Organic Electrosynthesis: From Laboratorial Practice to Industrial

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Organic Electrosynthesis: From Laboratorial Practice to Industrial Applications David S.P. Cardoso, Biljana Šljuki#, Diogo M.F. Santos, and César A.C. Sequeira Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.7b00004 • Publication Date (Web): 17 Jul 2017 Downloaded from http://pubs.acs.org on July 17, 2017

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Organic Process Research & Development

Organic Electrosynthesis: From Laboratorial Practice to Industrial Applications

David S.P. Cardoso, Biljana Šljukić, Diogo M.F. Santos and César A.C. Sequeira*

Materials Electrochemistry Group, Center of Physics and Engineering of Advanced Materials (CeFEMA), Instituto Superior Técnico, Universidade de Lisboa, 1049-001 Lisbon, Portugal *

corresponding author e-mail: [email protected]

Abstract Organic electrosynthesis has received great attention as a powerful green tool for synthesis, affording less waste production, less chemicals spent, and often fewer reaction steps than conventional methods. Functional group interconversion and C-C bond generation by imposition of a proper electrode potential is what lies behind organic

electrosynthesis

processes.

Paired

electrochemical

reactions,

indirect

electrosynthesis, electrochemical microreactors and the use of ionic liquids are some of the highlighted means that contribute to optimization of the overall process. Necessity to use specific organic solvents combined with supporting electrolytes is one of the main limitations to be overcome to make the electrochemical process more economically feasible when compared to non-electrochemical processes. Numerous examples from the bench scale to industrial routes such as adiponitrile, substituted benzaldehydes, anthraquinone, fluorinated products and succinic acid production are well described throughout this review.

Keywords: organic electrosynthesis; industrial processes; microreactors; organic reactions; ionic liquids.

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1. Introduction Basic chemistry of organic and inorganic processes is, per definition, the foundation for chemical industry. In particular, along the last 120 years, synthetic organic chemistry is being a conventional and largely used tool in chemical synthesis, both at laboratory and technical scales. Nowadays, significant advances in photo-redox chemistry, enzymatic processes, organo-catalysis, and other methodologies are contributing to the increased establishment of chemical synthesis in the chemical industry. Still, modern society demands new synthesis processes, namely in terms of clean alternative processes. Thus, it is advisable to achieve high product yields with considerably lower/no environmental emissions, avoiding environmentally complicated byproducts; to extend the lifetime of materials and equipment; to pay much attention to the work up of process streams, simple isolation, simple recycling of solvents and other important preconditions for the realization of new synthetic processes in industry.1-4 Present availability of electrochemical expertise and equipment on the market, the emergence of new suppliers and developing countries searching for new clean technologies, make electrosynthesis with its intensive use of electrons (note that electrons on a molar scale are in the same low cost range as hydrogen or oxygen at an integrated chemical plant using these gases for hundreds of processes) a competitive technology with a very good potential (but not a general solution). These potential technical and/or economic advantages over conventional and/or competitive processes are patented in many situations such as pollutants treatment,5,6 sustainable energy production7,8 and synthesis of chemical products.8–12 Organic electrosynthesis, enabling the replacement of dangerous and toxic chemicals by electric current, or “clean” electrons, together with its high versatility, has attracted great attention at the laboratorial3,9,13 and industrial scales in areas of fine chemicals, environmental mitigation, pharmaceuticals, agrochemicals, and others.14,15 The advantage of imposing a certain cell voltage to handle the selectivity of a process is crucial to avoid unwanted products obtained by side reactions. In this review, key topics within this area will be addressed, from the theoretical fundamentals to the industrial scale.


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2. Basic concepts in organic electrosynthesis In a chemical synthesis, it is frequent that the main reaction does not occur spontaneously under the initial set of conditions. Typically, the high activation energy of a process is one of the critical barriers that has been exhaustively studied. The use of catalysts to decrease the activation energy of a chemical reaction often requires high temperatures. One way to overcome this limitation is by using alternative methods, such as electrochemical ones, where the reaction can occur under mild conditions and key products are obtained using greener approaches.16 Electrochemical reactions of organic compounds can proceed by different paths depending on the experimental conditions, but in all of them, the electron transfer converts the original molecule (RX) into a reactive intermediate and subsequently into the desired product (Scheme 1).1 In the first step at the cathode side, an electron is removed from the electrode surface (Sox) and consequently transferred to the lowest unoccupied molecular orbital (LUMO) of the organic compound, resulting in its reduction (RX•-). The opposite process occurs at the anode, in which an electron from the highest occupied molecular orbital (HOMO) of the molecule is removed resulting in its oxidation (RX•+). The intermediates obtained in this step are so unstable that can react easily with other compounds depending on the electrolytic conditions: a nucleophilic substitution happens when the leaving group is replaced by a nucleophilic one via electrode oxidation; or in the same logical reasoning can occur in the cathode an electrophilic substitution; in the presence of an excess of radicals, a dimerization via radical addition shall occur.



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Scheme 1. Electrochemical functional group interconversion pathways. This environmentally-friendly technique has several advantages compared to conventional synthesis methods, since the use of electric energy avoids employing hazardous reagents; the suitable choice of the electrodes and electrolyte conditions are used to control the selectivity; the adjustment of the potential or current density applied are good to regulate the reaction rate; the reactions mostly operate at mild conditions, such as room temperature and atmospheric pressure.17–19 This electron-transfer-driven method is more favorable when the reduction is carried out at more negative potential and oxidation at more positive potential. However, owing to the instability of the intermediate species, the reaction can take different pathways. When the HOMO levels of the species are adjacent to each other it is difficult to oxidize a substrate without affecting another. Thus, a functional group known as electroauxiliary (EA), may sometimes be used to accomplish a more controlled and selective electron-transfer route, essentially for an oxidation (Figure 1).20 The use of an EA leads to an increase of the key substrate HOMO level and consequently this powerful method promotes a desired selective oxidation. Therefore, the position where the electron-transfer should occur and the subsequent formation/cleavage of the chemical bonds to obtain the key product need to be considered. To optimize the yield of the process, the reactivity of the species and the selectivity of the process should be electroanalytically studied by cyclic voltammetry (CV) and coulometry21 and optionally coupled with analytical techniques that are performed for physical organic chemistry applications.1,19,22,23


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Figure 1. Diagram for selective and non-selective electron-transfer of the substrate. In order to perform these reactions, electrochemical reactors (known as cells) are needed, having typically one of the two possible configurations: an undivided cell (Figure 2A) or a divided cell (Figure 2B).24,25 For the undivided cells, two electrodes (anode and cathode) are immersed in an electrolyte solution that contains the electroactive species without any physical separation. This cell has cost benefits, not only due to its simpler design, but also because of its lower internal resistance and longer lifetime. In the case of divided cells, the separator between anolyte and catholyte solutions is usually a membrane or ion-permeable barrier that increases the cell resistance, owing to its resistivity and the fact that it increases the interelectrode spacing. Moreover, mechanical properties and chemical stability of this physical separator usually limits the cell lifetime.26 When organic electrosynthesis is applied in an undivided cell, both reduction and oxidation occur in the same compartment. Consequently, this setup is not appropriate if processes at the counter electrode affect either intermediates or products of the reaction of interest. A divided cell with two distinct compartments is commonly used to overcome this limitation. For laboratory scale applications, a simple divided H-cell is typically employed, where glass frits and ion-exchange membranes are typically chosen as suitable cell separators. In particular cases where a charge transport resistance is observed, a Nafion membrane can be employed, thus enhancing the ion transport and keeping the high conductivity of the cell.1,21



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Figure 2. Schematic diagrams of typical (A) undivided and (B) divided electrochemical cells.

The applied electrode potential is given relative to a reference electrode (RE), typically Ag/AgCl or saturated calomel electrode (SCE).9 When performing constant current experiments, a current is imposed and the electrode potential starts to rise. For anodic oxidation, the electrode potential will rise until the redox potential is attained and the oxidation discharge takes place. The electrode potential will keep fairly constant until the electroactive species are fully oxidized at the electrode surface. Afterwards the electrode potential rises to a more positive value, which corresponds to a second electroactive species or solvent to be oxidized. So, the redox potential for the oxidation of the electroactive species must be known, otherwise undesired reactions may occur.9 The selection of electrolyte conditions may carry some restrictions in terms of cell conductivity and mass transfer on the surface of the electrode. As the recovery of the electrolyte may involve extra costs, lower concentrations of the supporting electrolyte shall be used or even created in situ.27 The use of micro flow cells with reduced distance between the electrodes can be an alternative to deal with this limitation.28,29 On the other hand, the solution has to have high conductivity to ensure the charge transport process. Recently, ionic liquids have received much interest for being ecological supporting electrolytes that may be used in reactions run at room temperature. These salts show high conductivity at wide potential range and can be recovered and recycled after the reactions take place.30–32


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Other important concept regarding the optimization of the overall process is the paired electrochemical process where the two electrochemical reactions are performed in parallel to obtain one or more different products.3,33 This allows a significant reduction not only in the addition of supporting electrolyte but also in energy consumption, as the electric energy spent is both used for anodic and cathodic reactions.34 As referred above the reaction rate can be controlled by means of electrical parameters. Typically, the operation modes in electrolytic cells are potentiostatic and galvanostatic. The first one relies on the use of constant cell voltage and is used for the development of batch applications in which the reaction kinetics can be studied over a wide range of reactant and product concentrations, with these parametric studies being carried out with minimum consumption of chemicals. It is rarely applied in larger-scale cells, which are extremely expensive due to the power required. Galvanostatic operation employs constant cell current, which is simpler, cheaper, and easier for charge balancing when compared with the potentiostatic mode. This case is appropriate for continuous operation in steady state and is typical of industrial operation. Batch applications in galvanostatic mode may only be realized if solely harmless side reactions can occur; otherwise potentiostatic mode is recommended.35,36 The following sections will summarize contributions to organic electrosynthesis processes from the laboratorial practice to industrial applications.

3. Electrochemical reactions for organic synthesis Over the last few decades, important progresses in the understanding of the underlying mechanisms of electrolysis have been achieved. Electrolysis can be classified as direct or indirect electrolysis. The former is based on the direct electron transfer between the electrode and the compound, whereas the latter is focused on a mediated electron transfer by adding redox mediators dissolved in the electrolyte.37-39 The present section describes a variety of such conversion reactions with yields mostly above 80%. 3.1.

Anodic functionalization of organic compounds

Organic substrates can be interconverted at the anode via one of the following reactions: anodic oxidation, addition, substitution or cleavage. Anodic oxidation of molecules in organic solvents involves, for example, reaction between the electrolyte and the



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dissolved substrate in which the functional groups from the solvent are inserted in the organic substrate. Additionally, to optimize this process, the oxidation can be coupled with hydrogen production occurring in the cathodic compartment of the electrochemical cell.40 One important industrial reaction focused on this anodic conversion is the oxidation of p-methoxytoluene into p-anisaldehyde produced by BASF (section 4.2). Over the past few years, methoxylation of organic compounds has been one of the most highlighted anodic addition reactions. Oxazolidinones belong to a group of antimicrobial agents that are effective against gram-positive pathogenic bacteria.41 Saravanan et al.42 reported a methoxylation of a 2-oxazolidinone using boron doped diamond (BDD) or graphite as anode (Scheme 2). Higher yields were obtained for BDD, with a maximum value of 88% obtained for a current density of 50 mA cm-2. Beyond that current density, yields start to decrease due to the electrochemical degradation of the starting material and the solvent oxidation.

Scheme 2. Anodic methoxylation of a 2-oxazolidinone.

Considering alkyl aromatic derivatives in solution, they tend to lose a benzylic proton to form a stable benzyl radical, which is consequently oxidized to the cation and further attacked by the electrolyte compounds.

Recent studies43 reported that 1-

(trifluoromethyl)benzene dissolved in dry acetonitrile/Bu4NBF4 becomes oxidized to 2(trifluoromethyl) acetanilide with 86% yield allowing new routes to many synthetic therapeutic agents.44 Several different electrolyte conditions and selective pathways for the oxidative intermolecular coupling of arylethers, arylamines and phenols were reported by Schäfer.45 Intramolecular cyclizations were also performed by Schäfer and one example can be found in Scheme 3.46 Isoquinolines (Scheme 3a) and benzazepines (Scheme 3b) were isolated by the intramolecular cyclization of enaminones in MeOH with NaClO4 as supporting electrolyte. Yields obtained using glassy carbon anode and Pt cathode were 50% and 55% for isoquinolines and benzazepines, respectively.


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Scheme 3. Synthesis of (a) isoquinolines and (b) benzazepines.46

Typically anodic substitutions can take place in alkanes, aryl compounds as well as in organics activated by an alkoxy, thio, aryl, amino group or even by a C=C double bond. In case of aromatic compounds, the C-H bonds can be replaced by acetamide, acetate or other nucleophiles via anodic oxidation of the aromatic compound to its cation radical.3 C=N double bond substrates such as azines and oximes can be synthesized from electrochemical oxidation of hydrazones and alcohols, respectively, using platinum anodes (Scheme 4).47,48 Zhang et al. performed the oxime synthesis by using indium tin oxide (ITO) as cathode and SnCl2 as the mediator.48 Oximes and azines are used for synthesis of pharmaceuticals and conducting polymers, respectively.

Scheme 4. Anodic synthesis of (a) azine via hydrazone47 and of (b) oxime via alcohol.48



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As reported,49 several anodic cleavages in stilbenes were applied to form the corresponding aldehydes with 93 to 98% yield using triphenylamine derivatives as electrocatalysts in acetonitrile solutions. Fernández et al.50 did a detailed study of the mechanism of glycerol electrooxidation to CO2 at Pt electrodes using isotopically labeled glycerol, and gained insight into the glycerol C–C bond cleavage. It should be mentioned that glycerol electrooxidation creates 14 F per mol, i.e., more than twice the methanol energy content, so this study opened new perspectives for efficient electrocatalysis in direct alcohol fuel cells. Kolbe electrolysis is one powerful method to obtain symmetrical dimers. The oxidative decarboxylation of carboxylic salts via radicals can result in formation of a dimer by coupling according to Scheme 5, path (a). Depending on the reaction parameters (electrode material, current density, additives), the radical can alternatively be oxidized to a carbocation (Scheme 5, path (b)). In the latter case, the cation is further subjected to solvolysis and rearrangement to obtain products such as esters, ethers, olefins or amides, the process is known as non-Kolbe electrolysis.3,51

Scheme 5. Oxidative decarboxylation via (a) Kolbe electrolysis and (b) non-Kolbe electrolysis.

3.2.

Cathodic conversion of organic compounds

The electroreductive cleavages are often applied to R-X bonds, where X is an electroactive group, mostly a halogen substituent. The overall reaction results in a dissociative electron transfer to form a radical R• and an anion X-, normally followed by the radical reduction to the corresponding carbanion R- (Scheme 1). These cathodic cleavages have extensive use in analytical, synthetic and environmental applications.52 Exhaustive studies showed that this mechanism is mainly influenced by the molecular structure, position of the halogen substituent (benzylic, aliphatic, aromatic, i.e., the


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halogen group type and the steric hindrance effect), the solvent proticity and electrode surface.53–55 Over the last few years, electrochemical hydrogenation has been studied as an alternative route to catalytic hydrogenation under benign conditions.56 What lies behind this alternative process is a multistep mechanism: first an adsorbed hydrogen is formed on the metal surface, followed by the adsorption of the organic compound and the electrocatalytic hydrogenation of the organic molecule.57,58 Sáez et al.59 performed a study of a two-electron reduction of acetophenone to form 1-phenylethanol that has several applications in pharmaceutical and fine

chemical industries.60 The

hydrogenation using Pd/C 30 wt.% in ethanol solutions showed 90% selectivity applying 2 F charge and 10 mA cm-2 current density (Scheme 6).

Scheme 6. Electrochemical hydrogenation of acetophenone. Other authors studied the electrochemical hydrogenation of coal in the presence of PVPNiB/SiO2 catalysts under clean and mild reaction conditions as an alternative to the conventional coal hydrogenation.61 It was observed that structural and electronic effects influence the electrocatalytic performance. Thus, partial electron transfer from B to Ni and weaker bond strength of Ni-H facilitates the coal hydrogenation by activating the adsorbed hydrogen. Furthermore, compounds with higher BET areas and better dispersion of the Ni active nanoparticles exhibited electrocatalytic activity. However, excessive amount of catalyst contributed to agglomeration, covering the active sites and thus reducing activity.

3.3.

Electrogenerated acids

Some catalytic reactions can be induced due to the in situ generation of protons in an anodic process. These strong acids acting as catalysts for alternative routes in applied electrosynthesis are called electrogenerated acids (EGAs).1 A pioneer of this method



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was Torii that studied deeply multiple induced reactions including acetalization of carbonyls,62 cyanation and allylation of acetals,63,64 epoxide opening leading to ketones65 and alcohols,66 protection-deprotection of alcohols67 and cyclization of isoprenoids.68 Carbohydrates were reported as raw materials to produce other organic products via dehydration by electrogenerated acid. The high efficiency of this method is directly related with the acidity promoted by the in situ EGA formation at the anode surface (Eq. 1). Therefore, DMSO acts as the driving force to further dehydrate fructose (Eq. 2) and sucrose (Eq. 3), and consequently synthesize 5-hydroxymethylfurfural (HMF) with at least 90% yield.69 DMSO + H2O → DMSO2 + 2H+ + 2eC6H12O6

DMSO/H

C12H22O11

(1)

+

DMSO/H

C6H6O3 + (CH3)2SO2 + 2H2O + 2H+ + 2e-

(2)

+

C6H12O6 + C6H6O3 + (CH3)2SO2 + H2O + 2H+ + 2e-

(3)

Formation of well-defined aryl-tethered films is another example of process proceeding in the presence of the EGA. Firstly, the EGA is formed via oxidation of N-Ndiphenylhydrazine close to the electrode surface. Therefore, the protons obtained were used to convert an aryltriazene to form the corresponding aryldiazonium salt. Upon negative polarization of the working electrode, the aryldiazonium ions were reduced to form the aryl radicals that consequently facilitate the grafting process and create welldefined aryl-tethered films, with arene unit anchored to the electrode surface (Scheme 7).70


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Scheme 7. Electrografting of an aryltriazene in the presence of electrogenerated acid.69

3.4.

Electrogenerated bases

Anion radicals or anions can be generated by electroreduction and act as bases to deprotonate or initiate base-catalyzed reactions. These compounds known as electrogenerated bases (EGBs), can be obtained in situ in aprotic solvents to overcome problems related with handling strong bases.18,71 Li et al. reported an electrochemical synthesis of N-bromoamino acid using benzylideneaniline as raw material (Scheme 8).71



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Scheme 8. Electrochemical synthesis of N-bromoamino acid from benzylideneaniline.71

At the cathode, a carboxylate anion with carbon dioxide is formed by reduction of R4+ cation and that anion deprotonates the imino group of the radical anion formed by reduction of benzylideneaniline proceeding in parallel with R4+ cation reduction. At the same time, at the anode, bromide ion is oxidized to hypobromous acid which, being a strong oxidant, easily oxidizes the deprotonated anion, leading to the synthesis of Nbromoamino acid. Several organic compounds were synthesized by Feroci et al.72–75 using EGBs such as oxazolidinones, carbamates and lactams. Imidazolium-based ionic liquids were found to have an important role as good precursors in the generation of heterocyclic species containing a carbene carbon.76–78 These excellent ligands known as N-heterocyclic carbenes were shown to have numerous applications as electrocatalysts in chemical industry and to enable a huge variety of organic reactions.79

3.5.

Ionic liquids (ILs)

Room-temperature molten salts known as ionic liquids, have received great attention in electrochemistry due to their specific properties, mainly good ionic conductivity, nonvolatility, thermal stability, nonflammability and reusability.30,80,81 Still, problems related to difficult isolation of desired product, ILs high viscosity, some environmental instability and price of ILs might pose some restrictions to their use.


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In organic reactions, most reagents are not soluble in aqueous solutions which brings a considerable limitation for organic electrosynthesis applications. The use of ILs overcomes this drawback, as they typically have in their structure an organic cation providing the solubility of the organic substrate during the reaction (Figure 3) and thus operate without the addition of supporting electrolytes.30 Furthermore, they allow the replacement of hazardous organic solvents that have volatility and flammability restrictions. Figure 3 summarizes the typical IL ions employed in electrochemical reactions, with bulky organic cations generally being coupled with weakly coordinating anions. Their wide electrochemical potential window, wide liquid range and tunable solvents properties are peculiar advantages that caught the attention of researchers to employ these promising solvents for organic electrosynthesis applications.82

Figure 3. Structure of some ionic liquid cations used in electrochemistry. Typical counter-ions include AlCl4-, BF4-, HF-, N(CF3SO2)2-[NTf2], PF6- and SCN-. Halogenated organic compounds gained a lot of attention for having an important role in the development of several pharmaceuticals and agrochemicals.83,84 Anodic partial fluorination became very attractive for being carried out under mild conditions in the absence of hazardous reagents.80,85 Still, when organic solvents are employed, anodic passivation can occur, leading to a decrease of the process efficiency.30 Several studies reported the enhancement of the fluorides reactivity when employing the ILs in the preparation of fluorinated molecules.86–89 Other authors90–92 showed good yields (> 80%) when performing the reactions under aprotic solvents containing HF salt ionic liquids in presence and absence of imidazolium ionic liquids (Et3N·nHF, n=1-5) (Scheme 9).



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Scheme 9. Anodic fluorination of phthalide (a),90 tetrahydrofuran (b)91 and 1,4difluorobenzene (c).92

The electrochemical synthesis of conductive polymers has been developed by several researchers since these materials present interesting features for numerous electronic devices.93,94 Alkyl-imidazolium and alkyl-pyrrolidinium derivatives have proved to be suitable solvents for the electrosynthesis of polypyrrole,95,96 polythiophene97–99 and polyaniline.100 Ionic liquids have also been tested as electrolytes for the synthesis of other compounds, mainly via electrooxidation of alcohols,101,102 carboxylic acids103,104 and aromatic derivatives.47,105

3.6.

Indirect electrosynthesis

Indirect electrolysis describes a particular case of an organic electrosynthesis in which the electron transfer occurs in another redox intermediate (homogeneous), instead of in the electrode/electrolyte interface (heterogeneous) as shown in Scheme 10. In turn, this intermediate called mediator (M), allows the transformation of the organic compounds (RH) at lower oxidation potentials compared to the substrate molecule.38 During this indirect electrooxidation process, mediators are involved either in an electron transfer derived from the RH without the formation of an intermediate with compounds of the solution (outer-sphere oxidation, i.e., oxidation process in which electron transfer


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occurs between chemical species that remain separate and intact during the transfer, redox catalysis) or converted into oxidants during the electron transfer (inner-sphere oxidation, i.e., oxidation process in which electron transfer occurs between redox sites connected by a chemical bridge, chemical catalysis).38,106 The summarized multi-step process is represented in Scheme 10. The mediator is initially oxidized (Mox) and then it can be either regenerated to its original outer-sphere form by oxidizing the RH or it can oxidize the substrate species to form a radical (R•) by adsorbing an inner-sphere proton by the mediator and originate an intermediate (MH+). Then, a base leads to a deprotonation of the outer-sphere oxidation product and contributes to the regeneration of the mediator. Finally, the key products are obtained by the oxidation of R•. The mediators also contribute to the selectivity of the process where the secondary product with difficult separation can be avoided.38 Some processes of indirect oxidation of organic substrates include: 1) generation of hydrogen peroxide (H2O2) by cathodic reduction of dioxygen; 2) homolytic cleavage of electrogenerated H2O2 under the action of a mediator; 3) substrate oxidation with the hydroxyl radicals formed (could be either a hydrogen atom abstraction from substrate or even in the case of aromatic compounds an addition to the substrate).38

Scheme 10. Anodic oxidation diagram of organic compounds by the use of mediators.

Indirect anodic electrooxidation reactions were already performed using different types of

mediators,

such

38,106,107,108

compounds,

as

2,2,6,6-tetramethylpiperidinyl-1-oxyl 38,106

Triarylamines,

dicyano-1,4-benzoquinone (DDQ),

112

arylimidazoles,

hypervalent iodine

109,110,111

113

(TEMPO)

2,3-dichloro-5,6-

orferrocene.114 Mediators

such as halide salts are more suitable for industry approaches due to their simple and easy separation from the mixture.115,116 In some cases, anodic oxidations of alcohols are unsuccessful due to the high potentials needed to complete their conversion. Thus, oxidation of primary and secondary alcohols



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at low potentials was developed with high conversion rates by using TEMPO derivative molecules.117–119 In alkaline solutions the benzyl alcohol is oxidized to benzaldehyde with 90% yield, where TEMPO mediator can be simultaneously recycled (Scheme 11).118

Scheme 11. Proposed mechanism for benzyl alcohol oxidation using TEMPO molecule as mediator.

Triarylamines can also be used as organic mediators for alcohols electrooxidation, although to perform a reversible oxidation process they need to be substituted in paraposition.120 Steckhan, one of the pioneers of this approach, reported several reactions using triarylamines mediators, such as deprotonation of thioacetals, oxidative cleavage of benzyl ethers, allylic and benzylic alcohols, oxidation of aliphatic ethers, among others.121,122 Lu et al.123 showed a pathway for 4-methoxybenzyl alcohol oxidation by using tris(4-bromophenyl)amine (TBPA) as mediator. Triarylamines are also used for anodic cleavages to form aldehydes starting from stilbene compounds.49 By opposition, the progress in indirect electroreduction processes has slowed down during the last decades. Recently, the studies have been focused on the use of fullerenes, transition metal salen complexes and carboranes as redox mediators for cathodic processes.106 Cathodic reduction of dihalides,124 catalytic reduction of CFCs125 and intramolecular cyclization of α-bromo β-propargyloxy esters126 are some of the reactions where redox mediators are used for cathodic reduction.


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4. Industrial electrosynthesis The overall know-how described in sections 2 and 3 opened new perspectives on the synthesis of organic compounds by electrochemical processes. For an industrial scale, the yield of the desired product, rate of production and energy consumption behind the synthesis, are some of the most important parameters for a successful compound production. Our previous report127 shows a table (Table 1) containing examples of compounds synthesized industrially with the respective company. Some of them have not reached the official commercialization mainly due to: (a) high energy costs; (b) pollution constrains; (c) low product selectivity. A wide variety of industrial processes supported by recent extensive studies in the field of organic electrosynthesis will be approached along this section. Table 1. List of typical industrial processes based on organic electrosynthesis.127 Product Commercial processes Acetoin Acetylenedicarboxylic acid Adipoin dimethyl acetal Adiponitrile 4-Aminomethylpyridine Anthraquinone Azobenzene Bleached montan wax Calcium gluconate Calcium lactobionate S-Carbomethoxymethylcysteine L-Cysteine Diacetone-2-ketogulonic acid Dialdehyde starch 1,4-Dihydronaphthalene 2,5-Dimethoxy-2,5-dihydrofuran 2,5-Dimethoxy-2,5-dihydrofuryl-1-ethanol Dimethylsebacate Gluconic acid Hexafluoropropyleneoxide m-Hydroxybenzyl alcohol p-Anisaldehyde Perfluorinated hydrocarbons Polysilanes Salicylic aldehyde Succinic acid 3,4,5-Trimethoxybenzaldehyde 3,4,5-Trimethoxytolyl alcohol Piloted processes 1-Acetoxynaphthalene 2-Aminobenzyl alcohol Anthraquinone Arabinose

Raw Material

Company

Butanone 1,4-Butynediol Cyclohexanone Acrylonitrile 4-Cyanopyridine Anthracene Nitrobenzene Raw montan wax Glucose Lactose Cysteine + chloroacetic acid L-Cystine Diacetone-L-sorbose Starch Naphthalene Furan Furfuryl-1-ethanol Monomethyladipate Glucose Hexafluoropropylene m-Hydroxybenzoic acid p-Methoxytoluene Alkyl substrates Chlorosilanes o-Hydroxybenzoic acid Maleic acid 3,4,5-Trimethoxytoluene 3,4,5-Trimethoxytoluene

BASF BASF BASF BASF, Monsanto Reilly Tar L. B. Holliday, ECRC Johnson Matthey Co. Clariant Sandoz, India Sandoz, India Spain Wacker Chemie AG Hoffman-La Roche CECRI Clariant BASF Otsuka Asahi Chemical Sandoz, India Clariant Otsuka BASF 3M, Bayer, Clariant Osaka Gas India CERCI, India Otsuka Chemical Otsuka Chemical

Naphthalene Anthranilic acid Naphthalene, butadiene Gluconate

BASF BASF Hydro Quebec Electrosynthesis Co.



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1,2,3,4-Butanetetracarboxylic acid Ceftibuten 3,6-Dichloropicolinic acid Ditolyliodonium salts Ethylene glycol Glyoxylic acid Hydroxymethylbenzoic acid Monochloroacetic acid Nitrobenzene 5-Nitronaphthoquinone Partially fluorinated hydrocarbons Pinacol Propiolic acid Propylene oxide Substituted benzaldehydes

4.1.

Dimethyl maleate Cephalosporin C 3,4,5,6-Tetrachloro-picolinic acid p-Iodotoluene, toluene Formaldehyde Oxalic acid Dimethyl terephthalate Tri- and di-Chloroacetic acid p-Aminophenol 1-Nitronaphthalene Alkanes and alkenes Acetone Propargyl alcohol Propylene Substituted toluenes

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Monsanto Electrosynthesis Co. Dow Eastman Chemical Electrosynthesis Co. Rhone Poulenc Clariant Clariant India, Monsanto Hydro Quebec Philips Petroleum Diamond Shamrock BASF Kellog, Shell Hydro Quebec

Adiponitrile

The electrohydrodimerisation of acrylonitrile (ACN) to adiponitrile (ADN) is one of the most commercialized processes of organic electrosynthesis. This method developed by Monsanto

in

the

1960s

became

important

to

obtain

the

precursor

hexamethylenediamine, which will form the well-known fiber Nylon-6,6 after reacting with adipic acid.25,128 While the main product in the anode is oxygen, the cathodic reaction can be described by Eq. 4. 2CH2=CHCN + 2H+ + 2e- → NC(CH2)4CN

(4)

Since the process has low conversion rate per mass, 24 electrochemical divided cells are operating in a batch reactor and the catholyte is continuously recycled using an external compartment (Figure 4). Each cell contains 16 electrode pairs using lead-silver as anode, lead as cathode and a cation-exchange membrane separator.129 The electrolyte contains a two-phase solution of an aqueous phase and a dispersed organic phase of ACN, ADN and propionitrile by-products.130,131 The system involves a stripper where the ADN product is removed and isolated whereas the unconverted reactant ACN is recycled back. This design was replaced by an undivided cell system, where the acrylonitrile is mixed with a phosphate-borate buffer solution and where a cadmium anode and a stainless steel cathode are employed.129 Quaternary ammonium salts (QS) used in this process are adsorbed on the cathode in preference to protons or water.127 The QS addition increases the solubility of ACN and decreases the propionitrile by-product production, contributing to an enhancement of the selectivity of the desired product.128 Moreover,


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the use of salts such as ethyltributylammonium will protect the cathode from corrosion. Annually, more than 300,000 t of adiponitrile are produced via acrylonitrile hydrocoupling.132

Figure 4. Scheme of industrial adiponitrile electrosynthesis process (ACN = acrylonitrile; ADN = adiponitrile; QS = quaternary ammonium salt).120

Compared with the conventional chemical procedure, this alternative route became more promising because it not only requires one reactor less, but also the use of water instead of HCN as hydrogen source making the process more ecological. Furthermore, it is believed that the dimerization reaction occurs within the cathode’s hydrophobic double layer, which facilitates dimerization and hinders the formation of propionitrile. Therefore, in order to improve the selectivity, a mathematical model was recently developed to provide estimation of the energy required for the voltage optimization.133 The authors studied the effect of the cathode overpotential on the selectivity of products by applying the input potential for cathode activation in the 0.27-0.67 V range. It was proved that the selectivity for ADN was around 0.25 for lower overpotentials, whereas by-products such as propionitrile and tricyanohexane were obtained for too high overpotential values. Therefore, a maximum selectivity of 0.85 was obtained for a cathode overpotential of 0.57 V.



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4.2.

Substituted benzaldehydes

Aromatic aldehydes are mainly used as additives in perfumes, flavoring additives or intermediates for synthesis of pharmaceuticals, and were firstly prepared by chemical oxidation of the substrates.134 However, the low selectivity and low yields of the desired product under harsh conditions led researchers to search for synthesis routes under milder conditions. One way can be via electrochemical oxidation of alkyl aromatic compounds directly at the electrode or reacting in a substrate that is further regenerated.135 Toluene derivatives can suffer an anodic acetalization in methanol and form dimethylacetal intermediates, which further hydrolyze in acid solutions to form the aldehyde product. A well-known example, 4-methoxybenzaldehyde, also known as panisaldehyde, can be synthesized by the oxidation of p-methoxytoluene, also known as 4-methylanisole (Scheme 12). BASF Company has been manufacturing the compound in a capillary gap cell since the 1960s and is currently producing 3500 t per year. Typically, the electrodes used are bipolar graphite rings employing a voltage range per gap of 4-6 V and a current density 3-5 A dm-2. This continuous bipolar electrode stack operates in a temperature range between 40-50 ºC using methanol as both solvent and reagent to obtain an overall conversion between 90-99% with yields higher than 80% and selectivity of 85%.39 Malloy et al. developed a cell that could operate in a voltage range between 2 and 30 V or a current density up to 1000 mA cm-2, with the temperature ranging from ambient to 50 ºC.134

Scheme 12. Reaction scheme for p-anisaldehyde production.

Another advantage compared with the conventional methods is that electrochemical methods do not require the use of concentrated acids that would form undesirable byproducts resulting in a decrease of the overall selectivity.


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Yield optimizations of substituted benzaldehyde products can be achieved by the use of RTILs,136 performing the synthesis in electrochemical microstructured reactors,137,138 or via indirect electrosynthesis,139 allowing a decrease in the supporting electrolyte quantity. A recent work was published testing different substrates in different imidazolium ionic liquid solutions.140 The synthesis of p-anisaldehyde in 3.1 M EMIMBF4 under a cell voltage of 1.45 V showed the highest selectivity and yield, with values of ca. 92 and 90%, respectively. Furthermore, an industrial paired electrolysis is performed by BASF where cathodic hydrogenation of dimethyl phthalate is occurring in parallel with the anodic substitution of 4-t-butyltoluene to form the dimethyl acetal and further the corresponding benzaldehyde (Scheme 13).3 Both products are obtained with high yield, with a yearly amount of 4000 t, and are used as intermediates for fragrances and agents for crop protection.138

Scheme 13. Reaction scheme of a paired electrolysis process for substituted benzaldehyde products.

4.3.

Anthraquinone

Anthraquinones (AQs) are natural pigments found in plants that find industrial applications in paper pulping and as natural dyes for foods, cosmetics and pharmaceuticals.141,142 Scheme 14a shows the synthesis of AQ by anodic oxidation of anthracene (A), which was firstly reported by Laurent in the 1830s.143 This process is restricted by availability of raw material coming from coal tar.144 Tetrahydroanthraquinone (THAQ) is an AQ derivative that has also important applications in the enhancement of paper pulping process. When naphthalene (C) reacts with oxygen using vanadium (V) oxide as catalyst, it oxidizes directly to naphthoquinone (D) and further reacts with butadiene via Diels-Alder reaction to form



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the THAQ (Scheme 14b). Still, the low selectivity due to the formation of by-products, such as phthalic anhydride (E), led researchers to study alternative mechanisms.144

Scheme 14. Synthesis of (a) anthraquinone and (b) tetrahydroanthraquinone. To overcome this drawback, commercial routes based on electrochemical methods have been developed. For example, since the 1920s Holliday’s Chemical Company produces AQ via indirect electrochemical oxidation of anthracene using cerium (III) methanesulphonate mediator.144,145 Also, British Columbia Research established an indirect electrooxidation mechanism shown in Scheme 14b using the redox couple Ce4+/Ce3+ in acid solutions. THAQ can be further oxidized to obtain AQ and the Ce couple regenerated.127 Concerning the global threat of persistent organic pollutants, the production of AQ through oxidation of naphthalene and anthracene have increased the attention of the researchers during these last years to push forward the process in ecological terms. Recent studies are being carried out regarding the use of substituted polycyclic aromatic hydrocarbons.146-148 Natarajan et al. developed methods for the AQ production reacting 9-anthraldehyde using N-bromosuccinimide in aqueous N,N-dimethylformamide147 or with HOBr generated in situ.148


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4.4.

Fluorinated products

Fluorinated compounds have been useful for several applications such as heat exchange agents, refrigerants, cleaning solvents and particularly the heterocyclic fluorochemicals for pharmaceuticals and agrochemicals owing to their specific physiological activity. First electrochemical fluorination was developed in 1940s by John Simons as a perfluorinated process where nickel (Ni) anodes were fluorinated under anhydrous hydrogen fluoride conditions.149 During these last years, Zhejiang Jusheng Fluorochemical Co., Ltd. developed a method to produce perfluorocyclo formyl fluoride derivatives in hydrofluoric acid (HF). The electrolytic solution is prepared by reaction of anhydrous HF with an electrolyte (benzoyl chloride, benzoic acid, phthalic acid chloride or cyclohexyl chloride) and a solubilizing agent (methyl benzoate, dimethyl phthalate or phthalic acid ammonium) at temperature ranging from 10 to 25 ºC and pressure ranging from 0.05 to 0.15 MPa for 1 to 5 h. The electrolyte solution is added to a tank and operated under mild conditions (temperature of 15-35 ºC and normal pressure) using Ni and SS as anode and cathode materials, respectively. A continuous 90-day operation allowed obtaining perfluoro cyclohexyl-formyl fluoride products with a yield between 80 and 89% (Scheme 15).150

Scheme 15. Schematic example of patented production process of perfluoro cyclohexylformyl fluoride.

Recently, an electrosynthesis process for fluorination of ethylene carbonate derivatives using polyhydrofluoride complexes of trialkylamines or tetraalkylammoniumfluorides as fluorinating agents was patented.151 The monofluoration performed during the electrochemical step had a current density range of 10-250 mA cm2 with a Pt, Pb, SS or Ni cathode and a gas diffusion layer (GDL) anode.151 Alternatively, electrochemical



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fluorination was proved to contribute to uranium recovery from used nuclear fuel by means of NF3 or XeF2 as fluorinating agent in a molten salt electrolyte solution.152 Recent approaches focused on the use of ionic liquids as solvents153 and aromatic compounds as substrates154–158 were found to be promising for further scale up of fluorination electrosynthesis.

4.5.

Succinic acid

Butanedioic acid also known as amber acid or succinic acid was purified for the first time in 1546 by Georgius Agricola.159 The reactivity of this dicarboxylic acid allowed its application in anti-tumor agents, foods, cosmetics or even as intermediate for the manufacturing of macromolecular materials.159–161 Due to the limited sources of fossil fuels, alternative sources such as bacterial and other microbial derivatives have become a great focus for succinic acid productions.162,163 However, the large amount of wastewater required (as bacteria source), low extraction efficiency and high production cost are some of the main limitations. In order to overcome these drawbacks, succinic acid production via electrosynthesis was proposed, in which a maleic anhydride hydrolysis typically occurs with further electroreduction under acid conditions (Scheme 16).

Scheme 16. Maleic anhydride electroreduction for succinic acid production.

Along these last few years several authors have patented the electrosynthesis methods that led to higher yields of succinic acid using different types of reactors (Table 2). Gao164 has disclosed a method to couple the maleic anhydride electroreduction with simultaneous oxidation of iodide ion resulting in a paired electrosynthesis process and therefore in a reduction of the overall cell voltage and cost production. By employing Ti supported RuO2-TiO2 as anode and Pb alloy as cathode it was possible to obtain a current efficiency value of 95%. Table 2. Results for succinic acid scale-up production using different types of reactors.


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# 1 2 3 4 5

Reactor type Fixed bed tank Not available Bipolar membrane Pipe reactor H-type

T/ºC 30-80 40-60 20-65 40-80 20-70

j / A m-2 200-1000 500-1000 100-1000 100-900 100-2000

Anode Pb Ti Graphite Pb Pb

Cathode Ti Ti/TiO2 Pb Pb Pb

Yield / % 92 89-91 >95 70-80 >90

Reference 165 166 167 168 169

Alternatively, an electrocarboxylation of ethylene was proposed to obtain succinic acid using Pt and Ni catalysts.170 Although the main products were obtained, side products were also formed and the kinetics were sluggish. Therefore, improvements are necessary before larger scale application of this synthesis method.

4.6.

Microreactors

Nowadays various industrial synthesis processes using macrobatch reactors are facing barriers that affect the global process owing to the interelectrode ohmic drop, mass transfer

phenomena,

selectivity

or

even

to

environmental

factors.138,171,172

Electrochemical microreactors (ECMRs) are suitable equipment to solve these limitations mainly in electroorganic systems where the electric conductivity is reduced. This ECMR concept is being used for the development of multiple organic synthetic routes with benefits including energy, time and space savings, increased current efficiencies, resources preservation, waste/emissions minimization, and fewer separation and synthetic steps required.34 In industrial scale, the most employed ECMRs have a plate-to-plate configuration containing a flow-through electrolyte in which the main reaction is concluded after electrolyte circulation for several times through the interelectrode space. Conductivity and reaction efficiencies are increased compared with the conventional electrolyzers due to the combination of short distance interelectrode spacing with high electrode-surface to reactor-volume.138 The electrodes typically used are graphite, Pt, Ni, and SS, where the working electrode is in contact with the heattransfer agent. The interelectrode spacer is a polymer material, for example a polyimide foil with 80-320 µm thickness (Figure 5).



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Figure 5. Scheme of an electrochemical microreactor in a plate-to-plate electrode design.

As discussed in section 4.2, BASF Company produces the p-anisaldehyde dimethylacetal intermediate via methoxylation in a capillary-gap cell since a few decades ago. Löwe et al.173,174 developed a microflow electrochemical reactor with a plate-to-plate design containing a 75µm-thick polyimide foil separator and the selectivity obtained was higher (98%) compared with the traditional macrobatch (85%).171 Alternatively, Bouzek and co-workers175 tested the synthesis of p-anisaldehyde dimethylacetal using microreactors not only for the main reaction, but also for the final product isolation. The separation of methanol from the electrolyte solution was performed in the first distillation column and the unreacted 4-methyl anisole was isolated from p-anisaldehyde dimethylacetal in the second column. Comparing with the conventional equipment, the authors reported that it was possible to save energy during the product separation step depending on the organic content in methanol recycled and on the yield of p-anisaldehyde dimethylacetal. Recently, the same mechanism was tested in bipolar electrochemical microreactors and the authors verified that it has great potential for industrial applications.176 Other processes were performed using different designs of ECMRs and some with higher yields are shown in Table 3. No requirement of high-conducting electrolytes, effective heat transfer without localized overheating and good throughput at high current density with low specific energy consumption are some of the main advantages


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of ECMRs compared with conventional batch reactors.138 Flow microreactor synthesis enables not only to save energy (since an increase in temperature and residence time generally allows increasing the conversion of starting material and product yield) but also to enhance the selectivity due to an easier control of the mass and heat transfer.177,178 Considering that the ECMR size can be a limitation for large-scale production, the scaling up can be easier accomplished and optimized when numbering-up the ECMRs.177,179,180 Yoshida et al.179 suggested a design for radical polymerization where, within the 8 microtubes, the ones with small diameter were only applied for the polymerization step. In the final stage, microtubes with larger channel size are always required in order to minimize the pressure drop with high production volume being obtained simultaneously. The same author tested Grignard exchange reaction in a pilot plant as well and during 24h continuous operation it was possible to obtain 94% yield of the main product.180



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Table 3. List of reactions using different ECMRs with their main results. #

Reaction type

1

Hydrogenation

2

Anodic methoxylation

3

Anodic methoxylation

4

Coupling reaction

Raw materials

Product

ECMR design

EtO C 2

CO Et 2

EtO C 2

CO Et 2

EtO C 2

CO Et 2

EtO C 2

CO Et 2

O

MeO

O

N

Iodination

Coupling reaction

Ni

92

28

glassy carbon

Pt

98

181

graphite

stainless steel

>84

182, 183

Pt

Pt

90

184

graphite

Pt

88

185

T-shaped micromixer and a microtube reactor

Pt

Pt

85

186

“Cation-flow” divided cell

Pt

Pt

91

187

2

2

R

CO Me 2

SH R

OH

OH

S

OH

OH

R OMe

MeO

MeO I

7

Pt

CO Me

CO Me

R

OMe

6

Reference

Plate-to-plate undivided cell

N

MeO

2

Coupling reaction

Yield / %

O

CO Me

5

Cathode

OMe

O

Br

Anode

CO2Me N

H2C SiMe

CO Me 2 N

3


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Other different chemical synthesis were performed in microflow reactors, including the fluorination

of

polymerization,190

sugars,188 and/or

the

reduction

regarding

of

phenomena

substituted such

as

benzaldehydes,189 electrophoresis,191

electrogenerated chemiluminescence192 and bipolar electrochemistry,193 opening new routes for organic electrosynthesis for different scale up purposes.

5. Concluding remarks and future prospects Herein, we discussed that electrochemical processes are instruments to produce novel and valuable products by using simple reactions and reactors, with minimum environmental problems coupled with reasonable prices. Chemists often encounter difficult situations when dealing with the synthesis of organic compounds. Requirements such as reduced activation energy, high electrocatalytic activity and low operation temperatures are not easy to achieve. Electrochemical synthesis can generally be carried out in a benign-environmental condition, at moderate or low temperature and pressures, with simple cheap facilities, just requiring the proper control of the working electrode potential, or the cell voltage (particularly in the cases of paired electrolysis), or of the cell current that is applied to the terminals of the electrolytic cell reactor. In general, the galvanostatic mode is the most used in industrial synthesis and then, the potential adjusts automatically to the compound with the least positive oxidation potential (anode) or the least negative reduction potential (cathode). This allows one to study oxidation (or reduction) chemistry of a variety of different compounds, essentially under the same conditions and without the need for testing different redox reagents. The main focus of this review is to describe practical applications of electrochemical pathways for organic synthesis, from bench to industrial scale. After a brief description of suitable operating conditions and appropriate electrochemical equipment, it is shown that the electron-transfer process within a chemical reaction is able to convert functional groups through mechanisms and reactive intermediates that are kinetically and environmentally more favorable than those of conventional methods. Being able to avoid hazardous and pollutant reagents, to reduce waste production, to work at or near room temperature, and to use the recent advances of electrochemistry, namely in the areas of microreactor engineering, fluid-flow electrochemistry, nanoelectrochemistry and bipolar electrochemistry, it is believed that soon electroorganic synthesis would



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occupy a prestigious place in science and engineering, contributing to the specific, efficient and widespread commercialization of organic electrode processes.

Acknowledgements The authors would like to thank Fundação para a Ciência e Tecnologia (FCT, Portugal) for financial support under the contract no. IF/01084/2014/CP1214/CT0003 under IF2014 Programme (D.M.F. Santos), for postdoctoral grant SFRH/BPD/77768/2011 (B. Šljukić) and for a research grant within project UID/CTM/04540/2013 (D.S.P. Cardoso).

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Organic Electrosynthesis: From Laboratorial Practice to Industrial

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