Alfie G Wills

Sylvain Charvet

Claudio Battilocchio

Christopher C Scarborough

Katherine M P Wheelhouse

Darren L Poole
email: darren.l.poole@gsk.com

Nessa Carson
email: nessa.carson@syngenta.com

Julien C Vantourout
email: julien.vantourout@univ-lyon1.fr

High-Throughput Electrochemistry: State of the Art, Challenges, and Perspective

Keywords:

à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

INTRODUCTION

High-throughput experimentation (HTE) is an enabling technology, involving running multiple designed experiments rapidly or in parallel to evaluate many combination of variables more efficiently than in one-ata-time fashion, allowing rapid acquisition of data for decision-making, and often incorporating the use of laboratory automation. 1 It enables fast testing of multidimensional hypotheses and high-risk, high-reward possibilities that would be impractical to explore one at a time. 2 HTE is commonly employed in pharmaceutical and agrochemical discovery and process development for everything from optimizing reaction conditions (e.g. solvents, catalysts, reagents, or reaction parameter ranges) 3 and robustness 4 to studying extractions 5 and developing crystallizations. 6 Recent reports describe the development of photoreactors suitable for highthroughput optimization of photochemical transformations, enabling screening of different controlled wavelengths, modulating of light intensity and control of temperature whilst evaluating different reaction components. 7 Not only does this enable more rapid screening of photochemical reactions, it also enables determination of key parameters crucial to robustness, reproducibility, and process understanding. 8 A system to enable high-throughput optimization of conditions for electrosynthesis reactions, including pertinent variables such as electrode materials, voltage, etc., would be similarly powerful. We review the state of the art of high-throughput electrochemistry devices through the lens of potential applications to small molecule research and development. Although highthroughput analytical electrochemistry has been widely explored, 9 this perspective focuses on high-throughput electrochemistry dedicated to reaction optimization and parallel small molecule synthesis.

THE RESURGENCE OF SYNTHETIC ELECTROCHEMISTRY

The recent commercialization of standardized electrochemical equipment has generated a resurgence of interest for the development of novel electrochemical transformations. Indeed, over the past few years, the number of reported novel electrochemical methods is constantly increasing and more than 200 papers were published in 2020 (Figure 1A). [START_REF]The graphic describe in Figure 1A was created with CAS SciFinder using the key word "synthetic electrochemical". (11) For a selection of reviews: a) Kärkäs, M. D. Electrochemical strategies for C-H functionalization and C-N bond formation[END_REF] This significant increase was accompanied by the disclosure of several key reviews that allowed the practitioners to familiarize themselves with the basis and fundamentals of electrochemistry (Figure 1B). 11 For example, Baran and coworkers assembled a user guide which enables nonelectrochemistry experts to understand the key concepts of synthetic electrochemistry and allow them to quickly set up electrochemical reactions. [START_REF] Kingston | A Survival Guide for the "Electro-curious[END_REF] With the clear resurgence of synthetic electrochemistry, it is important to analyse what has been achieved over the past few years and how it has impacted the field of organic chemistry. A careful examination of the recently published electrochemical methods elucidates two main categories:

(1) development and optimization of existing transformations (Figure 1C), and (2) development of unprecedented methodologies (Figure 1D). The first category can be exemplified by the recent Birch reduction reported by the Baran laboratory (Figure 1C, 1). [START_REF] Peters | Scalable and safe synthetic organic electroreduction inspired by Li-ion battery chemistry[END_REF] The authors extensively optimized previously reported conditions that were not general, afforded a limited substrate scope, and were associated with several limitations such as substrate reoxidation and electrode passivation. In stark contrast, the optimized conditions afforded a broad substrate scope, were scalable using both batch and flow apparatus, and were generalized to seven different reductive transformations. Consequently, this new protocol is a real alternative to the venerable Birch reduction that necessitates the use of ammonia. Similarly, Hansen and coworkers developed an electrochemical reductive cross-coupling between aryl and alkyl halides inspired by the work of Périchon (Figure 1C, 2). [START_REF] Perkins | Electrochemical Nickel Catalysis for sp 2 -sp 3 Cross-Electrophile Coupling Reactions of Unactivated Alkyl Halides[END_REF] This transformation is of high interest as it finds applications in both medicinal and process chemistry. While the initially reported conditions were limited to the formation of biaryl compounds and were not scalable, the new protocol that allows for the use of alkyl halide coupling partners usefully expanded the scope of the reaction. In addition, the reaction parameters can now be easily tuned, and the transformation was easily scaled up without stoichiometric amounts of reducing metal such as Zn or Mn powders.

Optimized synthetic electrochemical reactions have also been developed in the context of total synthesis (Figure 1D, 1). In 2020, the group of Chiba disclosed an intramolecular electrochemical C(sp 2 )-H cross-coupling and dehydrogenative indole synthesis which was applied to the synthesis of natural pyrrolophenanthridone alkaloids including oxoassoanine. [START_REF] Okamoto | Electrochemical Total Synthesis of Pyrrolophenanthridone Alkaloids: Controlling the Anodically Initiated Electron Transfer Process[END_REF] Interestingly, both the generation of a strong electrophilic radical cation and the benzylic oxidation of the same electron-rich indoline moiety were induced at the anode, but with excellent selectivity. Finally, it was also demonstrated that electrochemistry can considerably facilitate and accelerate drug discovery by replacing useful methods with more user-friendly protocols. As an example, Baran and coworkers readily synthesized tertiary alcohols from ketones in a complementary fashion to the use of Grignard reagents (Figure 1D, 2). [START_REF] Hu | Electroreductive Olefin-Ketone Coupling[END_REF] Reversal of the polarity of the ketone under electrochemical conditions produced an excellent nucleophilic radical that was able to react with unactivated alkenes. The steroid example presented in Figure 1D highlights the enabling nature of the reaction for multi-step synthesis. These examples clearly demonstrate how synthetic electrochemistry can dramatically accelerate reaction development and simultaneously impact several chemical fields.

As depicted in Figure 1E, the resurgence of synthetic electrochemistry has also motivated several groups to develop unprecedented transformations with significant applications. In 2019, the Noël group reported the electrochemical synthesis of both aryl and alkyl sulfonyl fluorides from ubiquitous thiol or disulfide starting materials in the presence of KF as fluoride source (Figure 1E, 1). [START_REF] Laudadio | Sulfonyl Fluoride Synthesis through Electrochemical Oxidative Coupling of Thiols and Potassium Fluoride[END_REF] Notably, no additional oxidants nor catalysts were required, and the mild reaction conditions afforded a broad substrate scope. This synthetic electrochemical method represents a novel approach for the synthesis of highly desirable sulfonyl fluorides and should find applications in both academic and industrial settings. More recently, Morandi, Waldvogel, and coworkers assembled an electrochemically assisted shuttle system for the simple and scalable interconversion of alkenes and vicinal dihalides (Figure 1E, 2). [START_REF] Dong | Merging shuttle reactions and paired electrolysis for reversible vicinal dihalogenations[END_REF] The reaction was demonstrated in a simple undivided cell equipped with inexpensive graphite electrodes under mild conditions. One of the major applications described in the paper is the full dechlorination of lindane (a hexachlorinated persistent pollutant found in polluted soils) to benzene using simple alkene acceptors. This electrochemical approach is a step forward to the direct remediation of lindane-contaminated soils.

SYNTHETIC ELECTROCHEMISTRY ENABLES GREENER PROCESSES

Sustainable transformations have been an influential goal for the chemical industries in recent years, in the drive to minimize environmental impact. For example, since 2007, the ACS Green Chemistry Industry Pharmaceutical Roundtable has identified several key areas of synthetic chemistry and aspirational reaction types that would result in more efficient pharmaceutical processes and production, a number of which may benefit from the application of electrochemistry. Synthetic electrochemistry has a number of positive impacts on chemical process sustainability. [START_REF] Matthews | Electrochemistry. Examples and Challenges[END_REF] Electrons are an essentially massless reagent, replacing the need for stoichiometric (and often environmentally dubious) oxidants or reductants. [START_REF] Horn | Synthetic Organic Electrochemistry: An Enabling and Innately Sustainable Method[END_REF] Additionally, the "greenness" of these processes is expected to increase yet further as society moves from the use of fossil fuels toward more renewable and sustainable sources of electricity.

Numerous literature examples of electrochemical oxidations and reductions provide alternatives to traditional stoichiometric reagents: too many to cover in this perspective. Two pertinent examples include the electrochemical Birch reduction (Figure 1C.1), and the 4acetamido-TEMPO mediated oxidation of alcohols and aldehydes to carboxylic acids developed by Stahl and coworkers, which both provide a mild alternative to classical methods employing stoichiometric metal-or chlorine-containing oxidants (Figure 2A). [START_REF] Rafiee | Electrochemical Oxidation of Alcohols and Aldehydes to Carboxylic Acids Catalyzed by 4-Acetamido-TEMPO: An Alternative to "Anelli" and "Pinnick" Oxidations[END_REF] Typically, electrochemical reactions take place at or close to ambient temperature, [START_REF] Yoshida | Modern Strategies in Electroorganic Synthesis[END_REF] negating the cost and high energy consumption required for heating or cooling on scale. Ambient temperature also provides further environmental and safety benefits, namely reducing the risk of corrosion, reactor failure, and accidental release. 19 A key, industrially-relevant example of electrochemistry enabling lower process temperature is the oxidation of toluene derivatives to benzaldehydes at a carbon anode conducted by BASF. Compared to the traditional approach of high-temperature chlorination followed by hydrolysis, the lower temperature and choice of methanol as reagent and solvent together provide a clear sustainability benefit (Figure 2B). 24 In two recent examples, the groups of Lin and Baran independently published electroreductive functionalizations of olefins, conveniently effecting transformations traditionally conducted at cryogenic temperatures with organometallic reagents (Figure 2C). [START_REF] Dong | Merging shuttle reactions and paired electrolysis for reversible vicinal dihalogenations[END_REF][START_REF] Zhang | Electroreductive Carbofunctionalization of Alkenes with Alkyl Bromides via a Radical-Polar Crossover Mechanism[END_REF] One difference between an electrochemical reaction and a standard chemical reaction is the requirement for a supporting electrolyte species to reduce the resistance of the electrochemical cell. While many electrolytes employed in organic electrosynthesis are cheap and readily-available (e.g. alkali metal halides), others such as tetraalkylammonium salts can be expensive. Also, many common electrolytes are incompatible with standard industrial wastewater treatments used, detracting from the sustainability of an electrochemical processalthough recovery and recycling of the electrolyte can minimize costs and improve sustainability. [START_REF] Noël | The Fundamentals Behind the Use of Flow Reactors in Electrochemistry[END_REF] Another method to reduce quantities of electrolyte is to conduct the reaction in a flow cell, where small interelectrode distances reduce resistance between the electrodes, minimizing or even removing the need entirely for a supporting electrolyte. 27

THE ADVANTAGES OF ELECTROCHEMICAL SYNTHESIS IN FLOW

Flow electrochemical reactors may also provide many additional benefits in carrying out electrochemical reactions. These include improving mass transfer, and thus improving the reaction rate where the electrochemical reaction is not charge transfer-limited. This can be achieved in two ways in flow electrochemical cells: either by the introduction of static mixers to intensify mass transport, or by the use of flow microreactors with small interelectrode gaps, decreasing the time taken for a species in solution to diffuse to the electrode of interest. [START_REF] Noël | The Fundamentals Behind the Use of Flow Reactors in Electrochemistry[END_REF] Conducting electrochemical reactions in flow also facilitates the careful control of reaction temperature due to the more efficient heat exchange in flow systems, which can have a positive impact on reaction selectivity and on leading to more controlled and reproducible results upon scaling. [START_REF] Tanbouza | Bridging Lab and Industry with Flow Electrochemistry[END_REF] As most electrochemical flow reactors use the electrodes as two of the walls of the flow cell, there is an inherent increase in the surface area of the electrode relative to the reactor volume, which further improves reaction efficiency. [START_REF] Noël | The Fundamentals Behind the Use of Flow Reactors in Electrochemistry[END_REF][START_REF] Tanbouza | Bridging Lab and Industry with Flow Electrochemistry[END_REF] Numerous electrochemical flow reactors and microreactors have been reported, [START_REF] Noël | The Fundamentals Behind the Use of Flow Reactors in Electrochemistry[END_REF][START_REF] Tanbouza | Bridging Lab and Industry with Flow Electrochemistry[END_REF][START_REF] Apletcher | Flow Electrolysis Cells for the Synthetic Organic Chemistry Laboratory[END_REF] and a number are also commercially available. [START_REF]The Ammonite Family of Electrolysis Cells[END_REF] Given the benefits of scaling electrochemical reactions in flow, it is clear that the ability to perform high-throughput experimentation in a flow microreactor, and a full understanding of the electrochemical parameters, could have significant benefits in taking a process from conception through to reactions on a multigram or even kilogram scale, without the requirement for extensive reoptimization.

AN IDEAL ELECTROCHEMICAL HIGH-THROUGHPUT SCREENING APPARATUS

The optimization of conditions for a given chemical transformation can be an arduous task even in the absence of electricity, and the addition of unique electrosynthesis-associated variables significantly increases the complexity of the variable space. Beyond "typical" factors involved in optimization of a chemical transformation (temperature, concentration, solvent, additives, etc.) The parameter space of electrosynthesis is therefore highly complex, underpinning HTE as an ideal approach. Do the needs of an electrosynthesis HTE kit depend on the nature of the research? When approaching electrosynthesis, a chemist may be interested in either applying a known transformation to their substrate of interest, or possibly developing a novel transformation. Within these two approaches, the availability of the starting material is a key factor: is the starting material easily accessed on multi-gram scale (e.g. commercially available or part of a process development campaign), or is the starting material precious and scarce (e.g. late in a total synthesis, or an advanced intermediate in a medicinal or agrochemical synthesis campaign)? Thirdly, with modern interest in machine-learning applications for the development of reactivity models, would it not be best to regularly screen a wide array of conditions across an array of chemically-diverse substrates to generate a reactivity model? Despite the numerous scenarios requiring electrosynthesis studies, the goals of an electrosynthesis HTE kit unify under this concept of reactivity models. That is, even when repeating a single literature transformation, a desirable outcome is to collect sufficient data on the target of interest and other chemically-diverse targets to address future needs from that reaction, instead of repeating the studies when a new substrate of interest arises. Hence, the generation of a large dataset is invaluable for any new transformation, whether known for related substrates or novel, and such an effort would address each scenario above if the full dataset could be generated rapidly from a small amount of substrate, perhaps no more than 100 mg.

A complicating aspect of electrosynthesis is that translation of results from one cell to another is not often straightforward.

This can inhibit uptake of electrosynthesis by the community because of challenges in reproducibility without common equipment, and when all parameters are not accurately described. For example, mixing is highly complex in an electrosynthesis reactor, while also being important for processes like electrochemistry that occur at solid-liquid interfaces. Mixing depends on factors such as interelectrode distance, the electrode surface area (poorer mixing toward the center of the interelectrode region) and bubble and heat generation (related to current density). Furthermore, when transitioning from batch to flow, mixing changes significantly owing to the nature of flow (laminar vs. turbulent) and the generation of volumes of gas commensurate with reactor volume. Finally, production-scale electrosynthesis generally occurs in flow in galvanostatic mode, at higher current densities than are possible in small batch reactors owing to heat generation, and on scales where turbulent mixing is normative. On the other hand, promoting turbulent mixing in very smallscale flow cells with significant gas generation is a major challenge, meaning that scaling up between different flow reactors is not straightforward. Nonetheless, it is our view that the most general electrosynthesis HTE kit would run in flow with turbulent mixing to enable smooth translation to higher scales. Also, in the transient periods before and after steady state concentrations are reached in galvanostatic flow electrochemistry, undesired reactivity such as overoxidation is enhanced, when the full current is applied to a small fraction of the reaction mixture. [START_REF] Maljuric | Translating Batch Electrochemistry to Single-Pass Continuous Flow Conditions: An Organic Chemist's Guide[END_REF] Since the steady state period is short on very small scales, potentiostatic mode is preferred for very small-scale flow HTE. However, galvanostatic conditions are often preferred in batch, regardless of scale, due to a simpler setup and greater reliability and reproducibility. [START_REF] Tanbouza | Bridging Lab and Industry with Flow Electrochemistry[END_REF][START_REF] Schotten | Making Electrochemistry Easily Accessible to the Synthetic Chemist[END_REF] Finally, electrode fouling can cause reproducibility challenges if the electrodes are not properly treated between usage, so an ideal electrosynthesis HTE kit would make use of small, disposable, and inexpensive electrodes.

The technical challenges of achieving an ideal electrosynthesis HTE kit are significant:

-Turbulent flow on microliter scales in electrochemical flow cells with an array of disposable electrodes that manages rapid pressure changes due to gas formation -Independent electrical control of each cell, where potentially hundreds of cells are needed to effectively map the variable space across a range of diverse substrates -Divided cells testable with an array of different membrane materials -Miniaturization of reliable reference electrodes to allow for precise potentiostatic electrolysis

Similarly, for operational simplicity and material conservation, HTE reactions will ideally be conducted on <300 µL volume in batch and yet lower in flow, to run as many concomitant reactions as possible. For example, high-throughput photoredox chemistry in flow has been conducted down to nanoliter scale. 7c With these desired characteristics in mind, we next evaluate state-of-the-art flow and batch electrochemistry screening kits, which highlights the remaining unsolved challenges.

RECENT HISTORY AND STATE OF THE ART OF FLOW ELECTROCHEMICAL SCREENING EQUIPMENT

Flow electrosynthesis has evolved rapidly in the last decade, with many suppliers making flow cells with diverse functions available. Flow cells can lead to much improved electrosynthetic performance, due to the narrow electrode gap and the ability to run reactions under pressure and improve mixing. Despite the many advances, there is no full practical solution which can yet be directly applied to HTE. [START_REF] Pletcher | Flow Electrolysis Cells for the Synthetic Organic Chemistry Laboratory[END_REF] However, there are some efficient designs which represent steps toward the "holy grail" of a flow cell to address HTE needs.

Waldvogel and coworkers have pioneered not only the resurgence of batch electrochemistry, but also of flow. Their recent paper reports an extremely modular flow cell (Figure 3A). [START_REF] Gütz | Highly Modular Flow Cell for Electroorganic Synthesis[END_REF] This cell allows easy adjustment of interelectrode distance, as well as facile replacement of electrodes, with the possibility to switch between divided or undivided cell formats. The electrode material is thermally positioned into a Teflon piece, allowing the use of expensive and nonmachinable electrode materials like boron-doped diamond or glassy carbon. The flexible cell design creates opportunities for chemists, including those with lesser practical experience in flow chemistry, and competes with classical preparative approaches in terms of performance and productivity. A drawback of the cell is mixing within the flow channel, where flow is laminar and gas generation is not controlled. Ley and his group have been pushing the boundaries of enabling technologies in the last 15 years, particularly with flow chemistry. [START_REF] Ley | A Comment on Continuous Flow Technologies within the Agrochemical Industry[END_REF] In one recent work, they demonstratehow flow electrochemistry can be utilized to generate molecular diversity. [START_REF] Kabeshov | Expedient Preparation of Nazlinine and a Small Library of Indole Alkaloids Using Flow Electrochemistry as an Enabling Technology[END_REF] A commercially-available system (i.e.: Syrris electroflow cell) was used to perform a Shono oxidation on a series of derivatives, before telescoping the reaction output to generate nazlinine analogues (Figure 3B). The commercial system used for this work is a flexible setup, which is useful for lab research applications.

State of the Art of Flow Electrochemical Screening Equipment

Another interesting application was reported by Richard Brown and coworkers in collaboration with AstraZeneca and Eli Lilly, using a system developed and commercialized by Brown: the Ammonite, a spiralshaped electrochemical flow cell with narrow interelectrode gap (Figure 3C). [START_REF] Green | Electrochemical Deprotection of Para-Methoxybenzyl Ethers in a Flow Electrolysis Cell[END_REF] Here, the authors explore the electrochemical deprotection of pmethoxybenzyl ethers in MeOH solution, using an undivided electrochemical flow reactor. Notably, this method avoids the need for chemical oxidants, and the electrolyte can be recovered and reused. High conversions were obtained from several substrates in a single pass, albeit so far in the literature largely being performed with a "one factor at time" approach.

Hilton, Lam, and coworkers have also described a lowcost, 3D-printed electrosynthesis flow cell, that interfaces with the IKA commercial ElectraSyn 2.0 system (vide supra). [START_REF] Van Melis | Supporting-Electrolyte-Free Electrochemical Methoxymethylation of Alcohols Using a 3D-Printed Electrosynthesis Continuous Flow Cell System[END_REF] This system allowed them to improve their previously-developed methoxymethyl-protection of aliphatic alcohols 39 by eliminating the need for a supporting electrolyte, and avoiding overoxidation of substrates such as benzylic alcohols.

One recent work by Schouten et al. describes one of the very few literature reports to create a HTE flow electrochemical system for the screening of electrode materials used for electrosynthesis in electrochemical parallel plate reactors (Figure 3D). [START_REF] Becker | A Scalable High-Throughput Deposition and Screening Setup Relevant to Industrial Electrocatalysis[END_REF] The reactor is composed of 64 microflow cells that can be operated in different configurations, allowing screening of 64 different anode/cathode combinations, with the systems separated by a membrane. The authors go some way to addressing the dissimilarity between small-scale screening setups and larger-scale flow cells as well as the scalability of the setup to yet larger setups: to obtain a system amenable to scaleup, the authors miniaturize and further parallelize the parallel plate reactors to form a matrix of flow cells that can be run at industrial current densities.

Industrial colleagues from Syngenta have described the design of an electrochemical flow cell that provides excellent mixing by incorporation of a turbulence promoter in the flow channel, which enables high current densities to be achieved on research-relevant scales (≤1 g, up to 10 g scale; Figure 3E). [START_REF] Lehmann | An Electrochemical Flow-Through Cell for Rapid Reactions[END_REF] The use of high current densities is a very relevant factor relating to potential for scalability and brings value when it comes to translating an electrochemistry concept from small scale process research toward the development environment. The cell design embeds a turbulence promoter and cooling layers, and was operated with a current density of 1000 mA/cm 2 for the oxidative dimethoxylation of furan.

Work by Jensen and coworkers describes a microfluidic platform that enables automated THE for electroorganic synthesis at a 15-µL scale (Figure 3F). [START_REF] Mo | A Multifunctional Microfluidic Platform for High-Throughput Experimentation of Electroorganic Chemistry[END_REF] Two THE modules are demonstrated: rapid electrochemical condition screening for a radical-radical cross-coupling reaction on micro-fabricated, interdigitated electrodes, and measurements of kinetics for mediated, anodic oxidations using microliter-scale cyclic voltammetry.

RECENT HISTORY AND STATE OF THE ART OF BATCH ELECTROCHEMICAL SCREENING EQUIPMENT

In addition to flow electrochemical screening equipment, the batch approach has also been developed and different techniques have emerged offering the practitioners several options when running a highthroughput screening campaign. These can be separated into systems using many electrodes and one electrolyte, one electrode and many electrolytes, or full screening capabilities with many electrodes and many electrolytes. Here, the term 'electrolyte' refers to a reaction solution that is physically separated from neighbouring solutions, and should not be confused with a 'supporting electrolyte', an additive that may or may not be present.

Many electrodes, one electrolyte

Initial research into a high-throughput approach to electrochemistry focused on the synthesis and analysis of libraries of modified electrode surfaces. The first report details the combinatorial synthesis of an electrode array containing 645 unique alloys of platinum group metals with the aim of developing an optimal electrocatalytic surface for methanol oxidation. [START_REF] Reddington | Combinatorial Electrochemistry: A Highly Parallel, Optical Screening Method for Discovery of Better Electrocatalysts[END_REF] Catalytic activity was determined using a pH-dependent fluorescent dye to identify areas of low pH on the surface of the array, indicative of methanol oxidation. This was followed by a more general method using a computer-automated screen to allow direct serial electrochemical analysis of organosulfur monolayers on a 64-electrode array. [START_REF] Sullivan | Automated Electrochemical Analysis with Combinatorial Electrode Arrays[END_REF] These early methods are examples of 'many electrode, one electrolyte' systems in which multiple electrode surfaces are submersed in a single electrolyte, forming one electrochemical cell (Figure 4A). This is advantageous as it simplifies the electrochemical equipment required for the screen and allows it to be scaled relatively easily. The principal disadvantage for synthesis of this format is the inability to screen electrolytes, the components of which constitute most of the independent variables of a reaction that are desirable to screen. A many electrodes, one electrolyte method has also been applied to the highthroughput synthesis of conducting polymers via electrochemical polymerization. [START_REF] Kulikov | Equipment for Combinatorial Electrochemical Polymerization and High-Throughput Investigation of Electrical Properties of the Synthesized Polymers[END_REF] This allows for their combinatorial synthesis on a 96-electrode array followed by high-throughput analysis of the relevant electrochemical properties. In a more recent example, a high-throughput screen of a library of 60 glassy carbon electrodes covalently modified with Ru(II) or Zn(II) complexes was used to identify an optimal surface modification for NADH oxidation. [START_REF] Richter | Water-and Ionic-Liquid-Soluble Branched Polythiophenes Bearing Anionic and Cationic Moieties[END_REF] Other examples of many electrodes, one electrolyte methods outside of reaction optimization include the synthesis of addressable microelectrode arrays pioneered by Moeller. 47 This technique allows site selective functionalization of individual microelectrodes in the array with proteins or other small molecules that can then be used in biological assays. Numerous reactions have been adapted for these functionalizations including electrochemically enabled Wacker oxidation, Suzuki-Miyaura coupling and reductive amination. [START_REF] Tesfu | Building Addressable Libraries: The Use of Electrochemistry for Generating Reactive Pd(II) Reagents at Preselected Sites on a Chip[END_REF][START_REF] Hu | Building Addressable Libraries: Site-Selective Suzuki Reactions on Microelectrode Arrays[END_REF][START_REF] Tesfu | Building Addressable Libraries: Spatially Isolated, Chip-Based Reductive Amination Reactions[END_REF] The selective reaction of individual electrodes in a single electrolyte is ideal for the synthesis of functionalized electrode arrays; however, it is not directly applicable to the high-throughput screening of electrochemical reaction conditions.

One electrode, many electrolytes

A fully-automated screening platform for highthroughput electrochemical analysis has been developed using an alternative, one electrode, many electrolyte approach for high-throughput chemical analysis (Figure 4B). [START_REF] Briehn | Single-Compound Libraries of Organic Materials: From the Combinatorial Synthesis of Conjugated Oligomers to Structure-Property Relationships[END_REF] The setup consists of a 96-well plate acting as an array of electrochemical cells, and a single three-electrode probe that can be inserted consecutively into each cell to obtain cyclic voltammograms. While first being used to build structure-activity relationships for conducting polymers, this analytical method has also been applied to the automated screening of Ru(II) hydrogenation catalysts. [START_REF] Lindner | Combinatorial Micro Electrochemistry. Part 4: Cyclic Voltammetric Redox Screening of Homogeneous Ruthenium(II) Hydrogenation Catalysts[END_REF] In addition to cyclic voltammetry, this system has been adapted for the microscale electrochemical synthesis of combinatorial compound libraries including iminoquinol ethers and triazolopyridinium ions, as well as the electroreductive coupling of α,β-unsaturated esters and allyl bromides. 52 These compounds were synthesized on 200-µL reaction scale in a microtiter plate, with reaction progress monitored by steady state voltammetry and product formation screened by HPLC-MS. These methods can be classified as 'one electrode, many electrolytes' systems in which a conserved bundle of electrodes is introduced to each cell in a sequential fashion, followed by cyclic voltammetry or preparative electrolysis. This approach allows the high-throughput screening of many electrolyte samples in a single plate and is better suited to screening reaction conditions than a many electrode, one electrolyte method. Another significant advantage of this system is the successful miniaturization of the cells, enabling the screening of a large number of reactions using a small amount of material. Limitations of this format include the increased time it takes to run a screen due to the consecutive nature of the reactions as well as the relative difficulty of screening different electrode materials. The reuse of electrodes between reactions also has the potential to introduce electrode passivation and cross-contamination between cells.

Many electrodes, many electrolytes

A third paradigm of high-throughput electrochemistry was established during Yudin and coworkers' development of a spatially addressable electrolysis platform (SAEP) for the combinatorial electrosynthesis of α-alkoxy carbamates, amides, and sulfonamides. [START_REF] Siu | Parallel Electrosynthesis of α-Alkoxycarbamates, α-Alkoxyamides, and α-Alkoxysulfonamides Using the Spatially Addressable Electrolysis Platform (SAEP)[END_REF] The platform was constructed using a 4×4 array of stainless steel cathodes and graphite anodes, each contained within a Teflon or glass vessel, giving a 16-well plate of individual electrochemical cells. The electrodes were then connected in parallel to allow galvanostatic electrolysis from a single power source. This is the first example of a many electrode, many electrolytes approach, in which each set of electrodes is contained within their own electrolyte, forming a set of independent electrochemical reactions (Figure 4C). This format has the significant advantage of allowing variation of both the electrode material and the constituents of the electrolyte in a single screen. It also permits simultaneous electrochemical reaction of different substrates, making it well-suited for library synthesis. [START_REF] Bouloc | A Solid-Phase Iterative Approach[END_REF] Another literature example of a many electrode, many electrolytes method is an electrochemical microtiter plate (eMTP) designed for parallel spectroelectrochemical measurements. [START_REF] Ley | An Electrochemical Microtiter Plate for Parallel Spectroelectrochemical Measurements[END_REF] A 24-well plate was used to house 8 cells, each containing 1 mL of electrolyte and three electrodes suspended from a circuit board lid. The cells of the eMTP were connected to an 8channel potentiostat, allowing independent potentiostatic control of each cell. A proof-of-concept study demonstrated the ability to conduct cyclic voltammetry and chronoamperometry using the device and the eMTP was subsequently applied to the screening of cytochrome P450 monooxygenase muteins and reaction conditions for electroenzymatic synthesis. 56 A more advanced system, designed specifically for electrosynthetic screening, has been developed by Waldvogel and coworkers. This consists of eight Teflon cells housed in a steel block for temperature control during electrolysis. [START_REF] Gütz | Electrochemical Screening for Electroorganic Synthesis[END_REF] In this "Screening System", the cells are designed for facile changing of electrodes between reactions and can accommodate up to 6 mL of reaction mixture. The setup is typically controlled with an 8-channel DC power source allowing galvanostatic control of each cell independently. Alternatively, it can be run potentiostatically using an 8channel potentiostat. This system can also accommodate six divided cells, making it a singular example of highthroughput screening capability for divided electrolysis. This system has been used to develop methodologies including oxidative cross-coupling of electron-rich aromatics, 58 reductive dehalogenation, [START_REF] Gütz | A Novel Cathode Material for Cathodic Dehalogenation of 1,1-Dibromo Cyclopropane Derivatives[END_REF] and deoxygenation, 60 as well the electrochemical dehydration of aldoximes to nitriles. [START_REF] Hartmer | Electroorganic Synthesis of Nitriles via a Halogen-Free Domino Oxidation-Reduction Sequence[END_REF] The most recent development in batch high-throughput electrosynthesis has been reported as a preprint by the group of Lin in collaboration with Merck. The authors present a 24-well, plate-based system (called HTe-Chem) constructed from a commercially-available, high-throughput photochemistry reactor (Figure 4D). This format makes it compatible with automated reagent addition systems and existing highthroughput analytical equipment, further expediting the setup and subsequent analysis of reaction screens. It features widely-available, parallel, cylindrical rod electrodes that are readily interchanged to allow for screening of electrode material. The individual cells have a reaction volume of 200 -600 µL, the smallest so far in high-throughput organic electrosynthesis, and a notable improvement on existing systems. In addition, the authors propose that the design is theoretically scalable to a 96-well format without major design modifications. The housing block allows for temperature control and is compatible with both magnetic and tumble stirring, while a silicon rubber gasket functions as a septum for each cell, limiting solvent evaporation and enabling reactions to be conducted under inert conditions. A 6 × 4 vial arrangement with each row of cells connected in series allows screening of four distinct currents or potentials across the plate. A disadvantage of this setup is that failure of one cell causes the whole row to fail, and so a 'skipper pin' has been developed to bypass individual cells. This also allows for crucial, no-electricity control experiments to be conducted concurrently with electrochemical reactions. The HTe-Chem has been applied to various transformations and showed a 2.2% standard deviation in yield across the plate with no impact from vial position in a proof-of-concept study. Finally, basing the system on a photochemistry reactor allows light to be delivered to the cells, further increasing the scope of the device. One disadvantage is that small-diameter rod electrodes make the use of reticulated electrode materials like RVC and nickel foam challenging. That being said, this newlydisclosed device fulfills the majority of the requirements for the ideal high-throughput electrochemistry system, and commercialization of a reactor of this type would represent a significant step toward accessible, highthroughput reaction development in organic electrosynthesis. [START_REF] Rein | Unlocking the Potential of High-Throughput Experimentation for Electrochemistry with a Standardized Microscale Reactor (Version 2)[END_REF]

State of the Art of Batch Electrochemical Screening Equipment

IKA enabled simplification of electrochemistry

Although organic electrochemistry has been used for many years to improve or develop chemical reactions, the lack of intuitive electrochemical equipment limited the uptake of this useful technique. The development of FIGURE 5. IKA equipment for standardizing synthetic electrochemistry. standardized and user-friendly equipment was needed to create a resurgence of the electrochemical field. [START_REF] Yan | Synthetic Organic Electrochemistry: Calling All Engineers[END_REF] Therefore in 2018, IKA developed a new electrochemical product in collaboration with Phil Baran: the "ElectraSyn 2.0" (Figure 5A). 64 ElectraSyn 2.0 combines three devices in one: (1) a stir plate, (2) a potentiostat, and (3) analytical capabilities; avoiding complicated multi-equipment setups (computer, potentiostat, cables, separate stir plate, etc.) to simply run electrochemical reactions. In addition, consumables such as vials and electrodes have been standardized to allow the practitioner to reproduce reported reactions without hardship. IKA provides two types of vials: micro and standard (Figure 5B). Micro vials can contain volumes from 1 to 2 mL while standard vials start from 5 up to 20 mL allowing for different scales. In addition, the diversity of electrodes, in both size (micro or standard) and material offers access to a broad range of reactivity. Although ElectraSyn 2.0 represented an important advance for the field of synthetic electrochemistry, the biggest drawback remained that reactions could only be carried out one at a time. To overcome this limitation, IKA developed several screening equipment (Figure 5C) for performing parallel reactions: the "IKA carousel" and the "IKA e-Hive". The first transforms ElectraSyn 2.0 from a single reactor to the six-reactor Screening System, with individual vial detection and a constant current or voltage through all six vials in series. The second provides a constant-voltage screening platform for a maximum of 24 parallel reactions, but with no individual control. An important feature of this device is that inner and outer electrodes of different materials may be screened. IKA also decided to commercialize the aforementioned electrochemical Screening System which can stir and heat up to eight undivided cells or six divided cells simultaneously and individually (Figure 5D).

IKA Device and Equipment for Standardizing Synthetic Electrochemistry

Despite IKA's efforts to render electrochemistry accessible to anyone, much remains to be done especially from a high-throughput experimentation standpoint. Indeed, the IKA Carousel or IKA e-Hive do not provide heating options, which considerably limits their range of reactive chemistry. Additionally, a limitation of the e-Hive is that the cathode surface is twenty times larger than the anode, which necessitates electrode size to be reoptimized for scaleup. Furthermore, only constant voltage can be used. Finally, the device features an opaque case, preventing its use with photochemical apparatus. For parallel synthesis or reaction optimization, the most broadly desirable option seems to be the IKA Screening System: the main constraints being that only a maximum of eight reactions can be performed at once, and that a minimum reaction volume of milliliters is required.

Use of batch high-throughput electrochemistry outside organic synthesis

Outside organic synthesis, the prevailing format for electrochemical high-throughput screening is many electrode, one electrolyte systems, which have been used to screen electrode materials and surface modifications for battery, 65 fuel cell, 66 and sensing 67 applications. One example of screening potentially amenable to organic electrosynthesis comes from a high-throughput screen of electrolyte additives to improve the performance of Li ion batteries. [START_REF] Matsuda | High-Throughput Combinatorial Screening of Multi-Component Electrolyte Additives to Improve the Performance of Li Metal Secondary Batteries[END_REF] In this many electrode, many electrolyte method, 96-well microplates were used with a liquidhandling dispenser and a 96-channel electrochemical analyser to screen samples containing combinations of Li salts. Battery components (anode, cathode, and separator) were placed in each well along with 100 µL of electrolyte to create a plate where 96 individual cells could then be analysed by intermittent pulse amperometry. The use of a robotic arm to fully automate the process gave a throughput of 400 samples/day and allowed the authors to rapidly identify the optimum combination of Li salts with a high degree of accuracy. The miniaturization and automation demonstrated by this method has enabled a throughput exceeding that achieved using existing many electrode, many electrolyte systems in organic electrochemistry. However, adaptation from an electrochemical analyser to a device capable of preparative electrolysis in each well could be a challenge and a barrier to adoption for reaction development. Furthermore, while the robotic arm greatly increases throughput, the associated cost and large footprint could be prohibitive in some settings.

Screen printed multielectrode sensor arrays are another technology that has enabled high-throughput electrochemical screening outside organic synthesis. These arrays were first designed to detect nucleic acids in multiple samples after polymerase chain reaction amplification, [START_REF] Wojciechowski | Multichannel Electrochemical Detection System for Quantitative Monitoring of PCR Amplification[END_REF] and have since been applied to the detection of other biomolecules. 70 The arrays generally consist of 96-well plates containing two carbon electrodes that have been screen printed onto a printed circuit board. In addition to biomolecule detection, screen printed multielectrode arrays have been adapted for the highthroughput screening of enzyme libraries generated from directed evolution. [START_REF] Abdellaoui | A 96-Well Electrochemical Method for the Screening of Enzymatic Activities[END_REF]72 In these systems, the electrodes in each well are covered with 35-200 µL of electrolyte, and the enzymatic activity determined using intermittent pulse amperometry. This many electrode, many electrolytes approach has been used to select enzymes for biofuel cells [START_REF] Abdellaoui | A 96-Well Electrochemical Method for the Screening of Enzymatic Activities[END_REF] and synthetic biology, 72 as well as the screening of enzyme inhibitors. [START_REF] Aymard | Innovative Electrochemical Screening Allows Transketolase Inhibitors to Be Identified[END_REF] Screen printed multielectrode arrays have also been developed in a threeelectrode format to allow more precise control over electrode potential. 74 These techniques also have the advantage of enabling electrochemistry to be conducted on a smaller scale and with higher throughput than current electrosynthetic methods. Their application to organic synthesis would require consideration of the power source used to control the array as well as the possible requirement for the anode and cathode to be collocated at the bottom of the well, something that would not be consistent with the parallel electrode setup used in preparative electrolysis. Screen printed electrodes are used extensively for sensing applications including pharmaceutical and biological assays, 75 however their use in organic electrosynthesis is limited. The few available examples involve the use of interdigitated platinum electrodes, screen printed on alumina and applied to the mediated oxidation of feedstock chemicals. 76 Screen printed electrodes have a relatively small surface area. While this is advantageous for sensing applications where microliter quantities of analyte may be required, it is a limitation for preparative electrolysis during organic synthesis. Secondly, screen printed electrodes are generally less robust than electrodes made of a bulk material, requiring frequent replacement. Interestingly, these qualities support their use in high-throughput screening of organic electrochemical reactions where both microliter reaction scale and single-use electrodes are desirable. Developments in the field have also led to the commercial availability of screen-printed electrode materials commonly used for organic synthesis, including platinum, carbon, boron-doped diamond, and nickel, [START_REF] Metrohm | Swiss-quality products for chemical analysis[END_REF] and those resistant to organic solvents. 78

SUMMARY AND OUTLOOK

The parameter space of electrochemical reactions includes not only classical reaction optimization variables such as solvent, reagents, and reagent loadings, but also specialized factors such as electrode material and current density. Careful consideration and exploration of these is particularly important for scaleup of electrochemical processes. High-throughput experimentation is a valuable, enabling capability for the rapid generation of data to optimize and ensure robustness of reactions within this complex parameter space. Presently, features such as disposable electrodes, independent electrical control of individual cells, and microliter-scale flow experiments are possible. The HTe-Chem system recently developed by the Lin group, featuring readilyinterchanged electrodes and low reactor volumes in a familiar format suitable for automated reagent dispensing is a particularly welcome advance that forges an accessible path for high-throughput organic electrochemistry. Alternative modalities such as flow electrochemistry combined with automated liquid handling techniques provide yet further opportunities for rapid screening of both chemical and electrochemical parameters down to microliter scale, with significant recent advances having been reported in this area. The possibility of disposable, screen printed electrodes for organic electrochemistry has not been well-explored but presents another intriguing possibility for the future.

High-throughput electrochemistry could allow inherently-scalable optimization of electrochemical processes, enabling trust in electrochemistry from discovery stage chemistry onward, while simultaneously facilitating rapid development of new reactions and access to new areas of chemical space. We believe that these encouraging technological developments herald a future of reduced barriers to electrochemistry at all stages within the pharmaceutical and agrochemical industries.

FIGURE 1 .

 1 FIGURE 1. The resurgence of synthetic electrochemistry in recent years.

The

  Resurgence of Synthetic ElectrochemistryA. Number of "Synthetic Electrochemical" publications per year B. Selection of important reviews published since 2018 Baran et al. and optimization of previously reported methods 70% (+)Mg/(-)GSW 10 mA, DMU LiBr, TPPA, THF, rt [ammonia/amine free] [30 examples] [scalable in batch and flow] [7 other reductive transformations] 1. Electrochemical Birch reduction Baran Science 2018 Previously reported conditions: not general -limited substrate scope -substrate reoxidation -passivation 2. Electrochemical reductive cross-coupling [10 examples] [tunable parameters] [good selectivity] [scalable] aq , rt, N 2 C(+)/Fe(-), 20 mA Hansen Org. Lett. 2017 Previously reported conditions: biaryl only -limited substrate scope -high current -no large scale example E. Development of unprecedented methods 1. Electrochemical sulfonyl fluoride synthesis Noël JACS 2019 Br Alk NiCl 2 dme (5 mol%), dmbpy (5 mol%) BrAlk (1.3 equiv), NaI (0.2 M) DMA, 65 ºC, N 2 Zn(+)/RVC(-), 10 mA, 2 F.mol -1

  , variables unique to electrochemistry include: -Cell geometry o Batch cell geometry (e.g. shape, volume, electrode size(s), interelectrode distance) o Flow cell geometry (e.g. laminar vs. turbulent flow, interelectrode gap, presence/absence of a heat exchanger) -Cell type o Undivided cell o Divided cell § Nature of the dividing material (e.g. glass frit, cation or anion exchange membrane) -Material of the anode -Material of the cathode -Current density (not easily calculated or controlled with non-plate electrodes like RVC or metal foam electrodes) -Mixing in the inter-electrode region (liquid-solid interface and fluid dynamics in the gap) -Nature and concentration of supporting electrolyte -Electrode surface modification over time

FIGURE 3 .

 3 FIGURE 3. State of the Art of flow electrochemical screening equipment. (A) Reprinted with permission from Org. Process Res. Dev. 2017, 21, 771-778. Copyright 2017 American Chemical Society; (C) Reprinted with permission from Org. Lett. 2017, 19, 2050-2053. Copyright 2017 American Chemical Society. (D) Creative Commons images reproduced from Catalysts 2020, 10, 1165; (E) Reprinted with permission from Ind. Eng. Chem. Res. 2020, 59, 7321-7326. Copyright 2020 American Chemical Society.

A

  . Waldvogel flow cell B. Flow electrosynthesis of Shono oxidation products, followed by microwave-assisted nazlinine analogue synthesis C. Spiral flow electrochemical cell from CRD D. HT flow electrochemistry sysyem, composed of 64 microcells E. Electrochemical flow cell with turbulence promoter F. System for flow electrochemical HTE developed by Jensen

FIGURE 4 .

 4 FIGURE 4. State of the Art of batch electrochemical screening equipment. (A) Reprinted with permission from Anal. Chem. 1999, 71, 4369-4375. Copyright 1999 American Chemical Society; (B) Reprinted with permission from Electrochim. Acta 2005, 50, 2753-2762. Copyright 2004 Elsevier Ltd; (C) Reprinted with permission from J. Comb. Chem. 2000, 2, 5545-5549. Copyright 2000 American Chemical Society (D) Creative Commons images reproduced from ChemRxiv (CC-BY-NC-ND 4.0).

A

  . One electrolyte, many electrodes B. One electrode, many electrolytes [modified electrode surfaces] [96-well plate] [one electrode] C. Many electrodes/electrolytes D. Lin/Merck e-HTE [24 undivided cells] [control of each row] [16 undivided cells]

  -Tungsten -Niobium -Copper -Magnesium -Zinc Platinium -Gold -Silver -Nickel -Tin -Boron -RVC -Nickel -Cobalt 2. IKA E-Hive [Individual vial detection] [Six-reactor screening] [Constant currant through all six vials] Inner and outer electrodes can be adjusted with different materials Potentiostat Stir and heating plate Divided cells

19 FIGURE 2. Examples of sustainable alternatives through electrochemistry. Sustainable Electrochemical Processes A. Electrochemical alcohol oxidation Me O O Me Me OH O O

	5 mol% ACT
	0.1 M aq. NaHCO 3 0.1 M Na 2 CO 3	Me Me	O
			OH
	99% ee	99%,99% ee

N NHAc Me Me Me Me O ACT Typical conditions: Metal oxidant or Swern/Dess-Martin, then Pinnick

	B. Electrochemical
	[metal free] [15 examples] [scalable in batch and flow]

benzylic oxidation tBu tBu OMe OMe anodic oxidation MeOH Typical conditions: Benzylic halogenation, then hydrolysis tBu Me CHO Lysmeral ®

	Stahl ACS Catalysis 2016	BASF
	(+)RVC/(-)Pt, 0.7 V, rt
		[>10,000 tonnes per annum]
	OMe [transition metal free] [70 examples] [DMF, H + and CO 2 electrophiles] 83% OMe tBuBr LiOTf CHO C. Electroreductive coupling Lin JACS 2020 tBu DMF (+)Mg/(-)C, 10 mA +	[scalable to 100 g in flow] [organometallic free] [50 examples] [mechanistic investigations] 61% O N N N Baran JACS 2021 N N nBu 4 Br OH DMF nBu nBu nBu nBu (+)Zn/(-)Sn, 10 mA +	N

Process Research and Development, 2021, 25 (12), pp.2587-2600. 10.1021/acs.oprd.1c00167. hal-

ACKNOWLEDGMENTS

Financial support for this work was provided by the CNRS, French Ministry of Research and the University of Lyon I. A. G. W. thanks the GlaxoSmithKline/University of Strathclyde Collaborative PhD program and the EPSRC for funding via Prosperity Partnership EP/S035990/1. S. C. thanks the ICBMS for a Master fellowship.

ORCID

Claudio Battilocchio: 0000-0002-4601-8527 Nessa Carson: 0000-0002-2769-1775 Sylvain Charvet: 0000-0003-1612-9338 Darren L. Poole: 0000-0001-5050-5996 Christopher C. Scarborough: 0000-0001-7714-1643 Julien C. Vantourout: 0000-0002-0602-069X Katherine M. P. Wheelhouse: 0000-0002-1963-1465

AUTHOR INFORMATION

Corresponding Authors *julien.vantourout@univ-lyon1.fr *nessa.carson@syngenta.com *darren.l.poole@gsk.com

Author Contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

NOTES

The authors declare no competing financial interest.

Table of Contents


Sylvain Charvet

Maurice Médebielle

Julien C Vantourout

Mn-Mediated a-Radical Addition of Carbonyls to Olefins: Systematic Study, Scope, and Electrocatalysis

A systematic study of the manganese-mediated a-radical addition of carbonyl groups to olefins is presented. After an in-depth investigation of the parameters that govern the reaction, a first round of optimization allowed the development of a unified stoichiometric set of conditions which was subsequently assessed during the exploration of the scope. Due to observed limitations, the knowledge accumulated during the initial study was reengaged to quickly optimize promising substrates that were so far inaccessible under previously reported conditions. Altogether these results led to the creation of a predictive model based on the pKa of the carbonyl compound and both the substitution and geometry of the alkene coupling partner. Finally, a departure from the use of stoichiometric manganese was enabled through the development of a robust and practical electrocatalytic version of the reaction.

INTRODUCTION

One of the central challenges of our century is the development of sustainable chemical processes. [START_REF]For a selection of book chapters and reviews: (a) Horváth, I. T. Introduction: Sustainable Chemistry[END_REF] Following this concept, the use of first row transition metals has become essential in catalysis. [START_REF] Alig | First-Row Transition Metal (De)Hydrogenation Catalysis Based on Functional Pincer Ligands[END_REF] Manganese is abundant, inexpensive, non-toxic, and participates in myriad of transformations due to the wide range of oxidation states it can adopt (from 0 to +7, [Ar]3d 5 4s 2 ). [START_REF] Carney | Recent Advances of Manganese Catalysis for Organic Synthesis[END_REF] In the framework of a new research programm dedicated to manganese catalysis, we are particularly interested in the systematic study of reactions previously neglected due to low practicality and lack of mechanistic understanding.

For our first study, we selected the field of a-alkylation of carbonyls as it is a central and well-established transformation in organic synthesis that could still benefit from improvement (Figure 1). [START_REF] Lamoureux | C. A Comparison of Several Modern Alkylating Agents[END_REF] Indeed, the coupling of enolates with nucleofuge-containing molecules under basic conditions is extensively employed, but its low atom-economy makes it often industrially impracticable. [START_REF] Smith | First Asymmetric Total Synthesis of (+)-Sparteine[END_REF] Similarly, modern procedures employing a combination of a metal-based catalyst with directing amines have allowed the use of alkenes as coupling partners, which circumvent any waste generation. [START_REF] Nakamura | α-Alkylation of Ketones by Addition of Zinc Enamides to Unactivated Olefins[END_REF] However, the expensive catalysts and/or reagents employed in these protocols make them difficult to implement on scale. Despite the current limitations associated with the Mn-mediated carbonyl a-radical addition to olefins (vide infra), we identified this transformation as a full atom-economy alternative to existing enolates and metal-based systems. Therefore, we decided to systematically investigate the parameters that govern this reaction to assemble a general and robust set of conditions that would supplant existing procedures.

STATE OF THE ART

Since the seminal 1968 back-to-back publications of Finkbeiner and Heiba, Mn(III) has emerged as an ideal catalyst to promote various oxidative free-radical reactions. [START_REF] Bush | Oxidation Reactions of Manganese(III) Acetate. Formation of Gamma-Lactones from Olefins and Acetic Acid[END_REF][START_REF] Heiba | Oxidation by Metal Salts. IV. A New Method for the Preparation of g-Lactones by the Reaction of Manganic Acetate with Olefins[END_REF] In these pioneering reports, a non-activated olefin reacts with solvent quantities of AcOH in the presence of stoichiometric amount of Mn(OAc)3 and KOAc at reflux to afford the corresponding lactone (Scheme 1A.1). Two years later, the group of Nikishin demonstrated that a large excess of carbonyl compound (20 equivalents) was also able to react with alkenes in an intermolecular fashion to deliver the a-functionalized ketone 2, albeit in low yield (Scheme 1A.2). [START_REF] Vinogradov | Preparation of Acetonyl Radicals in the Oxidation of Acetone with Manganese Triacetate[END_REF] Indeed, Mn(III) is able to oxidize carbonyl compounds to generate an a-keto free radical, which can subsequently react with an unsaturated substrate to deliver the desired coupled product. 11 The detailed mechanism of this reaction has been extensively studied and proposed by Peterson and Snider. [START_REF] Fristad | Mechanisms for Manganese(III) Oxidations with Alkenes[END_REF][START_REF] Snider | Mechanisms of Mn(OAc)3-Based Oxidative Free-Radical Additions and Cyclizations[END_REF] It subtly depends on the nature of the carbonyl starting material but can generally be summarized as depicted in Scheme 1A.3. It begins with the coordination of carbonyl 3 onto the Mn(OAc)3 catalyst to form complex 4, followed by loss of the a-proton assisted by one of the acetate groups to generate enolate 5. The latter is oxidized by Mn(III) to give the free-radical intermediate 6 that subsequently reacts with the olefin, forging the C-C bond and affording the more stable radical species 7. This sequence may also be concerted if the enolate oxidation step is sluggish. [START_REF] Snider | Mechanisms of Mn(OAc)3-Based Oxidative Free-Radical Additions and Cyclizations[END_REF] Finally, a termination step via hydrogen atom transfer (HAT) allows the formation of desired product 8.

The reaction tolerates a wide range of ubiquitous carbonyl compounds including ketones, esters, keto-esters, diesters, aldehydes, and carboxylic acids. 11 In addition, the possibility for the carbonyl moieties to react with non-activated olefins using earth abundant manganese renders this transformation highly attractive and broadly applicable, especially in the context of natural product synthesis (Scheme 1A.4). 14

While the Snider group amongst others reported several intramolecular polycyclization cascades, 15 the Mamdapur groups applied the intermolecular version of the Mn-mediated a-radical addition of carbonyl groups to olefins as a key step for their synthesis of Queen Bee Pheromone 9 and Himasecolone 10, respectively. 16 Despite all the advantages it offers, the intermolecular version of the reaction still suffers from major limitations such as: (1) the absence of a general set of conditions; (2) the need for a large excess of carbonyl starting material to be employed (usually more than 10 equivalents); (3) the use of acetic acid as the solvent which lowers the functional group tolerance and ( 4) the lack of understanding with regards to some reaction parameters including temperature, concentration, atmosphere and more importantly the nature of the alkene coupling partner (Scheme 1A.4). These limitations hamper the widespread use of this powerful transformation. Another significant drawback that reduces the broad application of this

R 2 R 1 O R 3 R 1 R 5 R 4 R 5 R 4
R 1 + R 5 O R 2 R 3 R 4 R 5 R 4 O R 1 R 2 R 3

Selected applications

General reaction scheme

[Mn] carbonyl (3 equiv) Mn(OAc) 3 (1.5 equiv) EtOH as solvent reaction is the (over)stoichiometric amount of Mn(OAc)3 catalyst often required to afford satisfactory yields. 11 Such excess of manganese catalyst leads to tedious workup as exemplified in several studies. 15e To overcome this issue, several groups have attempted to run the reaction under oxidative conditions to regenerate Mn(III) from Mn(II). 11,17 As a selected example, the Ishii group reported the coupling between cyclohexanone 3 and octene 11 to afford desired product 12 in 59% yield (Scheme 1A.5). [START_REF] Kagayama | A Remarkable Effect of Bases on the Catalytic Radical Addition of Cyanoacetates to Alkenes Using a Mn(II)/Co(II)/O2 Redox System[END_REF] This set of conditions only requires 0.1 mol% of Mn(OAc)2 catalyst and 0.05 mol% of Co(OAc)2 co-catalyst to be employed under a mixed atmosphere of oxygen and nitrogen. However, the large excess of ketone starting material and the use of AcOH as solvent remain two major limitations which reduce the applicability of the reaction. As an alternative to chemical oxidative conditions, it was demonstrated that Mn(II) could be oxidized to Mn(III) under electrochemical conditions (Scheme 1A.5). [START_REF] Shundo | Selective Coupling of Non-Activated Olefins with Ethyl Cyanoacetate by Mn 3+ -Mediated Anodic Oxidation[END_REF] In these studies, the products are obtained in good yield using low Mn(II) catalyst loadings (down to 10 mol%). Nevertheless, the use of solvent quantities of AcOH, the necessity to run the reaction in a divided cell, and the absence of a general procedure reduce the synthetic value of this catalytic approach.

The aforementioned limitations have certainly lowered the uptake of the Mn-mediated a-radical addition of carbonyl groups to olefins, 11f and although this reaction has been exemplified multiple times in the literature it has only been sporadically studied. 20 We recognized that if rendered practical, such a reaction could undoubtedly impact the field of carbonyl a-functionalization. Therefore, we decided to: (1) investigate the parameters that govern this transformation;

(2) assemble a general set of stoichiometric reaction conditions;

(3) evaluate the scope and its limitations; (4) reengage the knowledge accumulated during the initial study to quickly optimize low yielding substrates and ( 5) depart from the use of stoichiometric manganese with the development of a general electrocatalytic version of the reaction (Scheme 1B).

RESULTS AND DISCUSSIONS

Systematic study of the reaction parameters

We began our investigation by studying the parameters that govern the Mn-mediated a-radical addition of carbonyls to olefins between cyclohexanone 3 and 1-hexadecene 13 (Scheme 2A). As most of the existing intermolecular processes suffer from the requirement for a large excess of carbonyl compound to be used under oxidative conditions, the excess of ketone 3 was limited to three equivalents and the reaction was run under argon. Based on previously reported conditions, Mn(OAc)3 was selected as the stoichiometric catalyst source and the reaction was conducted at 70 °C. Inspired by the elegant Mn(III)-catalyzed intramolecular cyclization study disclosed by the Snider group, where the authors described the impact of the solvent and especially the beneficial effect of using EtOH to enhance the HAT termination step, we initially studied this parameter. 21 To our surprise, AcOH, which is the preferred solvent for the majority of previously reported conditions, only afforded 14% of desired product 14 (Scheme 2A.1). This is potentially due to the limited amount of ketone (3 equivalents) used in the reaction, which cannot compete with the competitive lactone formation reported by Finkbeiner and Heiba (Scheme 1A.1). DMA, DME, DMF, MeCN, DCE, and HFIP were also tested but only delivered moderate yields (22-46%, Scheme 2A.1). This trend can be rationalized by the reduced ability of these solvents to facilitate the final HAT process as the Hatom source, constraining the ketone starting material or the desired product to serve this role. The subsequent radicals can then result in the formation of unwanted by-products (See SI for details). As expected, based on Snider initial disclosure, out of all the solvents that were screened, EtOH conferred the best result (74% yield) while toluene provided a moderate yield of 58% (Scheme 2A.1). 21 This result matches Snider initial observation In each case, the corresponding stabilized a-hydroxy or benzylic radical afforded by the HAT termination step can explain why these solvents offered an improved outcome. The remarkably enhanced conversion observed in EtOH can also be supported by several studies which previously highlighted its ability to enhance the reactivity of manganese-based processes. 22 Screening of commercially available catalyst sources was then attempted using EtOH as the solvent (Scheme 2A.2).

Unfortunately, Mn(dpm)3 and Mn(acac)3 resulted in none and 14% conversion to product 14, respectively. The steric hindrance engendered by dpm or acac ligands surrounding the metal-center obstructs the formation of coordinated intermediate 4, which impedes product formation. In addition, such ligands could lead to the formation of undesired a-functionalized by-products. Non-commercially available Mn(pic)3 catalyst was also tried under the reaction conditions but did not provide satisfactory yield compared to Mn(OAc)3 (See SI for details). Unsurprisingly, the use of Mn(OAc)2 did not afford any product as oxidation to Mn(III) is impossible under an argon atmosphere. The influence of temperature on the reaction was also investigated (Scheme 2A.3). Temperatures lower than 60 °C considerably diminished the yield as it decreased the solubility of the manganese catalyst, while temperatures higher than 70 °C significantly increased by-product formation. The impact of the amount of manganese was then studied (Scheme 2A.4).

While increasing the number of equivalents from 1 to 1.5 improved the yield of compound 14 from 70% to 74%, lowering the loading from 1 to 0.5 equivalents resulted in a decreased yield of 51%. This result is in accordance with the proposed mechanism where Mn(III) is reduced to Mn(II) to generate keto-radical 6. Under inert conditions, Mn(II) cannot be re-oxidized and a (super)stoichiometric amount of manganese needs to be employed. Of note, using a large excess of manganese catalyst (e.g., 3 equivalents) resulted in low conversion to the desired product (44%), possibly due to precipitation of the catalyst. Several additives were screened and their impact on the reaction efficiency was studied (Scheme 2A.5). Doping the reaction with acidic additives such as AcOH, PivOH and B(OH)3 resulted in unexpectedly lower conversions. Unintuitively, adding external bases including KOAc, Et3N, DIPEA, imidazole, NaOEt or t BuOK to facilitate the deprotonation step did not increase the yield of the reaction, and instead considerably hampered conversion. We next turned our attention to the atmosphere under which the coupling reaction was being conducted. Running the reaction under argon provided 70% of desired product 14 while an atmosphere of oxygen only afforded 44% (Scheme 2A.6). A careful analysis of the by-product distribution allowed us to explain the drastic differences observed between an inert and oxidizing environment (See SI for details). Indeed, under air or oxygen the ketone starting material is consumed by undesired processes leading to dimeric and a-oxidized species, thus lowering the overall yield of the reaction. Based on the elegant study from the group of Ishii, the impact of using a Co(II) cocatalyst was also reevaluated (vide supra). [START_REF] Kagayama | A Remarkable Effect of Bases on the Catalytic Radical Addition of Cyanoacetates to Alkenes Using a Mn(II)/Co(II)/O2 Redox System[END_REF] Attempts to apply these conditions to our system resulted in low efficiency and only gave a 21% yield of desired product 14. A reduction in ketone stoichiometry (1 or 2 equivalents) diminished the yield considerably, and compound 14 was only obtained in 27% and 34% yield respectively (Scheme 2A.7). The use of a large excess of ketone (5 or 10 equivalents) delivered high yields, matching with previously reported results from the literature. 11 Finally, as both solubility of the manganese catalyst and overall concentration of the ketone starting material appeared to greatly impact the yield of the reaction, we hypothesized that the concentration should also play an important role in the outcome of the transformation (Scheme 2A.8). Moving from a concentration of 0.5 M to 0.1 M significantly decreased the yield from 70% to 38%. Similarly, the yield of the reaction was markedly lowered when the concentration was too high due to catalyst insolubility and lower stirring efficiency.

Optimized stoichiometric set of reaction conditions

Using the knowledge gained throughout this in-depth study a simple and general Mn-mediated a-radical addition of carbonyls to olefins was developed (See SI for details). Running the reaction with a slight excess of Mn(OAc)3 in EtOH at suitable temperature (70 °C) and concentration (0.75 M) under an atmosphere of argon delivered desired product 14 in 67% isolated yield with only 3 equivalents of carbonyl starting material (Scheme 2B).

Scope of the reaction

With the optimized conditions in hand, we first started to assess the carbonyl scope (Scheme 3A). Ketones such as cyclopentanone, acetone and indanone delivered compounds 15, 16 and 17 in 70%, 59% and 40% isolated yields, respectively. Noteworthy, the conversion for compounds 16 and 17 (83% and 97%, respectively) was much higher than the isolated yield due to challenging purification. a-Tetralone, which was known to be unreactive under previously reported conditions, afforded compound 18 in 17% yield. Boc-protected piperidin-4-one afforded desired product 19 in 63% isolated yield. Strikingly, this compound was only obtained in trace amount following the original literature conditions which highlights the importance of using EtOH instead of AcOH to improve functional group tolerance. Nitroacetate did not give the desired linear product but the cyclized compound 20 in a moderate isolated yield of 33%.

Other carbonyls including diester, keto-ester and cyanoacetate proved compatible under the reaction conditions with compounds 21, 22 and 23 obtained in good yields (63-74%). Unfortunately, due to higher α-C-H pKa values, amides and esters did not react under the reaction conditions (compounds 32 and 33, Scheme 3C). Similarly, compound 34 issued from the coupling between methyl isopropyl ketone (MIPK) and 1-hexadecene 13 was only detected in negligeable amounts (traces in GCMS).

Regarding the alkene scope, stabilized disubstituted olefins such as prop-1-en-2-yl acetate when reacting with cyclohexanone 3 delivered product 27 in 61% isolated yield. Alkynes were also successfully coupled under the reaction conditions with alkene 29 obtained in 43% yield (14:1 E/Z ratio). Functionalization of valuable alkenes such as camphene and (+)-b-citronellene afforded different outcomes with compounds 30 obtained in 66% while only trace amount of compound 31 was detected. In addition, cyclohexene when coupled with indanone delivered compound 28, in 16% isolated yield highlighting that 1,2-disubstituted non-stabilized olefins are challenging compounds to functionalize. This trend was further confirmed when 1methylcyclohex-1-ene, (E)-non-4-ene, or (Z)-non-4-ene were used as alkene coupling partners with no desired or trace product formation observed.

Regarding functional group tolerance, the optimized reaction conditions proved highly efficient. Indeed, ester (21-23 and 27), cyano (23), nitro (20), free (25) or TBS (24) protected alcohols, and acetyl groups (27) were all tolerated under the reaction conditions and afforded the desired products from moderate to good yields (27% to 74%). Notably, halogen moieties were also stable under the reaction conditions with bromine containing compound 25 obtained in 56%. To further assess the functional group tolerance, a robustness test was performed by adding one equivalent of an additive bearing a specific reactive handle (Scheme 3D). [START_REF] Collins | A Robustness Screen for the Rapid Assessment of Chemical Reactions[END_REF] While phenol, amide and carboxylic acid moieties did not impact the outcome of the reaction, amine-and nitrobased compounds hampered both conversion and yield. Interestingly, pyridine lowered the conversion (73% instead of 92%) but afforded a serviceable yield (53% instead of 74%).

All these results can be rationalized based on the nature of the olefin or carbonyl coupling partners. Alkenes that afford secondary radicals are not oxidized by Mn(III) allowing the HAT step to proceed efficiently. However, when they react with highly reactive carbonyl, the secondary radical can engage with the oxygen and then undergo oxidation to give lactones or dihydrofurans such as compound 20. 1,2-disubstituted alkenes work poorly since the initial addition is slow. Finally, 1,1-disubstituted alkenes and styrenes are the most reactive alkenes, but the radicals issued from the initial addition step are subsequently oxidized so there is little or no HAT product as exemplified by compound 30. Overall, the optimized set of reaction conditions delivered a broad scope but some unexpected and contrasting results highlighted the difficulty to identify a truly general set of conditions, especially with respect to the alkene coupling partners. To equally compare our newly developed conditions to the previously reported ones, we decided to run a control where 10 equivalents of carbonyl was used in AcOH in the presence of 2.0 equivalents of Mn(OAc)3 at 70 °C. Strikingly, except for nitroacetate, our reaction conditions outperformed the control experiments. More importantly, for compounds 18, 28, 31, 34 and 37 our conditions always afforded product, while previously reported ones were ineffective. This observation motivated us to try to understand the reaction further to optimize for those low yielding substrates.

Rapid optimization of low yielding substrates

We envisioned that we could re-apply the knowledge accumulated during our systematic study to identify key parameters that should impact the outcome of the reaction. If successful, this approach would allow the practitioner to quickly identify optimal reaction conditions to give at least some product under the general stoichiometric set of conditions for challenging substrates. Throughout our initial investigation of the Mn-mediated aradical addition of carbonyls to olefins, parameters such as solvent, temperature, manganese loading, and concentration were found to dramatically impact the reaction outcome (Scheme 2). Due to its importance in previously reported conditions by the Snider group, AcOH was also a variable that needed to be considered. 11g With those parameters in mind, eight sets of conditions were designed and assessed on eight substrates containing seven ketones and two alkenes. Depending on the substrates and the conditions used, huge reactivity differences were observed matching with the observed difficulty to develop a truly general protocol (vide supra). As an example, cyanoester afforded high conversions to desired product 23 under all tested conditions even at room temperature. This extremely high reactivity can explain why it is one of the most frequently used substrates in literature reports. 24 [Control] carbonyl (10 equiv) Mn(OAc) 3 (2.5 equiv) AcOH, 70 °C, air Reaction conditions

(3 equiv) R 1 + R 5 O R 2 R 3 R 4 R 5 R 4 O R 1 R 2 R 3 A.

D. Robustness test

(1 equiv) (3 equiv) R 1 + R 5 O R 2 R 3 R 4 R 5 R 4 O R 1 R 2 R 3
Condition A Mn(OAc) 3 ( 1

reaction R R 1 EDG R 2 R 1 R 2 R 1 R 1 R 2
C 14 H 29 R 3 R 1 R 2
several changes impacted the conversion to product 20 which results from the coupling between nitroacetate with hexadecene. Running the reaction with more equivalents of manganese (from 1.5 to 2.5 equivalents), higher temperature (from 70 °C to 90 °C), higher concentration (from 0.75 M to 1 M) or using AcOH as an additive (5 or 10 equivalents) provided better conversions versus the original conditions. The reactivity of a-tetralone, which already delivered reasonable conversion (25%), was enhanced by simply adding 5 equivalents of AcOH to afford 56% of desired product 18. Similarly, compound 38 was obtained in a moderate yield of 43% by increasing the amount of manganese from 1.5 to 2.5 equivalents. While trying to optimize compounds 28, 34 and 39 proved more difficult, several conditions still afforded decent conversions (20-50%). Therefore, it was envisioned that the combination of all promising set of conditions could significantly increase the yield of initially low conversion reactions. This merged approach was attempted on several substrates, and the results are highlighted in Scheme 4B. Outstandingly, compounds 34, 18, 28 and 20, which were initially only observed in trace amounts or isolated in low yields using the initial set of conditions, were obtained in 50%, 49%, 44% and 66% isolated yield, respectively. Testing of these simple parameters (manganese loading, temperature, concentration, AcOH additive), can quickly identify optimized conditions for challenging substrates. However, we thought it would be even better if the practitioner could predict the reaction outcome based on the nature of the carbonyl and the olefin.

Predicting reaction outcome

The systematic optimization, scope evaluation and the subsequent re-optimization of low yielding compounds afforded copious data on reaction outcomes and allowed for a predictive model that relied on (1) the pKa of the carbonyl and ( 2) the geometry and substitution of the olefin to be assembled (Scheme 4C). Several studies have highlighted the importance of steric hindrance and pKa depending on the nature of the carbonyl coupling partner. 11,25 However, no general trends have been reported due to the complexity of the transformation and the myriad of conditions associated to it. Based on our stoichiometric set of conditions, the reaction outcome can be predicted by simply using the pKa of the carbonyl starting material (Scheme 4C.1). Carbonyl compounds with a pKa lower than 24 will provide good yields under the optimized stoichiometric conditions. For carbonyls with pKas between 24 and 29, the approach developed for the low yielding compounds should be applied to obtain satisfactory yields. Compounds with pKas higher than 29 such as esters and amides won't deliver the desired product. As highlighted by several reviews, the impact of the substitution and geometry of the alkene coupling partner has not been deeply studied. 11 Indeed, most of the examples reported in the literature focus on the functionalization of terminal non-substituted and cyclic olefins. The evaluation of the reaction scope and the optimization of its limitations allowed us to rationalize outcomes based on the nature of the olefin (Scheme 4C.2). Terminal alkenes and alkynes as well as stabilized disubstituted olefins are well tolerated under the reaction conditions and should afford good yields using the standard stoichiometric protocol. For non-stabilized, cyclic, and cis/trans alkenes the eight conditions designed using the systematic study should deliver moderate yields. When the olefin is too encumbered no desired product should be expected.

Development of an electrocatalytic set of conditions

With the stoichiometric set of conditions, the knowledge accumulated from the systematic study, and the ability to predict the reaction outcome, the practitioner will be able to confidently run the Mn-mediated a-radical addition of carbonyls to olefins. However, the need for a stoichiometric amount of Mn(OAc)3 was still a serious limitation from a sustainability and scalability standpoint. The development of a catalytic version was therefore sought. As mentioned in the introduction electrochemical alternatives have been attempted for Mn(III)-mediated reactions but have either not proven general, were not deeply investigated, or suffered from limitations such as the requirement for a divided cell and limited substrate scope. 15e, 19,24b,26 Therefore, the development of a robust electrochemical version of the Mn-mediated carbonyl a-radical addition to olefins was undertaken. The oxidation of Mn(II) to Mn(III) was first studied in an undivided cell equipped with graphite anode and cathode (Scheme 5A). The reaction was conducted using Mn(OAc)2 as the catalyst in AcOH at room temperature under argon. AcOH was selected as solvent due to the dual role it would ensure through the course of the catalytic reaction. While proton reduction would occur at the cathode, the subsequently generated acetate would assist the regeneration of Mn(OAc)3 active catalyst at the anode. After 1 F•mol -1 the formation of Mn(OAc)3 was clearly detected. However, passivation of the electrodes was also observed due to accumulation of Mn-based species on the anode surface. Pleasingly, this undesirable phenomenon was easily suppressed by simply applying alternating polarity. Indeed, such a mode allow for the polarity of each electrode to be switched at a defined frequency lowering charge accumulation. With this proof of concept in hand, the carbonyl starting material was carefully selected. Indeed, cyanoacetate was an ideal coupling partner to start the optimization with as it allowed the reaction to be conducted at room temperature and tolerated the use of AcOH (vide supra, Scheme 4). The excess of carbonyl was maintained at 3 equivalents while the amount of Mn(OAc)2 was fixed at 10 mol%. Based on our earlier optimization studies, the impact of the [Mn]/[AcOH] ratio on the reaction outcome was first investigated (Scheme 5B). As expected, a high [Mn]/[AcOH] ratio did not lead to sufficient concentration of active catalyst and afforded the desired product in low yield. Conversely, too much AcOH in the reaction gave a low [Mn]/[AcOH] ratio and reduced the efficiency of the transformation. The optimal [Mn]/[AcOH] ratio was obtained using 7.5 equivalents of AcOH which afforded the desired product 22 in 88% yield. With this optimized ratio in hand, we turned our attention to the electrochemical reaction conditions (Scheme 5C). To maximize the conversion, 15 mol% of Mn(OAc)2 catalyst was used in the presence of 11.3 equivalents of AcOH to maintain the [Mn]/[AcOH] ratio (0.02). Under these conditions, the desired product was obtained in more than 95% yield. A control experiment without AcOH led to extremely low conversion. In the absence of alternating polarity, compound 23 was only obtained in 15% yield supporting the detrimental impact of electrode passivation on the reaction outcome. Using 1.5 F•mol -1 instead of 3.0 F•mol -1 only delivered 49% of the desired compound, while using 10 mA instead of 5 mA also lowered the yield to 68%. To avoid scalability issues associated with the use of perchloratebased electrolytes, LiBF4 was used instead of LiClO4 which maintained high conversion to product 23 and good isolated yield (77%). Finally, aware of the beneficial effect of running the reaction at high concentration, the electrochemical conditions were concentrated up to 0.5 M (instead of 0.25 M) and compound 23 was isolated in 84%. We then decided to synthesize several molecules to assess the efficiency of the electrochemical protocol (Scheme 5D). Compound 40 bearing a halogen moiety was isolated in 40% yield. As expected, compounds 14 and 21 which usually require higher temperature to proceed in good yield, did not give satisfactory results at room temperature. Simply heating these reactions to 70 °C afforded good yields (71% for 14 and 67% for 21). In addition, the reaction was easily scaled-up to 6 mmol in a single 20 mL ElectraSyn vial by adjusting the current to 25 mA. Finally, the knowledge gained throughout the study was easily transferable to the electrochemical protocol with compound 34 obtained in 59% by using 20 equivalents of AcOH in toluene at 90 °C. Altogether, these results not only highlight the efficiency of the optimized paired electrochemical protocol but also demonstrate its scalability. 27

SUMMARY

The key mechanistic features of the developed conditions are summarized in Scheme 6. To increase the practicality of the Mn-mediated a-radical addition of carbonyls to olefins, the goal of this study was to lower the amount of carbonyl starting material to 3 equivalents. Fixing this parameter impacted the first step of the mechanism where the carbonyl moiety needs to coordinate the Mn-catalyst. Therefore, increasing the concentration (from 0.1 M to 0.75 M) was crucial to obtain the desired product in good yield (Scheme 6, panel A). The following loss of proton is afforded through an intramolecular deprotonation process where the presence of the acetate ligands proved essential. Indeed, external bases or additives were detrimental for the reaction to occur with high efficiency (Scheme 6, panel B). The oxidation of the resulting enolate has been extensively studied in the literature and none of the reaction parameters we have investigated improved it (Scheme 6, panel C). Conversely, for the free radical addition step, our study systematically highlighted the importance of the alkene geometry and substitution (Scheme 6, panel D). The high concentration also favored this step of the mechanism. The use of EtOH instead of AcOH, in addition to increasing the functional group tolerance, positively impacted the final HAT step (Scheme 6, panel E). Finally, the use of electrochemical conditions to reoxidize Mn(II) to Mn(III) allowed the development of a robust and general catalytic set of conditions where a precisely controlled [Mn]/[AcOH] ratio was found to be critical (Scheme 6, panel E).

CONCLUSION

An in-depth study of the Mn-mediated a-radical addition of carbonyls to olefins has been assembled allowing the development of a new and general set of reaction conditions. A wide range of functional groups including ester, cyano, nitro, free and TBS protected alcohols, and acetyl groups were tolerated, and several carbonyls and olefins proved competent coupling partners. Understanding the effect of solvent, concentration, temperature, amount of catalyst as well as the impact of additives has enabled us to identify a list of eight key experiments that can quickly be executed to optimize challenging reactions. This approach was successfully applied to four different initially low yielding substrates, proved highly efficient, and led to the creation of a predictive model based on the pKa of the carbonyl compound and both the substitution and geometry of the alkene coupling partner. Finally, development of a robust and practical electrocatalytic version of the reaction enabled the departure from stoichiometric manganese loadings. The eprocedure requires only 3 equivalents of carbonyl starting material to achieve good conversions, uses two inexpensive graphite electrodes and a safe electrolyte. Importantly, this paired electrochemical process does not require the use of an undivided cell and was straightforwardly scaled-up to 6 mmol in a single 20 mL vial. Overall, both stoichiometric and electrocatalytic protocols should find applications in academic and industrial environments and will enable the development of new Mn-based catalytic systems.

ASSOCIATED CONTENT

R

C

Mn(III) is able to oxidize the enolate affording the formation of the alpha-keto radical and Mn(II).

D

Alkene substitution and geometry are essential and afford different reaction outcomes. Concentration (0.75 M) was also an important parameter to optimize to favor this step.

E

The HAT step is important as it delivers the desired product. EtOH or toluene proved optimal.

7

 7

Figure 1 .

 1 Figure 1. Introduction to a-alkylation of carbonyls.

  Scheme 1. Introduction. (A) State of the Art, and (B) Core of this study.

1 .

 1 First back-to-back reports, Finkbeiner and Heiba (1968)

Scheme 3 .

 3 Scheme 3. Scope of the reaction. (A) Carbonyls, (B) Alkenes, (C) Limitations, and (D) Robustness test. Yields refer to GCMS yields using 1,3,5-trimethoxybenzene as an internal standard. Isolated yields are shown in brackets. a Acetone used as solvent.

Scheme 4 .

 4 Scheme 4. Broadening the scope of the reaction. (A) Reengaging data from the systematic study, (B) Rapid optimization of initially low yielding compounds, and (C) Predicting reaction outcome. Yields refer to GCMS yields using 1,3,5-trimethoxybenzene as an internal standard. Isolated yields are shown in brackets.

2 .

 2 Impact of the alkene substitution and geometry good conversion to product low conversion to product no

Scheme 5 .

 5 Scheme 5. Electrochemical Mn-mediated a-radical addition of carbonyls to olefins. (A) e-oxidation of Mn(II) to Mn(III), (B) Optimum [Mn]/[AcOH] ratio, (C) Optimization, and (D) Scope. Reactions were conducted on a 0.6 mmol unless otherwise state. a GCMS yields using 1,3,5-trimethoxybenzene as an internal standard. b Isolated yields are shown in brackets. c Reactions were conducted on a 1.2 mmol scale in EtOH (0.5 M) at rt. d Reactions were conducted on a 1.2 mmol scale in EtOH (0.5 M) at 70 °C. e Reaction was conducted on a 1.2 mmol scale using 20 equivalents of AcOH in toluene/EtOH (1:1, 0.5 M) at 90 °C.

Scheme 6 .

 6 Scheme 6. Key mechanistic features of the developed conditions.

  amount of carbonyl(3 equiv) was lowered compared to reported conditions, concentration (0.75 M) and amount of catalyst(1.5 equiv) were crucial parameters to optimize. B pKa of the carbonyl proved important (Scheme 4C.1). The deprotonation occurs via an intramolecular mechanism and therefore the nature of the ligand (acetate) on the manganese catalyst is important. External bases did not afford any improvement and proved detrimental for the reaction outcome.

F

  Regeneration of the Mn(III) active catalyst was not possible under argon atmosphere and chemical oxidants increased the amount of by-products. Electrochemical conditions using a controled amount of AcOH (optimum ratio Mn/AcOH) enabled the development of robust and easily scalable catalytic conditions.

example of oxidative conditions Selected example of electrochemical conditions

						5. Intermolecular catalytic approaches
									Mn(OAc) 2 (0.1 mol%)
								Co(OAc) 2 (0.05 mol%)
									AcOH, 80	°C
									O 2 /N 2			12, 59%
				O	Me Me	O			Mn(OAc) 2 (20 mol%) KOAc, EtOAc/AcOH	O
	Me	O	OAc	Me	Me	EtO	CN	C 7 H 15	C(+)/C(-), 20 mA 40 °C, air,	EtO	CN	C 7 H 15
					AcO
		queen bee pheromone (9)		himasecolone (10)

1, 74% 4. Intermolecular stoichiometric approaches ■ AcOH as solvent ■ large excess of ketone ■ high temperature ■ limited functional group tolerance ■ no general set of conditions ■ limited understanding of reaction parameters ■ ubiquitous SM ■ applications in synthesis ■ manganese ■ AcOH as solvent ■ large excess of ketone ■ co-catalyst needed + ■ divided cell ■ no general set of conditions ■ use of excess AcOH 60% Selected

Scheme 2. Development of a unified stoichiometric set of conditions. (A) Study of the influence of key parameters, and (B) Optimized set of reaction conditions. Reactions

  Ar, 16 h.; A4: cyclohexanone (3 equiv), hexadecene (1 equiv), Mn(OAc)3 (equivalents), EtOH (0.75 M), 70 °C, Ar, 16 h.; A5: cyclohexanone (3 equiv), hexadecane (1 equiv), Mn(OAc)3 (1 equiv), EtOH (0.75 M), additive (3 or 5 equiv, see SI for details), 70 °C, Ar, 16 h.; A6: cyclohexanone (3 equiv), hexadecene (1 equiv), Mn(OAc)3 (1 equiv), EtOH (0.75 M), 70 °C, atmosphere, 16 h.; A7: cyclohexanone (equivalents), hexadecene (1 equiv), Mn(OAc)3 (1 equiv), EtOH (0.75 M), 70 °C, Ar, 16 h.; A8: cyclohexanone (3 equiv), hexadecene (1 equiv), Mn(OAc)3 (1 equiv), EtOH (concentration), 70 °C, Ar, 16 h. Yields refer to GCMS yields using 1,3,5-trimethoxybenzene as an internal standard. Isolated yields are shown in brackets.

run on 0.25 mmol scale. A1: cyclohexanone (3 equiv), hexadecene (1 equiv), Mn(OAc)3

(1.5 equiv)

, solvent (0.75 M), 70 °C, Ar, 16 h.; A2: cyclohexanone (3 equiv), hexadecene (1 equiv), catalyst (1 equiv), EtOH (0.75 M), 70 °C, Ar, 16 h.; A3: cyclohexanone (3 equiv), hexadecene (1 equiv), Mn(OAc) 3 (1 equiv), EtOH (0.75 M), temperature,

  Conversely,

					Mn(OAc) 3 (1.5 equiv)
		(1 equiv)
		C 14 H 29	O	OEt	C 14 H 29	O	OMe	C 14 H 29	O	OMe
				NO 2	O	OMe		CN
			O
	TBSO
	O
					O
	AcO	Me	O
			Me				O
		C 14 H 29			O
				OMe		Me

from alkyne) 54% (43%, 14:1 E/Z), [Control]: traces

  Carbonyls

	O		O	O	C 14 H 29		O	C 14 H 29	O
	C 14 H 29	C 14 H 29	C 14 H 29	Me
	14, 74% (67%)	15, 83% (70%)	16, a 83% (59%)	17, 97% (40%)	18, 25% (17%)
	[Control]: 63%	[Control]: 51%	[Control]: 7%	[Control]: 12%	[Control]: n.r.
	C 14 H 29	O			C 14 H 29	O	Me
		N Boc				O	OMe
	19, 71% (63%)	20, 45% (33%)	21, 95% (63%)	22, 81% (74%)	23, 96% (72%)
	[Control]: traces	[Control]: 80%	[Control]: 45%	[Control]: 43%	[Control]: 85%
	B. Alkenes
	24, 90% (50%)	25, 58% (46%)
	[Control]: 50%	[Control]: 15%
						O
						Me
						Me
	NH 2 27, 70% (61%) (1:1 dr) O C 14 H 29 [Control]: 21% C. Limitations	28, (16%) [Control]: n.r.	O 29, (Me C 14 H 29 Me Me Me O 30, 66% (3:1 dr) [Control]: n.r. 31, traces [Control]: n.r.
								36, (from trans)	37, (from cis)
	32, n.r.		33, n.r.	34, traces		35, n.r.		n.r.	traces
	[Control]: n.r.	[Control]: n.r.	[Control]: n.r.	[Control]: n.r.	[Control]: n.r.	[Control]: n.r.

C 14 H 29 OEt O NO 2

	O
	O 2 N	OEt
	20	14	18	39
	23	28	38	34
			30.0
			O
			Me	OMe
	R
	good conversion to product under standard conditions	user guide should be used	no reaction

ACKNOWLEDGMENT

This work was supported by the CNRS, the French Ministry of Research, the ICBMS and the Université Claude Bernard Lyon 1. The NMR and Mass Centres of the Université Claude Bernard Lyon 1 are thanked for their contribution. We thank J. Merad, A. Amgoune, A. Tlili, G. Tran, E. Metay, F. Popowycz, K. S. McClymont, S. Gnaim and P. S. Baran for insightful discussions.

Supporting Information

The Supporting Information is available free of charge on the ACS Publications website.

The Supporting Information contains experimental procedures and graphical abstracts for both the stoichiometric and catalytic reactions, investigation of the reaction parameters, optimization of the reaction conditions (stoichiometric and catalytic), the optimization of low yielding substrates, analysis, and compound characterization data.

AUTHOR INFORMATION

Corresponding Author

*Julien C. Vantourout: julien.vantourout@univ-lyon1.fr -ORCID: 0000-0002-0602-069X

Authors

Sylvain Charvet -ORCID: 0000-0003-1612-9338 Maurice Médebielle -ORCID: 0000-0002-6032-4790

Author Contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.