into a single, efficient, and automated flow configuration is provided by continuous flow. Fig. S6 (Supporting information) displays the continuous flow cell setup for gram scale reaction.

  This method could provide significant safety and economic advantages by eliminating the need for a quench or purification step to be carried out separately and instead doing both in-line. Reactions that yield highly reactive intermediates are particularly relevant to multi-step syntheses in flow. These species, as well as any other poisonous or dangerous substance, may be produced on-site under extremely strict controls and then injected straight into the following reactor to initiate the desired reaction. Using this method, Wirth et al. developed unstable hypervalent iodine reagents in flow that were then utilised in successive in-line processes inside the same flow setup [151]. This strategy has made it possible to access the reactivity of these extraordinarily flexible but highly unstable chemicals. Using trifluoroethanol 54, iodobenzene 55 was anodically oxidised in an undivided flow cell with glassy carbon/platinum electrodes to produce the corresponding hypervalent iodine species in high yields without damage. Acetoxylation, tosyloxylation, heterocycle synthesis, and oxidation chemistry were carried out by coupling the reaction to a second reactor (Fig. 17).

  Figure 17

  

  Figure 17.  (a) Examples of advancements in flow electrosynthesis include the in situ electrochemical synthesis of hyperiodine species; (b) commercial electrochemical flow cell setup. Reproduced with permission [151]. Copyright 2019, Wiley Online Library.

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  2.9 Reproducibility as a key parameter in electro-organic synthesis development

  To establish electro-organic synthesis in laboratories, the reproducibility of experiments is a key criterion. Reproducibility is accompanied by a number of parameters including the active electrode area, electrode preparation, electrode distance, cell design, galvanostatic current density, potentiostatic applied potential, reference electrode, temperature, concentration, electrode material, and supporting electrolyte concentration. Electro-organic chemistry faces challenges in providing data sets, as important parameters are often unknown to newcomers. Standardizing data sets and providing low-cost, easily applicable arrangements for both amateur and experienced researchers is crucial. Initial advancements were made by Waldvogel et al. with a package for electro-organic synthesis in flow-reactors and a screening system for up to eight simultaneous reactions in divided or undivided cells [24].

  These systems are preferable than rough homemade flasks with poorly designed parameters that were utilised in the past. For example, employing basic batteries as electricity sources reduces reproducibility and does not provide enough control over the reaction, despite demonstrating the ease of application of electro-organic setups [152].

  Frequently overlooked but essential for successful electrochemical reactions are parameters such as the electrode distance [153]. It is critical that the literature makes a distinction between basic examples of potential electrolysis and their implementation in a practical laboratory synthetic process. Through the widespread implementation of electro-organic synthesis in education, these obstacles can be addressed.

  2.10 Electrochemistry in the synthesis of natural products and APIs

  The introduction of electrochemical transformations into complex total synthesis procedures has been stimulated by the advancement of a number of electricity-dependent syntheses [154]. The use of AEE-based photoelectrochemical reactions has expanded to include active pharmaceutical ingredients (APIs) and encouraged scaffolds for late-stage functionalization of commercially available drug molecules under blue light. Convergent paired electrolysis has been employed to investigate electro-photochemical insertion reactions of carbene anion radicals.

  High yields of 1-Boc-hexahydro-1,4-diazepine (61a−d), theophylline (61e−i), and olaparib (61j−k) were selectively alkylated via the AEE site without compromising the functional groups. As expected, also here, AEE generated higher yields compared with DC electrolysis (Scheme 17). It is noteworthy that under DC conditions, graphite anodes were corroded substantially in these reactions, where in AEE, all electrodes were least altered or corroded [42].

  Scheme 17

  

  Scheme 17.  Application of AEE and direct current electrolysis (DCE) in the production of APIs and their late stage functionalization.

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  If carbon allotropes are employed as electrodes, the main benefit of electro-organic synthesis over conventional transformation is the absence of metal contamination in the products, which is greatly preferred in the synthesis of active pharmaceutical ingredients (APIs) [155]. Selectivity challenges and scalability issues prevent electroorganic methods from being used in complete syntheses. The cyclization method utilised by Moeller et al. to produce (-)-alliacol A 64 is a well-known and early example of late stage functionalisation in electro-organic synthesis. An intramolecular carbon–carbon bond was formed between a furan moiety and a protected enol [152]. The synthesis of dixiamycin B 62 is an example of an electro-organic molecule that can only be produced using electricity and/or cannot be obtained through conventional methods. A direct intermolecular anodic N–N coupling reaction between two xiamycin B molecules was used to generate this natural product (Scheme 18) [156].

  Scheme 18

  

  Scheme 18.  Natural products and active pharmaceutical ingredients with electro-organic fundamental transformations.

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  One important class of naturally occurring substances that are utilised in medicine is alkaloids. Thus, it is crucial to have faster synthesis processes for (-)-thebaine 65 and kopsidine A 63 [157,158]. When methanol was added, an intramolecular C–O bond was formed for ring closure as a consequence of an oxidation at the bridging nitrogen during the synthesis of kopsidine A 63. A trioxygenated laudanosine derivative underwent regio- and diastereoselective anodic C–C bond formation to yield (-)-thebaine and (-)-oxycodone.

  The quick synthesis of finerenone 66 an API for treating heart disease has been documented. This was accomplished by racemising an inappropriate enantiomer using an anodic and cathodic sequence to recover the substrate (Scheme 19) [24].

  Scheme 19

  

  Scheme 19.  API synthesised by Bayer via electro-organic racemisation.

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  2.11 Selectivities and electro-auxiliaries in organic electrosynthesis

  In organic synthesis, electrochemical techniques are effective ways to form and break chemical bonds. The following two factors are crucial for selective electrochemical reactions to occur:

  ⅰ. The subsequent chemical process should occur selectively to break the specific bond or construct a bond in the specific site.

  ⅱ. Electron transfer should occur selectively at the position in a substrate molecule that is required for that step [159].

  The use of electrons in synthetic organic transformations is expected to gain renaissance due to safety, atom economy, sustainability and environmental friendliness. However, achieving stereo-control requires advanced knowledge and chiral information installation for natural compound synthesis [160-162]. The term “asymmetric electrochemical synthesis” describes electro-organic reactions that add one or more additional chiral components to a target molecule. Using appropriate chiral sources allows for the electrochemical induction of asymmetry into achiral substrates. Modern methods of asymmetric electrolysis rely on chiral mediators, while early methods concentrated on chiral supporting electrolytes, solvents, and asymmetric functionalisation of electrodes. The utilisation of electrons as sustainable reagents in widely studied asymmetric organic synthesis is made possible by electro-catalytic asymmetric synthesis (Scheme 20). Using recyclable electro-auxiliaries, chiral auxiliaries allow pre-functionalisation with the necessary stereo information [160,162]. For a variety of possible uses, particularly in the pharmaceutical and cosmetic industries, the enantioselective synthesis of chiral molecules is essential [163]. The combination of asymmetric catalysis and electrochemistry offers a promising green approach to the synthesis of non-racemic chiral compounds [164].

  Scheme 20

  

  Scheme 20.  Asymmetric electrolysis modes with considerable enantiomeric excess.

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  Carbon electrodes containing biomolecules, polymers or organometallic complexes are commonly employed as chiral frameworks with high turnover numbers (TON) for the transformation of electrode surfaces with chiral compounds [162]. For example, to achieve greater coating efficiencies and higher enantiomeric excesses, a contemporary method employing poly-L-valine or spiroxyl motifs is illustrated in Scheme 21 [165].

  Scheme 21

  

  Scheme 21.  Asymmetric electrolysis using spiroxyl-modified graphite felt (GF) as anode.

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  Novel techniques for achieving enantiomeric excesses of up to 80% in pulsed electro-organic synthesis use cheap, easily accessible materials for chiral electrode surfaces. Metals like Ni or Pt are deposited on liquid crystals, imprinting asymmetric molecules. Mesoporous metals with stable cavities prevent undesirable enantiomer synthesis, unlike traditional metal electrodes producing racemates (Scheme 22) [163,166].

  Scheme 22

  

  Scheme 22.  Schematic representation of the process for developing a chiral imprinted Pt or Ni electrode via 3D metal deposition on a liquid crystal containing adsorbed chiral molecules, along with an example of enantiomer discrimination during electrolysis at the imprinted electrode surface.

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  The generation of the desired stereoisomer in improved optical yields is correlated with the growing interest in the use of chiral mediators, particularly for organic molecules. Commonly utilised chemicals include iodoarenes and N-oxyl motifs [167], which is the first report on the enantioselective electrochemical lactonization of derivatives of diketo acid 69 employing chiral iodoarenes I as redox mediators. Both the intermolecular α-alkoxylations 70 and the lactonization 71 derivatives of diketo ester show good to high stereoselectivities (Scheme 23) [168].

  Scheme 23

  

  Scheme 23.  Asymmetric electrochemical production of intermolecular α-alkoxylations 70 and the lactonization 71 derivatives of diketo ester.

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  Transition metal complexes are customised catalysts because they benefit from ligand fine tailoring. Unfortunately, the products then become contaminated with unwanted metals. Two potent areas of this that have found extensive use in organic chemistry are Lewis-acid catalysis and electrochemistry [169]. A chiral-at-rhodium Lewis acid and a redox mediator are combined in this catalytic asymmetric indirect electrolysis to produce the elusive enantioselective nucleophilic α-C(sp³)−H alkenylation of ketones. In particular, high yields (up to 94%) and remarkable enantioselectivities (≥99% ee) of 2-acyl imidazoles 72 react with potassium alkenyl trifluoroborates 73 without the need for additional stoichiometric oxidants. This innovative indirect electrosynthesis is used to synthesise intermediates of the natural product cryptophycin A and a cathepsin K inhibitor in an easy-to-scale, gram-scale manner (Scheme 24) [164].

  Scheme 24

  

  Scheme 24.  Asymmetric indirect electrolysis for the production of enantioselective nucleophilic α-C(sp³)−H alkenylation of ketones.

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  Asymmetric electrosynthesis coupled with a chiral Ni catalyst has also been reported to produce exceptional yields and excellent enantioselectivities (up to 97% ee) in an intermolecular alkylation reaction. The required adducts 77 are thought to be produced by a selective reaction between the benzylic radical species 75 and the Lewis-acid-bound radical intermediate 76 from a single-electron anodic oxidation (Scheme 25) [169].

  Scheme 25

  

  Scheme 25.  Lewis-acid catalysed asymmetric electrosynthesis.

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  Biocatalysis is a popular method for stereoselective epoxidation, combining electro-catalysis and chiral auxiliaries [170]. Electrochemical organic synthesis employs techniques involving functional groups (are known as electroauxiliaries) to regulate substrate reactivity and reaction pathways, accelerating challenging reactions and achieving desired products [159]. There are two varieties of electroauxiliaries. One group is called the organic group and includes elements of the IVA group such as silicon, tin, and germanium. The other group is called the organothio group. Electroauxiliaries in electroorganic synthesis reduce substrate oxidation potential, increase HOMO energy, and speed up electron transport, improving reaction selectivity and breaking unique bonds with targeted nucleophiles [171]. The use of electroauxiliaries in electro-organic synthesis is covered in this section. Selective C–EA bond cleavage occurs when organic compounds with a heteroatom or π-system with an electroauxiliary (EA) undergo anodic oxidation. Depending on the characteristics of the EA, this process results in the selective emergence of a carbocation via either path A or B (Scheme 26). The resulting carbocation combines with different nucleophiles to produce the desired molecules. The following sections provide examples of these kinds of selective electron-transfer-driven processes.

  Scheme 26

  

  Scheme 26.  Proposed mechanism for the use of electroauxiliaries in electro-organic synthesis.

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  Anodic oxidation is a potent technique that can be used to generate a wide range of organic molecules with intriguing biological activity and possession of heteroatoms such as nitrogen [172]. An electroauxiliary is a useful tool for these kinds of conversions, for example, Scheme 27 illustrates how electrochemical methoxylation of unsymmetrically substituted carbamates 78 typically results in the development of a mixture of two regioisomeric products 79 and 80 [173]. However, Yoshida and coworkers discovered that the aimed product 79 was predominantly formed when a silyl group was added as an electroauxiliary which regulated the reaction pathway [174].

  Scheme 27

  

  Scheme 27.  Use of electroauxiliaries in enantioselective electro-organic synthesis.

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  Moreover, it has proven successful to build functionalised peptidomimetics using the idea of an electroauxiliary [175]; functional groups containing arylthioethers are useful electroauxiliaries for controlled oxidations (Scheme 28). Compared to first-generation 4-methoxythiophenyl- and 4-nitrothiophenyl-substituted derivatives, second-generation glutamine building blocks bearing 2,4-dimethoxythiophenyl and 2,4-dichlorothiophenyl-derived electroauxiliaries enhance standard solid phase peptide synthesis (SPPS) efficiency and allow fine-tuning of the electrochemical window for selective anodic oxidation reactions. The new building blocks for iterative functionalisation’s are demonstrated in practice by installing them onto a section of involucrin, a protein component in human skin [176].

  Scheme 28

  

  Scheme 28.  Use of electroauxiliaries for controlled oxidations in electrochemical synthesis.

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  To summarise, this field has experienced a number of optimistic findings, with the scientific community being encouraged despite the limitations related to the use of metals and low enantiomeric excess.

  2.12 Mechanistic investigations as the key to novel pathways

  Electro-organic conversions have quickly gained popularity and offered various approaches to attain target molecules. Typically, reports offer a mechanical explanation for the electro-organic change that is experienced, however, cyclic voltammetry (CV) is typically the only method used to support the proposed mechanism [75].

  2.12.1   CV applications in organic electrosynthesis (measurement & data elucidation)

  CV is a useful analytical method for calculating the redox potentials of electrochemical processes. Dempsey and coworkers developed a clear manual on CV designed especially for synthetic chemists [75].

  Standard three-electrode setups are used in cyclic voltammetry cells that consist of a reference electrode (that maintains a constant potential), the working electrode (its potential is represented in reference to reference electrode) and a counter electrode (whose potential is regulated with a potentiostat so that the working electrode's potential difference from that of the reference electrode equals the supposed applied potential: ΔE_applied = E_work (t) – E_ref.) The electrochemical circuit should be closed, which also requires the counter electrode) and a working electrode (to which a potential ramp is supplied and current is monitored) (Fig. 18).

  Figure 18

  

  Figure 18.  A cyclic voltammetry experiment in an electrochemical cell consisting of a typical three-electrode setup submerged in a 0.1 mol/L supporting electrolyte and 1 mmol/L analyte solution. N₂ or Ar gas can be sparged into the system via an inert gas intake. Reproduced with permission [12]. Copyright 2022, Springer Nature.

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  A cyclic voltammogram (Fig. 19b) is produced during a CV experiment when the current is measured and the potential at the working electrode is scanned cyclically using a triangle waveform (Fig. 19a). In practice, the goal is to minimise the amount of chemicals required to conduct the experiments by choosing a cell that permits the three electrodes to be dipped in the least amount of solution. To minimise the resistance of the system, it is recommended that the three electrodes be spaced no more than 1 cm apart. This is particularly important if, out of concern for potential contamination, the counter and reference electrodes are to be kept isolated from the majority of the solution using a porous sintered glass filter. The cell is normally filled with a 0.1 mol/L supporting electrolyte solution. Sparging the solution with argon or nitrogen gas eliminates and excludes oxygen from the system. After that, the analyte is added to generate a 1 mmol/L solution. Supplying 10–100 times more supporting electrolyte than analyte is essential because a smaller ratio would cause the analyte to migrate and to become a current carrier, which causes an ohmic drop and a biased response. Because organic species have a tendency to adsorb quickly onto electrodes, especially carbon electrodes, it is best practice to polish the electrode in between experiments to prevent signal distortion and sensitivity loss. If the electrode is submerged in an aqueous suspension of diamond or nanometric alumina, this can be accomplished with ease. Despite commercially available disposable screen-printed 3-electrode setups are more expensive, they eliminate the requirement for polishing because each experiment uses a new configuration. Since diffusion is the basis of cyclic voltammetry, it is crucial to ensure that the solution is not subjected to stirring during analysis. Instead, it is preferential to agitate the solution in between CV scans. After establishing this configuration, the working electrode is subjected to a linearly increasing or lowering potential (E) ramp at a precise sweeping rate denoted ν (V/s), and the system's current (I) response is noted (I vs. E; Fig. 19). In practical terms, the potential is raised from an initial potential (E_i) to a final potential (E_f) at a specified scan rate. The recorded current is only capacitive up until the oxidation potential (E) of the analyte. On the other hand, the analyte is oxidised, and a positive current is detected once the critical oxidation potential is attained. Analyte from the area close to the electrode rapidly depletes due to local electrolysis, and current decreases until a plateau is attained (diffusion current). At this time, the diffusion of the analyte from the bulk solution, in the absence of stirring, controls the electrolysis rate. Following the reversal of the potential sweep, the back scan may reveal a reductive current, which would give arise to the well-known “duck” shaped CV curve, depending on the system being studied.

  Figure 19

  

  Figure 19.  Fundamentals of voltammetry in cycles. (a) First sweep with a linearly increased potential up to a fixed threshold (potential scan). (b) The initial sweep's observed current response is plotted against potential in section a. (c) Reverse sweep, with the potential linearly returning to the initial level (at the same rate as the initial sweep). (d) The reverse sweep's observed current response in relation to potential. (e) A typical cyclic voltammogram labelled with relevant parameters: I_pa (anodic peak current), I_pc (cathodic peak current), E_pa (anodic peak potential) and E_pc (cathodic peak potential). Reproduced with permission [12]. Copyright 2022, Springer Nature.

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  A typical example of a cyclic voltammogram is displayed in Fig. 19e. The analyte exhibits an anodic peak (E_pa and I_pa) after becoming oxidised. During the back scan, the oxidised form of the analyte will be reduced back and the opposite current, I_pc, will be recorded, provided that it is stable and does not undergo any further chemical or electrochemical reactions. Next, it is claimed that the system is chemically reversible; the anodic I_pa and the cathodic I_pc must be equivalent in a chemically reversible system. Eq. 3 can be used to measure the potential difference between the cathodic and anodic peaks in order to calculate the number of exchanged electrons.

  $ \left|E_{\mathrm{pc}}-E_{\mathrm{pa}}\right|=2.2 \frac{\mathrm{R}T}{\mathrm{nF}} \approx \frac{56.5 \mathrm{~mV}}{\mathrm{n}} \text { at } 25^{\circ} \mathrm{C} $

  (3)

  where T is the temperature, E_pa is anodic process potential, F is the Faraday constant, n is the number of electrons, and E_pc is the cathodic process.

  Chemically irreversible systems are unstable electrolysis products that react quickly on the CV experiment time scale. Digital simulation programs can help deriving thermodynamic and kinetic data from a single voltammogram. The scanning rate determines a systems’s chemical reversibility, with increased scan rates revealing partially reversible systems. Reversibility is often used to refer to chemical reversibility or electrochemical reversibility, with slow electron transfers indicating irreversible systems and rapid electron transfers resulting in reversible systems [12].

  2.12.2   Recognising basic voltametric data

  The response displayed via the resulting current (i) is shown by the y-axis, while the x-axis depicts a parameter that is imposed on the system, in this case the applied potential (E). There are scenarios when the current axis on the graph is designated only with a scale bar inset. CV data is typically reported using two conventions; however, a statement describing the sign convention used to get and plot the data is rarely supplied (Fig. S7 in Supporting information). But the potential axis provides a hint about the convention that is applied. The US convention, which is applied here, and the IUPAC convention are the two accepted formats for reporting CV data. The data presented in the two conventions will seem to be 180° rotated visually [75]. If a potential is raised without causing a redox reaction, current will flow until species are depleted at the electrode surface, producing a peak. The redox potential is located in the middle of E^a (anodic) and E^c (cathodic) potentials, making understanding a redox system easier using CV. A CV experiment's potential window is determined by the electrolyte, solvent, and design of working electrode (Fig. S8 in Supporting information) [177]. The reference electrode used determines measured potentials, with variations resulting from different electrodes. Specified redox systems such as the ferrocene/ferrocenium (Fc/Fc⁺) redox pair serve as internal benchmarks and calibrated against electrode potential reference [71].

  2.12.3   Recording the cyclic voltammogram

  Experiments can commence once the cell is built, oxygen is sparged, and safety measures are implemented to reduce ohmic drop. The potentiostat is attached to the electrodes, and its respective software is used to select the experimental parameters. The basic parameters are the number of segments/scans, the scan rate, and the potential window to be scanned (determined by the initial, switching, and final potentials). Various software will require various values for these factors. With certain potentiostats, the scan can be initiated at the open circuit potential (OCP), which is the passive current flow between working and reference electrode. Typically, unique to each manufacturer, advanced parameters include an automated or manual R_u adjustment. It is essential to recognise that the initial cycle of a cyclic voltammogram frequently differs from subsequent cycles when recording one. This may be the result of passive layers depositing or being removed from the electrodes during a cycle. As a result, it is necessary to record and assess multiple cycles. A potential with no current flowing should be selected as a starting point. The potential scan rate may significantly impact the cyclic voltammogram, depending on the system. Nevertheless, some processes may not be entirely reversible, resulting in an unsymmetrical pair of peaks where the reverse peak is smaller or perhaps disappears totally. Since this depends on the reaction time scale, semi-reversible reactions can frequently be seen more clearly with faster scan rates.

  In Supporting information, the application of electroanalytical technique (CV analysis) contributed to understand the disulphide 81 oxidation mechanism has been discussed [178].

  2.13 Industrial applications of electrosynthesis (new techniques and processes)

  The chemical industry pushing for the incorporation of sustainable chemical methods have spurred the electrification of organic synthesis [79]. The necessity to move toward self-sustaining processes while keeping up with the modernisation of industry and a fast-paced economy has given rise to the movement for sustainability, as well as a growing worldwide awareness of climate change [179]. Electro-organic conversions yield novel reaction pathways with highly tuneable selectivity due to their unique reactivity. The ability to produce intermediates that are only available in this manner encourages the use of electro-organic conversions in upcoming organic chemical synthesis and makes it possible to carry out transformations that are challenging to complete using traditional methods.

  Currently, the industrial sector consumes 40% of the world's energy, of which 26% is utilised for refining and fundamental chemical processes. In addition, it contributes 32% of the world's greenhouse gas emissions [180]. As a result, increasing energy efficiency and minimising environmental effect will depend on the development and application of sustainable operational concepts [138]. The industrial sector could decarbonise and innovate through the development of effective electrochemical processes that use renewably sourced electrons. These processes could reduce plant costs through modularity and process intensification, improve safety and lower reactor costs through mild reaction conditions, and increase flexibility through tuneable product generation. The scientific community has been able to keep up the pace during the past few decades, and over 900 organic electrochemical reactions have been documented to date. These reactions include numerous advances in producing transformations that were previously unattainable [4]. Despite organic electrosynthesis having an explosive growth in academia, businesses have been sluggish to adopt these novel techniques into their operations. Industrial scale electrochemical processing of organic chemicals has been performed from about the turn of the century with production in the early years of chemicals such as benzidine, sorbitol, mannitol, pinacol, vanillin, hydroquinone, p-aminophenol, chloroform, iodoform, chloral, anthraquinone and indigo. Only two chemicals of this list, namely p-aminophenol and anthraquinone, have survived to date. However, 15% of the electrochemical techniques that have been published have been piloted, and about 7% of them have been commercialised (Fig. 20) [181]. The number of processes in the chemical production business is insignificant in comparison to this little proportion. There are more than 100,000 chemicals on the market at the moment [182]. Approximately, 75% of them are organic molecules [41]. It is crucial to remember that an industry exists to satisfy requirements of society, turn a profit, and maintain itself over time in order to understand the causes of this discrepancy. It will seek to achieve this by utilising low-cost technologies that transform the most affordable source of energy and raw materials into the desired product [183].

  Figure 20

  

  Figure 20.  Overview of fine chemicals produced via electrochemical methods. Reproduced with permission [147]. Copyright 2020, Cell Press.

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  An electrolytic step needs to make sense from an economic, logistical, and long-term industry perspective in order to be added to a product's production process. It is crucial to remember that a chemical process will typically involve a complicated series of multiple phases or processes. This implies that every step that goes into a synthetic plan will be evaluated from a broad perspective. If at least one of those steps is electrochemical, it could be combined with another transformation without requiring the removal of any redox reagents that would have otherwise been present. It might even allow divergent synthesis, which could be used to adjust electrochemical conditions to favour the further development of certain reactions. By conducting more research using electrochemical flow cells, some of the obstacles that may be preventing the widespread use of these novel organic electrochemical reactions in a commercial context could be removed [147].

  However, industrial operations are conducted on a large scale. For example, the fluorination of hydrocarbons in the Simons process, the manufacture of nylon precursors by the Baizer process or the production of perfumes. In addition to these, several smaller-scale electro-organic transformations are conducted in the industry to produce antibiotics, anti-inflammatories, and agrochemicals [22,137]. Fig. 21 briefly describes a number of electro-organic processes for commercial scale.

  Figure 21

  

  Figure 21.  A number of electro-organic processes on the industrial scale. Reproduced with permission [24]. Copyright 2020, Royal Society of Chemistry.

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  High levels of safety, excellent reliability and quality, high selectivity and yield, and low energy and atom consumption are the four main requirements for the adoption of electrosynthesis in an industrial context. Adoption of the approach is almost impossible if any one of these fundamental principles is violated. Table S1 provides an overview of the several commercial and pilot electrochemical methods that are currently being utilised in the chemical industry [79]. The production of adiponitrile 86 is among the most well-known electrochemical processes [184]; polyamides such as nylon-6,6 are made from adiponitrile 86.

  It is used to generate hexamethylenediamine (HMD), which is a raw material for the manufacturing of nylon 6,6 fibres, resins, and adipic acid. Adenosine diphosphate (ADP) has been generated in considerable quantities via the hydrocyanation of butadiene, a technique invented and commercialised by DuPont, in addition to the commercial electrochemical synthesis of adiponitrile utilising the Monsanto technology. Adiponitrile 86 is made by Solutia in Decatur, Alabama, USA; Asahi Chemical in Nobeoka, Japan; and BASF in Seal Sands, UK, using the electrochemical method. Chemically, ADP is produced by Butachimie, a joint venture between DuPont and Rhodia, in Chalampé, France, and by DuPont in Texas, USA. Adiponitrile 86 was produced worldwide in 2000 at a rate of 1.375 million metric tons annually, of which 32.8% came from electrochemical processes, according to a report from the petrochemical market intelligence provider ICIS. According to an assessment in 2005, the contribution from the electrochemical method decreased to 30.8% (0.481 million metric tons annually) while global production scaled to 1.564 million metric tons annually. According to a market research company, PCI Nylon, 1.197 million metric tons of ADP were manufactured in 2010, with acrylonitrile 121 accounting for just 29% of that proportion. The manufacturing of HMD and ADP, which has stayed largely stable over the previous ten years, is driven by the demand for nylon 6. Unfortunately, the butadiene route of ADP manufacturing has experienced a slight drop in its contribution to worldwide production due to lower raw material prices for the electrochemical synthesis of ADP. The process of synthesising ADP via butadiene requires natural gas, which has become less expensive recently. Economic factors, supply and demand for the organic compound, and the cost of related materials such as the cost of the raw materials used in competing processes, all play a role in determining whether a synthesis process can be advanced from pilot plant scale to industrial production level [185]. Using a cathodic hydrocoupling that uses water and releases oxygen, Mosanto's Baizer process presently produces over 300,000 tons annually for consumption worldwide. For additional optimisation, research is continuously being conducted on the procedure [41].

  Anodic methoxylation of substituted toluenes is an extensively researched area (Scheme 29). p-Tolualdehyde, a precursor required for producing the fragrance lysmeral, is produced in excess of 10,000 tons annually by BASF [22]. More people are familiar with BASF due to their extensive p-anisaldehyde production. Since the 1960s, more than 3500 tons of p-methoxytoluene 118 have been produced annually by the anodic methoxylation process utilising a capillary gap cell [186]. The production of this compound can alternatively be achieved more effectively by paired electrolysis, in which the anodic methoxylation of p-toluene is linked to the cathodic hydrogenation of dimethyl phthalate [8]. By using this procedure, BASF is able to produce 4000 tons of each product annually. Moreover, Otsuka, BASF, and Hydro Quebec have performed anodic methoxylation on additional substituted toluene compounds. Furthermore, anodic methoxylation of additional substituted toluene compounds has been carried out at Otsuka, BASF, and Hydro Quebec, yielding more than 1000 tons annually. Both ECRC and Hydro Quebec have employed a comparable procedure to enable the conversion of anthracene 114 or a mixture of napthalene and butadiene into anthraquinone 106, respectively (Scheme 29). ECRC has reported to produce more than 1000 tons of anthraquinone 106 annually. The generation of succinic acid electrochemically has made it easier for it to be used in a variety of industries, including food, medicine, and cosmetics, in addition to being used a raw material for synthesis. Maleic anhydride has been electro-reduced for at least 80 years, and as a result, CERCI produces over 30 tons of it annually [186]. This is favoured over the widely used fermentation techniques because electroreduction is a more efficient choice than fermentation, which produces ten tons of waste water for every ton of succinic acid synthesized. Otsuka also uses anodic methoxylation to manufacture the flavour enhancer maltol 117, which is produced at a rate of 150 tons per year. The intermediate produced by the oxidation of 2-hydroxy-ethylfuran 116 is rearranged to get the desired maltol 117 (Scheme 29) [22].

  Scheme 29

  

  Scheme 29.  Summary of several established industrial electrochemical syntheses.

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  2.14 Photoelectrocatalysis

  Photoredox catalysis, or so-called visible light photoredox catalysis [187], is ascribed to a single-electron transfer between the excited state of a photocatalyst and an organic substrate or reagent to form a route to a desired product via highly reactive intermediate species. This has emerged as a powerful tool in organic synthesis, building upon the foundation set by early pioneers in the areas of radical chemistry and photochemistry [188]. Photoredox chemistry forges new bonds via open shell facilitation and pathways that lead to the fast assembly of complex products and to new areas of chemical space [189].

  Photoelectrocatalysis (PEC) is a method of producing chemical solar cells that harvest sunlight and transform it into chemical energy, producing oxygen and hydrogen. It combines solar cell elements with electrocatalysis to direct solar energy towards the target reaction. The first photoelectrocatalysis reaction was demonstrated by Honda and Fujishima describing the water splitting to hydrogen and oxygen. The electrolysis was carried by using the TiO₂ as n-type semiconductor and Pt electrodes, as shown in Fig. 22. The process starts when the surface of the TiO₂ electrode is irradiated with a wavelength shorter than 410 nm; current flows to generate oxygen and hydrogen at the surfaces of the TiO₂ and Pt electrodes, respectively. TiO₂ is excited under irradiation to form electron–hole pairs, and the holes in the valence band move to the surface, resulting in oxidation of water, while the electrons in the conduction band move into the bulk and then further move through the external circuit to the counter Pt electrode to reduce protons. This suggests that water is decomposed by visible light into oxygen and hydrogen, without the application of any external voltage, according to Scheme 30. This is an innovative breakthrough and is sometimes referred to as the Honda–Fujishima effect.

  Figure 22

  

  Figure 22.  Photochemical cell with TiO₂ electrode. Reproduced with permission [188]. Copyright 1991, Nature Publishing Group.

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  Scheme 30

  

  Scheme 30.  The decomposition of water by visible light into oxygen and hydrogen.

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  2.14.1   Practical reaction setup

  Photo-electrolysis in organic chemistry is carried out in electrolytic solution under visible light irradiation circuits [190], generally equipped with two electrodes, where two half-reactions will occur: an oxidation and a reduction reaction. The reactional solution, in which the electrodes are immersed, needs to be electrically conductive, which need in this case the presence of a supporting electrolyte. Similar to the above, photoelectrochemical cells can be assembled in two ways: undivided (Fig. 23a) and divided cells (Fig. 23b) [191], under constant current (galvanostatic) or with constant potential (potentiostatic). Since most of the organic compounds cannot absorb visible light very well by themselves, they need to absorb light energy with the help of photocatalysts. In both cases the photo-electrocatalytic reactions needs a photocatalyst, such as Mes-Acr⁺, DDQ, riboflavin tetraacetate (RFT) and 1,3-diisopropylthioure.

  Figure 23

  

  Figure 23.  Set-up of photo-electrocatalytic experiments: (a) undivided cell; (b) divided cell. Reproduced with permission [191]. Copyright 2020, Wiley online Library.

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  In photoredox catalytic reactions, the photocatalyst acts as a reducing or oxidising agent. After absorbing visible light, the photocatalyst transitions from the ground state to the excited state, which has stronger oxidation and reduction properties, and in majority cases, it interacts with substrates or reagents through the single electron transfer (SET) pathway to return to the ground state and obtain a highly active intermediate, which is generally a radical species. In the SET process, the excited photocatalyst can be returned to the ground state by reduction quenching and oxidation quenching [192]. Alternatively to the SET pathway, the excited state photocatalyst can also exchange energy with the substrate through an energy transfer pathway to directly excite the substrate into the active intermediate (Scheme 31).

  Scheme 31

  

  Scheme 31.  Typical quenching types of photocatalysis.

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  2.14.2   Advantages of combining electrochemistry & photochemistry

  Electrochemical methods and photochemical methodologies have affirmed new and efficient access to some of the most reactive intermediates [193,194], including radicals [195,196], radical ions, and charge transfer complexes. This capability enables reaction discoveries and potential new bond disconnection strategies that are difficult or impossible through alternative means. In addition, the external stimuli employed in electro- and photochemical reactions, namely, electrons and photons, allow intimate and precise control over the reaction progress. Moreover, the combination of electricity and light as clean energy sources eliminates the reliance on strong chemical oxidants and reductants, thus allowing electro- and photochemical reactions to proceed under milder conditions and often with reduced environmental impact. In fact, these approaches operate under mild conditions in a sustainable fashion with a high atom-economic [9].

  The main application of electrochemistry & photochemistry is the photoelectrocatalytic oxidation of pollutants, such as colourants removal and the mineralisation of organic compounds. This has led to a huge interest in the use of photoelectrocatalytic oxidation to treat organic pollutants since the early 1990s [197-200]. Some of the most popular photocatalysts in photoelectrocatalysis include TiO₂, WO₃, ZnO, CdS, Fe₂O₃, and SnO₂ [201].

  Recently, a new assemblage of electro-photocatalytic strategies has been reported [202], organically merging the power of photochemical activation and orthogonal electrochemistry to achieve oxidising and reducing potentials that were previously unimaginable. It should be emphasised that, in many ways, using a basic photovoltaic device to directly power an electrochemical reaction, is a novelty. A more advanced photo-voltaic array would be used to capture enough energy to power a typical potentiostat in a more complex system or large-scale electrolysis. Due to the ability to precisely control the current flowing through the reaction and maximise the electrochemical process' efficiency, this would lead to a significantly more selective electrolysis [203]. Fig. S10 (Supporting information) displays a fundamental and readily available solar cell used for electrolysis.

  2.14.3   Photo-electrodes applications

  Photocatalysis and electrochemistry share aspects in manipulating organic substrates, with knowledge from each area being transferable. An intriguing development area involving merging these methodologies, combining homogeneous photocatalytic systems with electrochemical cells. In 2019, Stahl and coworkers reported an intramolecular C−H amination (Hofmann−Loffler−Freytag) that relies on discrete electrochemical and photochemical processes. In the field of C–H functionalisation, direct amination of C(sp³)–H bonds is of great interest due to the widespread use of amines and nitrogen heterocycles in drugs and natural products.

  Previous attempts at electrochemical Hofmann−Loffler−Freytag (HLF) reactions suffered from limited functional group tolerance due to high anodic potentials. To produce pyrrolidine, an undivided cell was utilised, fitted with a platinum wire cathode, Ag/Ag⁺ reference electrode and a graphite anode. After being evacuated with nitrogen for 20 min, a mixture of 122 (0.5 mmol), 0.5 mmol of KPF₆ (supporting electrolyte), TBAI (0.05 mmol), and TFE (8.0 equiv.) in acetonitrile (5 mL) was electrolysed at 0.5 V versus Fc/Fc⁺ with magnetic stirring. During bulk electrolysis, the mixture was exposed to a CFL (20 W) of radiation to obtain the pure products 123 (Scheme 32).

  Scheme 32

  

  Scheme 32.  Gram scale photo-catalyzed electrochemical production of pyrrolidine 123.

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  In this strategy, electrochemically generated I₂ reacts with a tosylamine substrate in the presence of a base to form the N-iodo intermediate. This photochemically labile species then undergoes homolysis under irradiation, producing amidyl radical that further proceeds to complete the HLF reaction. By using I₂ as a multifunctional electrocatalyst that enables photoinduced substrate activation, the required potential for reaction was reduced to as low as 0.3 V (vs. Fc/ Fc⁺). Under such mild conditions, a broad scope of functional groups including oxidatively labile electron-rich arenes can be tolerated (yield up to 82%). Reactivity schemes similar to Stahl’s work demonstrate that the two stimuli may operate in discrete cycles and provide promise for new and elegant designs that could be made possible by combining electro- and photochemical activation [204]. Fig. S11 (Supporting information) illustrates reaction set-up (undivided cell) of iodide mediated dehydrogenative C−H/N−H coupling (Hofmann−Loffler−Freytag) involving discrete electrochemical and photochemical processes.

  An example of the photo-induced electrochemical alkylation reaction for the production of product 126 with an 89% yield (13.03 g) with a uniform decagram scale has been given in Scheme S2 (Supporting information).

  A few other examples of the photo-induced electrochemical production of organic compounds are also described in Scheme S3 (Supporting information).

  3. Limitations and challenges of practical electrosynthesis

  It is also important to note that, despite the fact that only a small number of organic electrochemical processes have been developed in industry to date, the applications of these modern approaches speak well for the industrial production of all kinds of chemicals. In order to fulfill the high needs for organic synthesis in the future, it is hoped that a variety of techniques based on various principles would be utilized in organic electrochemistry [205]. In organic chemistry, electrosynthesis has certain drawbacks despite its many advantages. For example, a complete electrochemical device is needed, and it is frequently costly to purchase and maintain. The transmission of electrons in solution also usually requires the use of a supporting electrolyte, and selecting a solvent for electrosynthesis can occasionally be difficult due to the weak conductivity of solvents such as toluene, tetrahydrofuran. Because most metal cations can be easily reduced to zero-valent metals at the cathode and because very expensive ion exchange membranes must be utilized to separate the anode and cathode in electrochemical reactions conducted in divided cells, the use of metal catalysts in electrochemical reactions under easily accessible undivided cells is comparatively limited [20].

  Unfortunately, there is frequently little to no attention paid to this characteristic of the electrode employed in many electro-organic synthesis processes. Specifically, a lot of organic syntheses are carried out with homogeneous catalysts, which are exceptionally expensive complexes of non-abundant metals like Pd(OAc)₂, Co(OAc)₂, [CpRhCl₂]₂, and [RuCl₂(p-cymene)₂] [48]. There are certain electrode materials where a high gas evolution can cause issues. Moreover, deposition can cause electrode surfaces to become inactive, which over time raises resistance. Additives or the implementation of changing polarity are solutions for these problems [29]. Organic chemists are not yet familiar with the problems pertaining to the stability of carbon electrodes. Therefore, in the near future, scientists should devise a technique to increase the stability of the carbon electrode in aqueous media within a narrow window of electrochemical potentials ranging from −2.0 V to 2.0 V [53]. It is important to remember that challenges with mass transfer, selectivity, scalability, overoxidation/reduction, and other issues are common in individual electrochemical reactions. Nonetheless, these restrictions have been reduced slightly with the development of more modern methods [42]. The flow electrochemical approach offers various advantages, but due to the setup's complexity and cost, it is only utilized in a few chemical and pharmaceutical companies. The implementation of this technique in an industrial setting may be limited due to the generation of insoluble particulates as a byproduct, which could impede uniform flow. The nitrogen and hydrogen gasses generated during electrochemical synthesis have an additional effect on the product's quality [206]. In practical applications of asymmetric electrolysis, major difficulties stem from the chiral catalyst's instability or incompatibility with the electrochemical conditions at the electrode-solution interface [164].

  4. Conclusion and future perspectives

  In conclusion, electro-organic synthesis is evolving from a niche technology to a commonly utilised synthetic process. For this reason, electrosynthesis needs to play a role in teaching and student training. The application of this strategy will be necessary at both a technical and academic level due to its many attributes, e.g., sustainability. Electrochemistry, where electrons serve as the reagents, is a benign, environmentally friendly, and atom-efficient means of achieving functional complexity. Despite the potential need for stoichiometric electrolyte levels, this approach can still provide significant selectivity benefits over conventional chemical techniques.

  This review includes guidance on where to begin one’s exploration of electrochemistry as well as information on the setup and mechanism of an electrochemical reaction. There are examples provided to show the range of synthetic electrochemistry. The goal is to explain the strategies and potential applications of organic electrochemistry as simply as possible to scientists who are not necessarily skilled electrochemists and who wish to use this potent and increasingly more common tool in their field of study. Various types of electrolysis carried out using galvanostatic, potentiostatic, and alternating current are demonstrated, and methods for conducting divided, undivided, and quasi-divided electrolysis are also discussed.

  To overcome the limitations of the existing electrode materials, such as mercury lead, innovation in electrolyte and electrode systems is continuously required. A substantial overpotential for unwanted side reactions and corrosion resistance are important features of modern electrode systems. Synthetic carbon allotropes with modified surfaces and BDE electrodes have shown to be a step in the same direction. Additionally, solvents should be sufficiently studied as a tool to modify selectivity in the electrosynthetic pathway as well as a reaction medium. Other areas of electrochemical synthesis, such as supporting electrolytes and electrolysis cells, also provide a great deal of opportunity for advancement. Electrochemical reactions have the potential to become a mainstream synthesis process rather than a niche technology due to its sustainability. A completely new arena in catalysis has been opened by the use of electricity to accomplish chemical transformations, which have historically required tedious processes. The application of novel ideas and techniques from other disciplines, such as magneto-electrochemistry [207] and ultrasonication [208], is advancing the science of electrosynthesis.

  A concise explanation is provided using a few examples of the application of direct/indirect as well as multiple types of paired electrolysis. This study also gives an overview of the advantages of alternate electrode electrolysis. This work also describes the cyclic voltammetry (CV), which is generally the only technique utilised to support the postulated mechanism. Flow-electrolysis enables the economically advantageous continuous manufacture of value-added products. A growing number of scientists find organic electrochemistry appealing due to this benefit and the requirement to conserve resources.

  Electrophotochemistry (EPC) is strategically employed to solve a pertinent problem, such as to remove a chemical oxidant or reductant that degrades the catalyst, to generate highly re-active intermediates under mild conditions, or to access extremely oxidising or reducing potentials for inert bond activation. The strategic merger of electrochemistry and photochemistry will have broader applications in organic synthesis, especially for reactions that require activation at strongly oxidising and reducing potentials under mild conditions free of potent stoichiometric chemical agents. The independent successes of electrochemistry and photochemistry, two related yet orthogonal modes of redox activation, piqued interest in employing both of these tactics in a single reaction system to promote organic transformations. It is important to note that EPC differs from reaction techniques that employ semiconductor electrodes to generate photocurrent to promote chemical transformations, which is commonly known as photoelectrochemistry (PEC). The EPC will present researchers with new opportunities as well as new challenges. Among these challenges are the identification of new catalysts, in-depth understanding of mechanisms of EPC activation, and design of practical reactor systems. Future developments in these directions will continue to push forward this nascent research area. Future studies will focus on functionalising the redox mediator to boost its stability in order to maximise the conversion and product selectivity.

  Moreover, methods to produce heterogeneous mediators or immobilise redox mediators onto a substrate will reduce the redox mediators' susceptibility to self-degrade and simplify the processes of product separation and purification, particularly for large-scale applications. When many features of electro-organic synthesis are considered, it becomes clear that this process is promising and has yielded significant innovations as well as an abundance of unexplored treasures that have led to further advancements. Specifically, the application of abundant and fluctuating power to produce chemicals with additional value will revolutionise chemical operations in the future.

  In summary, while market economics will always have a greater influence on the application of organic electrochemistry, the field's advancement will be essential to confirming that electro-organic chemistry may find applications in the synthesis of chemicals.

  Declaration of competing interest

  The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

  CRediT authorship contribution statement

  Sadia Rani: Writing – original draft, Methodology. Najoua Sbei: Writing – review & editing. Seyfeddine Rahali: Writing – review & editing. Samina Aslam: Writing – review & editing. Tomas Hardwick: Writing – review & editing, Writing – original draft, Project administration, Methodology, Investigation. Nisar Ahmed: Writing – review & editing, Writing – original draft, Visualization, Validation, Supervision, Resources, Project administration, Methodology, Investigation, Funding acquisition, Formal analysis, Data curation, Conceptualization.

  Supplementary materials

  Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.cclet.2025.111216.

  
  
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• 

  Figure 1  Basic principles of organic electrosynthesis. (a) Conventional setup for a batch electrochemical cell. (b) Typical categories of organic electrochemical reactions. Reproduced with permission [25]. Copyright 2022, Elsevier.

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  Figure 2  Initial reaction setting.

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  Figure 3  Modes of operation for organic electrosynthesis (a) galvanostatic and (b) potentiostatic mode.

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  Figure 4  Potential behavior in existing electrosynthesis techniques. (a) DC (direct current); (b) AC (alternating current); (c) rAP (rapid alternating polarity) and (d) pulsed electrolysis. Reproduced with permission [42]. Copyright 2024, ACS Publications.

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  Figure 5  Different shaped working electrodes. Reproduced with permission [31]. Copyright 2014, Wiley.

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  Figure 6  Different operation modes of electrodes in electrosynthetic applications. (a) Inert electrode, (b) active electrode, (c) high surface electrode; and (d) sacrificial electrode. Reproduced with permission [24]. Copyright 2020, Royal Society Chemistry.

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  Figure 7  Examples of reference electrodes: (a) saturated colomel electrode (SCE); (b) Ag/AgCl electrode; (c) Ag/Ag⁺ electrode. Reproduced with permission [31]. Copyright 2014, Wiley.

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  Figure 8  Cell design and schematic operating concept of (a) an undivided cell: the preferred and most simple setup; (b) a divided cell: separation of anolyte and catholyte suppress side reactions at the counter electrode; and (c) a quasi-divided cell design with two electrodes that differ greatly in surface area.

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  Figure 9  Notations for electrodes and typical (a) undivided and (b) divided cells in this review.

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  Figure 10  Alternating electrode electrolysis (AEE). (a) Cell setup, AEE cycle (b) cell potential behaviour (combined effect of two pairs of anodes and cathodes. Reproduced with permission [42]. Copyright 2024, ACS Publications.

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  Scheme 1  Electrochemical production of monoketal derivative of benzoquinone 4 via alternate electrode electrolysis.

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  Scheme 2  Applications of AEE in organic electrosynthesis. (a) Benzonitrile 5 reduction. (b) Hydroxylation of fluoro-acetophenone 7 and (c) phthalimide 9 reduction reaction.

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  Scheme 3  Robust anodic carbon-carbon bond production with selectivity for the cross-coupling reaction >100:1 at various current densities.

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  Figure 11  Synthetic applications of anodic production of high-performance oxidisers during water splitting. Reproduced with permission [24]. Copyright 2020, Royal Society of Chemistry.

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  Scheme 4  Electrochemical production of 1-phenylethanol 16.

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  Figure 12  Overview of paired electrosynthesis. Reproduced with permission [92]. Copyright 2021, Wiley Online Library.

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  Scheme 5  Paired electrolysis of product.

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  Scheme 6  Gram-scale electrochemical production of 19 and its proposed mechanism.

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  Figure 13  Schematic representation of an experimental device. Reproduced with permission [79]. Copyright 2020, Royal Society of Chemistry.

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  Scheme 7  Operational design and example of practical application of parallel paired electrolysis.

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  Scheme 8  Schematic representation and a practical example of the application of a divergent paired electrolysis.

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  Scheme 9  Schematic representation and an example of a practical application of a convergent paired electrolysis.

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  Scheme 10  Schematic representation and an example of a practical application of a sequential paired electrolysis.

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  Scheme 11  Schematic representation and an example of linear paired electrolysis via oxidation of hydroxylamines 35.

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  Scheme 12  Bromination of cyclohexene 37 by linear paired electrolysis.

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  Figure 14  A comparison of schematic principles of (a) direct and (b) indirect electrolysis.

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  Figure 15  Economic analysis of carbon dioxide reduction products. The prices of various products are derived from the current international market prices. eCO₂RR, electrocatalytic CO₂ reduction reaction. Reproduced with permission [110]. Copyright 2023, Wiley Online Library.

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  Scheme 13  Gram-scale electrochemical production of benzimide 40 and its proposed mechanism.

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  Scheme 14  Gram-scale organo-mediated electrochemical production of boronate ester 44 and its proposed mechanism.

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  Scheme 15  Examples of organo-mediated electrochemical production.

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  Scheme 16  (a) Gram-scale electrochemical production of quinoxalinone 43 and its proposed mechanism. (b) Pharmacologically relevant compounds containing 3-alkylated quinoxalinones motifs 43a-43c.

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  Figure 16  The fundamental components of an electrochemical flow setup. Reproduced with permission [147]. Copyright 2020, Cell Press.

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  Figure 17  (a) Examples of advancements in flow electrosynthesis include the in situ electrochemical synthesis of hyperiodine species; (b) commercial electrochemical flow cell setup. Reproduced with permission [151]. Copyright 2019, Wiley Online Library.

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  Scheme 17  Application of AEE and direct current electrolysis (DCE) in the production of APIs and their late stage functionalization.

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  Scheme 18  Natural products and active pharmaceutical ingredients with electro-organic fundamental transformations.

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  Scheme 19  API synthesised by Bayer via electro-organic racemisation.

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  Scheme 20  Asymmetric electrolysis modes with considerable enantiomeric excess.

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  Scheme 21  Asymmetric electrolysis using spiroxyl-modified graphite felt (GF) as anode.

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  Scheme 22  Schematic representation of the process for developing a chiral imprinted Pt or Ni electrode via 3D metal deposition on a liquid crystal containing adsorbed chiral molecules, along with an example of enantiomer discrimination during electrolysis at the imprinted electrode surface.

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  Scheme 23  Asymmetric electrochemical production of intermolecular α-alkoxylations 70 and the lactonization 71 derivatives of diketo ester.

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  Scheme 24  Asymmetric indirect electrolysis for the production of enantioselective nucleophilic α-C(sp³)−H alkenylation of ketones.

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  Scheme 25  Lewis-acid catalysed asymmetric electrosynthesis.

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  Scheme 26  Proposed mechanism for the use of electroauxiliaries in electro-organic synthesis.

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  Scheme 27  Use of electroauxiliaries in enantioselective electro-organic synthesis.

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  Scheme 28  Use of electroauxiliaries for controlled oxidations in electrochemical synthesis.

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  Figure 18  A cyclic voltammetry experiment in an electrochemical cell consisting of a typical three-electrode setup submerged in a 0.1 mol/L supporting electrolyte and 1 mmol/L analyte solution. N₂ or Ar gas can be sparged into the system via an inert gas intake. Reproduced with permission [12]. Copyright 2022, Springer Nature.

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  Figure 19  Fundamentals of voltammetry in cycles. (a) First sweep with a linearly increased potential up to a fixed threshold (potential scan). (b) The initial sweep's observed current response is plotted against potential in section a. (c) Reverse sweep, with the potential linearly returning to the initial level (at the same rate as the initial sweep). (d) The reverse sweep's observed current response in relation to potential. (e) A typical cyclic voltammogram labelled with relevant parameters: I_pa (anodic peak current), I_pc (cathodic peak current), E_pa (anodic peak potential) and E_pc (cathodic peak potential). Reproduced with permission [12]. Copyright 2022, Springer Nature.

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  Figure 20  Overview of fine chemicals produced via electrochemical methods. Reproduced with permission [147]. Copyright 2020, Cell Press.

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  Figure 21  A number of electro-organic processes on the industrial scale. Reproduced with permission [24]. Copyright 2020, Royal Society of Chemistry.

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  Scheme 29  Summary of several established industrial electrochemical syntheses.

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  Figure 22  Photochemical cell with TiO₂ electrode. Reproduced with permission [188]. Copyright 1991, Nature Publishing Group.

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  Scheme 30  The decomposition of water by visible light into oxygen and hydrogen.

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  Figure 23  Set-up of photo-electrocatalytic experiments: (a) undivided cell; (b) divided cell. Reproduced with permission [191]. Copyright 2020, Wiley online Library.

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  Scheme 31  Typical quenching types of photocatalysis.

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  Scheme 32  Gram scale photo-catalyzed electrochemical production of pyrrolidine 123.

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  Table 1.  Typical components of organic electrochemical cells.

  Typical components	Features
  Electric power supply	It supplies either direct current (DC) or alternating current (AC)
  Anode	It is connected to the power supply's positive pole and oxidation occurs at this electrode
  Cathode	It is linked to the power supply's negative pole and reduction occurs at this electrode
  Reaction vessel	It is usually a pot-shaped or H-type cell with a separator if needed
  Reaction solution	It usually consists of substrates and solvents along with electrolytes and other additives if required
  Reference electrode	This additional electrode is needed for complex conversions that need accurate control over the cell potential

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  Table 2.  Brief summary of parameter adjustments for electrochemical processes.

  Galvanostatic mode (Constant current)	↑ ↓ Electrolyte concentration, surface area, stirring	↓ ↑ Potential and resistance	Constant reaction rate
  	↑ ↓ Electrode gap	↑ ↓ Potential and resistance	Constant reaction rate
  Potentiostatic mode (Constant potential)	↑ ↓ Electrolyte concentration, surface area, stirring	↑ ↓ Current density and reaction rate
  	↑ ↓ Electrode gap	↑ ↑ Current density and reaction rate

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  Table 3.  Some frequently used solvents in electrochemical reactions.

  Solvent	Dielectric constant (ε)
  Electrochemical oxidation reaction
  1,2-Dimethoxyethane	3
  Dichloromethane	9
  Propylene carbonate (PC)	64
  Nitromethane	37
  Electrochemical reduction reaction
  Tetrahydro-furan (THF)	7
  Benzonitrile	26
  Hexamethylphosphoramide (HMPA)	30
  N,N-Dimethylformamide (DMF)	37
  Dimethylsulfoxide (DMSO)	47
  Redox reactions due to its high upper and lower potential
  Acetonitrile	38

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  Table 4.  An overview of the differences between standard divided and undivided industrial electrochemical configurations.

  Parameters	Cell deign
  	Undivided	Divided
  Operation mode	Batch or continuous
  Electrode geometry	2D	3D
  Pair of electrodes	Single	Multiple
  Electrode movement	Static	Dynamic
  Electrode material	Noble metals, carbon, nickel, steel
  Interelectrode gap	Narrow	Capillary
  Electrode connection	Monopolar	Bipolar

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