Towards sustainable chemistry: Advances, challenges and opportunities in organic electrosynthesis

8 3 4 (61%) (17%) (3) Because of its diverse application in industry and compatibility in green chemistry, the electro organic synthesis (E.O.S.) is expected to provide the important organic synthetic tools in a near future. The brief review about the E.O.S. was introduced by us. Our continuing efforts to develop the E.O.S. utilizing alternated Mg electrodes, the synthetic routes from the nitro aromatic compounds to the azo compounds and the reductive coupling of aromatic mono halides were reported by our laboratory. For further expansion of the our E.O.S. reaction, the benzal bromide 1 was exposed to our optimized aromatic mono halide coupling reaction. The important reaction conditions were the following : Mg metal for both of anode and cathode and LiClO4 as an electrolyte at the room temperature under a constant current (current density = 42 mA/cm). The current of anode and cathode were altered at an interval of 30 second in order to minimize the consumption of metal. The two major spots were separated from the reaction residue in a low yield. They were characterized by TLC and by spectroscopic methods with the authentic samples. (Eq. 1)

On the way to study electro organic synthesis (EOS) utilizing alternating Mg electrodes, a novel synthetic route from the nitrobenzenes to symmetric azobenzenes was discovered in our laboratory. The brief review about EOS was introduced by us. The EOS is expected to be an important organic synthetic tool in future because of its diverse application in industry in addition to compatibility with green chemistry. In the previous paper, we reported the optimized reaction conditions for the electro reductive coupling of aromatic halides: Mg rod for both of anode and cathode under a constant current, LiClO4 as a electrolyte, THF or glyme 7 as a solvent. We have tried to extend EOS to other functional groups. Since nitrobenzenes were readily reduced under the various mild reaction conditions, we exposed several nitrobenzenes under EOS reaction conditions. Our reaction conditions were Mg for anode and cathode, LiClO4, THF, room temperature under a constant current (current density = 42 mA/cm). The currents of anode and cathode were alternated at an interval of 30 seconds in order to minimize the consumption of the metal. The reaction mixture was carefully monitored by TLC and then worked up when nitrobenzene 1 was completely disappeared. The new spot was isolated and characterized fully by TLC and spectroscopic methods with an authentic sample. To our surprise, it was azobenzene 2 instead of aniline 3 based on the previously reported paper. The optimized yield of 2 was 87.6 % with no trace of the desired aniline 3. The amount of Mg consumed during the reaction was less then 5.0% for every attempt (eq. 1).

With the importance of “green and sustainable” chemistry continuing to grow and be appreciated, electroorganic synthesis has gained greater attention as one of the most environmentally friendly approaches for organic synthesis (1). However, it does require the use of large amounts of supporting electrolyte in order to provide sufficient ionic conductivity. Frequently this causes separation and waste problems following the electrolysis and creates unwanted difficulties when researchers seek to apply electroorganic synthesis to green and sustainable chemistry. In an effort to overcome these problems, researchers have explored the use of ionic liquids (ILs) as a surrogate for conventional supporting electrolytes. However, the main limitation in the performance of neat ILs arises due to their high viscosity and low conductivity, which limit the ion mobility, the mass transfer and possibly heterogeneous electron transfer rate of electroactive species in the ILs. This is mainly due to ion association, leading to the formation of ion pairs, which do not contribute to the overall conductance of the electrolytic medium (2). Recently, researchers have reported the enhanced self-diffusion coefficient and conductivity of the electrolyte for a dye-sensitized solar cell, and attributed it to a disruption of ionic interaction between the IL’s cation and anions when in the presence of carbon nanoparticles (3). Inspired by this finding, we have designed, synthesized and are testing a new recyclable “polymeric ionic liquid (PIL) and super P® carbon black composite” as a surrogate for conventional supporting electrolytes (Scheme 1). Our “composite” combines the features of a PIL to serve as an electrolyte, and the properties of the Super P®carbon black to generate a dispersion (4). Hence, it enables one to perform an electrolysis without additional supporting electrolyte, and to efficiently recover and reuse the composite in subsequent electrolyses. Refer to Scheme 1.below In the first part of this presentation, a variety of electrochemical oxidations of aromatic alcohols will be described using the “composite” in an effort to demonstrate its reusability as well as the nature of the workup procedure for the reuse of the composite. In addition to the formation of a composite and its use in preparative scale electroorganic synthesis, we have chosen a unified approach to synthesis wherein analytical electrochemical investigations focusing upon the kinetics of mass transport and heterogeneous electron transfer rates have been incorporated in an effort to establish a comprehensive view of the role played by the composite. In the second part of the presentation, electrochemical kinetic investigations of commonly used organic electron transfer mediators (i.e., triarylamine (5), triarylimidazole (6), and TEMPO (7)) in a composite dispersion will be presented and the results will be compared with data obtained in other media including a neat ionic liquid and a traditional organic solvent-electrolyte system. By using cyclic voltammetry, the diffusion coefficient of organic electron transfer mediators will be estimated from the gradient of the linear plot of anodic peak current vs. the square root of scan rate based on the Randles-Sevcik formulae for a reversible process (8), and the data obtained will be compared with the values obtained by pulsed gradient spin echo NMR (9). In addition, the heterogeneous electron-transfer rate constant will be determined by (a) chronoamperometry, analyzed by the Cottrell equation and (b) cyclic voltammetry, analyzed by the method of Nicholson (10).ACKNOWLEDGEMENTSWe are grateful to NSF Partnership for International Research and Education-Electron Chemistry and Catalysis at Interfaces (PIRE-ECCI) for a fellowship to SJY, and to Amgen for their support of education.REFERENCES1. B. A. Frontana-Uribe, R. D. Little, J. G. Ibanez, A. Palma, and R. Vasquez-Medrano, Green Chem., 12, 2099-2119 (2010).2. M. A. Gebbie, M. Valtiner, X. Banquy, E. T. Fox, W. A. Henderson, and J. N. Israelachvili, PNAS, 110, 9674-9679 (2013).3. F.-L. Chen, I. W. Sun, H. P. Wang, and C. H. Huang, J . of Nanomaterials, 1 (2009).4. T. Fukushima, A. Kosaka, Y. Ishimura, T. Yamamoto, T. Takigawa, N. Ishii, and T. Aida, Science, 300, 2072-2074 (2003).5. K.-H. G. Brinkhaus, E. Steckhan, and W. Schmidt, Acta Chemica Scandinavica, B37, 499 (1983).6. C.-C. Zeng, N.-T. Zhang, C. M. Lam, and R. D. Little, Organic Letters, 14, 1314 (2012).7. R. Barhdadi, C. Comminges, A. P. Doherty, J. Y. Nédélec, S. O’Toole, and M. Troupel, J. Appl. Electrochem., 37, 723-728 (2007).8. A. C. Herath and J. Y. Becker, J . Electroanalytical Chem ., 619, 98 (2008).9. A. Noda, K. Hayamizu, and M. Watanabe, J. Phys. Chem. B, 105, 4603 (2001).10. A. C. Herath and J. Y. Becker, Electrochimica Acta, 55, 8319 (2010).

Sonochemistry deals with the mechanical and chemical effects of Ultrasound (US). Ultrasonic vibration has been used to accelerate a large number of chemical reactions, to reduce the thickness of liquid films and to enhance mass and gas transfers. Electrochemical methods are of widely recognized importance in the generation of reactive intermediates, and organic electrosynthesis associated with sonochemistry can provide transformations to compounds which may be difficult to prepare by other techniques. Synthetic organic reactions performed under non-traditional conditions are gaining popularity, primarily to circumvent growing environmental concerns (Green Chemistry). The features of US-assisted organic transformations, namely the selectivity, ease of experimental manipulation, and enhanced reaction rates, are highlighted in this chapter. The use of this non-traditional tool helps to overcome many of the difficulties associated with conventional reactions, and offers both process-related and environmental advantages in organic synthesis. Keywords: sonochemical methods; green chemistry; organic electrosynthesis; sonochemistry; ultrasonic vibration; cavitation

Electroorganic synthesis is an attractive method, in which only electrons serve as reagent and therefore complies with a “green chemistry” condition. In addition, reactions of electroorganic synthesis can be regarded as a special heterogeneous catalytic one. Furthermore, products can be obtained with high selectivity and efficiency by optimizing a reaction condition, such as electrode materials, potential, and others. Recently, a boron-doped diamond (BDD) electrode attracts much attention in the field of electroorganic chemistry. This is particularly because the BDD electrode enables to generate active species such as a hydroxyl radical with high efficiency under an appropriate electrolysis condition. Here, we report on the electroorganic synthesis using BDD electrode, especially TEMPO-mediated oxidation of the 1,2-diol derivative. TEMPO (2,2,6,6,-tetramethylpyperidine-1-oxyl) has been widely used as a catalyst in organic synthesis, for converting primary alcohol to an aldehyde selectively even in the presence of a secondary alcohol. However, the conventional TEMPO oxidation reaction requires a co-oxidant such as sodium hypochlorite and a hypervalent iodine compound. First, we prepared an electrolyte solution of TEMPO (0.1 mmol) and LiClO4 (0.1 M in CH3CN) or n-Bu4N•PF6 (0.1 M in CH2Cl2). Cyclic voltammetry (CV) was performed to examine an electrochemical behavior of TEMPO. For CV measurementsusinan undivided cell, BDD, Pt wire, and Ag/AgCl electrodes were used as the working, counter, and reference electrode, respectively. Next, for an electrolysis experiment, a diol substrate, 3-phenyl-1,2-propanediol, was synthesized according to the previous report. The diol substrate (10 mmol) was added to the electrolyte solution (10 mL), and a constant current electrolysis (1 F/mol for the diol substrate) was conducted at room temperature. After electrolysis, a resulting compound containing in solution was evaluated by 1H NMR. For acetylation of a hydroxyl group in oxidized products, pyridine (20 mmol) and acetic anhydride (20 mmol) was added and stirred at room temperature for 6 h. The resulting acetylated products were analyzed by a thin layer chromatography (TLC). In the cyclic voltammogram of TEMPO solution, oxidation and reduction peaks of TEMPO were clearly observed at 0.8 V and 0.6 V (vs. Ag/AgCl), respectively. On the other hand, the reduction peak of TEMPO almost disappeared in the presence of 3-phenyl-1,2-propanediol. Based on the reaction mechanism of TEMPO oxidation, such a CV behavior would ascribed to oxidation of 3-phenyl-1,2-propanediol substrate by TEMPO catalyst. Next, we examined the solvent dependence of TEMPO-mediated electro-oxidation. When using CH3CN electrolyte solution, surface of the Pt cathode was covered with a black film and the current dropped immediately. On the other hand, in case of CH2Cl2 electrolyte solution, a couple of oxidized products were detected by a TLC analysis. Furthermore, in the 1H NMR spectrum, a signal at 10 ppm derived from an aldehyde group was detected. We investigated TEMPO-mediated selective electro-oxidation using a BDD electrode. First, we confirmed both oxidation and reduction of TEMPO on a BDD electrode. Next, TEMPO-mediated electro-oxidation of 3-phenyl-1,2-propanediol gave a couple of products containing an aldehyde group.

Chemical manufacturing accounts for 5% of US primary energy use and greenhouse gas emissions, primarily from fossil-fuel-derived heat driving conventional processes.1 Organic electrosynthesis offers a sustainable alternative by using renewable electricity directly, enabling efficient production under milder conditions with improved selectivity and reduced waste.2,3 Despite these advantages, the practical implementation of organic electrosynthesis at scale has been limited by several fundamental challenges. Limited mechanistic understanding and experimental insights into molecular processes at the electrode interface have made it difficult to address key challenges: controlling the concentration of reactive species at the electrode interface, managing mass transport limitations, and understanding the complex role of substrate and spectator ions in the electrical double layer. Furthermore, the presence of multiple competing reaction pathways often leads to unwanted by-products, particularly when dealing with organic mixtures.4-6 The adoption of electrochemical methods in industry has been historically constrained to processes where these challenges have been successfully addressed, as exemplified by the electrohydrodimerization of acrylonitrile to adiponitrile - the most successful industrial organic electrosynthesis process with annual production reaching 300,000 tons.7,8 While this process achieved practical viability through careful electrolyte design and reaction engineering, the fundamental molecular mechanisms enabling its success remain poorly understood, highlighting both the potential of electrosynthesis for sustainable chemical manufacturing and the critical need for mechanistic insights to guide the development of new processes.This work advances organic electrosynthesis through complementary approaches. First, we use in situ ATR-FTIR spectroscopy to show that tetraalkylammonium ions populate the electrical double layer, creating a microenvironment that favors interactions with organic molecules and enhances acrylonitrile concentration while expelling water molecules.9 Additionally, kinetic isotope effect studies reveal that propionitrile (PN) formation is rate-limited by proton transfer, while ADN formation likely is not. Electron paramagnetic resonance spectroscopy confirms the presence of free radicals during AN electroreduction, suggesting that coupling of PN radicals occurs primarily in the electrolyte. Finally, we demonstrate how electrochemical parameters governs product distributions in mixed-substrate electrosynthesis. Using high-throughput screening coupled with machine learning approaches, we systematically investigated the interplay between substrate composition, current density, and mass transport phenomena in the electrodimerization of acrylonitrile and crotononitrile mixtures. We reveal distinct reaction-limited and mass transport-limited regimes that dictate product selectivity, with preferential formation of adiponitrile occurring when radical generation from acrylonitrile outpaces that from crotononitrile under reaction-limited conditions. These findings establish a framework for understanding and controlling molecular processes at electrode interfaces in complex organic systems. The experimental techniques and reaction engineering strategies developed here open new possibilities for selective electrochemical transformations.1. U.S. Department of Energy. Manufacturing Energy and Carbon Footprints Report. (2018).2. Botte, G. G. Electrochemical manufacturing in the chemical industry. The Electrochemical Society Interface 23, 49 (2014).3. Frontana-Uribe, B. A., Little, R. D., Ibanez, J. G., Palma, A. & Vasquez-Medrano, R. Organic electrosynthesis: a promising green methodology in organic chemistry. Green Chemistry 12, 2099-2119, doi:10.1039/c0gc00382d (2010).4. Utley, J. Trends in organic electrosynthesis. Chemical Society Reviews 26, 157-167 (1997).5. Moeller, K. D. Using Physical Organic Chemistry To Shape the Course of Electrochemical Reactions. Chem Rev 118, 4817-4833, doi:10.1021/acs.chemrev.7b00656 (2018).6. McKenzie, E. C. R. et al. Versatile Tools for Understanding Electrosynthetic Mechanisms. Chem Rev 122, 3292-3335, doi:10.1021/acs.chemrev.1c00471 (2022).7. Danly, D. Development and commercialization of the Monsanto electrochemical adiponitrile process. Journal of The Electrochemical Society 131, 435C (1984).8. Seidler, J., Strugatchi, J., Gärtner, T. & Waldvogel, S. R. Does electrifying organic synthesis pay off? The energy efficiency of electro-organic conversions. MRS Energy & Sustainability 7, E42, doi:10.1557/mre.2020.42 (2021).9. Mathison, R. et al. Molecular Processes That Control Organic Electrosynthesis in Near-Electrode Microenvironments. J Am Chem Soc 147, 4296-4307, doi:10.1021/jacs.4c14420 (2025). Figure 1

Since the pioneering work of Kolbe, electrochemistry and electrosynthetic methods have been a part of the repertoire of the organic synthesis toolbox [1–2]. In general, only electrons are employed as reagents or the reagents are electrochemically regenerated. Consequently, waste can be avoided, and limited resources can be used in a careful and economic manner. Because alternative reaction pathways are employed by electrosynthetic methods, scarce and toxic elements can be replaced or are not required at all [3]. Moreover, in the foreseeable future regenerative sources of electricity, for example, photovoltaics and wind power, will provide a surplus of electricity as the current unsteady supply does not match the demand. Thus, the use of abundant electric power in electrosynthetic processes seems to be rational because high valorisation can be expected. Therefore, electrosynthesis fulfils all requirements for “green chemistry” [4]. When changing feed stocks and natural resources begin to play a more crucial role, electrosynthetic methodologies will not only be of ecological interest but also of economic significance. Unfortunately, the research in the past two decades was understated and considered as a niche methodology by the synthetic community. In addition, electrochemistry is mostly taught by physical chemists, which seems to create a natural barrier to preparative organic applications. However, the systematic use of cationic species as intermediates to avoid over-oxidation establishes new ways for functionalization of substrates and paves the way to novel synthetic tools [5–8]. Recently, a renaissance of electro-organic methods occurred in several fields, including the construction of rather complex molecules (e.g., natural products) [9]. Not only is the construction of biologically active molecules of interest but also the anodic degradation of drug-like molecules. Such electro-oxidative treatment generates potential metabolites that can be then biologically studied [10]. The combination of electrosynthesis with other powerful techniques, such as ultrasonic treatment and flow microcells, will push the electrosynthetic applications beyond current limits [11]. In addition, remarkable breakthroughs have been achieved regarding electrodes and electrolytes, which allow for expansion of the electrochemical window and/or novel reaction pathways. This leads to new electro-organic concepts and further applications for a sustainable synthetic methodology. The contributions within this Thematic Series demonstrate the broad use of electrosynthesis and represent a snapshot of this current and vividly developing field. I am convinced that electro-organic synthesis is an emerging field and that this issue will stimulate the reader to employ electrochemical methods in their own field. Siegfried R. Waldvogel Mainz, April 2015

The environmental and economic challenges of cross-coupling reactions arise mainly from reliance on expensive transition metals, toxic solvents, and harsh reaction conditions. These factors lead to high energy use, waste generation, and ecological harm, while the scarcity and cost of metals limit scalability. Organic solvents further increase carbon emissions and toxicity. Overcoming these issues is crucial for developing more sustainable and cost-effective cross-coupling methods. This study introduces a novel electrode design that employs a Cu-TCPP metal-organic framework (MOF)-modified oxidized Multi-Walled Carbon Nanotubes (o-MWCNT) for the efficient electro-organic synthesis of biphenyl derivatives 4(a-n) from chlorobenzenes 1(a-j) and triphenyl bismuthines 2(a-j). Conducted within a green urea/choline chloride (Urea/Chol-Cl) 3(a) DES system, the synthesis achieved remarkable yields of 90% to 97% in just 1 h at ambient temperature under a constant current of 10 mA. The characterization of the o-MWCNT-Cu-TCPP catalyst was performed using a various of techniques, including FT-IR, SEM, EDS, EDX mapping, XPS, cyclic voltammetry (CV), TGA, and BET analysis. The resulting biphenyl derivatives 4(a-n) were confirmed through melting point determination, 1HNMR, and CHN analysis. This work underscores the potential of Cu-TCPP MOF-modified electrodes as sustainable and efficient catalysts for organic synthesis, paving the way for further exploration of their applications in green chemistry.

Over the last two decades, the chemical industry has witnessed a 43% increase in greenhouse gas emissions, with organic chemicals contributing to 75% of the total chemical production [1]. While organic electrosynthesis is a promising method for reducing the environmental impact of chemical manufacturing, advancing this technology faces significant challenges due to the limited viability of membranes used in divided electrochemical reactors. Despite the need for suitable membranes for electrosynthesis, only a few studies have explored the use of ion-conducting membranes for electro-organic reactions [2-7]. In this study, we aim to provide additional insights into the role of membranes in electrosynthesis and their behavior when exposed to electrolytes containing organic components.We selected adiponitrile electrosynthesis, one of the largest industrial electro-organic processes, as a model reaction [2,3]. We used Nafion as a model membrane material. Electrolytes used in adiponitrile electrosynthesis contain tetraalkylammonium (TAA) ions to enhance the selectivity of electro-organic reactions. Here, we present a systematic study exploring how TAA ions impact Nafion's structure and transport properties. We exposed Nafion membranes to solutions with varying concentrations and sizes of TAA ions, including tetramethyl (TMA), tetraethyl (TEA), tetrapropyl (TPA), and tetrabutyl (TBA). We quantified TAA ion sorption in the membranes using ATR-FTIR. The results reveal that TAA ion sorption saturates when the solution concentration exceeds 0.02 M. Compared to the conductivity of Nafion equilibrated in pure water (9.8 x 10-2 S/cm), the membrane conductivity after exposure to TAA solutions exhibits a substantial decline, decreasing by up to 4 orders of magnitude. We performed small-angle X-ray scattering experiments to correlate the conductivity results with structural changes in Nafion. The measurements revealed that the spacing between Nafion's ion-conducting domains decreases as the TAA ion concentration increases. For example, when membranes are exposed to 1.0 M TBA solutions, the domain spacing drops from 4.9 nm to 3.76 nm compared to membranes equilibrated in pure water. Consequently, we infer those organic ions reduce the size of ion-conducting domains due to the diffusion of water from the membranes into the surrounding electrolyte, resulting in decreased conductivity. These results represent an important step in elucidating structure-property relationships in ion-conducting membranes used for organic electrosynthesis.Reference[1] 2022. Our Risks for Infectious Diseases Is Increasing Because of Climate Change. CDC:NCEZID [updated 2022 August 02]. https://www.cdc.gov/ncezid/what-we-do/climate-change-and-infectious-diseases/index.html.[2] N. Tanbouza. 2020 J. iScience. 23 101720[3] Suryanto, B. H. R.; Kristianto, H. A.; Yi, Z. "Electrosynthesis: An overview of green chemistry.” Current Opinion in Green and Sustainable Chemistry 16 (2019): 28-34.[4] Baizer, M.; Lust, E.; Williamson, S.E.; Connor, R.F. "Electrochemical Synthesis of Adiponitrile." Industrial & Engineering Chemistry Process Design and Development, 1966, 5 (1), 56–62.[5] D. E. Danly 1984 J. Electrochem. Soc. 131 435C[6] Blanco, D.; Prasad, P.; Dunningan, K.; Modestino, M. React. Chem. Eng., 2020, 5, 136[7] Katzenberg, A.; Angulo, A.; Kusoglu, A.; Modestino, M. Macromolecules 2021, 54, 5187−5195 Figure 1

Contributions of organic electrosynthesis to green chemistry

Organic electrosynthesis has a long history. However, this chemistry is still new. Recently, we have seen its second renaissance with organic electrosynthesis being considered a typical green chemistry process. Therefore, a number of novel electrosynthetic methodologies have recently been developed. However, there are still many problems to be solved from a green and sustainable viewpoint. After an explanation of the historical survey of organic electrosynthesis, this paper focuses on recent remarkable developments in new electrosynthetic methodologies, such as novel electrodes, recyclable nonvolatile electrolytic solvents and recyclable supporting electrolytes, as well as new types of electrolytic flow cells. Furthermore, novel types of organic electrosynthetic reactions will be mentioned.

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This article describes our recent results of electroorganic synthesis, especially focusing on new organic electrolytic systems toward green sustainable chemistry as follows: (a) Electroorganic synthesis using recyclable solid-supported bases, (b) electrocatalytic hydrogenation and dehalogenation using new electrolytic systems, (c) electrosynthesis of organofluorine compounds, conducting polymers, and others in ionic liquids.

Spin manipulation has emerged as a transformative strategy in boosting electrochemical reactions. Yet, its application in organic electrosynthesis involving diffusive radical intermediates remains less explored compared to aqueous systems. Herein, we report a systematic study of spin-controlled organic electrosynthesis via precise regulation of radical coupling and hydrogenation pathways in solution during the electroreduction of benzyl chloride. By leveraging ferromagnetic electrodes with external magnetic fields, spin-polarized electron transfer fundamentally alters the spin states of radical intermediate, selectively suppressing radical coupling by 70% while achieving 85% selectivity for hydrogenated product─performance unattainable through conventional potential control. Notably, the contribution of the MHD effect was further excluded with the absence of a magnetic field effect using nonmagnetic electrodes, highlighting the spin manipulation as the intrinsic mechanism underlying the observed magnetic field effects. Our findings establish spin polarization as an orthogonal methodology for reaction pathway engineering and selectivity enhancement in sustainable organic chemistry.

Electroorganic synthesis is a powerful sustainable tool for achieving greener and more efficient chemical processes across various industries. By adhering to the principles of green chemistry, atom economy, and resource efficiency, electroorganic synthesis can play a pivotal role in addressing environmental concerns and promoting a more sustainable future for chemical production. This review focuses on the latest advancements in the emerging application of electrochemistry in C-N bond formation through C-H/N-H cross-coupling. The first part of the review describes the electrochemical amination of arenes using metal catalysis (Cu, Co, Ni) with directing groups on the arene moiety. The next section addresses the same type of electrochemical C-N bond formation on arenes without directing groups, which represents a more general strategy enabling the synthesis of anilines and various heterocyclic-bound arenes in high yields. Further developments on benzylic systems are also discussed. This is followed by developments in the combination of photocatalysis and electrochemistry to activate C-H bonds in arenes, alkanes, and benzylic systems, including the use of flow reactor configurations for these reactions.