pubs.acs.

org/OPRD Article

Electrochemical Oxidation of Alcohols Using Nickel Oxide Hydroxide

as Heterogeneous Electrocatalyst in Batch and Continuous Flow
Wolfgang Jud, Chase A. Salazar, Joseph Imbrogno, Jenson Verghese, Steven M. Guinness,
Jean-Nicolas Desrosiers, C. Oliver Kappe, and David Cantillo*
Cite This: Org. Process Res. Dev. 2022, 26, 1486−1495 Read Online

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ABSTRACT: An electrochemical method has been developed for a mediated oxidation of primary alcohols to carboxylic acids. The
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method is compatible with a variety of alcohols bearing nitrogen-containing heterocycles in undivided batch and flow modes. The
use of a heterogeneous NiOOH electron−proton transfer mediator avoids the need for homogeneous catalysts that contribute to
more unit operations during downstream purging and increased process mass intensity. To demonstrate the applicability of this
method for continuous processing, a single-pass flow electrochemical oxidation of nicotinyl alcohol to nicotinic acid is demonstrated
with a 77% isolated yield. The NiOOH-coated anodes show no reduction in catalysis efficiency over 12 h, and minimal Ni metal
leaching (22.3 μg per liter) is observed.
KEYWORDS: alcohol oxidation, electroorganic synthesis, continuous processing, flow electrochemistry

■ INTRODUCTION
Electrochemical oxidations are attractive alternatives to
potential benefits of the electrochemical oxidations.14 An ideal
electrochemical oxidation process would use an inexpensive,
traditional chemical oxidations because they often reduce recyclable heterogeneous EPTM capable of oxidizing pharma-
ceutically relevant compounds.
process mass intensities (PMI), generate benign byproducts,
Nickel anodes coated with nickel oxide hydroxide (NiOOH)
and de-escalate safety risks.1,2 Chemical oxidants such as CrO3,
active layers15 offer an opportunity for the development of an
KMnO4, hypervalent iodine reagents, and pyridinium chlor-
inexpensive heterogeneous EPTM capable of oxidizing
ochromate are often avoided on scale due to toxicity hazards
pharmaceutical intermediates bearing alcohols to the corre-
and stoichiometric amounts of undesirable byproducts.3,4
sponding carboxylic acids. NiOOH, formed on nickel anodes
Electrochemical oxidation reactions typically generate H2 as a
upon oxidation under alkaline conditions, is a heterogeneous
benign byproduct5 that can be easily managed with proper gas
EPTM that has received relatively little attention during the
release strategies.6 The tunable control of the anodic redox
past two decades. The reactivity of NiOOH is analogous to
potential and electrode material/electrolyte combination allow
that of the conventional nickel peroxide, wherein multiple
for improved product selectivity.7
concerted hydrogen atom transfer steps occur with the
Electrochemical methods are a promising enabling technol-
addition of water to oxidize the alcohol to the corresponding
ogy for scalable oxidations in the synthesis of active
carboxylic acid.16 Most examples of electrochemical oxidation
pharmaceutical ingredients or their precursors;8 however,
of alcohols using nickel electrodes in alkaline media have been
some electrochemical oxidations come with significant
limited to relatively simple starting materials, such as aliphatic
development challenges. Many oxidations of organic molecules
alcohols, protected sugar derivatives, or unfunctionalized
require the transfer of two electrons and two protons.9 aromatics (e.g., benzyl alcohol).15,16 The utilization of nickel
Heterogeneous electrodes typically favor an outer sphere electrodes under alkaline conditions for the oxidation of
electron transfer mechanism resulting in single electron primary alcohols to carboxylic acids was first reported by
transfer (SET) from the substrate.10 Generation of the high- McKee and Heard back in the 1930s.17 During the second half
energy radical-cation intermediates requires a large over- of the 20th century, significant contributions to the knowledge
potential for some functional groups, resulting in poor product on the electrocatalytical properties of NiOOH toward alcohol
selectivity and synthetic utility.11 To overcome this challenge, oxidation were made by Fioshin,18 Nagy,19 Pletcher,20
homogeneous electron−proton transfer mediators (EPTM), Schäfer21 and others.15 This electrochemical strategy has
such as N-oxyl compounds, are often used to switch the
mechanism from sequential removal of electrons and protons
to a concerted processes (e.g., hydrogen-atom transfer or Received: February 28, 2022
hydride transfer).12 This modification results in a lower kinetic Published: April 24, 2022
barrier for oxidation and therefore a lower overpotential and
better synthetic utility. The downside to using these
homogeneous mediators is their relatively high cost, toxicity,13
and the need for downstream removal, which can offset the
© 2022 The Authors. Published by
American Chemical Society https://doi.org/10.1021/acs.oprd.2c00064
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Organic Process Research & Development
recently been applied to the conversion of 5-hydroxymethyl-
furfural (HMF) to 2,5-furandicarboxylic acid.22 Notably, it has
also been applied on an industrial scale: anodic oxidation of
diacetone-L-sorbose to diacetone-2-keto-L-gulonic acid, an
intermediate in the synthesis of ascorbic acid, was carried
out by F. Hoffmann-LaRoche in a 2 ton per day scale in the
1980s.23 We questioned whether this methodology is also
suitable for the oxidation of alcohols bearing heteroaromatics
relevant to active pharmaceutical ingredients and their
intermediates to the corresponding carboxylic acids.
Herein, we present a continuous flow process for the
electrochemical oxidation of primary alcohols bearing nitro-
gen-containing heterocycles, such as pyridine, pyridimidine, or
piperazine derivatives, catalyzed by a heterogeneous NiOOH
EPTM. The heterogeneous EPTM shows no loss in catalyst
activity over 12 h in a continuous single-pass flow reactor. The
heterogeneity of the catalyst was confirmed by ICPMS analysis
of the product stream that showed low homogeneous nickel
content (22.3 μg L−1). The heterogeneous nature of the
NiOOH EPTM coupled in a single-pass flow reactor cascade
demonstrates the applicability of scaling this methodology with
continuous manufacturing and opens opportunities for
reduced unit operations, decreased PMI, and integration with
downstream steps.
■
RESULTS AND DISCUSSION
Electrode Activation and Electrochemical Alcohol
Oxidation in Batch Mode. Upon contact with alkaline
aqueous solutions, a layer of Ni(OH)2 forms on the surface of
metallic nickel. If nickel is used as anode material in an
electrochemical cell containing alkaline water, this layer is
oxidized to nickel oxide hydroxide (NiOOH) with concurrent
hydrogen generation at the cathode (Scheme 1).15
Scheme 1. Formation of NiOOH from Ni(OH)2 by Anodic
Oxidation
NiOOH can oxidize alcohols to the corresponding carbonyl
compounds. Under electrolytic conditions, the layer of
NiOOH is constantly regenerated during the reaction, thus
acting as a heterogeneous redox mediator. Formation of
NiOOH on the surface of a nickel anode can be affected by the
surface properties (e.g., presence of other oxides) and, as
NiOOH is the active species for the oxidation of alcohols,
ultimately affect the efficiency of the electrochemical
process.24,25 To confirm this potential issue, the oxidation of
cyclohexanol (1) to cyclohexanone (2) using nickel electrodes
in alkaline water was evaluated as a simple model reaction
(Table 1). For this purpose, three nickel materials from
different commercial vendors were installed in electrolysis cells
(IKA ElectraSyn 2.0, 5 mL undivided cells) without any
surface treatment and tested for the reaction (Table 1, entries
1−3). The electrochemical reactions were carried out under a
constant current of 10 mA (ca. 6.6 mA cm−2). As anticipated,
the efficiency of the oxidation of 1 to the ketone 2 significantly
differed between the nickel materials. The best performing
anode (entry 1) was the original IKA electrode material. Yet, 6
F mol−1 of applied charge were required to achieve 93% GC
yield, which corresponds to a current efficiency of only 31%.
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Table 1. Effect of the Anode Pretreatment on the Efficiency
of the Electrochemical Oxidation of 1 to 2 Using Different
Nickel Materialsa
Applied Charge GC Yield
Entry Anodeb Pretreatmentc (F mol−1) (%)d
1 Ni-1 No 6 93
2 Ni-2 No 6 18
3 Ni-3 No 6 8
4 Ni-1 Yes 2 90
5 Ni-2 Yes 2 83
6 Ni-3 Yes 2 80
a
Conditions: 5 mL of IKA ElectraSyn vial, 3 mL of solvent, 0.3 mmol
of 1, constant current, 1000 rpm. bNi-1: IKA ElectraSyn nickel. Ni-2:
Nickel from Tifoo (Marawe GmbH). Ni-3: Nickel from Goodfellow.
c
NiOOH layer generated by electrolysis of 5 mL of an aqueous
solution of 0.1 M NiSO4, 0.1 M KOAc, and 0.005 M KOH (see
Experimental Section for details). dDetermined by GC-FID peak area
percent.
Other commercial nickel sources (entries 2 and 3) performed
poorly without surface pretreatment, with current efficiencies
below 10% in both cases. We anticipated that formation of a
NiOOH layer on a nickel anode under controlled conditions,
prior to the electrochemical reaction, would improve both the
efficiency of the alcohol oxidation and the reproducibility of
the results, independent of the source of the nickel material
utilized. Thus, a literature protocol24 for the generation of
NiOOH layers on metallic nickel surfaces was applied to the
three electrode materials. The pretreatment consisted of
cleaning the metal surface with sand paper and 1 M HCl
under sonication, to remove any undesired oxides from the
electrode, followed by electrolysis of a 0.1 M solution of NiSO4
in alkaline water (see Experimental Section for details). After
this process, a layer of NiOOH could be visually observed as a
black coating on the anode surface (Figure 1). Gratifyingly,
after this activation process, the performance of the three
electrode materials was significantly improved (Table 1, entries
4−6). The original IKA ElectraSyn nickel electrode only
required 2 F mol−1 to convert 90% of the cyclohexanol (1) to
cyclohexanone (2) (90% current efficiency). Most importantly,
all materials performed with analogous efficiency after
activation and similar GC yields were obtained for the
electrochemical alcohol oxidation in all cases. Notably, when
the activated electrodes were immersed in the aqueous
solution of the alcohol in the absence of electrical current,
the black layer of NiOOH disappeared. Thus, it is important to
rapidly turn on the cell current upon introduction of the
reaction mixture.
We next turned our attention to a more complex, pyridine-
containing primary alcohol such as nicotinyl alcohol (3a),
which forms nicotinic acid (4a) upon oxidation with NiOOH
(Table 2). In this case, 2 F mol−1 of charge were passed in all
experiments. Oxidation of 3a to 4a is a four-electron process,
and thus yields up to 50% were expected. This low amount of
charge was applied to observe more easily the different
performance of the nickel materials. As 4a absorbs slightly
better than 3a at the UV−vis wavelength selected for the
HPLC detector (215 nm), peak areas above 50% were
observed. Anode pretreatment was carried out using the same
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Figure 1. Visual aspect of the electrodes before (left) and after (right)
the activation process.
Table 2. Reproducibility of the Anodic Oxidation 3a to 4a
Using Different Nickel Materials after Surface Activationa
Applied Charge 4a HPLC
Entry Anodeb Pretreatmentc (F mol−1) Area %d
1 Ni-1 No 2 30
2 Ni-1 Yes 2 59
3 Ni-2 Yes 2 54
4 Ni-3 Yes 2 55
a amounts of unidentified side-products had been formed. The
Conditions: 5 mL of IKA ElectraSyn vial, 3 mL of solvent, 0.3 mmol
of 3a, constant current, 1000 rpm. bNi-1: IKA ElectraSyn nickel. Ni-2:
Nickel from Tifoo (Marawe GmbH). Ni-3: Nickel from Goodfellow.
c
NiOOH layer generated by electrolysis of 5 mL of an aqueous
solution of 0.1 M NiSO4, 0.1 M KOAc, and 0.005 M KOH (see
Experimental Section for details). d215 nm uncalibrated data.
procedure as described above. The electrolysis conditions were
analogous to those used for 1. Thus, alcohol 3a (0.1 M) was
dissolved in an aqueous solution of 0.1 M KOH. The solution
was placed in a 5 mL undivided cell (IKA ElectraSyn 2.0) and
electrolyzed under constant current. Importantly, the anode
activation using the pretreatment protocol also showed to be
essential for this transformation. The efficiency of the anodic
oxidation of 3a was twofold when an activated nickel anode
was utilized instead of a regular nickel electrode (Table 2, entry
1 vs entry 2). Moreover, similar yields (55−59%) were
observed for the electrochemical oxidation using all three
electrode materials (entries 2−4).
Optimization of the Batch Electrolysis and Reaction
Scope. The anodic oxidation of primary alcohols to carboxylic
acids using NiOOH-coated nickel electrodes was then
optimized using the synthesis of nicotinic acid (4a) from
nicotinyl alcohol (3a) as a model. The initial set of conditions
consisted of 10 mA (6.6 mA cm−2) constant current
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electrolysis of a 0.1 M solution of 3a in aqueous 0.1 M
KOH. Gradual increase of the amount of charge applied from
2 F mol−1 to 6 F mol−1 (Table 3, entries 1−3) revealed that
Table 3. Optimization of the Electrolysis Conditions for the
Oxidation of 3a to 4aa
KOH 3a Applied Charge 4a HPLC
Entry (M) (M) (F mol−1) Area %b
1 0.1 0.1 2 59
2 0.1 0.1 4 79
3 0.1 0.1 6 81
4 0.2 0.1 6 85
5 0.5 0.2 6 87
6c 0.5 0.1 6 88
a
Conditions: 5 mL of IKA ElectraSyn vial, 3 mL of solvent, constant
current, 1000 rpm; Ni*: Ni anode activated with a NiOOH layer.
b
215 nm uncalibrated data.
the reaction progress halted after 4 F mol−1. This issue was
ascribed to the fact that the acidic product neutralizes 1 equiv
of KOH. Thus, as the reaction progresses, the pH of the
reaction solution becomes less alkaline than that required to
maintain a stable NiOOH layer on the anode. Formation of 4a
could be improved by increasing the concentration of KOH to
0.2 M (entry 4) (85%) and then to 0.5 M (entries 5 and 6).
Under these conditions, 0.1 and 0.2 M solutions of 3a could
efficiently by transformed into 4a. Increase of the current
density from 6.6 mA/cm2 to 13.2 mA/cm2 had a negative
effect on the amount of product generated (84%), while a
decrease of the current density to 3.3 mA/cm2 did not change
the reaction outcome. HPLC analysis revealed the alcohol
starting material had been nearly consumed (>95%), and small
acidic nature of 4a enabled an extractive isolation procedure.
The crude reaction mixture (entry 6) was extracted with Et2O
to remove all neutral organics (e.g., remaining substrate).
Then, the aqueous solution was acidified to ca. pH = 4 with 3
M HCl. The water was removed under reduced pressure, the
residue was suspended in EtOH, and the solid (KCl) was
filtered-off. Evaporation of EtOH yielded pure nicotinic acid
(79%). This data correspond to a current efficiency of 53%.
The optimal reaction conditions were then applied to a
variety of nitrogen heterocycle-containing primary alcohols
(Table 4). Apart from nicotinic acid (4a), isonicotinic acid
(4b) could also be synthesized with very good yield. The
oxidized carbon did not need to be directly attached to the
aromatic ring, as shown by the synthesis of 4c. Importantly,
oxidative decarboxylation of the product, a potential side
product for aliphatic derivatives, was not observed. Pyrimidine
derivatives 4d and 4e were also prepared successfully using this
methodology from the corresponding alcohols, as well as
pyridazine-3-carboxylic acid (4f). The procedure was also
applied to quinoline-decorated primary alcohols, resulting in
acids 4g and 4h in good yields. It should be noted that very
good conversion of the alcohol starting material and selectivity
to the carboxylic acid was observed in most instances.
Formation of N-oxide side products was not observed in any
of the examples evaluated. However, isolation of the highly
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Table 4. Scope of the NiOOH-Mediated Anodic Oxidation of Alcoholsa

a
Conditions: 10 mL of IKA ElectraSyn vial, 10 mL of solvent, 1 mmol of substrate, constant current, 1000 rpm; Ni*: Ni anode activated with a
NiOOH layer. b215 or 254 nm uncalibrated data (see Experimental Section). ctBuOH added as cosolvent in a 1:1 ratio to solubilize the substrate.

polar nitrogen-containing carboxylic acids proved troublesome
in some cases, which explains why comparatively moderate
isolated yields were achieved for some products.26 Importantly,
the NiOOH layer on the surface of the activated anodes
showed excellent stability. An activated anode could be used
for a large number of experiments, including the complete
scope of the study without the need for regenerating the
NiOOH layer, which remained intact.
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Electrode Activation and Electrochemical Alcohol
Oxidation in Flow Mode. To provide a scalable alcohol
oxidation procedure, the electrochemical procedure described
above was transferred to a flow electrolysis cell. The scaleup of
electrochemical processes rely upon the use of flow electrolysis
cells.27 Flow cells are superior to their batch counterparts
owing to the narrow interelectrode gaps and the high electrode
surface area-to-volume ratio that characterize them.28 These
features improve the mass transfer and reaction efficiency, and
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Organic Process Research & Development
enable reliable cell performance independent of the reaction
scale.29 Translation of electroorganic reactions to flow cells,30
even initially on a small scale, is therefore essential to ensure
that the process can ultimately be scaled up. Indeed, examples
of electrochemical alcohol oxidation in flow cells based on
nitroxyl radical mediators31 or direct oxidation on carbon
anodes32 have been described in the literature in the past few
years.
Although electrochemical reactions in flow electrolysis cells
are often performed with recirculation of the electrolyte,27,28
realization of single-pass processing offers interesting advan-
tages, as it entails truly continuous processes that can be
readily integrated with other synthetic or workup steps.
Achieving high yields in a single pass through a flow
electrolysis cell is typically challenging due to the issues
related to gas evolution at the counter electrode (e.g.,
hydrogen formation at the cathode during an anodic
oxidation). In recirculation mode, however, the issue of gas
formation within the cell can be easily alleviated, as the
reaction mixture is usually pumped at a relatively high flow rate
and the gas can leave the reactor from the electrolyte reservoir
that is vented. An effective strategy to achieve single-pass
electrolysis conditions is to translate the conventional batch
process to flow electrolyte recirculation first.33 In this manner,
potential issues with the electrode materials or other cell
problems can be readily detected, as development of a
recirculation processing mode is relatively straightforward.
In addition to a continuous flow electrochemical alcohol
oxidation, we aimed to establish a protocol for the NiOOH-
based nickel electrode activation in flow mode. Such a
procedure should minimize contact with nickel salts during
the electrode preparation and avoid handling of the NiOOH-
coated electrode during cell assembly. Thus, the experimental
procedure for the generation of a NiOOH layer on the anode
surface was adapted to flow conditions in recirculation mode
(Figure 2a). The flow cell utilized, which has been recently
described in detail,34 consisted of a parallel plate arrangement.
It featured an electrode surface contact area of 6.4 cm2 and a
variable interelectrode gap (0.3 mm to 0.9 mm) (190 to 570
μL cell volume) (see Figure S1). To activate the anode, the cell
Figure 2. (a) Nickel anode activation for the flow electrolysis cell and
(b) visual aspect of the nickel material before (left) and after (right)
the activation procedure.
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was equipped with a nickel anode and a nickel cathode (5 × 5
cm), which had been polished and washed with 1 M HCl prior
to the cell assembly. Then, an aqueous solution containing 0.1
M NiSO4, 0.1 M KOAc, and 10−5 M KOH was pumped
through the cell and the mixture was electrolyzed under
constant current (Figure 2a). During the electrolysis, the
electrode polarity was inverted every 30 s for 3 min. Then, the
current was turned off and the cell was flushed with water to
remove the pretreatment solution. Gratifyingly, visual exami-
nation of the anode (the electrode that had acted as the anode
at the end of the activation process) after the pretreatment
(Figure 2b) confirmed the formation of a homogeneous layer
of NiOOH throughout the reactor channel. Inversion of the
electrode polarity during the activation process provides higher
quality NiOOH layers. This effect has been ascribed to
accumulation of a larger amount of Ni(OH)2 on the electrode
surface during the cathodic cycle, which is then oxidized when
the electrode becomes the anode.24 Importantly, only the
electrode that acts as the anode at the end of the process
contains the activation layer.
As mentioned above, the electrochemical oxidation of 3a to
4a using the flow cell equipped with an activated nickel anode
was initially attempted in electrolyte recirculation mode
(Figure 3). For these experiments, analogous conditions to
Figure 3. (a) Schematic view of the electrochemical oxidation of 3a to
4a in flow recirculation mode and (b) effect of the amount of applied
charge and KOH concentration on the reaction efficiency. Ni*:
NiOOH-coated nickel.
the optimal batch process were applied to assess whether the
NiOOH-activated electrodes performed well in flow mode. A
relatively high flow rate (5 mL min−1) was used to pump the
reaction mixture through the cell, to ensure that the hydrogen
gas generated at the counter electrode was rapidly removed
from the cell. Notably, the anode performance was analogous
to that observed in batch. The KOH concentration in the
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Organic Process Research & Development
electrolyte had a similar influence on the reaction outcome.
Thus, when a 0.1 M KOH solution was used (1 equiv) the
reaction progress stopped after 8 F mol−1 of charge had been
passed (Figure 3b), most likely due to the neutralization of a
large proportion of base by the product. The reaction
conversion increased with the concentration of KOH. Indeed,
with 0.5 M KOH 88% 4a was observed by HPLC, which was
in agreement with the optimal batch conditions.
Recirculation of the electrolyte through a flow cell is a very
useful approach to readily obtain gram quantities of material
even with a laboratory scale small volume cell. Thus, under
optimal conditions, 8 mmol of substrate in an 80 mL solution
were processed in the flow cell (190 μL). After 6 F mol−1 of
charge had been passed, the extractive workup described above
for the batch reaction was applied, yielding 0.78 g of pure 4a
(78%).
We next turned our attention to a single-pass continuous
flow electrolysis procedure. In this case, a solution of 3a in 0.5
M aqueous KOH was continuously pumped through the flow
cell under constant current electrolysis (Figure 4a). Single-pass
Figure 4. (a) Schematic view of the continuous flow setup for the
single-pass electrochemical oxidation of 3a to 4a. (b) Effect of the
flow rate and amount of applied charge on the formation of 4a. Ni*:
NiOOH-coated nickel.
processing is particularly challenging when gas is generated
during the reaction. In this process, in addition to hydrogen
gas evolution at the counter electrode, oxygen gas may also
form at the anode as a result of water oxidation, especially at
high conversions when the substrate concentration is low. For
this reason, the interelectrode gap was increased from 0.3 mm
to 0.9 mm. In this manner, the cell volume was increased, thus
decreasing the extent of electrode coverage by the gas. In an
initial set of experiments, the flow rate and the amount of
applied charge were screened (Figure 4b). Due to the relatively
low residence time of the solution within the reactor (ca. 0.5 to
4 min), a wide range of conditions could be rapidly screened.
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Interestingly, conversion to 4a was highest at low flow rates
and at the fastest flow rates evaluated (100 μL min−1 and 800
μL min−1 vs 400 μL min−1, Figure 4b). This effect was ascribed
to the lower current density used at low flow rates, which
typically leads to higher current efficiencies, and improved
mass-transfer at high flow rate. Yet, conversion to 4a beyond
68% could not be achieved due to the large amount of gas
generated within the cell, which reduced the electrode surface
contact area with the electrolyte and the residence time.
Indeed, increase of the applied charge from 2 F mol−1 to 10 F
mol−1 did not result in a significant increase of the amount of
product. In addition to the negative effect of the gas formation,
an increase of charge for a given flow rate was achieved by
increasing the current density, which may also negatively
impact the reaction outcome.
To improve the electrochemical conversion of 3a to 4a in a
continuous flow fashion, a reactor cascade was then evaluated
(Figure 5). Single-pass flow cell cascades have been shown as a
Figure 5. Schematic view of a single-pass flow electrolysis cell cascade
for the synthesis of 4a by anodic oxidation of 3a.
suitable approach to enhance electrochemical reactions in
which gas formation prevents high conversion in a single pass,
while maintaining the continuous character of the processing
(i.e., a reaction mixture can be continuously introduced into
the system).35 In a flow cell cascade, the reaction solution from
a cell output is introduced into consecutive cells. The gas
generated during the electrolysis can therefore be released
before entering the second unit, thus effectively acting as a gas
removal strategy. In our experiments, as only one flow
electrolysis cell unit was available, a reactor cascade was
emulated by passing a large volume reaction mixture through
the setup multiple times. Thus, a 100 mL reaction mixture was
processed through the cell and collected in a separate reservoir
under steady state conditions. Then, the complete solution was
processed a second and a third time. The electrolysis cell was
set to 64 mA, and the pump, to 100 μL min−1, which
corresponds to a charge passed of 4 F mol−1 after each pass in
the cascade. To our delight, a three-step cascade provided 88%
of 4a, which corresponds to the same HPLC yield as obtained
in batch and in flow with recirculation of the electrolyte. As 12
F mol−1 of charge were applied in total, a current efficiency of
ca. 30% was achieved for the single-pass flow cascade.
Subsequently, a long-run experiment was carried out using
the cascade approach to assess the stability of the flow reactor
and the activated anode material. The reaction conversion was
stable for more than 12 h, which enabled processing of 8 mmol
of 3a. Even after that period, no decrease in the reaction
conversion was observed. Extractive workup of the crude
solution obtained from the reactor cascade yielded 0.76 g
(77%) of 4a. The space-time yield achieved using this
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methodology is 32 kg L−1 h−1. It should be emphasized that
the activated anode could be used repeatedly for a large
number of experiments and even the long run experiment
described above without any degradation of the NiOOH layer.
Moreover, achievement of a continuous flow methodology
ensures that the process can readily be scaled, by employing
larger cells that keep constant the interelectrode gap,
numbering up, or the implementation of cell stacks.27−30
Nickel contamination is of paramount concern when
working with nickel salts and materials, as it is a known
carcinogen.36 Although the activated anodes utilized in this
work showed very high stability, with no degradation of the
activation layer or change in the visual aspect of the electrode
surface, a reaction mixture was analyzed by ICPMS to
determine the nickel content of the solution after electro-
chemical processing. In particular, aliquots of the crude
reaction mixture obtained during the flow single-pass cascade
described above were analyzed. Notably, only a very low
amount of Ni leaching was observed. The three aliquots
collected during the long run experiment had a nickel content
ranging between 19.9 μg L−1 and 22.3 μg L−1. Furthermore, a
significant amount of the nickel detected stemmed from the
KOH utilized to prepare the electrolyte (6 μg L−1). To put this
level of nickel in the crude reaction mixture into perspective,
the WHO recommends nickel levels below 70 μg L−1 in
drinking water.37
■
CONCLUSIONS
In summary, we have developed a sustainable and scalable
electrochemical procedure for the oxidation of primary
alcohols to carboxylic acids. The method is based on the
generation of a nickel oxyhydroxide (NiOOH) layer on the
surface of a nickel anode which, in alkaline aqueous media, acts
as a heterogeneous EPTM promoting the reagent-free alcohol
oxidation. As the heterogeneous electrocatalyst is attached to
the anode surface, a catalyst removal step is not required after
the electrochemical alcohol oxidation, and the catalyst can be
readily reutilized for subsequent reactions. The method has
been shown to be effective for the oxidation of a range of
primary alcohols containing nitrogen heterocycles, which are
relatively challenging substrates due to the electron-with-
drawing nature of the aromatic ring. A scalable continuous
procedure has been established by translating the batch
electrochemical protocol to a flow electrolysis cell. Electrode
activation by generating a NiOOH layer on the anode surface
has been achieved in flow mode, avoiding handling of the
active electrodes and preserving the active layer. Despite the
large amount of gas evolution during the reaction, high
conversion with single pass processing has been achieved by
executing the electrochemical reaction in a three-step flow
reactor cascade. The single-pass flow protocol and the active
electrodes have shown very high stability with a constant
reaction outcome over a > 12 h process. ICPMS analysis of the
crude reaction mixture has confirmed the high stability of the
NiOOH-coated anodes with low levels of Ni leaching (21.3 μg
L−1 on average).
■
EXPERIMENTAL SECTION
General Remarks. 1H NMR spectra were recorded on a
300 MHz instrument. 13C NMR spectra were recorded on the
same instrument at 75 MHz. Chemical shifts (δ) are expressed
in ppm downfield from TMS as the internal standard. The
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letters s, d, t, q, and m are used to indicate singlet, doublet,
triplet, quadruplet, and multiplet, respectively. GC-FID
analysis was performed on a Shimadzu GCFID 2030 with a
flame ionization detector, using an RTX-5MS column (30 m ×
0.25 mm ID × 0.25 μm) and helium as carrier gas (40 cm
sec−1 linear velocity). The injector temperature was set to 280
°C. After 1 min at 50 °C, the temperature was increased by 25
°C min−1 to 300 °C and kept constant at 300 °C for 3 min.
The detector gases used for flame ionization were hydrogen
and synthetic air (5.0 quality). Flash chromatography
purifications were carried out on an automated flash
chromatography system using cartridges packed with KP-SIL,
60 Å (32−63 μm particle size). For HPLC, the separation was
carried out on a Macherey-Nagel Nucleodur C18 HTec
column (150 mm × 4.6 mm, particle size 5 μm) at 37 °C using
mobile phase A (H2O/acetonitrile (9 + 1 v/v) + 0.1% TFA)
and B (acetonitrile +0.1% TFA) at a flow rate of 0.6 mL min−1.
The following gradient was applied: hold 5% of B for 2 min,
then linear increase from 5% B to 20% B in 6 min, followed by
a linear increase from 20% B to 100% B in 1 min, then hold
100% B for 1 min, followed by column equilibration time at 5%
B for 5 min. The detection of compounds was accomplished by
a diode array detector. Peak areas were integrated at 215 nm
(4a, 4b, 4d, 4h) or 254 nm (4c, 4e, 4f, 4g). ICPMS analysis
was carried out on an Agilent 7900 spectrometer. Homoge-
neous electrolyte samples were acidified with HNO3 and
diluted prior to ICPMS analysis. All chemicals were obtained
from standard commercial vendors and were used without any
further purification. All electrochemical batch reactions were
carried out in an IKA ElectraSyn 2.0 using IKA ElectraSyn 2.0
undivided cells (5 or 10 mL vials) equipped with standard IKA
ElectraSyn 2.0 electrodes. Electrochemical reactions in
continuous flow were conducted in an in-house constructed
electrochemical reactor, described previously.33 The 5 × 5 cm
Ni electrodes for the flow electrolysis cell were cut from 15 ×
15 cm Ni foil of 0.3 mm thickness and 99.98% purity,
purchased from Good Fellow.
Caution: The electrochemical oxidations described herein
produce stoichiometric amounts of H2 gas as byproduct, as
well as variable amounts of O2 from water oxidation.
Appropriate dilution of the gases generated with N2 to a
concentration below the explosion limit is recommended.
Electrode Activation for Batch Electrolysis. Two IKA
nickel electrodes were polished with sandpaper (3000 grit) and
then successively treated with 1 M aqueous HCl, ethanol, and
deionized water for 10 min each under sonication. After drying
at 50 °C overnight, the electrodes were placed into a 5 mL IKA
ElectraSyn vial containing 5 mL of an aqueous solution of 0.1
M NiSO4, 0.1 M KOAc, and 0.005 M KOH. Then, a constant
current of 15 mA (6 mA cm−2) was applied with a polarity
inversion every 30 s for 3 min. A black layer formed on the
electrode acting as the anode could be visually observed. The
electrodes were then rinsed with deionized water and used
directly in the electrochemical alcohol oxidations.
Electrode Activation in Flow Mode. Two nickel
electrodes (5 × 5 cm) were polished with sandpaper (3000
grit) and then successively treated with 1 M aqueous HCl,
ethanol, and deionized water for 10 min each under sonication.
After drying at 50 °C overnight, the electrodes were placed in a
flow electrolysis cell featuring a flow channel in the
interelectrode gap (Figure S1) (190 μL volume, 6.4 cm2
surface area). Then, an aqueous solution of 0.1 M NiSO4,
0.1 M KOAc, and 0.005 M KOH was pumped through the cell
https://doi.org/10.1021/acs.oprd.2c00064
Org. Process Res. Dev. 2022, 26, 1486−1495
Organic Process Research & Development
at a flow rate of 5 mL min−1. When steady state conditions
were reached, a constant current of 20 mA (3.1 mA cm−2) with
electrode polarity inversion every 30 s was applied for 3 min.
Further electrolysis at the same current without alternating the
polarity was then applied for 7 min. The reactor was then
purged with 80 mL of water and used for electrochemical
alcohol oxidations.
General Procedure for the Batch Electrochemical
Alcohol Oxidation. All batch reactions were performed in 10
mL IKA ElectraSyn 2.0 vials equipped with IKA Ni electrodes,
which had been preactivated following the procedure above. A
0.5 M aqueous solution of KOH (10 mL) and 1 mmol of
substrate were placed in the vial. The electrolysis cell was
assembled, and the reaction mixture electrolyzed under
constant current (20 mA, ca. 6.6 mA cm−2) under vigorous
stirring (1000 rpm) until 6 F mol−1 of charge had been passed.
After electrolysis, the reaction mixture was extracted with Et2O,
and the pH of the aqueous layer was adjusted to pH = 4 with 3
M HCl. The aqueous solution was then evaporated under
reduced pressure, the residue was suspended in ethanol, and
the solids were filtered off. Evaporation of the solvent yielded
the pure carboxylic acid.
Electrochemical Oxidation of 3a in a Flow Cell with
Recirculation of the Electrolyte. An aqueous solution of 3-
pyridinemethanol (3a) (777 μL, 8 mmol, 0.1 M) in 0.5 M
KOH was pumped through a flow electrolysis cell equipped
with an activated nickel anode (see activation procedure
above) and a nickel cathode with a flow rate of 5 mL min−1.
The reactor outlet was returned to the reaction solution to
recirculate the electrolyte. As soon as the reactor was filled with
reaction mixture, a current of 43 mA (6.7 mA cm−2) was
applied. After 6 F mol−1 of charge had been passed, the current
was turned off and the pump inlet was removed from the
reaction mixture vessel to empty the electrolysis cell. Then, the
solution was extracted with Et2O and the pH of the aqueous
layer was adjusted to pH = 4 with 3 M HCl. The aqueous
solution was then evaporated under reduced pressure, the
residue was suspended in ethanol, and the solids were filtered
off. Evaporation of the solvent yielded 0.78 g (78%) of 4a
(>99% purity by NMR).
General Procedure for the Single-Pass Flow Electro-
chemical Alcohol Oxidation. A 0.1 M solution of 3-
pyridinemethanol (3a) in aqueous 0.5 M KOH was pumped
through a flow electrolysis cell equipped with an activated
nickel anode (see activation procedure above), a nickel
cathode, and an interelectrode gap separator of 0.9 mm
thickness containing a channel (6.4 cm2 surface, 570 μL
volume) with a flow rate of 100 μL min−1. A current of 64 mA
was applied to the flow cell, which had been prefilled with 0.5
M aqueous KOH. The reaction mixture was collected in a
round-bottom flask as the reactor output. This procedure was
repeated two additional times in cascade. During the final pass
through the cell, the reaction mixture was collected under
steady state conditions for 800 min, which corresponds to 8
mmol of substrate. Then, the solution was extracted with Et2O,
and the pH of the aqueous layer was adjusted to pH = 4 with 3
M HCl. The aqueous solution was then evaporated under
reduced pressure, the residue was suspended in ethanol, and
the solids were filtered off. Evaporation of the solvent yielded
0.76 g (77%) of 4a (>99% purity by NMR).
Nicotinic Acid (4a). Following the general batch
procedure, the title compound was obtained after 6 F mol−1
as a white solid (98 mg, 79% yield); 1H NMR (300 MHz,
1493
pubs.acs.org/OPRD Article
Deuterium Oxide) δ 8.89 (s, 1H), 8.58 (d, J = 5.1 Hz, 1H),
8.46 (dt, J = 8.0, 1.6 Hz, 1H), 7.68 (dd, J = 8.0, 5.5 Hz, 1H).
13
C NMR (75 MHz, Deuterium Oxide) δ 168.4, 145.6, 143.2,
142.6, 135.4, 126.8.
Isonicotinic Acid (4b). Following the general batch
procedure, the title compound was obtained after 6 F mol−1
as a white solid (99 mg, 81% yield); 1H NMR (300 MHz,
Deuterium Oxide, after pH adjustment [potassium salt]) δ
8.54 (d, J = 5.5 Hz, 2H), 7.67 (d, J = 5.6 Hz, 2H). 13C NMR
(75 MHz, Deuterium Oxide, after pH adjustment [potassium
salt]) δ 173.3, 149.2, 145.2, 123.0.
3-(Pyridin-2-yl)propanoic Acid (4c). Following the
general batch procedure, the title compound was obtained
after 6 F mol−1 as a white solid (35 mg, 28% yield); 1H NMR
(300 MHz, Deuterium Oxide) δ 8.46 (d, J = 5.8 Hz, 1H), 8.27
(t, J = 7.9 Hz, 1H), 7.80−7.58 (m, 2H), 3.12 (t, J = 7.1 Hz,
2H), 2.58 (t, J = 7.1 Hz, 2H). 13C NMR (75 MHz, Deuterium
Oxide) δ 179.5, 156.8, 145.9, 141.1, 126.6, 124.4, 35.2, 29.8.
Pyrimidine-5-carboxylic Acid (4d). Following the
general batch procedure, the title compound was obtained
after 6 F mol−1 as a white solid (84 mg, 77% yield); 1H NMR
(300 MHz, Deuterium Oxide, after pH adjustment [potassium
salt]) δ 9.08 (s, 1H), 9.04 (s, 2H). 13C NMR (75 MHz,
Deuterium Oxide, after pH adjustment [potassium salt]) δ
170.4, 158.4, 157.4, 130.1.
Pyrimidine-2-carboxylic Acid (4e). Following the
general batch procedure, the title compound was obtained
after 10 F mol−1 as a white solid (55 mg, 44% yield); 1H NMR
(300 MHz, Deuterium Oxide) δ 8.85 (d, J = 4.6 Hz, 2H), 7.61
(t, J = 4.9 Hz, 1H). 13C NMR (75 MHz, Deuterium Oxide) δ
169.6, 159.9, 157.6, 122.7.
Pyridazine-3-carboxylic Acid (4f). Following the general
batch procedure, the title compound was obtained after 6 F
mol−1 as a slightly brown solid (42 mg, 34% yield); 1H NMR
(300 MHz, Deuterium Oxide, after pH adjustment [potassium
salt]) δ 9.11−9.10 (m, 1H), 8.05−8.02 (m, 1H), 7.76 (dd, J =
8.5, 5.1 Hz, 1H). 13C NMR (75 MHz, Deuterium Oxide, after
pH adjustment [potassium salt]) δ 170.5, 156.8, 152.2, 129.2,
128.2.
Quinoline-2-carboxylic Acid (4g). Following the general
batch procedure and using tBuOH as cosolvent (1:1 ratio with
water) to solubilize the substrate, the title compound was
obtained after 6 F mol−1 as a slightly brown solid (137 mg,
79% yield); 1H NMR (300 MHz, DMSO-d6) δ 8.70 (d, J = 8.5
Hz, 1H), 8.33−8.04 (m, 3H), 7.92 (t, J = 7.7 Hz, 1H), 7.78 (t,
J = 7.5 Hz, 1H). 13C NMR (75 MHz, DMSO) δ 165.4, 147.8,
145.3, 139.6, 131.5, 129.1, 129.0, 128.4, 128.3, 121.0.
Quinoline-3-carboxylic Acid (4h). Following the general
batch procedure and using tBuOH as cosolvent (1:1 ratio with
water) to solubilize the substrate, the title compound was
obtained after 10 F mol−1 as a slightly yellow solid (82 mg,
47% yield); 1H NMR (300 MHz, DMSO-d6) δ 9.32 (d, J = 2.1
Hz, 1H), 8.94 (d, J = 2.1 Hz, 1H), 8.18 (dd, J = 8.3, 1.5 Hz,
1H), 8.09 (d, J = 8.4 Hz, 1H), 7.88 (ddd, J = 8.4, 6.8, 1.5 Hz,
1H), 7.69 (ddd, J = 8.1, 6.8, 1.2 Hz, 1H). 13C NMR (75 MHz,
DMSO) δ 166.5, 150.1, 148.9, 138.1, 131.6, 129.5, 128.7,
127.3, 126.7, 124.8.
■
ASSOCIATED CONTENT
* Supporting Information
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.oprd.2c00064.
https://doi.org/10.1021/acs.oprd.2c00064
Org. Process Res. Dev. 2022, 26, 1486−1495
Organic Process Research & Development
Supplementary pictures, 1H NMR and 13C NMR spectra
of the prepared products. (PDF)
■
AUTHOR INFORMATION
Corresponding Author
David Cantillo − Institute of Chemistry, University of Graz,
NAWI Graz, A-8010 Graz, Austria; Center for Continuous
Flow Synthesis and Processing (CCFLOW), Research Center
Pharmaceutical Engineering GmbH (RCPE), 8010 Graz,
Austria; orcid.org/0000-0001-7604-8711;
Email: david.cantillo@uni-graz.at
Authors
Wolfgang Jud − Institute of Chemistry, University of Graz,
NAWI Graz, A-8010 Graz, Austria; Center for Continuous
Flow Synthesis and Processing (CCFLOW), Research Center
Pharmaceutical Engineering GmbH (RCPE), 8010 Graz,
Austria
Chase A. Salazar − Chemical Research & Development, Pfizer
Worldwide Research & Development, Groton, Connecticut
06340, United States
Joseph Imbrogno − Chemical Research & Development,
Pfizer Worldwide Research & Development, Groton,
Connecticut 06340, United States; orcid.org/0000-0002-
4670-9432
Jenson Verghese − Chemical Research & Development, Pfizer
Worldwide Research & Development, Groton, Connecticut
06340, United States
Steven M. Guinness − Chemical Research & Development,
Pfizer Worldwide Research & Development, Groton,
Connecticut 06340, United States
Jean-Nicolas Desrosiers − Chemical Research &
Development, Pfizer Worldwide Research & Development,
Groton, Connecticut 06340, United States
C. Oliver Kappe − Institute of Chemistry, University of Graz,
NAWI Graz, A-8010 Graz, Austria; Center for Continuous
Flow Synthesis and Processing (CCFLOW), Research Center
Pharmaceutical Engineering GmbH (RCPE), 8010 Graz,
Austria; orcid.org/0000-0003-2983-6007
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.oprd.2c00064
Funding
The Research Center Pharmaceutical Engineering (RCPE) is
funded within the framework of COMET - Competence
Centers for Excellent Technologies by BMK, BMDW, Land
Steiermark and SFG. The COMET program is managed by the
FFG.
Notes
The authors declare no competing financial interest.
■ ACKNOWLEDGMENTS
We gratefully acknowledge Prof. Walter Goessler (University
of Graz) for the ICPMS measurements.
■
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