Alternating current electrolysis for organic electrosynthesis: Trifluoromethylation of (hetero)arenes

Article abstract of DOI:10.1021/acs.orglett.0c01906

Paired electrolysis has a limited reaction scope for organic synthesis because it is often not compatible with reactions involving short-lived intermediates. We addressed this limitation using alternating current electrolysis (ACE). Using trifluoromethyla

Full text of DOI:10.1021/acs.orglett.0c01906

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Letter
Alternating Current Electrolysis for Organic Electrosynthesis:
Trifluoromethylation of (Hetero)arenes
Sachini Rodrigo, Chanchamnan Um, Jason C. Mixdorf, Disni Gunasekera, Hien M. Nguyen,*
and Long Luo*
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ABSTRACT: Paired electrolysis has a limited reaction scope for
organic synthesis because it is often not compatible with reactions
involving short-lived intermediates. We addressed this limitation using
alternating current electrolysis (ACE). Using trifluoromethylation of
(hetero)arenes as a model reaction, we showed that the yield was
improved from 13% using paired electrolysis to 84% using ACE. We
have also developed a theory for guiding the rational design of reaction
parameters for future applications of ACE.
rganic electrosynthesis has recently attracted much
Oattention from synthetic chemists because it is
sustainable and can provide unique reactivity.1−5 In typical
organic electrosynthetic reactions, only one electrode is
utilized to transform substrates of interest, while the other
entails the redox transformation of sacrificial species, making
these processes less sustainable than desired. Paired
electrolysis, in which two desirable half-reactions are
performed simultaneously at the two electrodes, is mostly
unexplored. As summarized by Baran et al.,6 only ∼20 out of
∼900 organic electrosynthetic methods developed between
2000 and 2017 were based on paired electrolysis. Paired
electrolysis is attractive because it not only improves the
energy efficiency by using both electrodes but also provides a
unique reaction environment where two redox-opposite
reactions of substrates take place in the same pot.7 The
limited reaction scope of paired electrolysis is because the slow
mass transfer of intermediates between two electrodes requires
stable intermediates.8−16 For reactions involving short-lived
intermediates, paired electrolysis generally leads to low yields
due to the loss of the intermediates during mass transfer
(Figure 1a).
To overcome this inherent limitation of paired electrolysis,
Mo et al. closely spaced the electrodes in a microfluidics
platform to reduce the mass transfer time.17 However, this
approach requires complicated device fabrication, and the
smallest interelectrode distance they examined (25 μm) can
only handle reactions with intermediates having a subsecond
or longer lifetime (estimated from the interelectrode diffusion
time). Here, we propose a more straightforward approach:
alternating current electrolysis (ACE). During ACE, an
alternating voltage ( V) is applied to drive the redox
transformations of the substrates sequentially at the same
electrode (Figure 1b). ACE has been largely underexplored for
Figure 1. Schematics of (a) paired electrolysis and (b) proposed
alternating current electrolysis (ACE) for a sequential reaction that
includes two redox-opposite steps.
organic synthesis.18−22 In this work, we hypothesize that, in
this reaction scheme, the intermediates do not have to migrate
between the two electrodes, enabling short-lived intermediates
to react immediately upon the electrode polarity reversal.
To test this proposed idea, we chose trifluoromethylation of
(hetero)arenes as the model reaction.23−27 Direct trifluor-
omethylation is of great importance for pharmaceuticals.28 The
trifluoromethylation reaction, developed by MacMillan et al.,29
proceeds via a sequential reaction mechanism: triflyl chloride
(1) is first reduced to form CF3 radical, then the reactive CF3
Received: June 6, 2020
https://dx.doi.org/10.1021/acs.orglett.0c01906
© XXXX American Chemical Society
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a
radical combines with aromatic systems; finally, the resultant
radical undergoes oxidation to form the product. In principle,
the same chemical transformations could be accomplished
electrochemically by performing the redox events at the
cathode and anode sequentially. Because the radical
intermediates formed by CF3 radical addition to (hetreo)-
arenes lost the aromaticity, they are unstable30,31 and can cause
low yields of trifluoromethylated products using the paired
electrolysis setup, which we hypothesize will be addressed by
ACE.
Table 1. Reaction Development
b
c
conversion
(%)
yield
5/6
d
entry
Vp (V)
f (Hz)
(%)
ratio
1
2
3
4
5
6
7
8
9
0
n/a
100
100
100
100
100
10
1000
60
100
n/a
<1
6
3.3 (AC)
3.6 (AC)
4.0 (AC)
4.4 (AC)
4.8 (AC)
4.4 (AC)
4.4 (AC)
4.4 (AC, sine)
27
48
100
44
21
<1
40
66
13
Figure 2a shows our experimental setup. The power supply
was a waveform generator, which can supply either a constant
44
84
24:1
19:1
44:1
0.75:1
e
10
11
4.4 (AC)
4.4 (DC)
64
a
Reaction scale: 0.5 mmol of 2 (1 equiv) in 4 mL of acetonitrile.
b
c
Conversion and ratio of 5/6 were determined by 19F NMR. Isolated
d
e
yield of 5. Chlorinated product was isolated in 16% yield. 1 mmol of
2.
desired product 5 was obtained in a comparable yield (64%,
entry 10). To compare, the paired electrolysis condition only
gave a 13% yield of 5 using identical chemical reagents at a
constant voltage of 4.4 (entry 11). The control experiment
established that, when no voltage was applied, there was no
reaction (entry 1). Overall, the results in Table 1 confirmed
our hypothesis that the ACE significantly improved the yield
compared to the paired electrolysis.
Figure 2. (a) Photographs of the experimental setup for ACE. A
square waveform was applied between two glassy carbon plate
electrodes by a waveform generator. (b) Proposed mechanism for
electrochemical trifluoromethylation of 2-acetylpyrrole (2) using
ACE.
Next, we investigated the critical role of Vp and f in the ACE
method. We measured the standard reduction potential (E1) of
1 and the oxidation potential (E2) of 3, which determines the
voltage required for trifluoromethylation to proceed. The
cyclic voltammogram of 1 (Figure 3a) showed an onset
potential for 1 reduction of approximately −0.7 V vs Ag/AgCl.
We estimated E1 to be −0.97 V using the inflection points of
the cathodic wave.32 To detect the oxidation of the unstable
intermediate 3, we used fast-scan linear sweep voltammetry.33
We first held the electrode potential at −1.2 V to reduce 1 and
generate a pool of radical 3. Subsequent scanning the electrode
potential positively at a high scan rate of 20 V/s enabled the
oxidation of 3 before it proceeded through other pathways. At
low scan rates, the electrochemical signal from the oxidation of
3 significantly diminished (Figure S2), confirming the
instability of 3. We observed an anodic wave starting from 0
V with a major peak at ∼0.7 V (Figure 3b). When the potential
was held at −0.4 V, wherein no CF3 radical was generated, no
anodic wave was observed, suggesting the anodic wave results
from the oxidation of 3. To further confirm this result, we
carried out two additional experiments. First, we elongated the
holding time at −1.2 V to generate more CF3 radicals. Second,
we increased the concentration of 2 in the reaction mixture. In
both cases, we observed a significantly increased current
(Figure 3), confirming the anodic wave arose from the
oxidation of 3. Accordingly, we estimated E2 to be 0.5 V using
the inflection points of the anodic wave.32 Based on these
results, we estimated the thermodynamic voltage for electro-
chemical trifluoromethylation, |E1 − E2|, is ∼1.5 V. It is worth
noting that the current took off after ∼0.85 V for all
experiments due to direct electro-oxidation of 2.34−36
voltage bias (DC) to perform paired electrolysis or an
oscillating square waveform (AC) to perform ACE. During
ACE, the reaction was initiated by reducing 1 to CF3 radicals
when the potential of an electrode was negative (Figure 2b).
The generation of CF3 radicals was confirmed by a radical
trapping experiment using TEMPO (Figure S1). CF3 radicals
then combined with 2-acetylpyrrole (2) to form the radical
intermediate 3. Upon the voltage polarity reversal, 3 was
oxidized to the allylic cation 4 at the same electrode.
Subsequent deprotonation of 4 was rapid, generating the
final product 5. During ACE, the same chemical trans-
formations were also taking place on the other electrode.
During reaction optimization (Table 1), we varied the
frequency f and amplitude Vp of the square waveform. We
found that trifluoromethylation of 2 at 100 Hz and 4.4 V
(entry 5) afforded the desired product 5 in 84% yield. The
mono/bistrifluoromethylated product ratio (5/6) was found to
be 19:1. Both f and Vp strongly affected the yield and
selectivity. At 100 Hz, 5 was predominantly formed with a 5/6
ratio of >20:1 (entries 4 and 6). In contrast, 6 became more
favorable at 10 Hz (entry 7). At 1000 Hz, no reaction took
place (entry 8). If Vp was set greater or less than 4.4 V, the
yield of 5 decreased. At Vp < 4.4 V, there was a significant
amount of unreacted 2 recovered after 24 h (entries 2−4). At
Vp = 4.8 V, although 2 was completely consumed, a chlorinated
side product was isolated in 16% yield (entry 6). Importantly,
the use of 60 Hz sine waveform (entry 9), the same waveform
as the household power supply, afforded the desired product 5
in 40% NMR conversion. The application to a large scale was
explored utilizing 1 mmol of 2-acetylpyrrole (2), and the
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Figure 3. (a) Cyclic voltammograms of 1 in MeCN. A Ag/AgCl wire
was used as the quasi-reference electrode. Scan rate: 50 mV/s. (b)
Fast-scan linear sweep voltammograms of a mixture of 1 and 2. Left
panel: Electrode potential was held at −1.2 V for 1, 2, and 3 s
followed by sweeping the potential positively to 1.2 at 20 V/s.
Concentrations of 1 and 2 were both 0.25 M. Right panel: Different
equivalents of 2 to 1 were added, and the holding time at −1.2 V was
3 s. Gray curve: Electrode potential was held at −0.4 V for 1 s before
the potential sweep.
Figure 4. (a) Measured voltage (Vreal) between two glassy carbon
electrodes during the ACE when Vp was set as 4.4 V. (b) Peak value of
Vreal vs reaction time. (c) Equivalent circuit of the electrochemical
system for ACE. (d) Theoretical modeling of the voltage available for
electrochemical reactions (Vec) vs the voltage pulse duration, t, at Vp =
4.4 V. The region highlighted in blue indicates the reaction zone
during a 5 ms voltage pulse of a 100 Hz square wave. (e) Predicted
ranges of Vec at different Vp and f. The error bars were calculated from
the variations in Vreal,peak during the reactions.
We continued investigating why our optimal voltage (4.4 V)
was much higher than the thermodynamic value of 1.5 V. We
identified two reasons.
First, waveform generators are not an ideal power source.37
As a result, the actual voltage output from a waveform
generator (Vreal) was lower than the set value of Vp during the
ACE reaction.38 We found Vreal oscillated between 2 V at Vp
= 4.4 V (Figure 4a). The peak value of Vreal (Vreal,peak) gradually
increased from 1.8 to 2.5 V and then stayed constant until the
reaction completion at 24 h (Figure 4b).
Therefore, trifluoromethylation only occurred between 1.7 and
5 ms in a single voltage pulse (Figure 4d).
The predicted ranges of Vec at different Vp and f using the
equation above and the measured Vreal,peak (Figure S7) are
summarized in Figure 4e. At all Vp, Vec passed the minimum
voltage of 0.7 V required by electrochemical trifluoromethy-
lation. At Vp = 4.8 V, Vec was also enough to oxidize 2 and
reduce 1 at the same time (>1.55 V). These results are
consistent with the experimental findings that (1) the desired
product 5 was observed at Vp ≥ 3.3 V; (2) the product yield
increased, and the unreacted 2 decreased until Vp reached 4.4
V; and (3) the chlorination product was observed at 4.8 V due
to the direct oxidation of 2.40 A similar analysis was conducted
for different f at Vp = 4.4 V. At 1000 Hz, Vec was always below
0.7 V and thus unable to drive the reactions. At 10 Hz, Vec
went beyond the voltage for direct oxidation of pyrrole, causing
significant side reactions.
Finally, we evaluated the substrate scope. As outlined in
Scheme 1, we kept the frequency at 100 Hz and varied the
voltage between 2.8 and 4.8 V to obtain the highest yields for
different substrates. The trifluoromethylation of pyrroles
proceeded smoothly to provide the trifluoromethylated
products 7−13 in good yield (42−61%) and high
regioselectivity. In the presence of a methyl group,
Second, there was a substantial iR drop in the electrolyte
solution between the two electrodes. Figure 4c shows the
equivalent circuit of our electrochemical system. The electro-
des are represented as an electrical double layer capacitor
(CEDL) and an electrochemical resistor (Rec) in parallel,
whereas the electrolyte solution between the two electrodes
is treated as a constant resistance, Relectrolyte.39 During the ACE,
positive and negative voltage pulses alternated. Upon one
voltage pulse, the voltage available for the electrochemical
reactions (Vec) can be described by the following equation (see
the derivation in the Supporting Information):
V = Vreal,peak(1 − exp(−2t/RelectrolyteCEDL))
ec
where Relectrolyte and CEDL were estimated to be 5 Ω and 2 mF,
respectively (Figure S5). For a 100 Hz square wave with Vp =
4.4 V, Vec is predicted to increase from 0 V at t = 0 to 1.57 V at
5 ms. Because the onset potentials for reducing 1 and oxidizing
3 were measured to be −0.7 and 0 V, the minimum voltage
required for electrochemical trifluoromethylation is 0.7 V.
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a
Scheme 1. Scope of Selective Trifluoromethylation
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01906.
Experimental details, characterization, and spectral data
(PDF)
AUTHOR INFORMATION
■
Corresponding Authors
Long Luo − Department of Chemistry, Wayne State University,
Detroit, Michigan 48202, United States; orcid.org/0000-
0001-5771-6892; Email: long.luo@wayne.edu
Hien M. Nguyen − Department of Chemistry, Wayne State
University, Detroit, Michigan 48202, United States;
Email: hmnguyen@wayne.edu
Authors
Sachini Rodrigo − Department of Chemistry, Wayne State
University, Detroit, Michigan 48202, United States
Chanchamnan Um − Department of Chemistry, Wayne State
University, Detroit, Michigan 48202, United States
Jason C. Mixdorf − Department of Chemistry, University of
Iowa, Iowa City, Iowa 52242, United States
Disni Gunasekera − Department of Chemistry, Wayne State
University, Detroit, Michigan 48202, United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01906
Notes
a
b
c,d
0.25−0.5 mmol scale. Yields were determined by 19F NMR. The
The authors declare no competing financial interest.
reaction time was 48 and 72 h, respectively.
ACKNOWLEDGMENTS
■
This work was supported by start-up funds from Wayne State
University to L.L. Financial support from Wayne State
University and Carl Johnson Endowed Chair for H.M.N. is
gratefully acknowledged. J.C.M. thanks University of Iowa
Graduate Dissertation Fellowship.
bistrifluoromethylated product 8 was observed as the only
major product under the optimized reaction condition. The
ACE method is also applicable to electron-rich arenes to afford
the trifluoromethyl products 14−16 in synthetically useful
yield (25−64%). Importantly, the preferential trifluoromethy-
lation of pyrroles over arenes enables the selective CF3
functionalization of pyrroles in substrates containing both
aromatic systems such as 11, 12, and 13. For furans and
thiophenes, the desired products 17−24 were obtained in
moderate yields (28−44%). The reduced yield is because
furans and thiophenes are more prone to undergo oxidation
than pyrroles (Figure S6). A current limitation of the reaction
is that highly electron-deficient heterocycles, such as imidazole,
were not compatible (25) because of inefficient CF3 radical
addition to the imidazole ring (Figure S3). The same
mechanism accounts for the different yields for activated
arenes (Figure S4).
In conclusion, we have presented a new electrochemical
approach using underdeveloped alternating current electrolysis
for trifluoromethylation of (hetero)arenes. We have also
established a theory for understanding the optimal reaction
conditions, essential for guiding the rational design for future
applications. This method is significant because it addresses
the long-standing limitation of paired electrolysis and will
significantly expand the library of electrosynthetic reactions.
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