STIRRING-FREE SCALABLE ELECTROSYNTHESIS ENABLED BY ALTERNATING CURRENT

Abstract

The present invention provides a stirring-free scalable electrochemical reactor enabled by alternating current and uses thereof in a method of performing electrosynthesis of organic reaction.

Description

BACKGROUND OF THE INVENTION

The efficiency of mass transfer largely determines the performance of the whole chemical process. This also applies to the field of electrosynthesis, where the mode of mass transfer in a particular experiment is defined by the design of the electrochemical reactor. The vast majority of electrochemical transformations are performed using habitual, batch or flow, reactor design and direct current (DC) electrolysis conditions.

Batch reactors are considered to have the simplest design for construction and further application; however, its potential for scalability is highly restricted by inefficient convective mass transfer and limited electrode surface area. Moreover, redox-neutral processes may suffer from decreased selectivity due to the hindered interelectrode mass transfer while performing DC electrolysis in batch reactors.

Flow reactors, in turn, provide an efficient way to scale-up electrosynthesis by improving mass transfer and allowing high electrode surface area, although this comes at the expense of significantly increased system complexity. Microflow setups have been reported to enable redox-neutral transformations with elusive intermediates; however, the reduced interelectrode distance causes unavoidable limitations, such as an increased chance of clogging which decreases the appeal and versatility of the method. The search for alternative reactor designs that provide an effective means of mass transfer and demonstrate scalability and simplicity remains a critical issue in electrochemical engineering.

SUMMARY OF THE INVENTION

According to various aspects of the presently disclosed subject matter, a reactor, which is filled with a fine net of 3D electrodes, is provided. An AC current applied to the electrodes, in combination with diffusion-driven mass transfer, enables uniform electrolysis across the whole volume of the reactor. The design of the reactor of the invention discards the need for stirring the reaction mixture while allowing higher volumetric surface area of the electrodes. The AC-derived approach for mass transfer circumvents major limitations in the scalability of DC-based batch electrosynthesis and retains the simplicity associated with batch reactors.

The feasibility and efficiency of the suggested approach were studied on the example of selected organic transformations with up to 50 mmol scale with a further investigation of the AC frequency effect on the reaction efficiency.

Thus, the present invention provides an electrochemical reactor comprising at least one apparatus comprising: at least one reactor body; at least one 3D porous electrode and at least one AC source (including in some embodiments an amplifier, functional generator and so forth); wherein said electrochemical reactor does not include a stirring element (i.e. the electrochemical reactor is steering free). Therefore, a reactor of the present invention does not require stirring or any stirring equipment taking volume in the reactor, allowing for using the reactor volume to include only the at least one electrode and reactants. In some embodiments, said reactor is devoid of stirring equipment or component.

When referring to an “electrochemical reactor” (also referred to as an electrolytic cell) it should be understood to relate to a device that generates a chemical reaction (electrolysis reaction) using electrical energy.

When referring to a “porous electrode” it should be understood to encompass a three-dimensional structure of an electrode that is permeable to electrolyte. The electrode-electrolyte interface then extends over a large surface area. The non-planar electrode typically improves the transport of redox species to the electrode surface increasing current density. Three-dimensional (3D) porous metal electrodes typically are in the form of meshes, foams, felts and any combinations thereof.

In some embodiments, said at least one 3D porous electrode is an RVC (reticulated vitreous carbon) electrode.

In other embodiments, said at least one 3D porous electrode has a porosity of at least 5 ppi (pores per inch).

In further embodiments, said at least one 3D porous electrode has a porosity of at least 10 ppi (pores per inch).

In yet further embodiments, said at least one 3D porous electrode has a porosity of between about 5 to 30 ppi (pores per inch).

When referring to the AC source (alternating current) it should be understood to relate to the flow of electric charge through said reactor and electrode that periodically reverses direction.

When referring to the electrochemical reactor that “does not include a stirring element” it should be understood to relate to a reactor that is free of any steering element or device.

In some embodiments an electrochemical reactor of the invention is a batch reactor.

In some embodiments an electrochemical reactor of the invention is a flow reactor.

In some embodiments an electrochemical reactor of the invention comprises at least one 3D porous electrode (in such embodiments another type of electrode may be comprised in said reactor of the invention). In some embodiments an electrochemical reactor of the invention comprises at least two 3D porous electrodes.

In some embodiments, each of said 3D porous electrodes is separated in said reactor by at least one glass separator. When referring to a “glass separator” it should be understood to relate to a separator that allows for the reactor to have at least two parts, each comprising at least one 3D porous electrode.

The invention further provides an electrochemical reactor as disclosed herein above and below for use in organic electrosynthesis.

The invention provides a method of performing an organic electrosynthesis comprising providing an electrochemical reactor as disclosed herein above and below; filling said reactor with electrosynthesis reactants; and applying AC through said filled electrochemical reactor; thereby performing said organic electrosynthesis.

In some embodiments, said electrosynthesis is selected from redox-neutral reaction, amination reaction, esterification reaction, etherification reaction and any combinations thereof.

In some further embodiments, an electrochemical reactor of the invention is scaled to industrial organic electrosynthesis reactions.

BRIEF DESCRIPTION OF THE DRAWINGS

The subject matter regarded as the invention is particularly pointed out and distinctly claimed in the concluding portion of the specification. The invention, however, both as to organization and method of operation, together with objects, features, and advantages thereof, may best be understood by reference to the following detailed description when read with the accompanying drawings in which:

FIG. 1A shows a schematic representation of a batch electrochemical reactor with rod electrodes; FIG. 1B shows a schematic representation of a flow electrochemical reactor with plate electrodes; FIG. 1C shows a schematic representation of an AC-enabled batch stirring-free reactor with 3D net electrodes.

FIG. 2A shows a photo of the electrochemical reactors, constructed and used in this work (20 ml vial is given for scale); FIG. 2B is a table listing physical parameters of the reactors; FIG. 2C is a simplified scheme of the external electrical circuit and its connection to the large reactor; FIGS. 2D and 2E illustrate, respectively, a general mechanism for redox-neutral sequential and convergent electrolysis.

FIGS. 3A-3G illustrate scopes of selected reactions, performed in the RVC-packed stirring-free reactors (isolated yields are given); FIG. 3H is a photograph of the purified products, obtained in 50 mmol scale electrosynthesis in the large RVC-packed reactor, in which (a) a voltage of 3.2 V was used, and (b) a voltage of 3.5 V and 0.2 M LiBr as supporting electrolyte were used.

FIG. 4A illustrates a Randles circuit; FIG. 4B illustrates a current decay curve for the Randles circuit; FIG. 4C is a graph depicting calculated approximate capacitance values for the RVC-filled reactors, used in this work (0.2M LiClO₄, DMF); and FIGS. 4D and 4E illustrate studies of the dependence of the electrolysis efficiency on the applied frequency n in the small RVC-packed reactor (0.2 mmol scale; NMR yields are given) of, respectively, Ni-catalyzed amination and reductive arylation of benzaldehyde.

It will be appreciated that for simplicity and clarity of illustration, elements shown in the figures have not necessarily been drawn to scale. For example, the dimensions of some of the elements may be exaggerated relative to other elements for clarity. Further, where considered appropriate, reference numerals may be repeated among the figures to indicate corresponding or analogous elements.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

In the following detailed description, numerous specific details are set forth in order to provide a thorough understanding of the invention. However, it will be understood by those skilled in the art that the present invention may be practiced without these specific details. In other instances, well-known methods, procedures, and components have not been described in detail so as not to obscure the present invention.

FIGS. 1A-1C shows the different approaches for designing electrochemical reactors. FIG. 1A shows a batch reactor with rod electrodes and FIG. 1B shows a flow reactor with plate electrodes. These represent the prior art electrochemical reactors. FIG. 1C is an embodiment of an AC-enabled batch stirring-free reactor with 3D net electrodes of the invention.

In order to investigate the suggested design for synthetic performance and further scalability, three RVC-packed (reticulated vitreous carbon) glass reactors were constructed (FIG. 2A) with the technical parameters, as depicted in FIG. 2B. The low porosity (10 and 20 ppi) of the RVC plates, used in the reactors, provided increased mechanical durability of the electrodes, and minimized the impact of capillary forces while working with viscous solutions. In all cases, the RVC electrodes, which were divided by a thin layer of separator material (PTFE or glass pieces), filled the entire working volume of the reactor allowing stirring-free electrolysis. The desired volume of the reactor can easily be adjusted by stacking the electrodes, which provided a straightforward means of scaling up/down the electrosynthesis. The connection of the small and medium reactors to the function generator (FG)—a tunable AC source—included a low-ohm resistor which enabled the real-time control of both current and voltage across the cell, using an oscilloscope. At the same time, the low ohmic resistance of the large reactor required the use of an amplifier to achieve the desired voltage across the electrodes (FIG. 2C).

Convergent and sequential redox-neutral transformations can be considered highly demanding in terms of the mass transfer efficiency and, therefore, represent an ideal example for testing the performance of the suggested design. The design implies the use of AC electrolysis which, in this case, provides not only uniform electrolysis across the whole volume of the reactor, but also eliminates the need in the interelectrode transfer of the reactive intermediates (FIG. 2D-2E). The performance of each selected reaction—Ni-catalyzed amination, Minisci-type alkylation, α-amine C—H arylation, trifluromethylation of (hetero)arenes and dehydration of aldoximes—was investigated using a range of substrates on 0.6-mmol scale, followed by 3.75-mmol and 50-mmol scale experiments.

Ni-catalyzed amination of aryl halides can benefit from the use of AC electrolysis. The proposed mechanism involves oxidative addition of aryl halide to the low-valent nickel species afforded via cathodic reduction, after which the anodic oxidation of Ni(II) species induces the reductive elimination of the coupled product. Using the small RVC-packed reactor, the coupling of 4-Bromobenzotrifluoride with Morpholine and Cyclohexylamine with the yields of 81% (1) and 63% (2), respectively, was achieved (FIG. 3A; in the present description, numbers presented in parentheses and in bold type refer to molecules illustrated in one of FIGS. 3A through 3G), and the formation of (3) with 67% yield. The scale-up electrosynthesis of (1) demonstrated steady yields (3.75 mmol-78%, 50 mmol-83% (9.57 g)) here, the use of lower frequencies and higher reaction times ensured full conversion of the starting material.

It has been found that Minisci-type alkylation of heterocycles with N-Hydroxyphtalimide (NHPI) esters may be performed using the presently disclosed reactor design in combination with AC electrolysis. The reaction of 4-Methylquinoline and methyl nicotinate with NHPI ester of pivalic acid yielded 86% (4) and 70% (5) of the desired products, respectively. The challenging addition of ethyl group to 4-Methylquinoline demonstrated 58% yield (6) (FIG. 3B). The AC electrosynthesis of (4) in the medium and large reactors showed slightly diminished yields (70% and 68% (6.77 g), respectively) of the desired product due to the formation of higher amounts of di- and tri-alkylated products.

Surprisingly, it was found that the use of AC may eliminate the need for a redox mediator, which is considered to be crucial to achieve good results using DC electrolysis. This transformation may be considered an example of a convergent redox-neutral process. Here, the parallel cathodic reduction of aromatic nitrile and anodic oxidation of aromatic amine results in the formation of highly reactive radical species, which yield the product after the following interaction. The reaction of N-(4-Tolyl)pyrrolidine with 1,4-Dicyanobenzene and Methyl 4-Cyanobenzoate afforded 81% and 29% yields, respectively. The yield of 54% was achieved for (9) in the reaction with less electron-rich amine. However, the scale-up experiments demonstrated noticeably lower yields of (7): 53% and 44% (5.77 g) for the reactions in the medium and large reactors, respectively. Most probably, these results were related to the pronounced sedimentation of sodium acetate base in the lower parts of larger reactors due to its low (poor) solubility in dimethylsulfoxide.

AC-assisted redox-neutral trifluoromethylation of (hetero)arenes may be performed using the presently disclosed reactor design. According to some examples, sodium perchlorate may be used as a supporting electrolyte in order to reduce the amount of chlorinated side products via precipitation of sodium chloride. In addition, a base of 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) may be used, e.g., to allow the reaction mixture to be homogeneous and help to reduce the required voltage due to in situ formation of reactive cationic species [DBU-Tf]+. The initial reduction of the trifluromethylating agent yields trifluromethyl radical species, which undergo addition to the (hetero)arene, and the subsequent oxidation affords the product. AC electrolysis in the small reactor demonstrated decent yields of 57% and 51% for the trifluoromethylation of 1,3,5-Trimetoxybenzene and Mesitylene, respectively. The yield of 34% was further achieved for the reaction with caffeine. The scaled-up electrolysis showed a yield of 58% and 55% for (10) on the scale of 3.75 mmol and 50 mmol (6.50 g), respectively. In all cases, di-trifluromethylated species were found to be the main side product, with 22% yield separated in the case of 50 mmol scale reaction.

Electrochemical dehydration of aldoximes using AC current may be performed using the presently disclosed reactor design. Halide ions, for example lithium halides, may be used as supporting electrolyte. According to the proposed mechanism, oxidation of aldoxime results in the formation of nitrile oxide species which are susceptible to the following reduction to the aromatic nitrile. The yields of 72% and 62% were achieved for the synthesis of (13) and (14), respectively, and 60% yield—for the dehydration of 1-Naphtylaldoxime. For the synthesis of (14), lithium bromide was used as supporting electrolyte in order to provide milder oxidation conditions while higher voltage was required to ensure the reduction of the electron-rich intermediate nitrile oxide species. In addition, the electrosynthesis of (13) demonstrated steady yields of 74% and 75% (5.45 g) on 3.75 mmol and 50 mmol scale, respectively.

Importantly, presented redox-neutral transformations were selected as model examples due to the higher demands for the mass transfer reactor efficiency for such processes; it is expected that net-oxidative and net-reductive transformations can be performed smoothly as well using the present invention's reactor design. Here, AC electrolysis ensures the desired redox process to take place across the whole volume of the reactor; at the same time, however, it provides less flexibility in the choice of the electrode materials, compared to DC electrolysis, since all the electrodes serve as both anode and cathode in this case. A couple of example reactions were tested using small setup—thus, oxidative trifluoromethylation of 2-AcetylPyrrole with sodium trifluoromethanesulfinate yielded 65% of (16) as the main product together with 7% of isomer (17) and 10% of di-trifluoromethylated product (18), comparable to the yields of 60% for (16) and 12% for (18) reported with DC electrolysis in similar system. The reductive decyanative coupling of 1,4-Dicyanobenzene and Benzaldehyde with 1,4-Diazabicyclo[2.2.2]octane (DABCO) sacrificial reductant afforded 73% yield of the desired product (19).

Overall, the demonstrated results indicate the feasibility of the suggested design of the electrochemical reactor for the synthetic purposes including redox-neutral, net-oxidative and net-reductive transformations. Importantly, the concept provides a straightforward approach for scaling up the electrosynthesis—the transformations on 3.75 mmol and 50 mmol scale were performed smoothly in most of the discussed cases without additional optimization required.

Provided herein an organic electrosynthesis using the electrochemical reactor described herein. In some embodiments, the electrosynthesis comprises amination of aryl halides, addition reactions, additions of heterocycles, methylations, trifluoromethylation, dehydration of aldoximes, oxidative reactions, oxidative trifluoromethylation of heterocycles, reductive arylation of aldehydes, cyanation of aryl halides, sulfination, amination, esterification, etherification, carboxylation of ethylene, decarboxylation of decyanative of a amine arylation, conversion of dicyanobenzene, or conversion of aryl halides.

According to the reported studies, the frequency of the applied alternating potential may have a significant impact on the selectivity and efficiency of the electrochemical process; therefore, a particular attention should be given for the proper choice of the AC parameters of the electrolysis. In a simplified way, the behavior of the electrochemical cell can be described using Randles circuit with the elements, related to the solution and electron transfer resistances and the capacitance of the electric double layer (EDL) forming near the electrodes (Rs, Ret and Cdl elements on the FIG. 4A, respectively). Here, the current, generated using a constant potential pulse (as in square waveform, used in the synthetic experiments), consists of two components: non-Faradic, related to the charging process of the EDL capacitor, and Faradaic, deriving from the occurring charge transfer on the electrode-electrolyte interface (electrochemical oxidation and reduction of the redox active species) (FIG. 4B). At the initial moments of the pulse, the capacitive component of the total current is predominant; therefore, the increase in the frequency lowers the electrical (Faradaic) efficiency of the process and prolongs the time, required for the full conversion of the starting material; the particular time, required to charge the EDL capacitor, can be evaluated knowing the capacitance and resistance values of the Randles circuit elements. The approximate lower-limit capacitance values for solvent-electrolyte system were calculated using chronoamperometric technique (FIG. 4C)—the value of 80 uF, 305 uF and 5.2 mF were obtained for the small, medium, and large reactors, respectively; the real capacitance values, however, are expected to be somewhat higher due to the higher concentrations of the charged species in the experiments—initially added, formed and electrogenerated. The solution and electron transfer resistances decrease significantly with the increase in the reactor size, explained by the rise in the effective surface area of the electrodes and more favorable parallel packing of the electrodes in case of the large reactor—thus, the upper-limit values of the solution resistance (obtained from electrical impedance spectroscopy measurements) changes from 63 Ohm to 3 Ohm for small and large reactors, respectively, while the observed values of electron transfer resistance (evaluated in accordance to FIG. 2B) varied in the range of 100-350 Ohm for the small and 2-6 Ohm for the large reactors. The obtained data indicate that tens of milliseconds of the pulse time are required to almost fully charge the capacitive element of the cell, setting, thus, the upper limits of frequencies to the values of tens of hertz. In addition, the upper frequency limit also depends on the rate of the chemical reaction which follows the electron-transfer event—thus, the use of too high frequency values will lead to the non-productive reversible oxidation and reduction of the substrate. On the other hand, the frequency value should be sufficiently high to maintain the uniform electrolysis—both anodic oxidation and cathodic reduction—throughout the whole volume of the stirring-free reactor; at the same time, redox-neutral reactions, which involve the formation of the reactive intermediate species and their following oxidation or reduction, may demonstrate lowered selectivity with the prolonged pulse time, favoring the use of the compromise values of frequency.

The viability of the given speculations was tested on the example of two reactions, conducted in the small reactor with a range of frequencies: redox-neutral Ni-catalyzed amination and net-reductive arylation of benzaldehyde. As expected, the redox-neutral process demonstrated its maximum efficiency at a particular optimal frequency—thus, it was observed that the highest 88% yield of the coupled product while using the frequency of 3 Hz. At the same time, the use of lower frequencies (0.01-1 Hz) also provided full conversion of starting material, however, with significantly higher amounts of side products formed (protodehalogenation and diaryl products) while the increased contribution of the capacitive element and non-productive reduction/oxidation cycles lowered or even zeroed the efficiency of the process with higher frequency values (10-100 Hz). The behavior of the reductive reaction was found to be similar at the high frequency region; however, the upper limit of the productive frequencies was found to be slightly shifted to the lower values (sharp decrease in the yields can be observed with the frequency values higher than 1 Hz compared to 3 Hz in amination)—probably, due to the lower rate of the chemical reaction, following the electron-transfer events. In contrast to the redox-neutral amination, the mechanism of the transformation does not involve the sequential reduction and oxidation events and, therefore, stable yields of the coupled product (73-76%) could be observed while using the whole range of lower frequency values (0.01-1 Hz).

The use of alternating current enables the concept of stirring-free reactor where the periodical change of polarity has a crucial role to provide the uniform electrolysis of the reaction mixture across the whole volume of the reactor. The feasibility of the suggested approach was demonstrated on the example of five redox-neutral reactions—thus, good yields were achieved even for reactions reported previously with the use of DC. Importantly, the presented concept suggests a convenient and straightforward way for scaling up of electrosynthetic experiment which was demonstrated on up to 50 mmol scale electrolysis; at the same time, the design can be used in order to perform stirring-free net-oxidative and net-reductive transformations in the similar manner. In addition, the effect of the AC frequency on the efficiency of the electrolysis was studied in detail: the existence of the particular favorable frequency region was demonstrated for the redox-neutral reactions involving the formation of transient intermediates, while, in contrast, other transformations provide stable results at the wide range of low and moderate frequencies.

While certain features of the invention have been illustrated and described herein, many modifications, substitutions, changes, and equivalents will now occur to those of ordinary skill in the art. It is, therefore, to be understood that the appended claims are intended to cover all such modifications and changes as fall within the true spirit of the invention.

Claims

1. An electrochemical reactor comprising at least one apparatus comprising: at least one reactor body; at least one 3D porous electrode and at least one AC source; wherein said electrochemical reactor does not include a stirring element.

2. An electrochemical reactor according to claim 1, wherein said at least one 3D porous electrode is an RVC electrode.

3. An electrochemical reactor according to claim 1, wherein said at least one 3D porous electrode has a porosity of at least 5 ppi.

4. An electrochemical reactor according to claim 1, wherein said at least one 3D porous electrode has a porosity of at least 10 ppi.

5. An electrochemical reactor according to claim 1, wherein said at least one 3D porous electrode has a porosity of between about 5 to 30 ppi.

6. An electrochemical reactor according to claim 1, wherein said reactor is a batch reactor.

7. An electrochemical reactor according to claim 1, wherein said reactor is a flow reactor.

8. An electrochemical reactor according to claim 1, comprising at least two 3D porous electrodes.

9. An electrochemical reactor according to claim 1, comprising at least two 3D porous electrodes; wherein each of said 3D porous electrodes is separated in said reactor by at least one glass separator.

10. An electrochemical reactor according to claim 1, being scaled to industrial organic electrosynthesis reactions.

11. A method of performing organic electrosynthesis, said method comprising providing an electrochemical reactor comprising at least one apparatus comprising: at least one reactor body; at least one 3D porous electrode and at least one AC source; wherein said electrochemical reactor does not include a stirring element; filling said reactor with electrosynthesis reactants; and applying AC through said filled electrochemical reactor; thereby performing said organic electrosynthesis.

12. A method according to claim 11, wherein said electrosynthesis is selected from redox-neutral reaction, amination reaction, esterification reaction, etherification reaction and any combinations thereof.

13. A method according to claim 11, wherein said at least one 3D porous electrode is an RVC electrode.

14. A method according to claim 11, wherein said at least one 3D porous electrode has a porosity of at least 5 ppi.

15. A method according to claim 11, wherein said at least one 3D porous electrode has a porosity of at least 10 ppi.

16. A method according to claim 11, wherein said at least one 3D porous electrode has a porosity of between about 5 to 30 ppi.

17. A method according to claim 11, wherein said reactor is a batch reactor or a flow reactor.

18. A method according to claim 11, comprising at least two 3D porous electrodes.

19. A method according to claim 11, comprising at least two 3D porous electrodes; wherein each of said 3D porous electrodes is separated in said reactor by at least one glass separator.

20. A method according to claim 11, being scaled to industrial organic electrosynthesis reactions.