Arenes and Heteroarenes C (cid:0) H Functionalization Under Enabling Conditions: Electrochemistry, Photoelectrochemistry & Flow Technology

: C (cid:0) H bond functionalization generates molecular complexity in single-step transformation. However, the activation of C (cid:0) H bonds requires expensive metals or stoichiometric amounts of oxidizing/reducing species. In many cases, they often require pre-functionalization of starting molecules. Such pre-activating measures cause waste generation and their separation from the final product is also troublesome. In such a scenario, reactions activating elements generating from renewable energy resources such as electricity and light would be more efficient, green, and cost-effective. Further, incorporation of growing flow technology in chemical transformation processes will accelerate the safer accesses of valuable products. Arenes & heteroarenes are ubiquitous in pharmaceuticals, natural products, medicinal compounds, and other biologically important molecules. Herein, we discussed enabling tools and technologies used for the recent C (cid:0) H bonds functionalization of arenes and heteroarenes.


Introduction
With the growing concern about the environment and the impacts on nature during chemical processes, the industry is constantly highlighting the need for synthetic methods with less residue formation.Considering this, chemists are seeking to develop synthetic methods to reduce or, even more desirable, avoid the generation of waste. [3]hus, the development and integration of new technologies in organic synthesis, as well as the use of more efficient and environmentally friendly routes are desirable. Although it may appear to be a disadvantage, there are situations where using a large amount of electrolyte is necessary in electrosynthesis reactions.This is often required to maintain efficient process performance or to control reaction conditions, and to ensure proper electrical conductivity.In systems with high electrical resistivity or low ionic mobility, a large amount of electrolyte may be necessary.Furthermore, using a large amount of electrolyte can increase the mass transfer of reactive species to the electrodes, improving the efficiency of the reaction.However, to overcome these limitations, new strategies are being developed, for example Little and co-workers have developed a polymeric ionic liquid-Super P carbon black composite. [6]The system allows electrolysis to be performed without adding an additional supporting electrolyte, with efficient recovery and reuse.
Commonly, to favor a chemical transformation it is necessary for an atom susceptible to cleavage, substitution, addition or migration.The CÀ H functionalization may represent a change in this logic, since it is possible to obtain a functionalization of CÀ H bonds even in the presence of apparently more reactive functional groups [7][8] , however regio-and chemoselectivity represent the greatest challenges for chemists.This process can be induced by an external energy source, a neighbor functional group with the electronic or steric features, and/or an external agent, making a specific atom more reactive for synthetic transformation. [9][24][25][26] Likewise, electrosynthetic processing of organic chemicals on an industrial scale has been carried out, with the production of compounds such as sorbitol, mannitol, benzidine, hydroquinone, 1,4-dihydronaphthalene, salicylic aldehyde, chloroform, iodoform, vanillin, pinacol, chloral, indigo, etc. [27] To help the reader understand the technique of electrosynthesis, we recommend the review article recently published by Gerhard Hilt [28] which highlights the basic strategies and types of applications in organic electrochemistry, as well as the article published by Charlotte Willans and co-workers [29] that aims to facilitate the exploration of electrosynthesis to newcomers.Likewise, we highlight an interesting discussion on the Nisar Ahmed obtained his PhD in organic chemistry with Brain Korea BK21 fellowship from POSTECH, Korea.Then, he moved to the University of Zurich, Switzerland for a postdoctoral stay with a Novartis Fellowship.Subsequently, he joined the University of Bristol as a research associate (Prof.Anthony P. Davis research group).Further, he started his academic career at Cardiff University (2017-present, COFUND/EPSRC ~AP/ UK Lecturer), United Kingdom.He also holds an Adjunct position at HEJ Research Institute of Chemistry.His fields of research include synthesis of value-added chemicals, fine chemicals, and pharmaceuticals with special focus on inert bonds activations using modern synthetic tools such as electrochemistry, photochemistry, sonochemistry, flow technology, digital & automation chemistry, and reaction engineering.
Bahareh Shirinfar obtained her Ph.D in 2014 in organic supramolecular chemistry, working in the group of Prof. Kwang S. Kim (POSTECH, Korea).Then, she moved to Switzerland to continue her career as a post-doctoral fellow at the University of Zurich.She arrived in Bristol in January 2015 to take up a Royal Society Newton Fellowship.Further, she was awarded Daphne Jackson Fellowship at University of Bath, UK (2020).She started her academic career as a Lecturer (2022) at West Herts College, Watford/Hertfordshire, London, UK.Her research interests are bio-molecular recognition & organic electrochemical sciences.

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advantages of electrosynthesis compared to traditional methods, presented by Lei and Yuan. [5]n addition to the advantages of electrosynthesis, combining it with other techniques such as organic photochemistry can lead to even more benefits.Organic photoelectrochemistry is a rapidly growing field that has gained significant attention in recent years due to its potential for renewable energy conversion and storage applications.However, with so many different sub-types and combination strategies, it can be challenging for readers to navigate the concepts and nomenclature of this field.Therefore, to aid readers in understanding the fundamental principles and current advancements in organic photoelectrochemistry, introductory reviews have been recommended.Herein, this review article aims to provide an overview of recent advances in electrochemical arenes/(hetero) arenes CÀ H functionalization through batch reactions, continuous flow, metalla-, photo-and organo-electrocatalysis.The development of methodology and mechanistic studies was emphasized, seeking to provide inspiration for future synthetic applications in the field of electrosynthesis in organic chemistry.

Arenes/Heteroarenes CÀ H Functionalization via Batch Electrochemistry
In the past ten years, CÀ H functionalization technologies have advanced significantly, as evidenced by the large number of publications that have been made in the literature and are attracting significant interest from researchers in various fields, [32][33][34] with the protocols being mostly in batch conditions. [33]So, neither flow nor batch are novel concepts.The real purpose of batch technology must be acknowledged, even when flow chemists urge getting rid of "outdated" batch technology.Batch synthesis allows you to perform a wide range of tasks without requiring you to learn numerous new skills.However, it can be highly inefficient in a world with narrow profitability margins and environmental concerns.
Batch technology is well-known, straightforward and versatile.The same batch reactor design is used for process development from the lab to the production scale, which speeds up research and lowers costs.The most cost-effective approach to carry out many chemical operations is still batch technology.In order to explain the CÀ H functionalization via batch electrochemistry, in 2018, Gooßen and co-workers reported that an open, simple and undivided electrochemical cell using sodium cyanide (NaCN) as the reagent allows for the electrochemical CÀ H cyanation of arenes and heteroarenes to occur at room temperature in methanol (MeOH).Adsorbed cyanide maintains the quality of the platinum electrodes, enabling the conversion of a remarkable variety of electronrich substrates all the way down to dialkylarenes.Due to the abundance of nucleophilic cyanide sources and the difficulty of handling and storing electrophilic cyanide reagents, electrochemical oxidation would be a highly advantageous technique for aromatic CÀ Hcyanations.The benzonitrile 2, along with hydrogen and one equivalent of base, would result from the electrochemical coupling of NaCN with 1,3-Dimethoxybenzene 1 in 84 % yield as a single isomer using methyl alcohol with low water content.NaCN was selected as cyanide source because it is non-volatile from a safety standpoint and because its ionic nature allows us to avoid using more expensive supporting electrolytes.At a current of 20 mA for four hours, galvanostatic electrolysis was performed. [35]The arene underwent sequential anodic oxidation to produce radical cation I, which was then attacked by the cyanide nucleophile to produce cyclohexadienylradical II, which experienced additional oxidation to produce benzonitrile 2 (Scheme 1).

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Hydrogen cyanide can be used to refill the cyanide electrolyte, providing the possibility of industrial CÀ Hcyanation without the use of salt (Scheme 2).
The 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) aryl ethers 4 were electrochemically obtained by Waldvogel and coworkers employing boron-doped diamond (BDD) electrodes in up to 59 % of yield (Scheme 3).Triethylamine (Et 3 N) was employed as a base because, when combined with HFIP, it creates a highly conductive medium, eliminating the need for additional supporting electrolytes.Design of Experiment (DoE) methodologies were used to optimise the synthesis and provide a thorough understanding of the importance of the experimental parameters. [36] procedure for the dehydrogenativeC(sp 2 )À H/NÀ H crosscoupling between arenes/alkenes and sulfonimides that is brought on by electrochemical oxidation has been developed.It was possible to complete this reaction without the need of a transition metal catalyst or a stoichiometric extra oxidant.A wide range of aryl sulfonimides and alkenylsulfonimides could be obtained using the electro-synthetic approach.The simplicity with which the reaction can be scaled up shows this technique's potential for synthetic synthesis.The electrooxidative CÀ H imidation using naphthalene 5 (0.4 mmol) as a template platform and dibenzenesulfonimide 6 (1.5 equiv.)as the nitrogen supply were considered.By utilising a carbon rodanode and a platinum plate-cathode in an undivided cell with a constant current of 10 mA for 4 hours at room temperature, the cross-coupling product 7 can be produced in acetonitrile with a 43 % isolated yield.The electrolyte and base utilised were both tetrabutylammonium acetate.A mix-solvent system, DCM/MeCN/HFIP = 20 : 4 : 1, provided the greatest result (76 % isolated yield). [37] possible mechanism was predicted (Scheme 4).Tetrabutylammonium acetate and the dibenzenesulfonimide NÀ H bond would first create a hydrogen-bonded complex I.The resultant adduct I would go through a coordinated protoncoupled electron transfer event along with a single electron oxidation on the anode, which would cause the NÀ H bond to homolyze and result in the generation of the crucial sulfonimidyl radical intermediate II.A new CÀ N bond and a vicinal radical III with a carbon core were produced by the following radical addition to naphthalene.The radical species was subsequently subjected to further oxidation in order to produce a carbon cation intermediate IV, which was subsequently aromatized in order to produce the aryl C-(sp 2 )À H imidation product 7 via proton deletion.During the course of the reaction, concurrent cathodic reduction of the obtained protons would produce hydrogen gas, avoiding the need for an external oxidant to complete the transformation.
Sulfones are extremely adaptable basic components that have several uses in the pharmaceutical, agrochemical, and functional industries. [38]Lei and co-workers proposed an oxidatively CÀ H sulfonylate anilines electrochemically without the use of a metal catalyst or external oxidant.When acetonitrile, water, and acetic acid (10.2 mL, 9/1/0.2,v/v/v) are used as the solvent and various sodium sulfinates as the electrolyte, the necessary products can be produced in an undivided cell at 18 mA constant current for two hours with up to 96 % yield. [39]Using n-Bu 4 NBF 4 as the electrolyte and CH 3 CN/H 2 O as co-solvents for 3 hours in an undivided cell (a three-necked round-bottomed flask) furnished with a carbon rod anode and a platinum plate cathode.In 2019, Wu and coworkers reported the preparation of an anodic CÀ H sulfonylation product with a 91 % yield. [40]he suggested mechanism in Scheme 5 is as follows.First, the anodic oxidation of sulfinate salts produces the arylsulfonyl radical IV.Aniline 8 underwent oxidation at the same moment, resulting in radical cation I.Then, through tautomerization, radical cationI would yield radical cation II.Arylsulfonyl radical IV and radical cation II undergo radical/ radical cross-coupling before being successively deprotonated and aromatized to produce the required sulfonated aniline 10.During the reaction, the co-solvent water or acetic acid may be reduced at the cathode to produce hydrogen gas (Scheme 5).
Recently, Cantillo and co-workers described for the first time that arenes and heteroarenes undergo cathodictrifluoromethylation.Mesitylene 11 was used as a template platform (Scheme 6), and graphite was used as the anode and cathode materials in an undivided cell arrangement (IKA ElectraSyn 2.0).In order to elucidate the oxidation product of the amine, in addition to Et 3 N, other bases were investigated.Likewise, assays with MeCN-d 3 helped to understand the electrochemical trifluoromethylation reaction. [41]he suggested reaction mechanism tells about a change that would mostly occur on the cathode surface.A neutral radical is produced when trifluoroammonium complex I is reduced by one electron.The process is based on an electrochemical reduction of an unstable triflyltriethylammonium complex produced in-situ from triflyl chloride and triethylamine, which results in the production of CF 3 radicals that are captured by arenes on the cathode surface.
Even having a long history, electroorganic synthesis did not for a very long time contribute to the mainstream of chemical study.This is most often caused by a lack of tools and established procedures.However, organic electrochemistry is currently experiencing a revival, and a wide variety of intriguing electrochemical transformations and techniques have been devised, not just for academic reasons but also for massive industrial production.Electrochemical processes can be naturally green, environmentally safe, and simple to manage to reach high degrees of selectivity, depending on the source of electricity.Furthermore, it is possible to produce and consume hazardous reagents and reactive or unstable intermediates in a secure manner.Electrochemical flow cells can be used to overcome some of the drawbacks of conventional batch-type electrochemical processes, such as the constrained electrode surface, the requirement for supporting electrolytes, and the challenges of scaling up.High surface-to-volume ratios in microreactors make it possible to precisely manage the temper-ature, residence duration, flow rate, and pressure.Furthermore, handling of small amounts, improved mass and heat transmission, and effective mixing reduce safety issues and simplify scaling-up procedures.In contrast to conventional batch-type electrolysis cells, electrolysis under flow circumstances lowers the likelihood of overoxidation because the reaction mixture is flown continually out of the reactor. [28]

Arenes/Heteroarenes CÀ H Functionalization via Flow-Electrochemistry
The interest in electrochemical CÀ H functionalization in organic synthesis is expanding quickly.The flow electrolysis procedure is more environmentally friendly and allows for optimum atom economy.As a result, reaction times can be speedier, workplaces can be safer, and selectivities can be higher.With the use of this innovation, the issue of overoxidation can be mitigated, and side products may even not form at all.Electrochemical processes can now be controlled without the requirement for a purposefully supplied supporting electrolyte thanks to flow electro-reactors, which have electrodes that are closely placed where the diffusion layers meet to generate the desired result.Despite its many benefits, this approach is only employed in a small number of chemical and pharmaceutical firms because of the elaborate and costly setting.The creation of insoluble substances as the primary or by-product, which might interfere with uniform flow, is one of the many difficulties that restrict the use of flow electrochemistry in the industrial field.Additionally, other gases including H 2 or N 2 are formed during electrochemical synthesis, which results in a gas-liquid phase and affects the product's quality.The implementation of electro-flow methodologies will undoubtedly benefit from additional advancement and research of micro-reactors with simple setup and affordable electrochemical flow microreactors. [42]igure 1 shows an undivided (a) and a divided cell (b) under flow conditions.In undivided flow cell (Figure 1a), pumping the reagent solution into a system of two electrodes (anode and cathode) separated by a spacer, with only a gap between electrodes, is usually all that is needed to perform electrolysis under flowing conditions.Because of the reduced ohmic resistance caused by the close proximity of the two electrodes, electrolysis can be performed with low concentration or no supporting electrolyte.The use of fluorinated

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ethylene propylene (FEP) spacer with flow channel in electrochemical cells can help to improve both the productivity and efficiency of the cell, by allowing for more controlled and efficient reactions to occur.Although the anode and cathode are physically separated, the cell still allows sharing of the electrolyte solution and/or gas flow path between the two electrode regions.This separation helps prevent unwanted side reactions or degradation of cell components, which can increase the efficiency and longevity of the electrochemical cell.In divided flow cell (Figure 1b), the addition of an ionexchange membrane (e.g., Nafion membrane) and a second flow channel allow a separation of the anodic and the cathodic processes.The separation of the electrode processes is advantageous as both the cathodic and the anodic reaction can be utilised and do not interfere with each other.Usually, the reaction products at the counter electrode in undivided cell reactions are wasted.However, in divided flow cell products are obtained at both electrodes, and unwanted side reactions or corrosion by reactive species at the other electrode can be prevented. [42]t is of special industrial significance since 3,3',5,5'-Tetramethyl-2,2'-biphenol is well known for being an exceptional fundamental basis for ligands in transition-metal catalysis.In highly modular narrow gap flow electrolysis cells, the dehydrogenative anodic homocoupling of 2,4-dimethylphenol 14 is shown to scale up successively from the laboratory scale to the technically applicable scale.Up to 62 % of the necessary biphenol might be produced.The electrolysis of 14 was completed using HFIP as solvent at a temperature of 50 °C in order to transfer the electrosynthesis of 15 into the 2 cm × 6 cm flow electrolysis cell (Scheme 7).Bromination can be efficiently controlled as a side reaction by supplying H 2 O to the electrolyte.For both electrodes, glassy carbon was utilized as the electrode material.To get the most thorough conversion to the intended 15, a small excess of charge of 1.2F was introduced.6.1 mA/cm 2 of applied current was a moderate amount.Additionally, a higher flow rate in the cascade mode can effectively convey the resultant gaseous hydrogen(H 2 ) out of the flow cell. [43]he anode material was changed from glassy carbon to BDD with the goal of creating an all-encompassing procedure that is also appropriate for other phenols.Because stainless steel is affordable and has a minimal impact on electrolysis, it was recommended as the cathode material.Me-Bu 3 NO 3 SOMe was used as a supportive electrolyte throughout the electrolysis process and was used in pure HFIP without any other additives.Additionally, electrolysis in cascade mode might greatly boost the output of 62 %. [44] Instead linear and oligomericbyproducts, like ortho, metacoupling product 16, and diaryl ether 17, can be obtained under neutral to acidic conditions in addition to the required bi-phenol 15.This substantially relies on the regioselectivity of the phenoxy radical I action.A dehydrotrimer of 2,4-dimethylphenol 18 as well as oligomeric compounds can develop because 15 is susceptible to overoxidation [44] (Scheme 8).
The intended isoquinoline 21 was synthesized by focusing experiments on the envisioned rhodaelectro-catalyzed CÀ H annulation with imidate 19 and unsymmetrical alkyne 20 in batch, adopting methanol as the solvent, 2.5 mol% [RhCp*Cl 2 ] 2 as the catalyst, sodium pivalate and pivalic acid as additives under air in an undivided cell, employing graphite felt(GF) anode and Nickel plate cathode.With this improved flow cell in hand, additional tuning allowed for the production of product 21 in 83 % yield at a constant potential of 1.5 V and a flow rate of 400 L/min while operating under 1 atm of oxygen at room temperature. [42,45] realistic catalytic cycle is suggested based on the mechanistic investigations and is shown in Scheme 9. Cp*Rh-(OPiv) 2 I, which is obtained via ligand exchange between the catalytic precursor and NaOPiv, is then directed by substrate 19 to supply the cyclometallated rhodium complex II through simple CÀ H activation. Rhoda(III)cycle III is then produced by alkyne coordination and migratory insertion.Rhodium(II) intermediate V is produced fast by anodic oxidation of rhodium(IV)cycle IV.The catalyst I is then regenerated via anodic oxidation, which can be quickened by oxygen.Aerobic and anodic oxidation appear to be plausible processes for the rhodium(II)-rhodium(III) reoxidation phase.Preventing cathodic reduction of extremely reactive rhodium intermediates, most likely rhodium(II) species, is another benefit of molecular oxygen.In contrast, rhoda(III)cycle VI can also produce product 21 directly together with a reduced rhodium species that may reoxidize at the anode.Overall, cathodic proton reduction produces only molecular hydrogen as a stoichiometric by-product, and rigorous head-space GC analysis has proven this to be the case.
Due to their advantageous excited-state characteristics, such as their high reduction potential and long lifespan, acridinium dyes are one of the most commonly investigated groups of organic photocatalysts.Modulating their catalytic performance through a structural change is still difficult.Xu and co-workers described a site-selective late-stage C(aryl)À H functionalization of the acridinium core using a continuousflow, two-step method for the production of functionalized acridiniumphotocatalysts.The parent acridinium dye is consecutively pumped through a photoreactor to achieve cross-coupling with an organotrifluoroborate and an electrochemical reactor for electrocatalytic dehydrogenation in order to perform the alkylation.A variety of different alkyl groups can be introduced at the 3-position of the acridinium dye using the two-step automated technique.A second alkylation of 3alkylated acridinium salts in the flow system results in 3,6disubstituted acridinium dyes.The reactor system comprises of an electrolytic microreactor and a photoreactor consisting of perfluoroalkoxy (PFA) tubing tied around blue light-emitting diodes (LEDs).It can be difficult to work with salts in microflow reactors because particles can precipitate and clog the microchannels 22 (0.05 M) and tBu-BF 3 K (0.075 M) was dissolved in MeCN/H 2 O (5 : 1) and fed into the reactor system to assure the solubility of salts.The 3,4-dihydroacridine 25 resulting from the photoreactor was difficult to oxidize and needed deprotonation to produce 3,10-dihydroacridine 26, which is easily oxidized.In order to combine with the photoreactor's eluent before entering the electrochemical reactor, pyridine (Py) was delivered via pump B together with the electrocatalyst 2,2,6,6-tetramethylpiperidine-1-oxyl (TEM-PO).In these circumstances, a 91 % yield of the required acridinium 24 was isolated [46] (Scheme 10).
Due to the widespread use of organophosphorus compounds in chemistry, biology, and the sciences of materials, it is crucial to create effective and sustainable processes for the creation of carbon-phosphorus bonds. [47,48]Xu and co-workers disclose an electrochemical CÀ H phosphorylation reaction of arenes in continuous flow without the use of a catalyst or external oxidant for the manufacture of aryl phosphorus compounds.In spite of extensive research on P-radicals, the formation of the CÀ P bond involves the reaction of arenes with anodically produced P-radical cations and a class of reactive intermediates.The gentle electro-synthesis conditions and strong reactivity of P-radical cations allow for both selective late-stage functionalization of complex natural products and bioactive chemicals as well as efficient reactions of arenes with a variety of electronic characteristics.An undivided continuous flow electrochemical cell with a graphite anode, a platinum cathode, and a flow channel carved out of a fluorinated ethylene propylene spacer with a 0.25 mm thickness was used to conduct the electrolysis.When a solution of benzoate 27 (1 equiv.),trialkylphosphite P(OR) 3 (5 equiv.),HBF 4 (2 equiv.), and H 2 O (2 equiv.) in MeCN was run through the flow cell at 0.2 mL/min, an ideal 70 % yield of phosphonate 29 was produced. [11]he mechanism of phosphorylation via CÀ H bond functionalization has been suggested (Scheme 11).Trialkylphosphite 28 is first oxidised on the anode to produce P-radical cation I, which then interacts with arene 27 to produce distal radical cation II.In order to create phosphonium III, the latter is further oxidised on the anode and then deprotonated.Phosphonium III then loses an alkyl group to a nucleophilic species in the reaction mixture, such as H 2 O or alcohol created from the hydrolysis of P(OR) 3 , or during the workup, in order to produce the final phosphonate product 29.Protons, the most readily reduced component in the reaction mixture, receive electrons at the Pt cathode in these acidic circumstances to produce hydrogen gas.Acidic additive HBF 4 prevents unintended cathodic reduction of electrondeficient molecules like III and 29 by promoting hydrolysis of P(OR) 3 and acting as a proton source for H 2 evolution.By reversibly forming an adduct IV with radical cation I, the HPO(OR) 2 produced in situ by the hydrolysis of P(OR) 3 delays the breakdown of I and prolongs the time needed for its reaction with the arene.
In a microflow reactor, aryl azoles 32 were synthesised electrochemically for the first timetime by Nöel and coworkers.Considering that the reaction depends on the anodic oxidation of the arylderivatives, no homogeneous transitionmetal-based catalysts are needed, which makes these substrates suitable to CÀ H functionalization with azoles 31.It is envisaged that this electrochemical azolation technique would be used in contemporary medicinal chemistry settings due to its operational simplicity and speed-up reaction times.Carbon anode and stainless steel cathode in the electrochemical microflow reactor were separated by a Teflon gasket, resulting in an interelectrode gap of 250 μm m and a volume of 700 μL.A solution of pyrazole (1.0 equiv.)and 1,3,5-trimethylbenzene 30 (6 equiv.) in hexafluoro-2-propanol (HFIP)/CH 2 Cl 2 (7 : 3) could be subjected to the galvanostatic conditions (20 mA, equivalent to 0.71 mA cm À 2 and 2.6 F mol À 1 ) for just 10 mi-Scheme 10.Electrochemical Synthesis of 3-alkylated acridinium salts 24, 25 and 26.

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nutes before 67 % of the required cross-coupled product 32 could be isolated. [49]he arene is oxidised at the graphite anode (+ 2.07 vs saturated calomel electrode (SCE) for mesitylene) to produce the aryl radical cation I, according to the mechanism that has been hypothesised to operate in the electrochemical flow reactor (Scheme 12).The subsequent attack on this molecule by the nucleophilic azole can result in the creation of the new CÀ N bond.After losing a second proton and an electron, II will produce the radical species III by a deprotonation phase, which will eventually give rise to the azolated product 32.As a synthetically advantageous consequence of the cathodic process, protons are reduced to create molecular hydrogen.

Arenes/Heteroarenes CÀ H Functionalization via Metalla-Electrocatalysis
Conventional techniques primarily rely on using stoichiometric levels of harmful and costly metal and chemical oxidants, despite their overall sustainability.Unwanted by-products are being produced in the meantime, which is troublesome for the scaling up process.However, a more effective method for achieving selective functionalizations has been shown to be electrochemical CÀ H activation via catalyst control strategy employing metals as mediators (instead of electrochemical substrate control approach).Thus, indirect electrolysis improves the potential range and reduces the likelihood of adverse responses.Here, we provide a summary of the metallaelectrocatalysis procedure for functionalization and activation of inert CÀ H bonds.These Metalla-electrocatalyzed CÀ H bond functionalizations are described in terms of the production of CÀ C and CÀ X bonds (where X is one of the halogens, N, O, or P). [50]Better chemoselectivities with a wide tolerance of sensitive functionalities are how one can describe the electrooxidative CÀ H transformations in the presence of metal catalysts.Additionally, metalla-electrocatalysis integration with flow and photochemistry will enable safe and efficient scale-up in the future and may potentially improve reaction kinetics, timings, and yields in order to address sustainability and green chemistry concerns. [51]hi and co-workers reported an electrochemical method for promoting directed CÀ H alkynylation with terminal alkyne by iridium catalysis.In this study, Ir(III) intermediate, which was identified by X-ray crystallography, was anodized to facilitate reductive elimination and to produce the necessary coupling products in good yields (up to 95 %) without the use of any additional external oxidants.With 2.5 % [Cp*IrCl 2 ] 2 , KOPiv acting as the base and electrolyte in methanol under argon, the reaction's ideal conditions are made clear.The target product 35 was obtained in a 92 % isolated yield when the reaction was carried out with RVC as the anode and Pt as the cathode under constant current conditions of 5 mA for 8 hours at room temperature.With H 2 as the sole by-product, this transformation works well for a variety of directing groups and allows for practical oxidative CÀ C bond synthesis (Scheme 13). [52]arth-abundant nickel catalysts were used to produce CÀ H phosphorylation with waste-free power acting as the redox mediator.Arylphosphonates, phenylphosphine oxides, and diazaphospholidine oxides of significance to bioactive chemicals and materials were successfully obtained by the strong nickela-electrooxidative CÀ H activation of arenes, heteroarenes, and olefins.The electrooxidative CÀ P synthesis with guanidine assistance avoided chemical oxidants.Byusing X-ray diffraction analysis, catalytically important nickel(II) and nickel(III) intermediates were identified and thoroughly characterised.It has been documented that nickela-electrooxidative CÀ H phosphorylation of benzamide 36 occurs nonsequentially with an undivided cell using unmasked phosphonate 37.The desirable product 38 was successfully obtained in high yields using a graphite felt (GF) anode and a nickel (Ni)  foam cathode in the presence of the organic base 1,1,3,3tetramethylguanidine (TMG) as an additive and Ni(DME)Cl 2 as a catalyst. [53]n Scheme 14, a possible catalytic cycle is shown.Coordination of substrate 36 and anodic oxidation at Ni(III) II results in first CÀ H activation. Later coordination of phosphonate 37 prepares Ni(IV) V for an oxidation-induced reductive elimination.It is suggested that the TMG addition will help VII form by facilitating coordination.The phosphine is postulated to stabilise an off-cycle species rather than directly take part in an on-cycle event, hence increasing the overall electrochemical stability.Through cathodic reduction, these newly generated protons providehydrogen gas.
Aryl CÀ H phosphorylation under Rh III catalysis without the need of stoichiometric metal oxidants was suggested by Xu and colleagues in 2020.H 2 is produced during the reaction.The method is useful for producing triarylphosphine oxides from diarylphosphine oxides, which are usually difficult coupling partners for reactions involving CÀ H phosphorylation that are catalyzed by transition metals.A wide range of aryl CÀ H and PÀ H coupling partners are compatible with it.In order to advance the electrochemical conditions for the previously unreported phosphorylation of N-(2-pyridyl)aniline 39, diphenylphosphine oxide 40 is initially added in these research.For the electrosynthesis, a Pt-cathode and an RVCanode were provided in an undivided cell.The finest outcomes were obtained when the reaction mixture of KPF 6 -supporting salt (1 equiv.),methanol-solvent, and Cp*Rh(OAc) 2 (5 mol%)catalyst was run at 65 °C with a constant current of 3 mA.In these conditions, 75 % of the yield of the required phosphorylated product 41 was obtained. [54]ing the production of 41, Scheme 15 depicts a potential mechanism for the electrochemical CÀ H phosphorylation process.The ortho CÀ H bond of 2-phenylpyridine undergoes a straightforward and reversible cyclorhodation reaction to produce the rhodacycle II.via exchanging ligands between II and 40, the more oxidizable organometallic complex III is created.Depending on the oxidation state of IV, the Rh III or Rh II complex is then generated, along with the CÀ H phosphorylation product 41, via oxidation-induced reductive elimination.Currently, it is unknown how many electrons III will lose before the reductive elimination.Since protons are reduced at the cathode to create hydrogen gas, external electron or proton acceptors are not required.
Metal catalyzed electrochemical CÀ H amination is an highly demanded transformation owing to the dominance of heteroarylamines and arylamines in pharmaceuticals and natural products.The electrochemical CÀ H aminations of arenes catalyzed by cobalt with secondary amines was independently developed by Ackermann [55] and Lei group. [56]n environmentally acceptable alternative to traditional procedures that call for caustic stoichiometric chemical  oxidants is electrochemical oxidation.However, up to now, most CÀ H functionalizations combining transition-metal catalysis and electrochemical methods have mostly relied on precious metals and divided cells. [57]The first examples of room-temperature electrochemical CÀ H aminations of arenes with copper as the catalyst using undivided electrochemical cells was proposed by Mei and co-workers in 2018, offering a workable solution for the production of arylamines.Scheme 16 provides up a novel route for electrochemical CÀ H functionalization processes mediated by transition metals.N-phenylpicolinamide 42 and morpholine 43 were initially used as reaction partners, and several reaction conditions were investigated in order to achieve the expected electrochemical CÀ H amination in an undivided cell with platinum electrodes.After thorough optimization, it was shown that under constantcurrent electrolysis at 3.0 mA, 10 mol% Cu(OTf) 2 , 50 mol% n-Bu 4 NI (redox mediator), and 2 equiv. of KOPiv in MeCN for 24 hours, 86 % isolated yield of the desired product 44 could be produced. [58]The aminated products might be obtained in good to excellent yields if the arenes exhibited various functional groups which are well-tolerated such as silyl, ether, alkyl, hyddroxyl, alkyne, trifluoromethyl, alkene, thioether and halogen etc. Co(OAc) 2 was the best cobalt precursor out of a representative group, with NaOPiv as the preferred base. [59]ocusing on fundamental research, a possible catalytic cycle that would start with the electrochemical SET of the aromatic benzamide 45 by anodic oxidation and end with the creation of a simple electrochemical catalyst has been proposed (Scheme 17).Following that, proximity-induced chelation aids in CÀ O production, ensuring high positional selectivity.The final result is the release of the desired product 47, and anodic oxidation is used to renew the catalytically active cobalt(III) species.

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For organic synthesis, the electrochemical CÀ H functionalization reactions catalyzed by palladium have appeared as an appealing tool.The distinct potential of electricity as a green terminal oxidant is highlighted by the fact that other regularly used chemical oxidants, such as PhI(OAc) 2 , t-BuOOAc, or NaNO 3 /O 2 , delivered the desired productin noticeably lower yields.Mei and co-workers reported the oxidative C(sp 2 )À H methylation 52 (yield = 89 %)and benzoylation 50 (yield = 65 %) of oxime ether 48 with methyltrifluoroborates 51 and benzoyl acetic acids 49, respectively, based on their preliminary findings (Scheme 18-a and 18-b).By using anodic oxidation, first instance of Pd(II)-catalyzed C(sp 2 )À H methylation and acylation was disclosed.This procedure represents an environmentally friendly way for cross-coupling potassium trifluoroalkylborates and α-keto acids with C(sp 2 )À H bonds, as opposed to traditional procedures that call for strong chemical oxidants.Oxime ether 48 was selected as the substrate for the reaction with potassium trifluoromethylborat (CH 3 BF 3 K) under electrochemical conditions in order to study the formation of C(sp 2 )À C(sp 3 ) bonds.The monomethylated product 52 was produced in 76 % (89 % GC yield) by treating 48 (0.3 mmol) with MeBF 3 K (2 equiv) in the presence of Pd(OAc) 2 (10 mol%) under constant-current electrolysis conditions at 1.5 mA (J = 0.75 mA cm À 2 ). [60]he acetoxylation of C(sp 2 )À H bonds with palladium has a successful electrochemical technique.The disadvantages of conventional acetoxylation techniques that use stoichiometric oxidants are overcome by this reaction, which proceeds at a low temperature without the use of harmful oxidants.Because the oxime moiety can be easily controlled and has a large amount of derivation potential, it was decided to employ oxime 48 as the substrate for the reaction under electrochemical circumstances to study the production of C(sp 2 )À O bonds.Fortunately, a 75 % isolated yield (scheme 18-c) of the monoacetoxylated product 53 was produced by the reaction of 48 with 10 mol% Pd(OAc) 2 in the presence of 1 equiv. of

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tetrabutylammonium acetate under constant-current electrolysis conditions at 1.0 mA (J = 0.75 mA/cm 2 ). [61][64] However, many examples of aryl CÀ H couplings catalyzed by Pladium using organoboron reagents have been established.In orgnic synthesis, these tranformations possess remarkable importance in convenient construction of CÀ C bonds, however, in these system the practical disadvantage is the requirement of the constituents of the transition metal chemical oxidant in stoichiometric amont.In an undivided cell, the electrochemical CÀ H alkylation was tested under various reaction conditions using MeBF 3 K and 2-(o-tolyl)pyridine 54 as reaction partners.A TFE/AcOH/ H 2 O solution (2 mL/2 mL/0.5 mL) containing 10 mol% Pd-(OAc) 2 and 2 equivalents of MeBF 3 K was found to be capable to producing a 70 % isolated yield of the target product 55 when electrolyzed at constant current at 1.0 mA after considerable optimization. [67]n light of the aforementioned experimental results, a plausible mechanism for the Pd(II)-catalyzed C(sp 2 )À H methylation through electrochemical oxidation is hypothesized (Scheme 20).The orthoÀ CÀ H bond is nearby due to the first interaction of the palladium catalyst with a nitrogen atom in substrate 48.C(sp 2 )À H activation comes next, leading to palladacycle III.Then, III might either interact with a methyl radical produced in-situ from MeBF 3 K or undergo a transmetallation with MeBF 3 K under anodic oxidation to produce a Pd(III) or Pd(IV) intermediate IV.The high-valent palladium intermediate would eventually be subjected to a reductive elimination to liberate the methylated product 52 and regenerate Pd(II) species.However, at this time, we were unable to rule out the possibility that Pd(II)/Pd(0) catalyzed this alkylation.The intermediate III is created by a ratedetermining CÀ H activation after the N atom of the oxime first aligns with Pd(II) to make the acetyloxy derivative.This  Pd(II) complex is directly oxidized at the anode to create Pd(IV) complex IV.The intermediate IV is then reductively eliminated to produce the desired product 53, concluding the catalytic cycle.

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In comparison to other noble metals, cobalt metal demonstrated a number of advantages, including special catalytic reactivity, low toxicity, and affordability.Cobaltcatalyzed CÀ H alkoxylation, arylation, and amination reactions have recently received a lot of attention.The necessity for an effective oxidant-free cobalt catalytic system arises because substrates may be directly or indirectly oxidized at the anode under electrolytic conditions.However, the majority of metal catalysts are designed to be reduced at the cathode, losing their catalytic reactivity in the process. Making valuable arylamines using an environmentally acceptable electrochemical approach has been developed as cobalt-catalyzed CÀ H amination of arenes.To produce CÀ N formation products without the requirement for external oxidants, various arenes and alkylamines are studied in divided cells.This eliminates the creation of unwanted byproducts and exhibits great atom economy.The reaction may be effectively prolonged to the gram level, which is significant.N-(quinolin-8-yl)thiophene-2-carboxamide 56 and morpholine 57 are utilized as typical substrates.[72] Path-a, in which Co(II) was converted to Co(III) at the anode, resulted in the production of Co(III)-complex II.Co(III) then acted in concert with N-(quinolin-8-yl)benzamide 56.Path-b: In the absence of a base, Co(II) coordinated to 56 to form Co(II)-complex I before electrolysis.This Co(II)-complex I underwent oxidation at the anode to create Co(III)-complex II.Morpholine attacked Co(III)-complex II in the presence of base, creating Co(III)complex III, which was then reductively removed to release   Jutand and co-workers in 2007 reported the first Pdcatalyzedelectroxidative C(sp 2 )-H alkenylation. [73]So, there is demanding to develop economically transition metal catalysed electroxidative CÀ H functionalization.Under anodic oxidation conditions, ortho-selective chlorination of N-quinolinylbenzamide derivatives 59 with hydrochloric acid was accomplished.The selective chlorination was successful when the directing group 5,7-dichloro-8-quinolinyl was used.Vismodegib was also successfully synthesised in two steps utilising the electrochemical CÀ H chlorination with palladium as the catalyst.Then, it was looked at how the o-methylbenzamide derivative 59 reacted.The ortho chlorination product 60 was produced via the reaction of 0.20 mmol of 59 with 10 mL of DMF over a 12 hours period at 2.5 mA in an isolated yield of 86 %. [63] According to proposed mechanism (Scheme 22), the palladium-catalyzed electrochemical CÀ H chlorination is thought to happen by first selectively cleaving the ortho CÀ H bond of benzamide 59 and then reacting with electrochemically produced chlorinating species (Cl + or an analogous species).

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It has become clear that metal-catalyzed chelation-aided CÀ H olefinations are effective methods for creating functionalized alkenes.Here, benzamide 61 and styrene 62 were subjected to a Rhoda-electrocatalyzed CÀ H activation/alkenylation process in the presence of [Cp*RhCl 2 ] 2 (2.5 mol%) and NaOPiv in t-AmOH/H 2 O (3 : 1), which produced product 63 with a 73 % isolated yield in an undivided cell.The product 63 was purified in an 85 % yield when the alkenylation procedure was carried out at a scale of 1 mmole.Thus, the olefinations of difficult electron-poor benzamides were carried out under electrochemical conditions in a totally dehydrogenative manner, avoiding stoichiometric chemical oxidants, and with hydrogen gas as the only by-product.This adaptable alkenylation reaction uses electricity as a green oxidant and has a wide range of substrates. [74]hodacycle I is formed, as shown in scheme 23, by directed cyclorhodation at the ortho-position after the N-atom of amide 61 is coordinated to Cp*Rh III .Then, alkene 62 insertion takes place to produce intermediate II, which proceeds through βhydrogen elimination to create 63 along with a rhodium(II) species that is created after the N-atom in III is broken up.The catalytic cycle is finished when the rhodium(II) species is reoxidized to rhodium(III) at the anode, producing molecular hydrogen(H 2 ) as a byproduct at the cathode.
The electrochemical CÀ H allylation with non-activated alkenes was made possible by versatile and powerful cobalt catalysis.Ackermann and co-workers described an electrooxidatively CÀ H allylate benzamide 64 with unactivated alkene 65 in a very user-friendly undivided cell setup.NaOPiv emerged as the best additive among many others.As a result, in the solvent γ-valerolactone(GVL) formed from biomass, allylated benzamide 66 was produced with high degrees of chemo-, position-, and regio-selectivityin 60 % output.With H 2 as the sole byproduct, the cobaltaelectro-catalysis generally accomplished resource economy by eliminating the usage of stoichiometric chemical oxidants. [75] base-assisted internal electrophilic-type substitution mechanism for the crucial CÀ H activation step was strongly supported by thorough mechanistic analyses.A possible catalytic cycle for the cobalt-catalyzed electrochemical CÀ H allylation has been provided in scheme 24 based on mechanistic findings.The 5-membered cobaltacycle III, which in a competition experiment may have a heteroleptic coordination environment, is formed first by anodic cobalt oxidation, which prepares the way for an effective BIES CÀ H scission with carboxylate assistance.To create the conformationally stiff 7membered metallacycle V, 1,2-migratory insertion of IV with the non-activated alkenes 65 is made possible by alkene coordination.Third, in order to produce the desired allylated product, the seven-membered metallacycle V primarily undergoes β-hydride removal from the allylic proton.Eventually, anodic oxidation is used to regenerate the active cobalt(III) catalyst II.H 2 generation is the only stoichiometric by-product of the cathodic half-reaction.
Additionally, the same author reported an electrochemical cobalt-catalyzed CÀ H acyloxylation.Because there were no expensive silver oxidants present, flexible cobalt electrocatalysis allowed for long-lasting CÀ H oxygenations of substituted benzamides67, with the only waste being molecular hydrogen.The CÀ H acyloxylation reaction was characterised by broad applicability in γ-valerolactone, a renewable solvent generated from biomass.Using affordable cobalt(II) salts and Na 2 CO 3 as the preferred base, the required benzoxylation product 69 with a 66 % yield was produced in an undivided cell arrangement at 80 °C. [76] catalytic cycle that is thought to be started by the electrochemical production of the catalytically competent cobalt(III) species IV via anodic oxidation has been postulated based on mechanistic results (Scheme 25).Following that, salt metathesis with carboxylic acid 68 results in the cobalt(III) intermediate III, whereas carboxylate-assisted CÀ H activation yields the cyclometalated complex I. Reductive elimination creates a cobalt(I) species III and yields the desired product 69.By anodic oxidation, the catalytically active cobalt(III) complex IV is ultimately replenished.

Arenes/Heteroarenes CÀ H Functionalization via Photo-Electrocatalysis
It is well known that photoelectrochemical (PEC) cells are a critical element for energy and environmental applications.PEC cells have also been aimed towards pollutant degradation, carbon dioxide reduction, and the creation of solar fuels.They are most frequently employed to manufacture hydrogen fuel from water splitting.Nonetheless, their use in organic synthesis is still in its early stages.The union of photochemistry and electrochemistry is envisioned to become a new strategy to assist modern organic chemists, driven by the quest for green and sustainable synthesis processes.PEC cells are appealing due to the sun's abundance, practicality, affordability, and cleanliness, the wide variety of photoelectrode materials and redox mediators, and their capacity to operate under mild reaction conditions.This section discusses some recent advancements in photoredox catalysis and electrochemistry combined in a single system for PEC-driven chemical synthesis.It has been specifically focused on reactions involving CÀ H activations, which result in the formation of new chemical bonds, whether they are for the late-stage functionalization of intriguing compounds or the union of two molecular building blocks.With high atom-and step-economies, this combination is proving to be a potent system that can perform reactions that would be challenging or impossible to do using more traditional methods. [77]or the conversion of solar energy into chemical fuels, the photoelectrochemical (PEC) cells are widely examined. [76]This protocol is effectively applied in several pharmaceutical molecules for late-stage functionalization owing to broad scope of this method.Usually, a photoanode is used for the oxidation of water to produce oxygen and photocathode is used for the reduction of water to produce hydrogen (Figure 2).On light illumination, a high oxidizing or reducing power might be generated under mild conditions using PEC cell and they are well appropriated to catalyse the redox transformations of organic molecules to produced value-added chemicals (Figure 2).Recently, for the oxidation of benzylic alcohol, [78] cyclohexane, [79] furan, [80] 5-hydroxymethylfurfural [81] and tetralin, [82] the oxidizing power of photoanodes like WO 3 and BiVO 4 was exploited.However, the broad scope for the synthetic methodologies of functional organic molecules utilizing PEC cells remains unexplored and further in this field more efficient organic transformations are possible. [83]

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Building on the groundwork laid by early pioneers in the fields of radical chemistry and photochemistry, so-called visible light, or photoredox catalysis has become a potent tool in organic synthesis.The quick construction of complicated

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products on the road to new regions of chemical space is made possible by photoredox chemistry, which also creates new bonds via open shell pathways.Through a variety of synthetic transformations, including but not limited to cross-coupling, CÀ H functionalization, alkene and arene functionalization, and trifluoromethylation, photocatalysts can open up access to completely new, previously inaccessible bond formations in the presence of visible light.Academic research teams, industrial chemists, and academic-industrial partnerships have all used photocatalysis with success.These efforts have led to new synthetic disconnections, inventive techniques, and a better mechanistic understanding of photoredox processes. [84]he synthesis of several 3,6-functionalized acridiniumphotocatalystsvia site-selective late-stage CÀ H alkylation has been demonstrated.Following 0.5 hours of blue LED irradiation, the addition of 2,2,6,6-tetramethylpiperidine 1-oxyl (TEM-PO) as the redox catalyst and KPF 6 as the supporting electrolyte induced the addition of organotrifluoroborate to 70 to occur.The intended 3-alkylated acridinium product 71 was obtained in high to excellent yields (73-97 %) during electrolysis of the resulting reaction mixture at a constant current of 10 mA without the presence of any other regioisomers.The 3,6-dialkylated acridinium product 72 can be produced in a good yield by repeating these settings.These reactions exhibit high scalability as well as broad functional group suitability.By adding a variety of electrically and sterically varied substituents to the cores of acridinium dyes, a synthetic technique makes it simple to adjust the photocatalytic capabilities of these dyes.The advantages of the structural variation in improving photocatalytic efficiency are revealed by the catalytic uses of the newly produced acridinium dyes in a benchmark process. [85]he CÀ H alkylation of acridinium dyes was hypothesised as a possible process (Scheme 26).When excited acridinium 70 reacts with tBu-BF 3 K in a SET reaction, it produces the radicals tBu * and I, which go via cross-coupling to produce 3,10-dihydroacridine II.Due to its smaller conjugation system and lack of reactivity, 3,4-dihydroacridinium III is produced by protonating II.It does not go through additional alkylation.While II (E 1/2 = 0.27 V vs SCE) is considerably easier to oxidise than III (E 1/2 = 2.10 V), III can revert to II by deprotonation by HO À , which is produced by cathodic reduction of solvent H 2 O.The electrocatalytic process results in the synthesis of alkylated acridinium product 71 by the TEMPO-mediated oxidation of II.
The trifluoromethylated compounds exhibits inimitable lipophilicity as well as bioactivity and thus highly demanded in pharmaceutical industries and medicinal chemistry. [57]Moreover, in contrast to conventional methods these trifluoromethylations have made the modifications to electrosynthesis and photoredox catalysis. [85]Additionally, Schefoldused vitamin B 12 as an electro-photo catalyst and explained the nucleophilic acylation of Michael olefins.An refined example of electrophotochemical transformations were described very recently by the researchers Stahl, [86][87] Lambert [88] and Hu [89] on the sustainability of CÀ H activation persuaded through photocatalysis.Arene CÀ H trifluoromethylation with the Langlois reagent CF 3 SO 2 Na (2 equiv.)has been made possible by electro-photochemistry under benign reaction conditions.The CF 3 radical was produced without the need of chemical oxidants thanks to the combination of electrosynthesis and photoredox catalysis.Undivided cells were used for the electrophotochemistry, which made it possible to tackle difficult CÀ H trifluoromethylations of inactive arenes and heteroarenes like the easily available mesitylene 11.A broad range, encompassing electron-rich and electron-deficient benzenes as well as naturally occurring heteroarenes, highlighted the robustness of the electrophotochemical manifold.A platinum plate cathode and a graphite felt (GF) anode were used in the orientation investigations, along with a costeffective LiClO 4 additive and [Mes-Acr + ] ClO 4 À as a photocatalyst (PC) in acetonitrile at 23 °C room temperature. [38,60,90] potential mechanism was presented in Scheme 27 based on mechanistic discoveries.The oxidised excited state Mes-Acr + * is produced when the organic dye Mes-Acr + is first

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exposed to radiation.The acridinyl radical and the CF 3 SO 2 radical are produced by a SET reaction between Mes-Acr + * and the sulfinate anion.The ground state catalyst Mes-Acr + is then renewed by anodic electrooxidation of the acridinyl radical.The trifluoromethyl radical attacks substrate 11 simultaneously, creating aradical I that then undergoes SET oxidation to create the cationic Wheland complex II.A might also undergo direct oxidation at the anode in the interim.In the end, proton abstraction produces the desired product 13, whereas at the cathode, protons are reduced to produce H 2 .CÀ H functionalizations of truly unactivated arenes and even de-activated e-poor arenes for heterofunctionalization is possible by a molecular photoelectrochemical strategy.Trisa-minocyclopropenium (TAC) ion catalyst is used in this process, and it is electrochemically oxidised to create cyclopropenium radical dication intermediate.By photoexcitation with visible light, the radical dication is able to oxidise benzene and halogenated benzenes via single-electron transfer (SET), which leads to CÀ H/NÀ H coupling with azoles 75.This excited-state species has an oxidising power of 3.33 V vs. SCE.Platinum cathode and graphite anode are used.The product 76 is produced with a 65 % yield under the parameters listed below.The stability of the catalyst is explained by a specific conformation of the cis-2,6-dimethylpiperidine moieties, and a reason for the significantly oxidising activity of the photoexcited species is given. [91]heme 26.Electrochemical synthesis of 3,6-dialkylated acridinium product 72.A bicatalytic system made of acridinium dye and (2,2,6,6tetramethylpiperidin-1-yl)oxyl (TEMPO) [92] and tri(parasubstituted)biarylamines(TPA) [93] catalyst are two more electrophotocatalytic techniques that have been developed for the dehydrogenative cross coupling of arenes 74 with azoles 75.

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Scheme 28 depicts a mechanistic explanation for these electrophotocatalytic processes.The radical dication II is produced by the electrochemical oxidation of the colourless TAC cation I.The reactive intermediate III that results from photoexcitation can then oxidise benzene 74 through SET to form the radical cation IV and concurrently direct regenerate I.The radical V results from the nucleophilic entrapment of IV by pyrazole 75 and subsequent deprotonation.The linked product 76 is revealed by further oxidising this radical by II or directly at the anode, followed by re-aromatization by proton loss.
It has been created to trifluoromethylate and perfluoroalkylate aromatic compounds electrochemically using a vitamin B 12 derivative as a cobalt-based catalyst.An effective technique for adding trifluoromethyl and perfluoroalkyl groups to aromatic compounds that works by creating radical intermediates in an electrocatalytic process when there is a catalytic amount of 77.Fluoroalkylating reagents (R f I) such as heptafluoropropyl iodide, trifluoroiodomethane, nonafluorobutyl iodide, henicosafluorodecyl iodide, and heptadecafluorooctyl iodide which are easy to use and affordable, are employed in this reaction.The 1,3,5-trimethoxybenzene 78 and n-C 3 F 7 I model reaction in this work has been revealed utilising an electrochemical approach.In an undivided electrolysis cell, three electrodes namely a platinum mesh cathode, a Zn-plate sacrificial anode, and an Ag/AgCl reference electrode were included.To get a greater yield, the reaction conditions were improved.When exposed to visible light at ambient temperature, after 9 hours, 100 % substrate conversion at a potential of À 0.8 V vs. Ag/ AgCl was achieved, yielding the desired product 79 in 84 % of the cases. [94]o(I) was first obtained from Co(II) via controlledpotential electrolysis at À 0.8 V vs. Ag/AgCl, and Co(I) then interacted with R f I to swiftly produce the Co(III)À R f complex (Scheme 29).The compound then emitted an R f radical when exposed to visible light.In order to deliver the desired product 79, the produced R f -Trimethoxybenzene radical then reacted with non-activated substrates such arenes and heteroarenes.This reaction was followed by a one-electron oxidation and proton loss.This is the first report of catalytic trifluoromethylation and perfluoroalkylation processes employing vitamin B 12 derivatives, despite the fact that trifluoromethyl-and fluoroalkyl-cobalamines have been created and described by Geremia and co-workers.Now a days, for the synthesis of organic compounds through photoelectrocatalytic approach to non-directed arene CÀ H amination has an attractive method.[94] To conduct the CÀ H amination in PEC set-up, involves the use of haematite (α-Fe 2 O 3 ) which is an earth abundant and strong photoanode (Figure 2).For the solar-driven water oxidation, haematite has been broadly investigated due to its high stability, appropriate band gap of 2.1 eV for strong light absorption and low cost.[95] The heterogenous nature of photoelectrocatalysis and and the stability of haematite in a PEC cell suggest impending advantages in the separation of product and life time of catalyst.Due to light ingathering the photoelectrocatalysis  comsumes less amount of energy, if compared it with direct electrocatalysis.Consequently, this presented method is operationally simple and thus might be utilized in the synthesis of wide range of nitrogen-containing heterocycles which are considered to be advantageous in the discovery of drug.Remarkably, for many substrates reverse selectivity is attained in contrast to previously described electrochemical and photoredox methods.[96][97] For late-stage functionalization of pharmaceuticals molecules, the utility of this method is broadly exercised by several examples.
For CÀ H amination reaction, the CÀ H/NÀ H coupling of anisole with pyrazole was investigated using nanostructured haematite [98] and under a blue light emitting diode (LED) the reaction was performed with a constant potential.With the photocurrent at about 2 ~3 mA cm À 2 , the potential was set at 0.73 V against a ferrocene/ferrocenyl (Fc/Fc + ) after some investigation and the reaction time period was set to about 10 hours.The tetrabutylammonium hexafluorophosphate (TBAPF 6 ) was initially used as electrolyte.Various organic solvents were experienced which benefit the organic media for the PEC oxidation, inspired after the work of Berlinguette and co-workers.In direct electrochemical oxidation, [99] the choice of solvent acetonitrile (CH 3 CN) was found to be ineffective.
The yield and selectivity were increased using LiClO 4 as the electrolyte and HFIP/methanol(4 : 1) as the solvent.The achievement of unusual ortho selectivity was most likely made possible by a hydrogen-bonding interaction between the substrates and the co-solvent, hexafluoroisopropanol.From this profile, the analysis of the rate order was convoluted by mass transfer to the photoanode, it was apparently observed that reaction began to down after about 6 hours.After ten hours of time period the substrate anisole remained about 10 % only but improving the reaction time beyond ten hours had partial impact on the yield.Without prefunctionalizing the substrates, a variety of heterocycles having an aryl CÀ N moiety can be made from basic arenes and azoles.The test reaction for the CÀ H amination was the CÀ H/NÀ H coupling of anisole 80 (0.2 mmol) with pyrazole 81 (2 equiv). [83]he photoelectrocatalysis has been explained by a reasonable mechanism (Scheme 30).Holes are produced at the valence band when haematite is illuminated.An electron-rich arene is converted by the holes into a radical cation that interacts electrophilically with an azole to produce intermediate I. Proton loss from I results in the intermediate II, which, after being oxidised and having one proton removed, produces the amination product.II may be oxidised at the photoanode either by the photogenerated holes or by a methoxy radical that may also be produced there.When photoexcited electrons migrate from the haematite's conduction band to the counter electrode and reduce protons into dihydrogen gas, the photoelectrocatalysis is said to be complete.
Different yields are obtained in the presence of different arenes. [100]dditionally, reactions of benzene 84 (0.4 mmol)with different alcohols, amines, and carboxylic acids produced the aryl ether 87, aryl amines 89, and ester 88 products, respectively (Scheme 32). [100]roposed mechanism for schemes 31 and 32 is illustrated (Scheme 33).The photoexcited DDQ causes single electron transfer (SET) oxidisation of an arene 84 to produce a radical cation IV that is capable of nucleophilic capture.The main distinction is that DDQ I would be produced by anodizing the reduced DDQH 2 III, and the electrochemical reaction would be finished by cathodizing protons to produce H 2 .Therefore, the use of a conventional oxidant like TBN is not necessary with this electrophotocatalytic arrangement.

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Simple access to functionalized heteroarenes from commercially accessible materials is made possible by dehydrogenative cross-coupling of heteroarenes with aliphatic CÀ H bonds.Standard procedures use stoichiometric chemical oxidants when heated or exposed to light.Without the need of metal catalysts or chemical oxidants, an effective photoelectrochemicaldehydrogenative cross-coupling of heteroarenes and C-(sp 3 )À H donors through H 2 evolution has been accomplished by Xu and co-workers, combining electrochemistry and photochemistry.As a model reaction, the dehydrogenative crosscoupling of 2-phenylquinoline 90 and cyclohexane 91 has been studied (Scheme 34).After initial optimization, a photo-electrochemical reaction using LEDs (392 nm, 10 W) and an undivided cell with a reticulated vitreous carbon (RVC) anode and a Pt cathode produced the desired product 92 in 92 % yield.HCl (6 equiv.)and Et 4 NCl (0.3 equiv.)were used in the reaction mixture as an acid and chloride source, respectively, in methylnitrile (CH 3 CN). [101]he C(sp 3 )À H donor is mechanically changed into a nucleophilic C-radical through the transfer of a hydrogen and chlorine atom, which is created by light irradiating anodically generated Cl 2 from Cl À .To produce alkylated heteroarene compounds, the C-radical is subsequently subjected to radical substitution with the heteroarene (Scheme 34).

Arenes/Heteroarenes CÀ H Functionalization via Organo-Electrocatalysis
In developing novel and challenging organic transformations, the revitalization of photo-redox catalysis and organocatalysis, both areas individually experienced enormous success, even in the greatly stereoselective manners.For the successful implementation of α-functionalization of amines and carbonyl compounds, the merger of visible light catalysis by asymmetric organocatalysis has turned out as an operative strategy.Newly, organocatalysis have revealed extraordinary compatibility with electrochemistry to yield stimulating organic transformations, which appears challenging to realize in the absence of catalytic systems.Several practical problems in terms of organic synthesis could be resolved with the applications of photoredox, organo-and electrocatalysis which offers several advantages and could lead to the development of novel organic transformations. [102]n the development of electrolysis, the toxic and dangerous redox reagents can be substituted by electric current or produced in situ, it is acknowledged as an environmentally friendly and safe methodology.This is all due to the fact that the need for excess amounts of supporting electrolytes comprises a severe drawback.From the reaction mixture the supporting electrolyte must be separated as the completion of reaction takes place, unless it is reused and recovered, thus it constitutes a cause of leftover.The tetraalkylammonium salts are often used, due to their good solubility in organic solvents and maximum electrochemical stability.However, as the reaction has completed, the good solubility of an electrolyte often leads to difficulties with the separation of the salts from the products.By the use of redox mediators, further separation issue is initiated.The electron transfer between substrate and electrode is facilitated by the use of such mediators, thus also influence the selectivity of the electrosynthetic methodology.As both the mediators and supporting electrolyte represent an expense factor and source of waste, therefore for industrial applications their reuse and recovery in terms of various cycle is highly demanded.
With regard to electrosynthesis thus by unlocking the potential of iodine(I)/iodine(III) redox couple, Francke and co-workers developed a mediator based on compound 93 (Scheme 35), containing a redox active unit of 4-iodopheny moiety, which is joined to a quaternary ammonium group and serves as a supporting electrolyte. [103]fter complete transformation with a substrate, it facilitates the reuse and separation of redox active salt as shown in The concentration of 96, current density, and electrolysis conditions have been optimised for the electrode material.It was discovered that using a glassy carbon working electrode in conjunction with a platinum counter electrode in an undivided cell while using a current density of 15 mA/cm 2 results in an optimum Faradaic efficiency of 70 % (0.2 M solution of 96 in HFIP).With these refined parameters at hand, research into potential applications began with direct oxidative CÀ N bond forming reactions that had previously been reported in the context of other hypervalent iodine reagents.Through the intramolecular cyclization of 2-(N-acetylamino)-biphenyls 98, N-acetyl carbazoles 100 have been created (Scheme 37). [103] These solvents are known for

R e v i e w T H E C H E M I C A L R E C O R D
their high polarity, low viscosity, and ability to dissolve a wide range of organic and inorganic compounds.Additionally, they can improve the selectivity and yield of the reaction.However, it is important to note that the high cost, toxicity, and sustainability issues associated with these solvents have limitations that need to be considered.Fluorinated solvents are known for their high cost, as they are often difficult and expensive to produce.They are also highly toxic and can pose a significant risk to human health and the environment if not handled properly.Moreover, the production and disposal of these solvents can have negative sustainability impacts, such as contributing to greenhouse gas emissions and polluting water sources.Therefore, while the use of TFE and HFIP can offer certain advantages in electrosynthesis reactions, researchers must consider the limitations and strive to find alternative solvents or methods that are more cost-effective, less toxic, and more sustainable.This can help to reduce the environmental impact of electrosynthesis and ensure the safety and well-being of those involved in the process.

Advantages of Electrosynthesis Compared to Traditional Methods
Electrosynthesis has several benefits, one of which is that it is environmentally benign.There are various factors that should persuade chemists to employ organic electrosynthesis from the perspective of practical operation.For instance, electrochemical processes typically show strong functional group tolerance in the absence of exogenous oxidants or reductants.Electrochemical reactions are typically carried out in milder conditions compared to traditional procedures, which frequently proceed at elevated temperature or pressure, offering an energy-saving alternative.Due to their high reaction efficiency, electrochemical processes typically have quick reaction times.Further reducing the reaction time is possible by tuning the current.The electrochemical system's capacity for oxidation or reduction can be optionally changed by adjusting the current or voltage, enabling processes that aren't possible with chemical oxidants or reductants.Electrochemical processes can be quickly stopped at any time by flipping the power switch, unlike conventional reactions that typically need quenching.Last but not least, the majority of electrochemical reactions may be readily scaled up and have enormous potential for commercial applications.For instance, the industrialization of the electrochemical synthesis methods for 1,4-dicyanobutane, sebacic acid, etc. has been effective. [5]he application of electrosynthesis proposes overcomingsome limitations of the directed CÀ H functionalizations. The use of electrosynthesis provides greater control of the reaction medium by electrical voltage, allowing the acceleration or stabilization of synthetic intermediates.In electrosynthesis, substrates can undergo redox processes directly at the electrodes, or even better redox control of the reaction mediators can be achieved by controlling the applied electrical potential.We can also mention a better control of the substrate with fluorinated solvents, allowing the modulation of the nucleophilicity and stabilization of the intermediates. [104]Additionally, reactions in photoelectrochemistry and flow chemistry are two promising techniques in electrochemistry.Photoelectrochemistry involves the use of electrical charges through the absorption of light and concomitantly through a source of electrical energy, while flow chemistry is characterized by the use of flow of reactants to promote electrochemical reactions in a continuous system.The environmental friendliness, high surface-to-volume ratio, and appealing mass transfers between phases make flow electrochemical technology beneficial in organic synthesis. [42]Sunlight is abundant, convenient, affordable, and clean.A wide range of photoelectrode materials and redox mediators are also available, and PEC cells may make use of moderate reaction conditions. [77]The combination of these approaches presents great potential for applications in solar energy and energy conversion technologies.Furthermore, these approaches have wide application in sectors such as chemical, pharmaceutical and food production, where the synthesis of chemical compounds is a critical step in the process.

Practical Limitations of Electrosynthesis
Despite many benefits, there are some disadvantages to using electrosynthesis in organic chemistry.For instance, a whole electrochemical device is required, and both its cost and maintenance are often expensive.Additionally, a supporting electrolyte must typically be used to facilitate the transmission of electrons in solution, and because solvents like tetrahydrofuran, toluene, etc. are poorly conductive, choosing a solvent for electrosynthesis can occasionally be challenging.The use of metal catalysts in electrochemical reactions under readily accessible undivided cells is relatively limited because most metal cations are readily reduced at the cathode to zero-valent metals, and when electrochemical reactions are carried out in divided cells, expensive ion exchange membranes are required for separating anode and cathode. [5]The flow electrochemical technique has several advantages, but due to the setup's complexity and cost, it is only used in a few chemical and pharmaceutical industries.The production of insoluble solids as a byproduct may obstruct uniform flow and limit the application of this strategy in the industrial setting.The product's quality is further impacted by the nitrogen and hydrogen gases produced during electrochemical synthesis. [42]

Use of Enabling Tools in Arenes/(Hetero)Arenes CÀ H Functionalization
The arenes/(hetero)arenes CÀ H functionalization has emerged as an elegant strategy in organic synthesis, and with technological advances as new tools, the perspective is of greater achievements for synthetic chemistry.Currently, it is observed that laboratories are being gradually updated with equipment to absorb these demands, such as flow systems, electrochemical, photochemical, ultrasound and microwave reactors, automation, etc.For this, a growing collaboration with engineers, computer scientists, electrical technicians, software developers and other areas of chemistry is required.
The modern world and its sustainable development trends are forcing the chemical industry to improve in an environmentally friendly direction and meet the requirements of "green chemistry."Additionally, it is worth mentioning the various advantages of electrochemical reactions, such as high yields, higher selectivity and mild reaction conditions provide an environmentally friendly route.In this sense, the electrochemical arenes/(hetero)arenes CÀ H functionalization methods in batch reactions, continuous flow, metalla, photo and organo-electrocatalysis were widely discussed in this review.

REVIEW
Herein, we review and summarize the recent advances in the electrochemical functionalization of C-H arenes and heteroarenes via batch, continuous flow, metalla-, photo-and organo-electrocatalysis reactions.The application of merging techniques to accelerate organic transformations in environmentally benign conditions is highlighted, seeking to serve as inspiration enabling tools in the field of organic chemistry.

Figure 1 .
Figure 1.Schematic representation of electrolysis under undivided (a) and divided (b) flow conditions.
the desired output and Co(I) species.The Co(I) species was reoxidized to Co(II) at the anode in order to complete the whole catalytic cycle of Co (scheme 21).