Highly Modular Flow Cell for Electroorganic Synthesis

Article abstract of DOI:10.1021/acs.oprd.7b00123

A highly modular electrochemical flow cell and its application in electroorganic synthesis is reported. This innovative setup facilitates many aspects: an easy adjustment of electrode distance, quick exchange of electrode material, and the possibility to easily switch between a divided or undivided cell. However, the major benefit of the cell is the exact thermal positioning of the electrode material into a Teflon piece. Thereby, the application of expensive and nonmachinable electrode materials like boron-doped diamond or glassy carbon can easily be realized in flow cells. By this geometry, the maximum surface of such valuable electrode materials is exploited. The cell size can compete with classical preparative approaches in terms of performance and productivity. The optimization of reaction parameters and an easy up-scaling to larger flow cells is possible. By using this cell, the starting material can be saved in the development of the electroorganic transformations. To demonstrate the utility of this particular cell, two transformations of important building blocks for the fine chemical and pharmaceutical industry were established including an efficient and simple workup protocol.

Full text of DOI:10.1021/acs.oprd.7b00123

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Full Paper
Highly Modular Flow Cell for Electro-Organic Synthesis
Christoph Gütz, Andreas Stenglein, and Siegfried R. R Waldvogel
Org. Process Res. Dev., Just Accepted Manuscript • Publication Date (Web): 26 Apr 2017
Downloaded from http://pubs.acs.org on April 26, 2017
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Highly Modular Flow Cell for Electro-Organic
Synthesis
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Christoph Gütz, Andreas Stenglein, Siegfried R. Waldvogel*
Johannes Gutenberg University Mainz, Institute for Organic Chemistry, Duesbergweg 10-14,
55128 Mainz, Germany
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ABSTRACT. A highly modular electrochemical flow cell and its application in electroorganic
synthesis is reported. This innovative setup facilitates many aspects; an easy adjustment of
electrode distance, quick exchange of electrode material, and the possibility to easily switch
between a divided or undivided cell. However, the major benefit of the cell is the exact thermal
positioning of the electrode material into a Teflon piece. Thereby, the application of expensive and
non-machinable electrode materials like boron-doped diamond or glassy carbon can easily be
realized in flow cells. By this geometry, the maximum surface of such valuable electrode materials
is exploited. The cell size can compete with classical preparative approaches in terms of
performance and productivity. Optimization of reaction parameters and an easy up-scaling to
larger flow cells is possible. By using this cell, starting material can be saved in the development
of the electroorganic transformations. To demonstrate the utility of this particular cell two
transformations of important building blocks for the fine chemical and pharmaceutical industry
were established including an efficient and simple work-up protocol.
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KEYWORDS. Electroorganic synthesis - flow electrolysis - isoxazole - nitrile - oxidation -
reduction.
INTRODUCTION
The development of novel, efficient and economically benign techniques for the synthesis of
fine chemicals and pharmaceutically active agent represents one of the major tasks of a process
chemist. Electroorganic synthesis is one of these reemerging technologies. The application of
electricity as reagent exhibits several advantages. For example, no oxidant or reducing agent is
required, thereby no reagent waste occurs and the atomic efficiency is considerably high.
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Moreover, electricity is quite inexpensive compared to reducing agents or oxidizers. An excellent
carbon footprint can be achieved when electricity originates from renewable energy sources,
resulting in a highly sustainable method.1-8 Many novel and powerful transformations were
recently published, like dehalogenations,9-14 allylic oxidations,15,16 oxidative cross couplings,17-20
N,N- or N,C-couplings.21
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One of the major disadvantages of many electrochemical methods, which are described in
literature, are that potentiostatic methods are applied. Up-scaling of these methods is problematic
in terms of the three electrode arrangement and additionally results in prolonged reaction times.
Therefore, only galvanostatic methods are used on a technical scale.22 As an additional challenge,
no standardized and commercially available equipment is on the market and every research group
applies their own home-made setup.
Recently, we presented an approach for the fast screening of electrolysis parameters on a small
batch scale for the development of electrosynthetic transformations.23 Nevertheless, this is only
the first step towards the development of novel state-of-the-art processes on a technical scale.
Simple up-scaling in larger batch cells is possible, but limited to reactor vessels of a few liters.
Larger systems face some major drawbacks: First, efficient mixing, which is significantly
important for a heterogeneous transformation, can be challenging in larger vessels. Secondly, heat
transfer is hampered, since most heat is generated at and in between the electrodes by the electric
resistance where no efficient chilling is possible. Thirdly, the volume-to-surface ratio decreases in
larger batches, which limits the contact between substrate and electrode.
To tackle these issues, a transfer to a continuous flow setup is desirable and advantageous. First
examples for electrosysnthesis in a flow setup are already known, and can be divided into two
major categories: On the one hand, micro flow cells are applied with quite low electrode surfaces
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and productivity.24-39 On the other hand, long channel flow cells are published, which can convert
the substrate in a multi-gram per hour rate.40-47 However, the scope of transformations is limited
to such electrolyses that tolerate a wide range of current densities. In both cases only undivided
systems were applied. Only one specialized system for the production of an important
pharmaceutical intermediate was realized in a divided cell.48 However, it was demonstrated that
the transfer is possible and exhibits the following advantages. First, a high surface-to-volume ratio
within the cell. Secondly, an adjustable electrode distance to decrease the electric resistance and
the amount of supporting electrolyte. Thirdly, instable products can directly be exploited by a
single passage through the cell. Fourthly, a good temperature control. Fifthly, a continuous
synthesis enabling an up-scaling by increasing the cell or simple numbering up. Thus, the
combination of flow chemistry and electrosynthesis represents the best way for large scale
electroorganic synthesis. So far, there is no commercially available system with a modular setup,
in which different kinds of electrodes can be applied. Therefore, a highly modular electrochemical
flow cell is presented, which is now commercially available (see Experimental Section).
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Results
Our flow cell consists of two Teflon pieces with a size of 100 x 40 x 16 mm. On one side, there
is a 60 x 20 x 3 mm open space for the electrode. At the center of the cavity and the backside of
the Teflon piece the connection for the power supply can be positioned. A gasket around the
electrical connector guarantees that the connector and the electrolyte do not come in contact. This
precaution avoids potential corrosion issues. The electrode (size 60 x 20 x 3 mm) is positioned
into the cavity, so that its surface is co-planar with the Teflon piece. This can easily be achieved
by thermal positioning using the following protocol: Teflon is heated up to 200 °C whereby the
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material expands strongly. The cold electrode is inserted. Upon reaching ambient temperature, the
Teflon contracts and seals the gap between electrode and Teflon. The soft and partially fluid
behavior of this particular polymer are beneficial. This thermal insertion ensures a very tight fit.
Removal of the electrode can likewise be performed upon thermal treatment. At both ends of the
Teflon-encased electrode there are inlets/outlets for the electrolyte, which can be connected to the
tubing. The electrolyte is distributed via dendritic feeder at the top providing a sufficient flow
across the electrode surface.
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Figure 1: a) Cross-section of the Teflon piece with connection for tubing, inlet, outlet and free
space for electrode. b) Complete half-cell containing the Teflon piece, the electrode and a
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stainless steel plate. c) Half-cell with gasket/spacer on top. d) Exploded drawing of a complete
divided cell. For the undivided mode, the Nafion membrane and one gasket/spacer is omitted.
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On top of the Teflon piece, a gasket with variable height can be installed so that the gap between
the electrode and the counter electrode can be adjusted between 0.12 mm (Teflon based gaskets)
and up to 2.0 mm (EPDM gaskets). By using two spacers and a Nafion® membrane, a divided
mode for the electrolysis cell is possible. A little overlap of the gasket with the electrode at the
longitudinal side can seal the corners of the electrode, if necessary. Additionally, by application of
pressure later the co-planar arrangement of electrode and Teflon piece is secured. When the second
Teflon piece with the counter electrode is installed at the top by eight screws and two stainless
steel plates, both electrodes press each other in the Teflon piece via the gasket. By this design, the
electrodes need no positioning by screws, which provides an advantage for brittle materials like
boron-doped diamond, graphite or glassy carbon.
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This setup provides an easy to use way to adjust the electrode distance, switching between a
divided or undivided cell as well as simple exchange of electrode material. We equipped the system
with common electrode materials such as platinum, gold, copper, nickel, stainless steel, leaded
bronze (CuSn7Pb15), lead, glassy carbon, boron-doped diamond, and graphite. For pumping the
electrolyte through gap of the flow cell, a membrane or peristaltic pump can be applied. Common
commercially available DC power supplies can be used (0-60 V, see Experimental Section).
To demonstrate the applicability and the performance of this modular cell, two test reactions
were investigated. For the application of an undivided flow cell, we decided to establish a protocol
for a domino-oxidation-reduction reaction we recently developed in batch.49 In this transformation
oxime 1 is first oxidized at a graphite anode to the corresponding nitrile-N-oxide 2 and then
reduced directly at the cathode to the desired nitrile 3. This electrochemical sequence is an
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excellent example for the ability of electrosynthesis to avoid harsh reaction conditions and reagent
waste since commonly P4O10, thionyl chloride, acetic anhydride and other corrosive reagents have
to be applied for the same transformation in conventional synthesis.50 As starting material for the
flow cell process, 2,6-dichlorobenzaldoxime 1 was chosen. This represents a quite challenging
derivative since in batch over-reduction to the monochloro by-product is observed. Furthermore,
the yield in batch is only 40%.49
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Figure 2: Domino-oxidation-reduction sequence for the synthesis of nitriles from aldoximes.
As initial parameters for our studies we employed the optimized conditions from the batch
process.49 Acetonitrile und methyl-tri-propylammonium methylsulfate (MTPS) served as
electrolyte. Lead was used as cathode and graphite as anode material. The gap between the
electrodes was 1 mm. An applied electricity of 2.47 F and a current density of 10 mA/cm2 were
selected. The conversion was monitored by gas chromatography.
Table 1. Optimization of domino oxidation reduction sequence in flow gap cell.a
Entry Electrolyte MTPS Flow Current density Spacer
Yieldb (%)
in CH3CN/H2O
[mL/h]
[mA/cm2]
[mm]
1c
2c
3c
0.012 M in 1:0
15
10
1
3 (18%), 2 (8%), 1 (19%),
by-productsf (15%)
0.012 M in 1:0
0.012 M in 4:1
7.5
15
5
1
1
3 (8%), 2 (29%), 1 (0%), by-
productsf (40%)
10
3 (20%), 2 (31%), 1 (33%)
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0.012 M in 4:1
0.012 M in 4:1
7.5
15
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1
3 (25%), 2 (34%), 1 (29%)
10
0.12
3 (21%), 2 (0%), 1 (52%),
6
by-productsf (6%)
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7c
8c
0.012 M in 4:1
0.1 M in 4:1
0.1 M in 4:1
7.5
15
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10
5
0.12
0.12
0.12
3 (39%), 2 (0%), 1 (31%),
by-productsf (8%)
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3 (32%), 2 (0%), 1 (30%),
by-productsf (6%)
7.5
3 (58%), 2 (0%), 1 (11%),
by-productsf (17%)
9c,d
10e
0.0 M in 4:1
7.5
8.5
5
5
0.12
0.12
3 (30%), 2 (0%), 1 (46%)
3 (80%), 2 (0%), 1 (7%)
0.0 M in 11:1
aReaction conditions: 1.38 g (7.26 mmol) 2,6-dichlorobenzaldoxime in 60 mL electrolyte,
cathode: lead, anode: isostat. graphite, electrode surface 12 cm2, room temperature. bDetermined
c
by GC integrals. Applied electricity 2.47 F. dElectrolyte temperature: room temperature or 50°C.
eApplied electricity 2.18 F. fSum of mono- and twofold dehalogenated product.
Initially, the gas chromatogram indicates a significant amount of dehalogenated by-product
(Tab. 1, Entry 1). A similar result was achieved with a lower current density and a corresponding
reduced flow rate (Tab. 1, Entry 2). Further observed by-products are dimerized or dehalogenated
nitrile-N-oxide and unidentified decomposition products of 3, 2, and 1. They might be formed
during both, electrolysis or injection into GC. By addition of water (ratio CH3CN:H2O = 4:1) the
dehalogenated by-product could be efficiently suppressed (Tab. 1, Entries 3+4). Nevertheless, only
a small amount of product 3 was obtained in respect to the starting material 1 and nitrile-N-oxide
2. The large amount of intermediate 2 indicates that the reduction to the nitrile at the cathode or
the diffusion from anode to cathode was not sufficient. Thus, we replaced the EPDM-based spacer
with a thickness of 1 mm by a Teflon spacer providing a gap of 0.12 mm to analyze the issue of
diffusion between the electrodes (Tab. 1, Entries 5+6). Indeed, no nitrile-N-oxide 2, but more
product 3, was identified, especially for a current density of 5 mA/cm2. To identify whether the
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amount of supporting electrolyte has an influence on the outcome of the electrochemical
conversion, an elevated concentration of supporting electrolyte was applied. This led to an almost
complete conversion of starting material 1 to the desired product 3, but also promoted the
dehalogenation as side reaction (Tab. 1, Entries 7+8). However, the use of no supporting
electrolyte in a 4:1 mixture of acetonitrile/water was successful with a similar applied voltage of
about 6 V. A mixture of starting material and product was obtained, but no dehalogenated by-
product was traced (Tab. 1, Entry 9). This finding demonstrates that the selectivity without
supporting electrolyte is much better, but mass transfer from anodic to cathodic regimes seems to
be inefficient. To increase mass transfer, the electrolyte mixture was pre-heated to 50 °C and then
employed in the electrochemical conversion. However, no change in the product composition was
observed, which underlines that the mass transfer is not problematic. A major drain of electricity
at the electrodes is attributed to the electrolysis of water. Consequently, by lowering the amount
of water within the electrolyte this pathway was efficiently suppressed. However, for sufficient
conductivity and suppression of the dehalogenation pathway to by-products a minimal amount of
water is required. Best results were found when a ratio of acetonitrile to water 11:1 was employed
(Tab. 1, Entry 10). Actually, this was the key finding to ensure a complete conversion of starting
material with an excellent selectivity. Even less applied electricity was necessary to achieve an
excellent conversion, reducing the retention time of the substrate in the cell down to 60 seconds.
To determine the yield of the process, 60 mL of electrolyte was applied and collected after passing
the flow cell. By applying two separate cells and connect them in a serial fashion the electrode
surface can be increased from 12 to 24 cm2 (setup see SI). This reduced the reaction time and
demonstrates the facile scalability of this setup. Thereby, the flow rate was doubled to 17 mL/h
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and reaction time was reduced to 3.5 h for 60 mL of solution. The productivity increased from 110
mg/h (12 cm2 electrode surface) to 220 mg/h (24 cm2 electrode surface).
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Figure 3: Concept of the work-up protocol.
Due to the high selectivity of the transformation a facile work-up protocol of the slightly yellow
solution could be applied (Figure 3). After electrolysis (Figure 4, in black), the solvent was
removed at reduced pressure (50 °C, 100 mbar) to obtain the crude product. The solvent can be
directly reused for subsequent electrolyses. Recrystallization of 3 from ethanol/water (2:1) at –30
°C gave the pure product in 63% yield (Figure 4, in green).
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Figure 4: Black: Gas chromatographic analysis of the electrolyte directly after passing the flow
cell. Green: Gas chromatographic analysis after crystallization.
Compared to the batch process, the yield could be significantly increased from 41% to 63%,
respectively.49 Furthermore, the work-up protocol is simple and no column chromatography is
required. With respect to sustainability issues, this process is exceptional since only electricity and
recyclable solvents are used. No supporting electrolyte or other reagents are necessary.
To test this flow cell for its applicability in a divided mode, we studied a second transformation.
As starting material, we used the same oxime 1 as before. The divided cell setup including a
separator will intercept the reduction of the nitrile-N-oxide 2 to the nitrile 3 at the cathode.
Consequently, the nitrile-N-oxide 2 was accumulated in the anolyte. 2 is an excellent precursor for
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1,3-dipolar cycloadditions.51-54 As reaction partner we chose methyl acetoacetate 4, since the
corresponding product 5 serves as an important building block in pharmaceutical applications, e.g.
for the synthesis of the penicillin derivative dicloxacillin 6 (Fig. 5) or novel FXR agonists.51,55,56
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Figure 5: Electrochemical oxidation in a divided cell followed by a 1,3-dipolar cycloaddition
and further formal transformation to dicloxacillin 6.57
Beside the implementation of an electrochemical process into the transformation, we tried to
circumvent time-consuming purification steps upon generation of the nitrile-N-oxide 2. Since in
the previous process, 2 was already observed as an intermediate, we decided to test first the
conditions used in the previous synthesis, wherein 2 was already observed as an intermediate.
Initially, it was important to elucidate if the cycloaddition can be performed in the established
solvent mixture. Hence, we ran some test reactions with nitrile-N-oxide 2 as starting material in
different electrolyte compositions (Table 2).
Table 2. Optimization of cycloaddition: variation of the electrolyte.a
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Entry
Electrolyte MTPS in
CH3CN/H2O
Base
Yield 5b
6
7
8
9
1
2
3
4
0.1 M in 1:0
0.1 M in 1:0
0.1 M in 4:1
0.1 M in 4:1
-
-
NEt3
-
-
-
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NEt3
100%
aReaction conditions: 30 mg (0.16 mmol) 2, 28 mg (0.24 mmol) methyl acetoacetate (4), 5 mL
solvent, 22 mg (30.5 µL, 0.22 mmol) NEt3, 134 mg (0.5 mmol) MTPS. Reaction time 1 h at 22 °C.
bDetermined by GC integrals.
The test reactions revealed that cycloaddition is possible and highly selective in a mixture of
acetonitrile/water (4:1) and triethylamine (Table 2, Entry 4). Without water or triethylamine no
conversion was observed (Table 2, Entry 1-3).
Subsequently, we focused on the optimization of the electrochemical oxidation to the nitrile-N-
oxide 2. Since in a flow process the parameters current density, flow rate and applied electricity
are not independent, it is more efficient to start the initial screening with batch-type cells. As
catholyte the previous mixture for the transformation in the undivided cell was applied, the anolyte
consisted of a mixture of acetonitrile, water and MTPS combined with 4 and triethylamine. As
cathode stainless steel and graphite as anode were employed at a current density of 10 mA/cm2
and an applied electricity of 2.5 F. Formation of the desired nitrile-N-oxide 2 was observed in
significant amounts, but no cyclization to isoxazole 5 occurred (Table 3, Entry 1). This result
suggested that triethylamine or 4 are decomposed during electrolysis before reacting with 2. We
then decided to separate both transformations and run the electrosynthesis without addition of
triethylamine and 4 and add them directly after electrolysis (Table 3, Entry 2). A significant
increase of isoxazole 5 was detected, demonstrating that addition, after electrolysis is preferable.
Nevertheless, a large amount of starting material was still not consumed. A possible reason for this
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could be the fact that during electrolysis the formation of a thin film on the graphite anode was
observed, which dissolved afterwards. This film formation or fouling can also be problematic for
a later flow electrolysis and should definitely be avoided. A gas chromatographic analysis of this
film revealed that pure 2 crystallized onto the electrode surface. It turned out, that water in the
electrolyte decreased the solubility of 2. However, water is only required for the successful
cyclization and not for the electrolysis in the anodic compartment. So, we excluded the water from
the anolyte. In contrast, for the catholyte the water is important, so that hydrogen can be evolved
at the cathode instead of decomposing the supporting electrolyte. By applying acetonitrile and
MTPS as anolyte and addition of water, triethylamine and 4 upon electrolysis we achieved the
desired isoxazole 5 in a high selectivity (Table 3, Entry 3). This demonstrated that water in the
anolyte had a quite negative effect onto the conversion.
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Table 3. Optimization of electrolysis parameters in batch cell.1
Entry
Electrolyte MTPS in
CH3CN/H2O
Addition for
Cyclization
Yieldd (%)
1a,e
2b,e
3c,e
0.063 M in 4:1
0.063 M in 4:1
0.063 M in 1:0
Prior electrolysis
After electrolysis
After electrolysis
5 (0%), 2 (52%), 1 (23%)
5 (17%), 2 (0%), 1 (30%)
5 (69%), 2 (0%), 1 (4%)
aAdditive solution added before electrolysis: 560 mg (4.82 mmol) 4, 560 µL (4.02 mmol) NEt3.
bAdditive solution after electrolysis: 560 mg (4.82 mmol) 4, 560 µL (4.02 mmol) NEt3.
cAdditive solution after electrolysis: 7 mL H2O, 560 mg (4.82 mmol) 4, 560 µL (4.02 mmol)
NEt3.
dDetermined by GC integrals.
e Anolyte: 600 mg (3.16 mmol) 1, 35 mL solvent, 600 mg (2.23 mmol) MTPS. Catholyte: 28 mL
CH3CN, 7 mL H2O, 600 mg (2.23 mmol) MTPS.
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With these optimized parameters in hand, we started to transfer the process to the flow
electroysis cell. As spacer between the electrodes and the Nafion® 324 separator we used a 1 mm
EPDM foil for each half-cell. To evaluate the efficiency of the flow electrolysis we first focussed
on the formation of the nitrile-N-oxide 2 without later cyclization.
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Table 4. Optimization of flow parameters for electrolysis.a
Entry Electrolyte MTPS Flow Current density
Applied
electricity [F] [mm]
Spacer
in CH3CN
[mL/h
]
[mA/cm2]
Yieldb (%)
1
2
3
4
5
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8
0.1 M
0.1 M
18.5
9.5
14.5
9.5
7.5
8.5
8.5
8.5
10
10
8
2
1
1
1
1
1
1
2 (26%), 1 (26%)
2 (34%), 1 (14%)
2 (29%), 1 (27%)
2 (40%), 1 (23%)
2 (47%), 1 (16%)
2 (62%), 1 (12%)
3.9
2
0.1 M
0.1 M
5
2
0.1 M
5
2.48
2.18
2.18
2.18
0.012 M
0.012 M
0.012 M
5
5
0.12 2 (27%), 1 (48%)
0.25 2 (10%), 1 (44%)
5
aReaction conditions: anolyte: 1.38 g (7.26 mmol) 1, 60 mL acetonitrile, supporting electrolyte
MTPS. Catholyte: 55 mL CH3CN, 5 mL H2O, supporting electrolyte MTPS. Anode: graphite,
cathode: stainless steel. Electrode surface: 12 cm2. bDetermined by GC integrals.
Initially, electrolyte composition was kept constant with a high concentration of supporting
electrolyte. In addition, we analyzed the influence of different flow rates, current densitiy and
applied electricity. It turned out that the best results were achieved at a current density of 5
mA/cm2, a flow rate of 7.5 mL/h and 2.48 F (Table 4, Entry 5). Comparable results were obtained
at higher flow rates and less applied electricity (Table 4, Entry 4). Higher current densities and
higher flow rates, however, led to a diminished production of nitrile-N-oxide 2 (Table 4, Entries
1-3). A decrease in the amount of supporting electrolyte to a concentration of 0.012 M of MTPS
gave the best result for the transformation (Table 4, Entry 6). Only when no supporting electrolyte
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was applied the cell voltage increased and the conversion decreased over a period of time, which
is due to a nitrile-N-oxide film formation on the graphite electrode. This effect is hampered by the
addition of supporting electrolyte. It is remarkable that a narrower gap between the electrode and
the Nafion® membrane of 0.25 or 0.12 mm decreases the efficiency of the process (Table 4, Entries
7 and 8). A reason could be the hydrogen evolution at the stainless steel cathode, which leads to
fast generation of bubbles and conductivity problems, especially at higher current density. Another
reason for the lower rate of conversion could be the decrease of the retention time from 8.5 min to
2.1 (0.25 mm gap) or 1.0 min (0.12 mm).
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For the determination of yield for the best electrolysis conditions (Table 4, Entry 6) we collected
60 mL of the electrolyte solution after passing the flow cell and added the corresponding amount
of triethylamine, water and 4 and stirred the solution for 1.5 h at 22 °C. Again, it is also possible
to combine two separate flow cells in a serial manner to increase the electrode surface from 12 cm2
to 24 cm2 (see setup in the SI). Thereby, the flow rate can be doubled, reaction time reduced to
half and the productivity increased from 176 mg/h to 353 mg/h. In the end, online mixing of
trapping mixture after electrolysis is viable by extra pumping (for triethylamine and water, and for
4, respectively, due to stability issues of 4 in basic media. Schematic setup see SI).
As described above, cyclization occurred very fast and efficiently resulting in a full conversion
of the nitrile-N-oxide 2 to 5. For work-up, we removed the solvent at reduced pressure. Fractioning
of layers was achieved by addition of ethyl acetate (Figure 6). To remove possible polymeric by-
products we filtered through a pad of silica gel (eluent ethyl acetate: cyclohexane, 1:1) and
removed the solvents (100 mbar, 50 °C) and volatile by-products at reduced pressure (75-80 °C, 1
* 10-3 mbar). The residue was distilled (100 °C, 1 * 10-3 mbar) or crystallized from n-heptane to
obtain the highly pure product (99% GC) as colorless solid in a yield of 60% (Figure 7). The same
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yield was obtained in a batch cell, which indicates that the transfer of the process into a flow cell
can be realized without loss of yield. Additionally, in comparison to the conventional synthesis of
this building block, the yield could be slightly increased from 53 to 60%.55
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Figure 6: Strategy for work-up when trapping 2 as isoxazole 5.
In addition to the increase of yield, the avoidance of reagent waste and work-up between the
generation of nitrile-N-oxide 2 and cyclization to isoxazole 5 saves time and makes this
electrochemical transformation much more sustainable and economic.
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Figure 7: Gas chromatographic analysis: Black: after passing the flow cell and prior trapping.
Green: 1.5 h after addition of 4, H2O and NEt3. Red: After distillation at 100°C, 1*10-3 mbar or
crystallization from n-heptane.
In summary, we were able to establish a novel highly modular flow cell for the transfer of
electroorganic conversions from batch cells to flow system. The setup allows easy adjustment of
electrode materials, electrode gap and flow. By thermal positioning of the electrode into the Teflon
frame even non-machinable electrode materials like boron-doped diamond or glassy carbon can
be applied. Additionally, the cell can operate in an undivided or a divided mode, which increases
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the utility of electrosynthesis in flow enormously. Fast determination of the process parameters in
a small, economic scale can be realized. Thereby, the setup represents the first step towards process
development of electroorganic transformations. This was demonstrated by the development of two
electrochemical conversions in flow. For both an increased yield was obtained, which exhibit the
potential of electrochemistry in organic synthesis.
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Experimental Section
General Information. 2,6-Dichlorobenzaldoxime (97% purity, Abcr) and acetonitrile (HPLC-
grade, Fluka) are commercially available and were used without further purification. Methyl-tri-
propylammonium methyl sulfate (MTPS) was synthesized accordingly to methyl-tri-
ethylammonium methylsulfate (MTES) in 90% yield.17 1H NMR and 13C NMR spectra were
recorded at 25 °C by using a Bruker AV II 400 (Bruker, Germany). Chemical shifts (δ) are reported
in parts per million (ppm) relative to traces of CHCl3 in the corresponding deuterated solvent. Gas
chromatography was performed on a Shimadzu GC-2025 (Shimadzu, Japan) using a ZB-5 column
(Phenomenex, USA; length: 30 m, inner diameter: 0.25 mm, film: 0.25 mm, carrier gas: hydrogen).
As power source a Z60-3.5 (TDK Lambda, Achern, Germany; dc output 0-60 V (±0.01V and 0-
3.5 A (±1 mA) was applied. The electric current was adjusted for the given current density,
whereas the voltage was set freely. For pumping the electrolytes membrane pumps “Dosierpumpe
Ritmo R 033/7-16” (Fink Chem + Tec GmbH & Co.KG, Leinfelden-Echterdingen, Germany) were
used. Recently, the electrochemical flow cell is commercially available as ElectraSyn flow from
IKA
Werke
GmbH
&
Co.
KG,
Staufen,
Germany
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(http://www.ikaprocess.de/Produkte/Kontinuierliche-Elektrosynthese-cph-45/). Filtration column
chromatography was performed on silica gel 60 M (0.060-0.200 mm, Macherey-Nagel GmbH &
Co, Düren, Germany). As eluent a mixture of ethyl acetate and cyclohexane was used.
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Synthesis of 2,6-dichlorobenzonitrile 3. 1.38 g (7.26 mmol) 2,6-dichlorobenzaldoxime 1 were
dissolved in 55 mL acetonitrile and 5 mL deionized water and pumped via a membrane pump
through the electrochemical flow gap cell equipped with a lead cathode, an isostatic graphite anode
(electrode surface 12 cm2) and a 0.12 mm Teflon spacer without any separator membrane. A
current density of 5 mA/cm2 (I = 60 mA) and a flow rate of 8.5 mL/h were applied which
corresponds to an applied electricity of 2.18 F. Alternatively, two electrochemical flow cells were
connected in series, which lead to a flow rate of 17 mL/h and a current I = 2 x 60 mA = 120 mA).
After passing the flow cell, the solvent was removed under reduced pressure and the residue (1.172
g) was recrystallized from ethanol / water (2:1, 17 mL) at -30 °C and washed with further 30 mL
of the mixture. Drying under reduced pressure gave the desired product 3 as colorless needles in
62% yield (774 mg, 4.5 mmol). Analytical data are in accordance with the literature.49
Synthesis of methyl 3-(2,6-dichlorophenyl)-5-methylisoxazole-4-carboxylate 5 via batch
electrolysis. The electrolysis was performed in a divided glass cell with a Nafion® 324 separator
(see SI) and an isostatic graphite anode and a lead cathode (total size 20 x 70 x 3 mm, immersion
depth 20 x 40 x 3 mm). The current density j was 10 mA/cm2, which corresponds to a current I of
80 mA, and the applied electricity was 2.18 F (664 C). As catholyte, a solution of 28 mL
acetonitrile, 7 mL deionized water and 600 mg (2.23 mmol) MTPS was applied. As anolyte a
solution of 600 mg (3.16 mmol) 2,6-dichlorobenzaldoxime 1, 35 mL acetonitrile and 600 mg (2.23
mmol) MTPS was used. After electrolysis the solution was transferred to a round bottom flask and
a freshly prepared solution of 560 mg (4.82 mmol) methyl acetylacetonate 4, 7 mL water and 560
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µl (4.02 mmol) triethylamine was added and stirred for 1.5 h at 22°C. The work-up protocol was
similar to that of the flow protocol.
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Synthesis of methyl 3-(2,6-dichlorophenyl)-5-methylisoxazole-4-carboxylate 5 via flow
electrolysis. For the catholyte, 0.2 g (0.74 mmol) methyl-tri-ethylammonium methylsulfate
(MTPS) were dissolved in 55 mL acetonitrile and 5 mL deionized water. For the anolyte, 1.38 g
(7.26 mmol) 2,6-dichlorobenzaldoxime 1 and 0.2 g (0.74 mmol) methyl-tri-ethylammonium
methylsulfate (MTPS) were dissolved in 60 mL acetonitrile. Each solution was pumped via
membrane pump through the electrochemical flow gap cell equipped with a stainless steel cathode,
an isostatic graphite anode (electrode surface 12 cm2) and two 1 mm EPDM spacer (each between
the half-cell Teflon piece and the membrane) with a Nafion® 324 separator membrane. A current
density of 5 mA/cm2 (I = 60 mA) and a flow rate of 8.5 mL/h were applied which corresponds to
an applied electricity of 2.18 F. Alternatively, two electrochemical flow cells were stacked which
lead to a flow rate of 17 mL/h and a current I = 2 x 60 mA = 120 mA). After passing the flow cell
1.026 g (8.8 mmol, 1.2 equiv.) acetoacetate methyl ester, 2.1 mL (1.53 g, 15.15 mmol, 2.1 equiv.)
triethylamine and 12 ml deionized water were added and the solution was stirred for 1.5 h at room
temperature (22 °C). The solvent was removed under reduced pressure and the residue was
dissolved in 50 mL ethyl acetate and 50 mL water. The organic phase was separated and the
aqueous phase extracted two time with 50 mL ethyl acetate. The combined organic phases were
washed with 50 mL brine, dried over magnesium sulfate, and the solvent was removed under
reduced pressure. The crude product was filtered through a pad of silica (3.5 cm Ø, 3 cm2 height),
eluent 70 mL ethylacetate / cyclohexane 1:1. Solvent was removed under reduce pressure and
volatile impurities were distilled at 75-80°C and 1 * 10-3 mbar. Distillation at 100 °C and 1 * 10-3
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mbar or crystallized from n-heptane (15 mL) provides the desired product 5 as white crystals in
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ASSOCIATED CONTENT
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Supporting Information.
8
9
The following files are available free of charge.
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Technical and explosion drawings and pictures of modular flow gap cell (PDF)
AUTHOR INFORMATION
Corresponding Author
* E-Mail: waldvogel@uni-mainz.de. Phone: +49 6131 39 26069. ORCID: 0000-0002-7949-
9638
Author Contributions
The manuscript was written through contributions of all authors. All authors have given approval
to the final version of the manuscript.
Funding Sources
Federal Ministry of Education and Research project MANGAN (FKZ 03S0506). Federal
Ministry of Education and Research project EPSYLON (FKZ 13XP5016D). Carl-Zeiss-Stiftung
project ELYSION.
ABBREVIATIONS
MTPS = tripropylmethylammonium methyl sulfate [Pr3MeN]OSO3Me.
REFERENCES
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