Biphasic organic synthesis with continuous electro-flow

Organic electrochemistry has recently witnessed a renais-sance in research as a green and cost-efficient method for activating small molecules. Although some of the critical challenges of batch electrosynthesis remain, flow electrosyn-thesis can overcome several issues arising from batch elec-troorganic systems, such as mass transfer, ohmic drop, and selectivity. The combination of flow technology with electro-chemistry affords practitioners a very precise control over reaction conditions, thereby enhancing the reproducibility of electrochemical processes. The use of gases in chemical reactions for the synthesis of value-added fine chemicals is of great significance. This review summarizes recent advances in flow electrochemistry for biphasic (gas – liquid) organic synthesis. We summarise recent examples of selective hydrocarbon oxidations using oxygen gas in an electrochemical flow reactor.


Introduction
The Chemistry 4.0 & Industry 4.0 initiative seeks to enhance the energy efficiency of the chemical industry through the incorporation of advanced technologies such as artificial intelligence, digitization, and process intensification [1,2].One idea of exploration involves diversifying energy sources, specifically by utilising electricity to optimise chemical processes.This approach, referred to as the "electrification of the chemical industry," holds promise for diminishing reliance on fossil fuels, reducing overall energy consumption, and elevating the efficiency and selectivity of reactions [3].
The recent resurgence of electrochemical synthesis as a secure and sustainable strategy for crafting organic molecules has generated considerable interest in scaling up this technology [4e7].The combination of flow technology with electrochemistry affords practitioners precise control over reaction conditions, thereby enhancing the reproducibility of electrochemical processes [8].In addition, electrochemical flow cells enable the safe generation and consumption of reactive intermediates and hazardous reagents, overcoming the limitations of traditional batch methods.Microreactors with typically very high surface-to-volume ratios provide precise control over reaction conditions, simplify scaleup and reduce safety concerns.Flow conditions in electrolysis reduce the risk of overoxidation compared to traditional batch cells [9].Despite significant contributions in flow electroorganic synthesis during the past decade [10e15], the exploration of flow electrochemistry in biphasic (gaseliquid) organic synthesis is not much developed.Gaseliquid electrochemical organic reactions are a mainstay in a variety of important organic synthetic transformations, such as hydrogenations [16e19], oxidations [20e24] and carboxylations [25,26].In batch, such reactions are typically performed in mechanically stirred vessels, either by sparging the gas into the liquid phase through bubbling to increase the interfacial area or through excessive mixing within the liquid phase to enhance the interaction between the two phases.While gas bubbling in batch reactors offers its own merits for conducting gaseliquid reactions (ease of access and assembly), it provides an inherent gaseliquid mass transfer limitation due to low specific interfacial areas [27].In addition to increased safety concerns, such mass transfer limitations result in prolonged experimental times and mass transfer-limited reaction kinetics, thereby hindering further developments of important gaseliquid electrochemical reactions for organic synthesis.
Different gaseliquid flow microreactor designs have been reported which have been developed to facilitate gaseliquid reactions in organic synthetic chemistry [28e32].Although the advantages of flow microreactor technology appear to be numerous, the renewed interest in organic electrochemistry has brought some old and tedious technological problems to the surface.Electrochemistry can be considered a heterogeneous process due to the use of solid electrodes that can be quite challenging to those unfamiliar with mass transfer effects.This means that both mixing effects and interelectrode distances are important parameters in the development process.Furthermore, the need for specialised equipment and the knowledge gap of most researchers in this often perceived as a specialized field are additional barriers to adopting electro-flow biphasic (gaseliquid) organic synthesis as viable alternative synthetic routes.
Continuous flow electrosynthesis can be performed using various techniques and technical variations, and currently, portable electrochemical reactors are available at a reasonable cost [33].The exchange of electrons occurring on the electrode's surface serves as the driving force for electrochemical reactions.Therefore, reagents and electron mediators must meet the electrode surfaces.Consequently, creating suitable systems relies on understanding mass transport phenomena and improving electron transfer rates.These factors become even more critical when developing bi-phasic flow systems as illustrated in Figure 1 [8].

Principles and advantages of multiphase continuous flow electrochemistry
From our perspective, the significance of multiphase continuous electro-flow chemistry in organic synthesis has been overlooked until now.Multiphase reactions are prevalent in synthetic chemistry, involving both gase liquid and liquideliquid transformations [32].In the realm of electrochemistry, gaseliquid reactions, such as hydrogen evolution at the counter electrode, are frequently encountered but pose engineering challenges due to the intricate nature of these reactions.The evolution of gas can result in a significant increase in ohmic resistance due to the formation of an insulating gas layer.However, the presence of gases can also enhance mass transport considerably.
Another critical aspect of multiphase electrochemistry arises when the reactant exists in a dispersed second phase.In this scenario, the reactant must either diffuse to the electrode or the continuous phase before undergoing the reaction.Rapid transport of the reactant to the second phase is essential for an efficient synthesis [32].
The utilization of microreactors (Figure 2) can address various challenges and technological hurdles encountered in biphasic electrochemical synthesis.Microreactors offer reduced distances between electrodes, increasing the ratio of electrode surface to reactor volume and concurrently minimizing ohmic resistance.This results in a significant enhancement of mass transfer on the electrode surfaces [34].Additionally, improving the interfacial contact area proves advantageous for facilitating reactions that are typically impractical in conventional batch electrosynthesis.Continuous flow setups offer better manageability, as their delivery can be controlled through dosingcontrolled flow volumes, leveraging higher internal pressures to aid dissolution [35,36].
Microreactors exhibit various flow regimes based on the individual flow rates of the two phases.Two extremes are annular flow and segmented flow (also known as slug flow or Taylor flow).In annular flow, one of the two phases flows at a higher velocity in the centre of the capillary, while the other phase contacts the electrodes as a thin film.Although relatively uncommon in flow electrochemistry, intimate contact between the wetting phase and the electrode phase could provide advantages in specific situations [37].In contrast, segmented flow is commonly observed in flow chemistry, characterized by alternating bubbles and liquid segments.Toroidal vortices form within these segments and bubbles, ensuring heightened mixing efficiency.Additionally, these fluid patterns play a crucial role in significantly improving mass transfer to the electrode surfaces [38].Gas-liquid flow regimes, including segmented and annular flow patterns, offer significant advantages in organic synthesis.They significantly enhance the mass transfer efficiency to the electrode surfaces by providing a large interfacial area and turbulent mixing, facilitating reactions such as absorption, stripping, and chemical reactions.They promote improved heat transfer efficiency, making them suitable for condensation and evaporation processes.These flow regimes typically exhibit lower pressure drop, reducing energy consumption and operational costs.Their capacity for high flow rates suits industrial-scale production.They also enable the use of smaller and more compact equipment, leading to cost savings and space efficiency.Additionally, reaction times can substantially be shortened using this flow microreactor technology, due to the shorter diffusion distances to the electrodes and the large electrode surface-to-volume ratios.With greater operational stability and versatility, segmented and annular flow regimes are well-suited for biphasic organic electrosynthesis.

Examples of selective oxidations using oxygen gas in an electrochemical flow reactor
Over the past decade, there has been a concerted effort by flow chemists and electrochemists to advance continuous electrochemical flow systems tailored for organic synthesis applications [5,6,12,39].Our research has been integral to the progress of electroorganic synthesis in continuous flow configurations [10,40,41].Initially, we utilized our in-house electrochemical flow cells, encompassing both first and second-generation models.Subsequently, we transitioned to employing the commercially available Vapourtec electrochemical Ion Reactor.This reactor presents numerous advantages, including the ability to adjust the reactor's temperature within the range of À10 to þ100 C, the capability to operate under pressures of up to 5 bar, significant flexibility in electrode spacing facilitated by various spacer options, the capacity to modify electrode area and reactor volumes, and the option to introduce a second flow stream into the reactor during electrolysis.Furthermore, it offers flexibility in the use of any electrode material, as electrodes can be easily changed or replaced.
As an example, we have shown a continuous gaseliquid biphasic electrochemical flow method to efficiently generate superoxide radical anions and oxidatively cleave di-and trisubstituted alkenes into their corresponding carbonyl compounds [42].This is a mild and straightforward approach that uses molecular oxygen in combination with flow electrochemistry.The proposed reaction mechanism is shown in Scheme 1.Initially, oxygen undergoes a one-electron reduction to form the corresponding superoxide radical anion A (O 2 e ) which is stable enough to capture the radical cation of the alkene B generated by the one-electron oxidation of the alkene.This could form the intermediate C followed by the generation of dioxetane intermediate D, which decomposes to the corresponding carbonyl compound 2a.
Recently, Einaga, Yamamoto, and their collaborators have developed a selective oxidation of cumene utilizing an electrochemical flow reactor [43].As the oxidation of the benzylic carbonehydrogen bond in cumene into cumene hydroperoxide is an important step of the cumene process for industrial phenol production, achieving cumene oxidation under mild conditions holds paramount importance.In their prior investigation involving batch electrolysis of cumene, cumene hydroperoxide suffered  In addition to environmental and economic advantages, drawbacks of overoxidation have been overcome in a flow setting, and even easily oxidizable substrates are good yielding.This could be explained by a variety of factors such as the short residence time of the solution in the electrochemical cell or the nature of the flow regime that is laminar and hence reduces the contact of the either product with the anode due to selective oxidation into the cumyl alcohol followed by its diffusion closer to the cathode where it is less likely to undergo subsequent oxidation.Similar to their previous work [44], the authors proposed the following mechanism for the flow electrolysis of cumene (Scheme 2).A hydroperoxide anion F generated at the cathode added to a cumyl cation E generated at the anode to form G. The OeO bond in G was cleaved anodically to form alkoxy radical H, which underwent a hydrogen atom transfer (HAT) with cumene 3a to yield 4a. Furthermore, 4a was oxidized into H, followed by b-scission to yield acetophenone.Therefore, it was suggested that the selective conversion of 3a into 4a in flow electrolysis was due to suppressing overoxidation of 4a into H.
Another interesting example involves the oxidation of C(sp 2 )eH bonds, in which cyclic olefins are converted into aliphatic (di)carboxylic acids in an electrochemical flow setup [45].This eco-friendly approach relies on nitrate salts serving a dual function as an anodic mediator and supporting electrolyte, with the added benefit of being recoverable and recyclable.The reduction of molecular oxygen as a cathodic counter reaction ensures efficient and synergistic utilization of both electrode reactions.By circumventing the use of transition metals and chemical oxidizers, this methodology establishes a sustainable oxo-functionalization process, making a significant contribution to the sustainable transformation of petrochemical feedstocks into synthetically valuable fine chemicals and commodities.In a small-scale trial, it was observed that cyclododecene 5a at a concentration of 0.05 mol L À1 in isobutyronitrile resulted in the formation of dodecanedioic acid 6a with a yield of 76%.In the context of larger technical applications, a shift in solvent was implemented, and a scalingup initiative was undertaken.Following several variation trials within the same set-up, optimization of the reaction was achieved by employing a non-toxic dimethyl carbonate/isopropanol (DMC/i-PrOH) mixture and adjusting the substrate concentration to 0.5 mol L À1 , yielding 6a with a 52%.
Based on the control experimental results, the proposed mechanism (Scheme 3) involves the electrochemical oxidation of nitrite I (serve as anodic mediator), which would react with alkene 5a and generate hydrocarbon radical K.For the C=C double bond cleavage, an addition of the nitrate radical I onto the double bond 5a is proposed, according to the findings of the control experiments and literature descriptions [46].The cathode counter reaction is provided by the reduction of dissolved oxygen and the resulting superoxide radical anion J is assumed to react with K to peroxide intermediates L. Further reaction with a superoxide radical lead via an unknown pathway to the formation of aldehydes M that are obtained as possible intermediates (HRMS analysis of the crude reaction mixture).Afterwards, literature described an autooxidation like mechanism from aldehydes M to carboxylic acids 6a [47].

Conclusion
Basic principles and advantages of continuous flow microreactors for carrying out multiphase synthetic organic electrochemistry are illustrated.This includes a discussion on the importance of mass and heat transfer, on multistep reaction sequences and enabling controlled biphasic reaction conditions.Recent examples show how to improve reaction selectivity, and scaleup of reactions.Despite significant contributions in the field of electroorganic synthesis under flow conditions over the past decade, multiphase electrochemistry remains underdeveloped, probably due to the lack of standardized protocols and detailed understanding.The deployment of continuous flow microreactors for multiphase synthetic organic electrochemistry holds the promise of exploring new and uncharted chemical spaces.The development of competitive and sustainable biphasic flow electrochemical processes for the manufacture of building blocks, APIs (i.e.Active Pharmaceutical Ingredients), and commodities is imperative for the advancement and continued growth of academia and manufacturing industries.

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.* * .Jayan K, Thadathil A, Varghese A: Electrochemical hydrogenation of organic compounds : a sustainable approach.Asian J Org Chem 2023, 12, e202300309.https://doi.org/10.1002/ajoc.202300309.This review aims to encourage researchers to focus on enhancing the efficiency of hydrogenation processes for both simple and complex organic compounds through modified electrodes.It guides and inspires researchers towards advancing the field of efficient and sustainable hydrogenation by comprehensively covers various strategies employed in past studies, encompassing electrochemical hydrogenation (ECH).The review explores electrode modification techniques, analyzes halfreactions for energy optimization, and investigates catalysts in various hydrogenation reactions.17.Li J, He L, Liu X, Cheng X, Li G: Hydrogenation with ammonia electrochemical hydrogenation with gaseous ammonia. .This article describes a streamlined approach for synthesizing ketonitriles involving electrochemical cleavage and functionalization of cyclic alkenes.The method employs environmentally friendly conditions, using TMSN 3 as a safe nitrogenation reagent and molecular oxygen as the oxidant to produce ketonitriles and a-azido aromatic ketones in moderate to good yields.

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. Hou Z, Zhang M, Yang W, Wang L: Catalyst-and oxidizing reagent-free electrochemical benzylic C(Sp 3 )−H oxidation of phenol derivatives.J Org Chem 2022, 87:7806-7817.https:// doi.org/10.1021/acs.joc.2c00455.This article reports an environmentally friendly, sustainable, and scalable electrochemical method for benzylic C(sp 3 )−H oxidation in phenol derivatives, facilitating the synthesis of aryl aldehydes, aryl ketones, benzyl methyl ethers, and methyl aryl formates with outstanding site selectivity.Operating at room temperature through straightforward direct electrolysis, this process boasts a wide substrate range, eliminating the requirement for catalysts or stoichiometric oxidants. .Zhuang W, Zhang J, Wright JS, Zhang X, Ni S, Huang Q: Scalable electrochemical aerobic oxygenation of indoles to isatins without electron transfer mediators by merging with an oxygen reduction reaction.Org Lett 2022, 24:4229-4233.https://doi.org/10.1021/acs.orglett.2c01545.A mediator-free electron transfer protocol for the electrochemical oxidation of various indoles to the corresponding isatins is reported.This process utilizes a straightforward undivided cell galvanostatic scalable method, ensuring good yields and accommodating various functional groups.The probable reaction pathway follows a radical pathway, involving single-electron anode oxidation of indoles and cathode one-electron reduction of O 2 , yielding a superoxide ion.

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. Liu X, Zhang K, Tao L, Lu X, Zhang W: Recent advances in electrochemical carboxylation reactions using carbon dioxide.Green Chem Eng 2022, 3:125-137.https://doi.org/10.1016/j.gce.2021.12.001.The review article focuses on the electrochemical carboxylation reactions of alkenes, organic (pseudo)halides, aldehydes, ketones, and imines utilizing CO 2 , particularly in the last three years.The highlighted reactions enable the environmentally friendly synthesis of high-value carboxylic acid products.This eco-friendly approach is attributed to the utilization of CO 2 as a C1 feedstock and the employment of electrons as the reductant, eliminating the need for stoichiometric metallic reductants..1038/s41467-023-40259-0.The authors of the article reports an electrochemical approach for the direct functionalization of both C(sp 3 )-H and C(sp 2 )-H bonds, allowing rapid access to valuable products from simple petrochemicals.The method converts cyclic alkanes and (cyclic) olefins into cycloaliphatic ketones as well as aliphatic (di)carboxylic acids employing nitrate salts, serving as both anodic mediator and supporting electrolyte, which can be fully recovered and recycled.Futhermore, the reduction of molecular oxygen as the cathodic counter reaction ensured an efficient convergence of both electrode reactions.

Figure 2 a
Figure 2 from over-oxidation to acetophenone[44].The current study employed a biphasic electrochemical flow method to mitigate overoxidation, aiming for the selective conversion of cumene into cumene hydroperoxide.Consequently, cumyl alcohol was selectively obtained, indicating successful suppression of the over-oxidation of cumyl alcohol into acetophenone in flow electrolysis.The authors also observed the superiority of flow electrolysis over batch electrolysis for cumyl alcohol synthesis within a specific reaction time, as illustrated in Scheme 2. While batch and biphasic electrochemical flow methods of cumene resulted in acetophenone and cumyl alcohol as the primary products, respectively, this study convincingly illustrates the ability to switch the product selectivity of cumene oxidation by a simple change in electrolysis mode[43].
CO 2 ) and electrochemistry, offering promising breakthroughs in mitigating the greenhouse gas CO 2 .Two main strategies are discussed in the review: the direct electrosynthesis of substrates followed by CO 2 capture, involving a process of CO 2 attacking carbanions; and metal-catalyzed electrocarboxylation, where metal catalysts activate substrates or generate reducible metallic CO 2 complexes.The latter introduces a new indirect-activation strategy for electrocarboxylation with CO 2 , holding promising prospects with the incorporation of novel metallic or organic additives.enabling and hybrid technologies.Front Chem Eng 2022, 4: 966451.https://doi.org/10.3389/fceng.2022.966451.This article reviews key synthetic technologies employed in process intensification, individually or in combination.This aligns with the overarching shift from batch to continuous-flow production, encapsulating the prevailing trend in manufacturing.Matsuoka R, Saitoh T, Einaga Y, Yamamoto T: Selective electro-oxidation of cumene utilizing a flow reactor equipped with diamond electrodes.Curr Res Green Sustain Chem 2023, 7:100378.https://doi.org/10.1016/j.crgsc.2023.100378.This study underscores the capability to alter product selectivity simply by changing the electrolysis mode.The authors reports that the selective oxidation of cumene utilizing an electrochemical flow reactor in contrast to batch electrolysis resulted in the selective formation of cumyl alcohol.Hence outperforming batch electrolysis in synthesizing cumyl alcohol within a specific reaction time.The success of the selective oxidation reaction was attributed to the suppression of side reactions facilitated by flow electrolysis.Saitoh T, Nishiyama S, Einaga Y, Yamamoto T: Electro-conversion of cumene into acetophenone using borondoped diamond electrodes.Beilstein J Org Chem 2022, 18: 1154-1158.https://doi.org/10.3762/bjoc.18.119.**.The article reports an electrosynthesis method for direct electroconversion of cumene into acetophenone using a boron-doped diamond (BDD) electrodes.The broad potential window of BDD facilitated the direct anodic oxidation of cumene, a crucial reaction intermediate not achievable with alternative electrodes like graphite and Ni.The method is reported as sustainable, scalable, and cost-efficient, requiring no specific catalyst and thereby minimizing reagent waste.Hofman K, Mossazghi S, Möller IC, Mondeshki D, Weinelt F, Baumann FE, Waldvogel SR: Electrochemical oxofunctionalization of cyclic alkanes and alkenes using nitrate and oxygen.Nat Commun 2023, 14:4565.https://doi.org/10