Electrosynthesis in Undivided Cells for Transition Metal Mediated Amination Reactions

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MSc Chemistry

Molecular Sciences Track

Literature Thesis

Electrosynthesis in Undivided Cells for Transition Metal

Mediated Amination Reactions

by

Jay Hanssens

12026417

Oktober 2019

12 EC Credits

June 2019 – Oktober 2019

Supervisor/Examiner:

Examiner:

Prof. Dr. Bas de Bruin

Dr. Chris Slootweg

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Abstract

For over two centuries, electrochemistry has received constant attention in the synthetic community. Its constant development has marked several major advancements in that time, allowing chemists to utilize it in a great variety of chemical transformations. In the past two decades there has been a strong resurgence in this field to the point of becoming a renaissance. More and more synthetic laboratories are developing methodologies by taking advantage of both traditional and novel concepts. Herein, we report on the basic principles of this very green and atom economical strategy with the aim to gain an understanding in how this technique works and what the applications and limitations of its use are. The latter are discussed alongside the important variables involved in electrochemistry (i.e. solvents, supporting electrolytes, electrode material and potential). It also features techniques such as: voltammetry, flow electrolysis and the cation-pool method. The disadvantages mainly involve the seemingly difficult reaction setups with many variables and equipment that can be hard to procure. The main advantages of the technique are that it offers a very atom economical and green synthesis strategy with the possibility of achieving oxidation states that can be difficult to attain utilizing other methods. Furthermore, as amination reactions represent such a valuable reaction type in most fields of chemistry, this thesis aimed to investigate what the recent advances are in electrocatalytic transition metal mediated amination reactions in undivided cells. The found reactions are categorized into three separate groups based on their mode of action (i.e. non-C-H activation, C-H activation and N-H activation reactions). Numerous transformations – providing a variety of products – are discussed along with their proposed mechanism; electrocatalytic diazidation of alkenes, olefin hydroamination, (aza)indole formation, arene amination and multiple annulation reactions. The involved transition metals comprise; manganese, iron, nickel, copper, cobalt and ruthenium.

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List of abbreviations

ACN Acetonitrile

API Active pharmaceutical ingredients CV Cyclic voltammetry

DCM Dichloromethane

DFT Density functional theory DMA N,N-dimethylacetamide

DMF Dimethylformamide DMSO Dimethyl sulfoxide GVL γ-valerolactone HFIP Hexafluoroisopropanol HMPA Hexamethylphosphoramide LSV Linear sweep voltammetry MeOH Methanol

PC Propylene carbonate PTFE Polytetrafluoroethylene RVC Reticulated vitreous carbon SET Single electron transfer SPE Solid polymer electrolytes SWV Square wave voltammetry TFA Trifluoroacetic acid TFE Trifluoroethanol THF Tetrahydrofuran TM Transition metal 1,4-CHD 1,4-cyclohexadiene

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Chapter 1: Introduction

As can be deduced from the title, this thesis revolves around the central subject electrochemistry. The following sections are aimed to provide an introduction to this topic, briefly explaining the setups, basic principles and methods of electron transfer. Subsequently, as an important sub-topic, the utilization of transition metals in such reactions will be discussed, providing examples on numerous metals and reaction types including a short section on electrochemical C-H activation reactions. Finally, the aim of this thesis presented.

1.1 A brief history of electrosynthesis

For over two centuries, the amount of knowledge acquired in the field of electrochemistry has increased significantly.1,2_{It started with the invention of the “Volta Pile”, the first electric battery, by}

Alessandro Volta.3_{This apparatus allowed for the continual movement of electrical current through a}

circuit; an essential trait for electrolysis experiments. Surprisingly, Volta neglected the importance of the chemical reactions observed at the electrodes. Consequently, the first electro-organic synthesis was reported only three decades later by Faraday, a true pioneer in the field.1,4_{His systematic efforts}

laid the foundation of electrochemistry. It was then that terms like electrolysis, anode, cathode and

electrolyte were first introduced. His electrolysis of acetic acid to form ethane provided the necessary

inspiration for the invention of the Kolbe electrolysis.2,5_{This reaction involved the electrochemical}

oxidation (anodic oxidation) of carboxylic acids to provide access to alkyl radicals. The dehalogenation of trichloromethanesulfonic acid reported after by Schoebein is presumed to be the first electrochemical reduction (cathodic reduction) of an organic compound.6_{After that, in the second}

half of the 19th_{century, many more electrochemical reactions were reported (e.g. oxidations,}

oxidative substitutions, dehalogenations, reductions of carbonyl derivatives and nitro compounds).1

In his paper on the stepwise reduction of nitro compounds, Haber was the first to recognize that by using a constant current density the effective reduction potential will gradually decrease and that keeping the potential at the working electrode constant is essential for the selectivity.7_{To this end,}

the invention of the potentiostat by Hickling in 1942 revealed a new dimension in electrochemistry; for the first time it would be possible to perform reactions under constant potential.8

In the first four decades of the 20th_{century the enthusiasm for organic electrochemistry was}

significantly lower with only a few publications appearing between 1910 and 1940. In that time, hardly any of these reactions became industrial processes. Some of the more significant ones merely involved reformation of an inorganic reagent as the electrochemical step.1_{The use of electroanalytical methods}

(e.g. polarization and voltammetry at solid electrodes) was more frequent between 1940 and 1960. In that time such methods were used for the analysis of organic compounds and more rarely for monitoring controlled potential electrolysis experiments. Perfecting these analytical techniques made it possible to determine the electrochemical potentials of the various moieties, making selective functional group manipulations possible.2_{In the same period, the utilization of aprotic solvents for}

both anodic and cathodic redox reactions had been established. The most significant implementation of organic electrolysis in the industry between 1940 and 1960 was the electrochemical fluorination. Various of such fluorinations were reported and certain electrochemical fluorination methods are still being used to this day.1,9_{After the 1960s many developments were reported in the field of}

electrochemistry. Progress in electroanalytical techniques like; cyclic voltammetry10_,

ultramicroelectrodes11_{and many more, greatly facilitated the study of the mechanisms of these}

reactions. Furthermore, indirect electrolysis via organic/organometallic mediators (e.g. triaryl amines12_{and nitroxyl radicals}13_{) was introduced and novel industrial implementations arose. In 1975,}

Miller invented the first chiral electrode opening up a new pathway in asymmetric catalysis.14

Discoveries such as these and many more not mentioned here have shaped the field of electrosynthesis to what it is today.1,2

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1.2 Electrosynthesis: the basics

1.2.1 The setup

As we have seen, electrochemistry has been a part of our world for more than two centuries. Although being greatly appreciated, there are few reports of its incorporation in the total synthesis of complex compounds. Chemists have generally been reluctant to integrate this technique into their synthetic toolkit. The causes, by speculation, are the apparent complexity of the reaction setup, the large quantity of reaction variables, the misunderstanding that merely aqueous solvents can be employed and that product purification with this method is problematic.15_{Moreover, the fact that there is no}

“standard” instrument for preparative electrolysis makes the method less appealing. The recent reports in literature mostly utilized home-made equipment. The following section will summarize the basic theory behind electrosynthesis, thereby explaining the basic principles, mode of action and what an electrochemical setup looks like.

Electrochemical reactions can be divided into two main categories; reductions and oxidations. A galvanic cell is an electrochemical reactor made up of two electrodes connected by a salt bridge which is made from an electrolyte solution.16_{The term “cell” comprises any setup that contains electrolytes,}

solvent, an electroactive species, various additives and at least two electrodes. In these cells, redox reactions take place at the surface of the electrodes. Oxidations take place at the anode (anodic oxidation), and reductions take place at the cathode (cathodic reduction).16_{After insertion of the}

electrodes into the solution and activation of the power supply, an electrical current is exerted between the electrodes. Anodic oxidation at one side is transferring electrons from the reaction mixture to the anode and cathodic reduction at the other transfers electrons to the reaction mixture from the cathode. This net transfer of electrodes from the cathode to the anode closes the circuit and permits the electron flow through the cell.17_{Figure 1 gives a general view of an electrochemical cell.}

Figure 1 General picture of an electrochemical cell with two electrodes in solution: cathode (black), anode (grey). One particular part of the setup that has been left out in the previous paragraph is the potentiostat. This is used to apply the potential over the electrical system. A potentiostat can be compared to a

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selective oxidations or reductions. This trait is what makes electrosynthesis so unique. A multitude of potentiostats are available which can be used for electrochemical experiments, ranging from basic models to top-of-the-line hand-held models.

Several parameters that have not been elaborated on thus far are the solvent, electrolyte and electrodes. The choice of solvent is crucial, as it can have a profound effect on the outcome of the reaction. Various solvents have been employed in electrosynthesis: water, acetonitrile, THF, TFA, MeOH, DCM, etc. Another essential variable is the supporting electrolyte. This usually involves a salt that makes a solution conductive by dissolving into ions. They also function as counterions for the compounds generated at the electrodes. Typical electrolytes include lithium perchlorate and numerous tetraalkyl ammonium salts.16,17_{As for the electrodes, these must be stable under reaction}

conditions and can be built from any conducting material capable of electron transfer in solution. The materials that are commonly employed are carbon (rods or plates), platinum (foil, wire, or mesh), stainless steel, magnesium, or reticulated vitreous carbon (RVC). RVC is a material that combines the properties of carbon and glass with a high surface area, high void volume, and chemical resistance.16

There have also been publications that reported the use sacrificial electrodes. These are depleted in the duration of the reaction and are generally made of zinc or lead. As is customary for all chemical reactions, electrosynthetic reactions require optimization in the use of solvent, electrodes, electrolytes and current density.

1.2.2 The different cell setups

There are various types of electrochemical cells, each with slightly different modes of operation than the other while retaining the basic mechanism. The two main options for an electrochemical reactor are; a divided and an undivided cell (Figure 2). Either of these cells could be used for both oxidations and reductions. Furthermore, both types can be used at either a constant potential or current while varying the other parameter.16

An undivided cell is merely the standard type of cell as discussed before and allows for both reductions and oxidations to occur within the same compartment. The substrate is therefore exposed to all components of the reaction.16,17_{As both electrodes are present, thought must be given to the}

influence of the auxiliary electrode – the electrode where the desired reaction is not taking place – on the reaction. This electrode is not implicated in the desired product formation, yet still has the capacity for a redox reaction.16_{In this respect, the products or unreacted starting material could be affected}

by byproducts formed in the course of the reaction. A solution to these potential problems is the use of a divided cell. This more complex setup consists of two solvent compartments, each with its own electrode, separated by a porous frit. This frit does allow for the transfer of charge but not of the substrate, thereby preventing the unwanted effects of the auxiliary electrode.16,17

Undivided cells with constant currents are most frequently encountered, owing to the simplicity of constructing the setup.16_{In a constant current experiment, the potentiostat is used to set the current}

while the potential increases at the electrode surface. The potential proceeds to rise until the

Potentiostat Potentiostat

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oxidation potential of the electroactive species is attained. From there, the potential remains the same up to the point that all the substrate at said potential is expended. It subsequently climbs before either reaching the electroactive potential of another substrate or that of the solvent. This process continues until the reaction is put to a halt.16,17_{A crucial part of executing such reactions is knowing the oxidation}

potential of the species involved, so the initial redox reaction is at the desired substrate.

As mentioned before, maintaining control over the potential of the reaction permits selective reactions in the presence of multiple functional groups.16,17_{If the potential should be kept to or below}

a threshold, a controlled potential experiment can be employed to establish selectivity. In such an experiment, a reference electrode is used to set the potential of the cell. Merely the electroactive species below this potential level will then undergo redox reactions. As a reference electrode is required, a third electrode must be used that is easily attained. They can simply be made but are also commercially available and cheap. In the course of the reaction, the consumption of the electroactive species causes a decrease in the current. As this happens, the reaction of the substrate becomes more difficult and will take more time. Therefore, driving these reactions to completion is difficult and it takes a much longer time to do so.16,17_{In a divided cell, the reference electrode is placed into the}

compartment with the working electrode, substrate, electrolytes and solvent. To the compartment containing the auxiliary electrode is added the solvent, electrolytes and a substrate capable of the opposite redox reaction. With the exception of the reference electrode, this same setup is used for a divided cell constant current experiment.16

1.2.3 Methods for electron transfer

It is well-known that electrosynthesis is based on the electron transfer between the electrodes and substrates. There are three main methods known for this transfer between electrode to substrate (Figure 3). The first and classical method is by utilization of an inert electrode. The electroconversion then occurs at the electrode surface and by application of the appropriate potential, selectivity can, as mentioned before, be attained.18

Complex molecules, however, contain many moieties that cannot be selectively targeted in this manner (e.g. alcohols and C=C double bonds). In order to do so, one requires an electrocatalytic approach. This can be done in one of two ways; using an active electrode or using a mediator. The surface of an active electrode is covered in an electrocatalytically active species which can be used as a compact electrochemically conductive coating. This coat can be regenerated in situ and can be considered an immobilized redox-active reagent.18,19_{With these active electrodes, now containing a}

redox filter, the applied potential exerts less influence on the electroconversion, thereby establishing unique reactivity. These types of electrodes are usually employed in undivided cells at a constant current. Furthermore, the redox-active coating retains its position on the electrode surface owing to the low solubility. Therefore, the electrodes are not consumed and are easily operable in flow cells.18

The third method for electron transfer is by means of a mediator. A mediator (or redox catalyst) is an electroactive species which can readily dissolve in the solvent and electrolyte. These redox active species can be regarded as electrochemically regenerated reagents, displaying unique reactivity and are capable of averting large over-potentials. Thus, lower potentials can be used to establish the same electroconversion.18,20

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1.3 Transition-metal-mediated Electrosynthesis

1.3.1 Transition-metal-mediators

As can be deduced from the previous sections, there are vast amounts of electrochemical processes known. Many of these reactions involved the electrolysis of organic substrates and reactions. Since the start of the 20th_{century inorganic compounds have also been employed as electrochemical}

mediators in electrolysis reactions.1,2_{As such a large amount of these reactions exist and transition}

metals as mere mediators are not a key component this thesis, only a few examples will be discussed here. In 1978, Pletcher et al.21_{reported a reaction of electrogenerated square-planar ionic nickel(I)}

complexes with organic halides to form alkyl radicals and regenerate the nickel(II) species. Another example is ferrocene, which can be reversibly oxidized to ferrocenium.22_{It can be prepared}

electrochemically utilizing cathodically generated cyclopentadiene and an iron anode.23

The indirect cathodic reduction of activated olefins has been studied by the group of Navarro.24_They

reported a nickel(II)-mediated reduction of cyclohexenone affording cyclohexanone while under similar conditions with an iron(II)-mediator and a sacrificial iron anode provided cyclohexanol as the major product (Scheme 1A).24_{In a follow-up publication, the same group reported on the nickel- and}

iron-mediated reduction of other unsaturated compounds e.g. conjugated carbonyls and dienes.25_Yet

another nickel-mediated reduction was reported by Duñach et al.26_{They developed the methodology}

for an electrogenerated low-valent nickel complex capable of the mild reductive deprotection of allyl carbamates. As a final example, olefin formation from vicinal dihalides can also be accomplished by electrochemical means. Fuchigami et al.27_{accomplished this by implementing a Co(II) Salen complex}

mediator in the cathodic reduction of open-chain and cyclic dibromides in ionic liquids affording the corresponding olefin (Scheme 1B).

Scheme 1 Electrochemical reduction of cyclohexenone (A). Electrochemical reduction of vicinal dibromides (B).

substrate intermediate/product substrate intermediate/product mediator mediator substrate intermediate/product A B C

Figure 3 The three different methods of electron transfer: inert electrode (A), active electrode (B) and mediated electrolysis (C).

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1.3.2 Homogenous transition metal electrocatalysis

A distinction can be made between the use of inorganic compounds as mediators in electrochemical reactions, and them being used in a customary homogenous fashion where the main electrochemical step is responsible for the oxidation or reduction of the catalyst. The main benefit in such a process is that it circumvents the use of stoichiometric harsh chemicals, allowing for a much greener, more sustainable and atom economical synthesis. The following section is devoted to the discussion of some of such reactions.

The first example is the use of the cobalt complex vitamin B12 and derivatives thereof. Researchers like Saveant28_{, Scheffold}29_{and Hisaeda}30,31_{have all reported reactions involving vitamin B12.}

Scheffold1_{reported a cycle where the Co(III) derivative of vitamin B12 is reduced to Co(I), which is}

capable of inserting into an alkyl halide bond. Upon reduction, the newly formed complex expels an alkyl radical which can sequentially add to an activated alkene. Hisaeda reported a cobalt catalyzed cathodic reduction of trichlorotoluene to afford amides and esters (Scheme 2).30_{This reaction also}

involved a radical reaction to the substrate from the electrogenerated Co(I) complex. The substrate could in turn be trapped with oxygen for further modification.31_{Other cobalt complexes have also}

been reported in electrochemical processes. Périchon et al.32_{reported a novel method for the}

electrochemical synthesis of aryl zinc compounds from aryl halides. Furthermore, Co(II) pyridine complexes have also been shown to facilitate cross-electrophile couplings under cathodic conditions between aryl halides and various functionalities e.g. allyl acetates/carbonates33_{and alkenyl}

(pseudo)halides34_.

Aryl halides have also been involved in electrochemical reactions with nickel as the active component. The formation of Ni(0) complexes via cathodic reduction of their respective Ni(II) precursors is beneficial as those species show high tendencies for oxidative additions to aryl halides. Nédélec utilized this approach to establish a nickel-catalyzed electroreductive conjugate addition (Scheme 3).35

Therein, the Ni(0) species undergoes oxidative addition with the aryl halide to afford the aryl-nickel complex which can subsequently react with the alkene toward the 1,4-addition product. The aryl-nickel species attained in this process could also be exploited in other reactions like in the synthesis of alkyl aryl ketones. Formation of the aryl-nickel intermediate in the presence of Fe(CO)5 and an alkyl

halide provided such compounds.36_{Another use for the aryl-nickel intermediate is in the}

Nozaki-Hiyama-Kishi reaction via transmetallation with chromium salts as reported by Périchon (Scheme 3).37

Cross coupling reactions have also been reported with alkenyl halides. Similarly to the aryl substrates, they can form alkenyl-nickel complexes capable of participating in cross-coupling reactions with various moieties (e.g. vinyl halides and activated alkyl halides).38_{By careful selection of the halides}

and slow addition of reagents, homodimerization can be averted in these reactions.

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Aside from the cobalt and nickel catalyzed reactions just mentioned, many other reports have employed palladium as the active component.2_{A prime example of a reaction requiring external}

oxidants is the Wacker reaction. Tsuji et al.39_{reported an electrochemical Wacker reaction with a}

benzoquinone mediator (Scheme 4). Mitsudo et al.40_{later reported a TEMPO-mediated anodic}

oxidation Wacker-type reaction. Another example of a palladium catalyzed reaction by the same group is the coupling of aryl boronic acids to terminal alkynes, a process which used TEMPO as mediator as well.41_{A palladium catalyzed Heck-type reaction was also reported with benzoquinone as}

mediator and N-acetylaniline as the substrate (Scheme 4).42_{This reaction is particularly interesting in}

that the mechanism differs considerably from the traditional Heck reaction. As opposed to initiation by C-X oxidative addition, a C-H activation takes place before the sequential addition to the alkene and β-hydride elimination. The resulting Pd(0) species has to be oxidized to Pd(II) to complete the cycle, which is accomplished by the benzoquinone mediator. Palladium complexes have additionally been used for conventional Heck reactions43_{, oxidations of alcohols}44_{, a sequential cross-coupling}

reaction45_{, alyllation of alkyl halides}46_{and electroreductive couplings of aryl halides in ionic liquids.}47

The “sequential cross-coupling reaction” is interesting in that it combines a palladium catalyzed coupling under both chemical and electrochemical conditions in one pot. The work by Suga shows the electrochemical dimerization of terminal alkynes where, upon switching off the electricity, the Pd catalyst no longer gets reoxidized, but rather undergoes a Suzuki coupling by oxidative addition with the aryl halide.45

Scheme 3 Nickel catalyzed electroreductive conjugate adition of aryl halides; conditions (top, left) and mechanism (right). Electrochemical ketone synthesis (left, middle). Electrochemical Nozaki-Hiyama-Kishi reaction (left, bottom).

Scheme 4 Palladium catalyzed electrochemical Wacker oxidation (top) and Heck reaction (bottom, left) with the mechanism of the benzoquinone mediated palladium oxidation (bottome, right).

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1.3.3 Transition metal catalyzed electrochemical C-H activation

One specific part in the previous section and a largely growing field in chemistry is electrochemical C-H activation. C-C-H activation in general has already sparked the interest of many chemists as it allows for direct C-C bond formation without the need for prior functionalization. These reactions, however, usually require the utilization of harsh and potentially toxic stoichiometric oxidants. Employing anodic oxidation omits the use of such chemicals, giving way to a much greener and atom economical synthesis. Various reviews have been published on the subject of electrocatalytic transition-metal-mediated C-H activation reactions.48–52_{The following paragraphs will shed light on some examples of}

these reactions.

Aside from the first reported example transition-metal-mediated electrochemical C-H activation mentioned previously, palladium has been applied for the electrocatalytic activation of sp2_carbon

centers with azine directing groups for the installation of various functional groups; halides53_,

phosphoryls54_{and acetoxy groups}55_{(Scheme 5). It was hypothesized that after initial coordination and}

insertion of the Pd(II) species leading to a palladacycle, an anodic oxidation takes place which facilitates reductive elimination to the final product. A recent publication reported the first Pd(II)-based C-H functionalization of sp3_{centers with oxime-based directing groups facilitated by anodic}

oxidation.56_{In the mechanism, after initial C-H activation, the formed Pd(II) complex is subjected to}

anodic oxidation affording the Pd(IV) complex. This high-valent intermediate favors reductive elimination leading to the final product. Another example was reported by Budnikova et al.57_{in 2012}

which included a nickel- and palladium catalyzed fluoroalkylation. Initial screening of the group 10 metals indicated nickel-catalysts to attain better results.

Another transition metal that has been applied in electrochemical C-H activations is cobalt. This metal is especially interesting in the synthetic community as it is an earth abundant and less toxic metal.58

Carbonylation reactions employing this metal have been reported by Lei et al.59_{They investigated}

carbonylation reactions of C-H bonds under CO atmosphere. A vital role was played by the bidentate nitrogen ligands in these reactions and the authors succeeded in the synthesis of heteroaromatic phthalamides (Scheme 6). The proposed mechanism commenced with coordination of the Co(II) to the substrate. Subsequently, anodic oxidation affording a Co(III)-complex facilitates C-H activation after which CO insertion and a successive reductive elimination afforded the final product. To close the cycle, Co(I) again undergoes anodic oxidation to provide Co(II) (Scheme 7). Ackerman et al.60

reported allylic and aromatic oxygenation reactions utilizing cobalt and anodic oxidation. Lei et al.61

demonstrated a methodology for the electrochemical Co-catalyzed C-H/N-H annulation of ethylene and ethyne.

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Scheme 6 Electrochemical cobalt catalyzed carbonylation.

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1.4 Aim

Although preparative electrolysis has received significant attention in the past century, until recently, chemists had mostly been disinclined to embrace its use. That being so, electrosynthesis has many potential benefits that are now gaining awareness.15_{The fact that electrons are employed as reagents}

as opposed to other chemicals makes this process very green and atom economical. As a consequence of this growing interest in electrosynthesis, the field is currently experiencing a renaissance.2,62_More

and more synthetic laboratories are developing methodologies by taking advantage of both traditional and novel concepts. In doing so, the range of application of this technology is becoming much broader. As the previous sections have shown, reagents that were previously employed stoichiometrically can be regenerated in situ giving way to an electrocatalytic process.

Electrosynthesis has many more benefits to offer. This thesis aims to provide an elaborate answer to the question: “How does electrosynthesis work and what are the applications and limitations of its use?” We have already seen both the potential complexity and simplicity of such setups. The amount of variables involved can be intimidating, but they are nonetheless crucial for the functioning of the experiment and are not as high an obstacle as they may seem.15_{In that respect, the most important}

variables in electrochemistry will be discussed (i.e. the potential, the type of electrodes, solvent, supporting electrolyte). Furthermore, various experiments that are frequently performed in electrochemistry will be explored (e.g. voltammetry, flow electrolysis and the cation-pool method). Experiments derived from the more primal methods like the use of supercritical fluids as solvents, employing redox tags, and combinatorial electrosynthesis are beyond the scope of this report. The techniques that are to be discussed will mainly involve transition metal mediated processes.

One specific reaction type that has been extremely interesting and useful in multiple fields of chemistry is the amination. The creation of a C-N bonds is imperative in most synthesis routes as most structures contain such bonds. In medicinal chemistry for example, nitrogen atoms are frequently employed as important binding moieties for the in vivo functioning and binding of medicines. Transition metal mediated amination reactions are now well known and are still constantly under development. Important reactions like the Buchwald-Hartwich coupling, the Chan-Lam coupling and the Ullmann reaction marked great advances in this area. With this in mind and in view of the general subject of this report, a section will also be devoted to the question: “What are the recent advances in electrocatalytic transition metal mediated amination reactions in undivided cells?” The sole discussion of such reactions in undivided cells is motivated by the fact that the setup of such reactions is simpler, requiring less complicated and more easily attainable equipment. Moreover, the reactions in undivided cells are not influenced by the effects of the auxiliary electrode, which is an interesting trait for the design of other electrochemical processes.

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Chapter 2: Electrochemistry

2.1 Variables and parameters

Having already touched upon the basics of electrochemistry, i.e. the setups, basic principles and the various methods of electron transfer, the different variables and parameters of an electrochemical setup can now be discussed in more detail. The following sections are devoted to shedding light on these subjects.

2.1.1 The potential

The potential is, as has been pointed out in the introduction, very important for an electrolysis experiment. This parameter is given in Volts (V) and can be expressed by (equation 1, Table 1). Here 𝑖 is the current in Amps and 𝑅 is the resistance of the cell in Οhm (Ω).16_{The concentration of the}

electrolytes is directly related to the resistance of the cell.

A certain amount of energy is needed for the transfer of electrons from the electrode to a substrate. The potential of the electrode is the determining factor in deciding if there is enough energy present to accomplish this process.16_{The electrode potential (𝐸) can be defined as the difference between the}

potential of the reference electrode and that of the working electrode. In a reversible reaction, it can be correlated to the change in free energy (equation 2, Table 1). Furthermore, it can also be related to the standard free energy (equation 3, Table 1). Here, 𝑛 is the number of electrons involved in the reaction and 𝐹 is Faraday’s constant (96,485 C mol-1_{). This is defined as the amount of electricity}

required for the transformation of one equivalent of the substrate. From a chemist’s point of view and in terms of stoichiometry, a Faraday can be seen as one molecular equivalent of electrons.16_The

change in free energy can also be expressed in thermodynamic terms (equation 4, Table 1). In this formula, 𝑇 is the temperature in K and 𝑅 is the ideal gas constant (8.314 J K-1_mol-1_{). The activity}

quotient (𝑄) can be defined as the activity ratio of the reactants versus the products. When combined, equations 2-4 become what is known as the Nernst (equation 5, Table 1). For reversible electrochemical reactions the Nernst equation is altered (equation 6, Table 1). Here, 𝑎𝑂𝑥 and 𝑎𝑅𝑒𝑑

represent the activities of the oxidative and reductive compounds respectively. Another adjustment can be made to the Nernst equation, namely; substituting the activities for concentrations. This can be done as activities themselves are seldom used (equation 7, Table 1). The new variables, 𝐶𝑂𝑥 and

𝐶𝑅𝑒𝑑, represent the concentrations of the to be oxidized and reduced compounds respectively.

Table 1 Table of equations.

Entry Calculates Equation

1 Potential 𝑉 = 𝑖𝑅

2 Free energy difference ∆𝐺 = −𝑛𝐹𝐸 3 Standard free energy ∆𝐺° = −𝑛𝐹𝐸° 4 Free energy difference ∆𝐺 = ∆𝐺° + 𝑅𝑇ln𝑄

5 Electrode potential 𝐸 = 𝐸° +𝑅𝑇 𝑛𝐹ln𝑄

6 Electrode potential (reversible

reaction) 𝐸 = 𝐸° + 𝑅𝑇 𝑛𝐹ln

𝑎𝑂𝑥

𝑎𝑅𝑒𝑑

7 Electrode potential (reversible

reaction) 𝐸 = 𝐸° + 𝑅𝑇 𝑛𝐹ln

𝐶𝑂𝑥

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The oxidation/reduction potential of a specific substrate can be defined as the amount of free energy required to accomplish an electron transfer to or from that substrate. This value is determined experimentally by use of voltammetry (discussed later) and is in turn used as guideline for reaction parameters.16_{The parameters can be adjusted to fit the desired requirements for the reaction in the}

attempt to optimize the output and selectivity.

2.1.2 The electrical double layer

As mentioned previously, the oxidations/reductions in an electrochemical cell take place at the surface of the electrodes. This is the main reason why the choice of the electrode material is so important. Charge being applied over an electrode gives rise to a strong electrical field at its surface in solution.16_{In the case of an anode, it causes a high concentration of negatively charges ions to}

propagate at the positively charged electrode. The ions now also attract anionic species from the solution, giving rise to another electrical field on the side of the solution. As the anode compensates for the majority of this field, it is significantly weaker than the field directly at the anode. The layers of electrical charge continue further from the solution in this manner and in doing so, the effective potential decreases with the increasing distance. The inner most layer – directly adjacent to the electrode – usually has a width of only a few Ångstroms and is called the compact inner layer.16_The

potential within this layer decreases linearly with increasing distance. As a result, the majority of the potential difference is lost at the end of this layer (termed the outer Helmholtz plane). Once this point is reached, the potential decreases exponentially through what is known as the diffuse layer. This layer is typically at a distance of between tens to hundreds of Ångstroms away from the electrode surface and it, along with the compact inner layer, are regarded as the electrical double layer (Figure 4). The point where the electrode potential is equal to that of the bulk solution marks the end of the diffuse layer. In general, redox reactions in an electrochemical cell are thought to occur in the compact inner layer at the surface of the electrodes.16_{The fact that diffusion from the compact inner layer into the}

bulk solution is deemed to be kinetically disfavored over intramolecular cyclizations, allows for the formation highly reactive radical ions in the presence of protic and nucleophilic solvents.

Figure 4 Depiction of the electrical double layer (left) with the separate layers: compact inner layer (CIL), diffuse layer (DL) and bulk solution (BS). A plot of the potential over the distance (d) is also given (rigth).

2.1.3 The electrodes

As mentioned previously, the selection of electrode materials is essential for the success of many

Anode CIL DL BS d₁ d₂ d d₁ d₂ d potential

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leads to complete racemization of the products. A nice review on electrode materials for electrosynthesis had been published three decades ago by Pletcher et al.64_{Therein, they already}

explained a great deal about the requirements of electrodes and the influence they can have on electrochemical reactions.

There are a number of important factors one must consider when choosing an appropriate electrode material: the physical stability, chemical stability, suitable physical form, rate and product selectivity, electrical conductivity, and cost/lifetime.64_{With regards to the stability, electrodes must be}

sufficiently strong, resistant to cracking, corrosion and erosion, and they must be inert under the reaction conditions. Moreover, shaping the electrode into a desired form can be an important in reactor design, a process in which the choice of metal can be essential. Furthermore, it is crucial that the chosen electrode promotes the desired conversion while preventing all other competing reactions. Finally, attaining a high electrical conductivity throughout the system is important to attain a uniform current and potential distribution.64_{As the majority of the conducting materials could be}

used as electrode and the development of an electrochemical transformation usually requires optimization of this parameter, the following sections are merely to inform on more specific cases and novel developments of electrode use.

The introduction has already briefly mentioned the use of sacrificial electrodes in electrosynthesis. Metals like magnesium and aluminum have frequently been used as such in cathodic reductions.1,63

The Mg electrodes that had been developed by Kashimura allowed for the synthesis of silylene-germylene copolymers and polysilanes with ordered frequencies.65,66_{Zinc electrodes developed by}

Nishiguchi have also shown their applicability in the double acylation and carboxylation of olefins.65,66

Modified sacrificial electrodes have also been employed previously (e.g. polysulfide anion containing sulfur-graphite electrodes).67

A multitude of modified electrodes have been reported which facilitate certain electrosynthetic transformations. The group of Kashimura published an alkali metal ion containing crown ether modified platinum electrode which can be used for paired electrolysis.68_{In this case, the authors could}

couple esters with THF. Another useful modification is the installment of hydroxyl groups on the surface of carbon electrodes. Such hydroxyl groups can be further modified to other functional groups to be used in electrosynthesis. One method for the installation of hydroxyl groups on carbon electrodes is by utilization of electrogenerated NO3 radicals.69 Omori et al.70 developed a means of

coupling alcohols to carbon electrodes by means of anodic oxidation. In 2008, a review appeared, written by McCreery, where an in-depth overview is given on carbon electrode materials.71_Savéant

et al.72_{developed one of the most reliable methods of electrode modification namely; the cathodic}

reduction of diazonium salts. Others reported the diazotization of aminotriarylamine and sequential electrochemical reduction for the establishment of triarylamine on graphite electrodes.73_Again

employing the cathodic reduction of diazonium ions for electrode modification is the group of Bélanger.74_{They used in situ generated diazonium cations in aqueous media for the alteration of gold}

and glassy carbon electrodes.

Aside from the above-mentioned methods, there have also been instances of non-covalently modified electrodes. One example is the optically active N-oxyl containing poly(acrylic acid) covered platinum electrode with the capacity for asymmetric alcohol oxidation.75_{The use of a novel electrode in the}

Kolbe electrolysis was also reported bij Nonaka.76_{Here it involved a hydrophobic PTFE-fiber-coated}

platinum electrode. Interestingly, this electrode is also fruitful in the electrochemical generation of quinines.77_{Research is constantly exploring electrode materials that avoid heavy metals, provide}

higher over-potentials for undesired side reactions, and should be almost impervious to degradation or corrosion making them almost maintenance free.18,63_{In this respect, the chemical inertness and}

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To this end, boron-doped diamond electrodes have been used for various electrochemical transformations.18,63,78,79_{These electrodes have shown to have a wide potential window and are highly}

stable.

2.1.4 The solvent

The choice of solvent for an electrochemical reaction is another imperative part of electrosynthesis. The media in which reactions are performed can exert a profound effect on the reaction outcome.62

In the case of electrosynthesis, the media are referred to as the electrolytes. These electrolytes consist of both the solvent and a supporting electrolyte, which are often employed to ascertain adequate electric conductivity. Many studies focus on the optimization of the supporting electrolyte, as varying the ionic charges and structuring near the electrode can have significant effects.80_{Although, the}

solvents also have a large influence on the reactions and play a pivotal role in reaction pathway populations. Nucleophilicity and redox potentials are solvent dependent and can be adjusted utilizing different solvents.80_{Similarly, the solvation of reaction intermediates can be fine-tuned to favor one}

over others in the pursuit of a specific reaction pathway. Additionally, the choice of a suitable solvent can significantly enhance the selectivity and yield of the reaction.

In electrochemistry, the solvents can mainly be categorized into two classes; protic and aprotic solvents (Table 2). There are many important factors to keep in mind when deciding on the appropriate solvent for electrocatalytic reactions: solubility of substrates and intermediates, solubility of electrolyte and if it is dissociable, temperature range, accessible potential range, toxicity, dielectric constant, viscosity, proton activity, vapor pressure and costs.80_{There is seemingly no clear connection}

between the solvents used and the involved redox transformation i.e. anodic oxidation or cathodic reduction. Whether or not the solvent will be subject of a redox transformation largely depends on the required potential. In that respect, the oxidation and reduction potentials are extremely important, especially in constant current experiments.16_{It is essential that the first}

oxidation/reduction involves the substrate as opposed to the solvent. This is generally the case for an electrochemical reaction and so also for cyclic voltammetry studies. Solvents containing functionalities like nitro and hydroxyl moieties are generally not used as these can more readily be reduced and oxidized respectively.16_{With this in mind, the type of solvent is dependent on reaction}

type and should be selected accordingly. For example, nucleophilic solvents can in some cases be tolerated in reactions where intramolecular trapping with a nucleophile happens rapidly in the electrical double layer whereas in other reaction types such solvents are not suitable.

Table 2 Examples of solvents used in electrosynthesis.

Protic solvents Aprotic solvents

Acetic acid Acetonitrile (ACN)

TFA Hexamethylphosphoramide (HMPA)

Water Dimethylformamide (DMF)

Sulfuric acid Propylene carbonate (PC) Ammonia Dimethyl sulfoxide (DMSO) 1,1,1,3,3,3-hexafluoropropan-2-ol (HFIP) pyridine

Methanol (MeOH) ethers

One of the well-known examples of a solvent dependent reaction is the Kolbe electrolysis. This process, where carboxylic acids are oxidized, is generally performed in ACN, DMF or aqueous solutions of MeOH.81_{Neutralization of the acids by use of a (mild) base typically provide better results. A figure}

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solvents, protic-water and neutral-water mixtures afford Kolbe dimerization. In contrast, basic and dipolar aprotic solvents favor the two-electron non-Kolbe pathway. Cyclopropane carboxylic acid, for instance, can be electrolyzed toward multiple products depending on the used solvent. The Kolbe dimer is the major product upon utilization of a pyridine-Et3N-H2O mixture, but in a NaOMe-MeOH

mixture the formation of cyclopropane is preferred.82

Figure 5 How the solvent, reaction type and reactive intermediates are interrelated. W: water, P: protic solvents, DA: dipolar aprotic solvents.80

Many other publications have appeared reporting solvent dependent reactions which shall not be discussed in detail here.83–90_{Some instances have even reported solvent participation in the reaction}

towards a product.91

As we have seen there are many solvents available for electrochemical processes, each with their own applicable properties. One solvent in particular is worth mentioning here namely: HFIP. On multiple occasions this solvent has already proven its value in stabilizing radical cations.1,80,87,88_{It has been}

reported that it develops a microheterogeneous structure formed by the hydrogen bonding interactions of the individual solvent molecules.80_{The hydroxyl moieties bind together via hydrogen}

bonding while the fluorinated alkyls cluster together without participating in these interactions. The hydroxyl groups function as both the donors and as acceptors. The clustering of the sections of the compound result in two different domains; one polar and the other fluorous. The bonding network can be altered by inclusion of additional components in the mixture; the number of polar domains can be changed, the HFIP molecules can be accelerated by creating a more flexible network and the diffusion constants of the individual components can be adjusted.80_{It is highly probable that polar}

compounds will participate in the hydrogen bonding network and become part of the polar clusters. This can provide the compounds present in an electrochemical reaction with the benefits of protection against over-oxidation, mineralization and unwanted side-reactions.80_{These traits provide a means to}

the development of many novel, selective and exceedingly original reactions.

2.1.5 The supporting electrolyte

In an electrochemical setup under conventional conditions, supporting electrolytes can be added to ensure adequate electrical conductivity of the solution.63_{Choosing and using the appropriate}

electrolyte for a certain electrochemical process is essential.16,18,62,63_{Depending on the used}

electrolyte, the reaction outcome could vary significantly. Usually, as mentioned in previous sections, the supporting electrolyte for a reaction is found via optimization of the conditions. One has to keep

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in mind that the concentration of the electrolyte is also important as it can be directly correlated to the resistance of the electrochemical cell.16

The choice of electrolyte is generally based on those applied in previous electrochemical processes.16

Although there are exceptions, most of the electrolytes are impervious to oxidations or reductions under the involved conditions. This is favorable as such redox reactions can lead to active intermediate formation which could have a detrimental effect on the reaction. Some studies have actually benefitted from this by involving the active intermediate in the reaction. For example, the oxidation of a halogenated electrolyte can afford a highly reactive “X+_{” species.}16_{Such species have previously}

been used for the production of N-acyliminium ions by reacting with the amide nitrogen to cause a loss of HX and form the N-acyliminium ion. Another study by Baran et al.92_{also reported the}

supporting electrolyte (Et4NBr) as mediator to afford a mild oxidative reaction. Interestingly,

electrolytes can also exert a positive effect on certain reactions and their involvement can lead to an increase in yield. A good example is the use of LiClO4 in nitromethane for electrochemical

reactions.18,62_{The Lewis acidity of the lithium cations and weak to noncoordinating counterions allow}

the mixture to accelerate and promote a variety of processes (e.g. Diels-Alder and cross-metathesis reactions).63

Tetraalkylammonium salts like Bu4NClO4, Bu4NOAc, Bu4NBF4, Bu4NOTs and numerous others are often

employed since they show good solubility in organic solvents.16,63_{Although, this solubility does pose}

a potential purification problem after completion of the reaction. For such problems, a purification by column chromatography is often needed and performed.63_{Bearing in mind the costs and wastes of}

industrial processes, recycling the supporting electrolyte is vital for the practice of green chemistry. It is, however, quite expensive and requires a great amount of energy to recycle tetraalkylammonium salts.63_{In the attempt to circumvent these issues solid-supported electrolytes have been developed}

allowing for electrochemical experiments without the need for supporting electrolyte. Ogumi et al.93

were the first to develop solid polymer electrolytes with the advantages of suppressing potential side-reactions and excluding the need for electrolyte separation and recycling.

2.1.6 Ionic liquid

A relatively novel reaction media that has gained much attention in electrosynthesis is ionic liquid. As we have seen in previous sections, the electrolyte in conventional electrochemical experiments consists of salts dissolved in a molecular solvent. These salts can also be melted down by counterbalancing the salt lattice energy through heating.94_{The resulting liquid does not contain any}

molecular solvent and consists of combinations of ions.63,94_{Applicable temperature ranges of these}

liquids are dependent on the melting point of the involved salt. Relatively high melting points can be lowered by the introduction of additional salts to afford a mixture.94_{In contrast, salts with low melting}

temperatures are liquid at room temperature. They have identical physicochemical properties compared to the higher temperature salts but are much easier to maintain and handle. In general, salts with a melting point below 100 °C are referred to as ionic liquids.94_{In an electrochemical reaction,}

such ionic liquids can be employed as electrolytes, thereby replacing the need for conventional solvents and supporting electrolytes.63_{In doing so, the use of ionic liquids is a relatively green}

approach as the use of hazardous, volatile solvents and supporting electrolytes is omitted. These liquids have previously been utilized in various types of transformations; reductions, electroreductive couplings, electroreductive carboxylations, electrochemical fluorinations and electrochemical epoxidations.63_{Although there are some practical issues, the liquids can be retrieved and recycled}

after reactions. Other advantages include; relative inertness, high polarity, non-flammability and miniscule vapor pressure.63_{Furthermore, they are also highly conductive and show wide potential}

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Generally, ionic liquids consist of bulky cationic species and weakly coordinating anions.63,94_Typical

cations include quaternary ammonium salts (e.g. tetralkylammonium and aromatic or saturated cyclic amines), imidazolium-, pyrrolidinium-, pyridinium-, piperidinium-, sulfonium- and phosphonium cations. Representative anions include inorganic halides and amides, and organic trifluoroacetic, triflate, amide, cyano and methide anions.94_{Some cyclic cations can be altered by introduction of}

additional moieties to the ring. One of the most important properties of an ionic liquid is the conductivity. As one would expect, different ionic liquids have different conductivities, but even the highest room temperature ionic liquid conductivity cannot compete with that of an aqueous electrolyte solution.94_{Although, conductivity values of one magnitude lower are observed from}

non-aqueous solutions. A mixture of an ionic liquid and a molecular liquid can have various properties depending on the salt concentration. An increasing salt concentration can increase the conductivity of the mixture to a maximum, after which it will again decrease at higher salt concentrations. The conductivity of an ionic liquid is related to both the viscosity and the temperature of the liquid. Lewandowski et al.94_{gave a detailed explanation on how exactly these parameters are related and}

what consequences arise from changing them.

2.2 Electrochemical experiments

2.2.1 Voltammetry

For electrochemical experiments, oxidation and reduction potentials of substrates can be used to guide parameters of the reactions.16_{They can be acquired experimentally by means of voltammetry.}

Cyclic voltammetry (CV) is used to measure the current response of a small electrode upon application of an excitation signal.95_{Kissinger and Heineman regarded this signal as a linear potential scan with a}

triangular waveform.95_{The triangular waveform includes potential values between two set values,}

ranging from one to the other and then back, thus commencing and terminating with identical potentials, EInitial and EFinal. The slopes of this waveform should have equal and opposite values.16

Moreover, oxidations and reductions will start with positive and negative values, respectively. Both single or multiple cycles of the waveform can be utilized. The response signal to the potential excitation is the current.

Resulting from the CV experiment is a voltammogram (Figure 6), which plots the current over the potential.16,95_{The graph provides information on the behavior of specific substrates at a certain}

potential. One can use it to determine the reversibility of the reaction (i.e. reversible, quasi-reversible and irreversible). The value of the potential given from the voltammogram is generally the half-peak potential, which can be defined as the value of E where the current 𝑖 =𝑖₂𝑝 .16_{Most preparative organic}

electrolyses are irreversible and thus provide irreversible CV plots. In this case, there is generally no need to study the reverse wave function. An experiment that is often seen where only the reduction or the oxidation wave is studied is known as linear sweep voltammetry (LSV).16_{The setup of such an}

experiment is the same as for CV, the only distinction being that the obtained LSV plot merely contains the forward scan.

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Figure 6 Voltammogram of irreversible (left) and reversible (right) reactions.16

2.2.2 Flow electrolysis

In the last two decades, electrochemical processes under continuous flow conditions have experienced a major development and evolution.18_{With the scale-up being so viable by simple}

addition of extra electrolysis reactors, flow cell electrosynthesis has generally been related to large-scale industrial processes. Although employing flow cells in electrosynthesis requires additional electrical equipment (e.g. pumps), it allows for a continuous synthesis under well-established conditions. Flow chemistry carries several advantages over traditional flask chemistry; it reduces the amount of required solvent and substrate, and it also facilitates process optimization.18_Another

benefit is that a homogenous electric field is generated. By taking advantage of microspace, the small size and large surface-to-volume ratio can be added to the list of pros of microflow systems.63

Furthermore, their use circumvents some of the problems accompanied by use of macrobatch electrochemical cells (e.g. the high ohmic drop between the electrodes and the problematic mass transfer on their surfaces).

The charge necessary for chemical change to occur can be calculated by means of Faraday’s law (equation 1, Table 3).96_{Here, 𝑄 is the amount of charge, 𝑚 represents the total amount of to be}

converted reactant, 𝑛 stands for the number of electrons necessary to effect conversion to one reactant molecule and 𝐹 is Faraday constant. As was explained in the previous paragraph on the electrical double layer, an electron transfer can only occur within molecular dimensions of the electrode surface.96_{Thus, the fastest chemical change under the control of the mass transfer regime}

(i.e. the speed at which reactants are transported to the electrode). This value is quantified by the mass transfer coefficient, 𝑘𝑚. The cell current, 𝐼𝑐𝑒𝑙𝑙, is what controls the rate of conversion in an

electrochemical reaction. In case a reaction is under mass transfer control and the fractional current efficiency for it is 1.0, the cell current is expressed as shown in equation 2, Table 3.96_{In this case, 𝐴}

stands for electrode area, whereas 𝑐 represents the concentration of reactant. As can be seen, the cell current is directly proportional to these variables. On the other hand, the formula for cell current is altered when assuming a cell with uniform current density, 𝑗𝐿, over the electrode (equation 3, Table

3).96_{The fractional conversion, 𝑋, of a mass-controlled reaction can be expressed as a function of time,}

𝑡, volume of the solution, 𝑉, and electrode area, 𝐴 (equation 4, Table 3).96_{As can be seen from this}

equation, the importance of the surface-to-volume ratio and mass transport efficiency cannot be sufficiently emphasized.

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Table 3 Table of equations.

Entry Calculates Equation

1 Amount of charge 𝑄 = 𝑚𝑛𝐹

2 Cell current 𝐼𝑐𝑒𝑙𝑙 = 𝑛𝐹𝐴𝑘𝑚𝑐

3 Cell current 𝐼𝑐𝑒𝑙𝑙 = 𝑗𝐿𝐴

4 Fractional conversion 𝑋 = 1 − 𝑒𝑥𝑝−𝑘𝑚𝐴𝑡 𝑉

Various electrochemical flow cells are known and have previously been employed in electrolysis experiments. One well known cell type is the parallel plate reactor with solution recycling (Figure 7).96

The simplest of such reactors consists of two electrode plates which are kept separate by a spacer. The center of these parts is cut away to function as the electrolyte flow chamber. In order to maximize mass transfer from the electrodes, the flow rate in such setups is kept as high as possible.96_{The cell}

current and rate of conversion are thereby maximized, but the conversion of the reactants is relatively low as a result of the low residence time in the cell. To improve on this matter, the solution is recycled from a reservoir to the cell to maximize the conversion. In the course of the experiment, the current drops exponentially as the concentration of the reactants decreases.96_{Thus, the productivity of a cell}

can be maximized by continuous addition of reactant throughout the reaction. The use of parallel plate cells carries numerous advantages: a constant narrow interelectrode gap can easily be achieved with polymer spacers; scaling can be readily achieved; with respect to the auxiliary electrode, all points on the working electrode are equivalent; uniform flow can be established in the gap between the electrodes; a separator can be easily introduced.96

Figure 7 Schematic depiction of a laboratory arrangement of a flow cell with recycling of the reactant solution in a undivided (a) and divided (b) cell.96

Various other flow reactors belong in the category of pseudo-parallel flow cells: solid polymer electrolytes (SPE) electrolyzers, pipe cells and the bipolar disk stack cells.96_{The SPE electrolyzers}

employ an ion-permeable membrane as electrolyte with one or both of the electrodes as mesh or porous structure on the membrane surface.96,97_{This has the benefit of feeding from the rear of the}

electrode on the membrane where non-ion-conductive feeds are permitted. Consequently, typical feeds include the reactant in a solvent without electrolyte, in apolar solvents, or in pure form. Pipe cells are similar to parallel plate cells in that they too have a uniform interelectrode gaps between the anode and cathode.96,98_{These cells still feature a narrow electrode gap; however, they contain a}

cylindrical graphite electrode inserted into a hollow steel pipe electrode. Such reactors also allow for electrolysis with low electrolyte concentrations, but as the residence time within the cells per cycle is relatively short, it only permits a low conversion for each cycle. The final successfully employed reactor design to be discussed is the bipolar disk stack cell.96,99_{These are built up of a stack of graphite disks}

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connected to electrical outputs in this bipolar cell. Furthermore, the reactant solution flows through the gaps between the discs. Typical smaller laboratory scale units consist of five graphite discs whereas the larger industrial units can go as high as 100 with a larger diameter. The disadvantage of this method is that the linear flow rate gradually decreases as reactant flows through the cell.96

Nevertheless, this effect is minimized by application of a high flow rate.

Some cells have also been designed to only require one pass through of the reactant solution to result in a high conversion.96_{Various approaches have been employed in the attempt to attain a suitable}

yield: utilization of a slower flow rate; three dimensional electrodes; and extending the reactor channel length. A review containing further elaboration and successful reactions utilize these methods has been published and so these will not be further discussed here.96

2.2.3 The cation-pool method

A large part of organic electrochemical reactions involves trapping of anodically generated cationic species by various nucleophiles. The drawback of such reactions is that they can be limited as the involved nucleophile can undergo competitive oxidation.2_{Yoshida et al.}100_{developed a method that}

would circumvent such problems: the “cation pool” method.2_{This methodology employs a divided}

cell wherein a high concentration of carbocations is generated via anodic oxidation. Decomposition of these cationic species is hindered by performing these reactions under cryogenic conditions.101_{It was}

previously regarded as problematic to apply such low temperatures as this would readily increase the viscosity of the solvent leading to decreased molecular motion of the ions and preventing them from optimally carrying electrical current.63,101_{This makes the choice of solvent and supporting electrolyte}

crucial. Utilization of a divided cell is beneficial as it prevents the cathodic reduction of the generated cations. After formation of the carbocations, they are sequentially allowed to react with nucleophiles. As they are not present in the cation generation process, any type of nucleophile can be utilized.101

Carbon based nucleophiles for example would otherwise be easily oxidized under such conditions. A typical supporting electrolyte and solvent employed in this method is tetrabutylammonium tetrafluoroborate and DCM respectively.101_{DCM is well suited here as it includes a low viscosity at}

cryogenic temperatures. The cathodic chamber is filled with trifluoromethanesulfonic acid to facilitate the cathodic process (i.e. the reduction of protons).

Utilizing this novel method, Yoshida at al. showed the capability of generating a broad range of cations: alkoxycarbenium102_{, N-acyliminium}100_{, glycosyl}103_{, alkoxysulfonium}104_{, thioarenium}105_,

arene106_{, diarylcarbenium}107_{, silyl}108_{, benzylaminosulfonium}105_{, iodine}109_{and thionium cations}110_{. A}

variety of products could be synthesized in high selectivity by employing this methodology. In certain cases, utilization of the cation pool method led to the formation of reactive radical cations. Consequently, multiple equivalents of reactant were required to form the product.111_{Radicals could}

also be formed via the reduction of a cation pool.18,101_{These could in turn dimerize or react with a}

radical accepting alkene to form a final product. Mediated formation of cations has also been reported with aryl disulfide mediators.112_{This method was particularly useful in processes where the generation}

of cations was less efficient. Mediators incorporated in the electrolysis could also undergo addition to the substrate, thus functioning as reaction partners.18

In the past few years, the group of Yoshida have directed their attention to the stabilization of the cations at higher temperatures. This could be achieved by incorporating the cations into a stabilizing structure.18_{One class of relatively stable compounds that are valuable intermediates in chemical}

oxidations is alkoxysulfoniumions. These compounds can be formed by reacting DMSO with the oxidized species of diarylsulfides or halogens.18,113_{Another stabilizing agent that has been previously}

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generated and accumulated. It is sequentially allowed to react with a precursor to afford the involved cation. Cross-coupling and homoallylation reactions have already been performed with this method.18,110

As the cation pool method allows for the formation of relatively unstable intermediates under green conditions (i.e. electrochemically), it is of great synthetic importance.18_{The downsides of the method,}

however, are that; it is difficult to scale up, requires a great deal of preparative effort and the setup of these reactions is fairly complex.