Electrochemically Promoted Asymmetric Transfer Hydrogenation of 2,2,2-Trifluoroacetophenone

Article abstract of DOI:10.1021/acs.joc.1c01030

The study reported an electrochemically promoted asymmetric hydrogen transfer reaction of 2,2,2-trifluoroacetophenone with a chiral Ru complex. (R)-α-(Trifluoromethyl) benzyl alcohol with a 96% yield and 94% ee could be obtained with only a 0.5 F mol^-1charge amount at room temperature and normal pressure.

Full text of DOI:10.1021/acs.joc.1c01030

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Electrochemically Promoted Asymmetric Transfer Hydrogenation of
2,2,2-Trifluoroacetophenone
Huan Wang,* Ying-Na Yue, Rui Xiong, Yu-Ting Liu, Li-Rong Yang, Ying Wang, and Jia-Xing Lu*
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ABSTRACT: The study reported an electrochemically promoted asymmetric
hydrogen transfer reaction of 2,2,2-trifluoroacetophenone with a chiral Ru complex.
(R)-α-(Trifluoromethyl) benzyl alcohol with a 96% yield and 94% ee could be
obtained with only a 0.5 F mol−1 charge amount at room temperature and normal
pressure.
Table 1. Influence of Solvent on the Enantioselective
hiral compounds, especially chiral drugs, are increasingly
Electroreduction of 2,2,2-Trifluoroacetophenone with a Ru
Catalyst
C
in demand in today’s society, so the research on the
a
synthesis of chiral compounds is becoming more and more
extensive. The preparation of chiral alcohols, which are
important intermediates in the synthesis of many chiral drugs,
is mainly realized by the asymmetric catalytic hydrogenation or
transfer hydrogenation of prochiral ketones. In the past few
decades, lots of transition metal complexes, such as Ir, Ru, and
Rh complexes, have been developed and used as (pre)catalysts
so that the product yields and enantiomeric excess (ee) values
have gradually increased and achieved >99%.1−4
b
b
entry
solvent
yield (%)
R ee (%)
c
1
2
3
4
5
6
7
DMF
DMF
26
16
66
24
96
62
56
64
26
91
83
94
49
78
d
DMF/EtOH (1:1)
DMF/i-PrOH (1:1)
EtOH/i-PrOH (1:1)
EtOH
Recently, due to its mild reaction conditions, low energy
consumption, and easy control of the reaction process, more and
more research studies on electroorganic synthesis have been
reported5,6 and reviewed.7,8 Among them, asymmetric electro-
synthesis has attracted great attention, in view of the
particularity of chiral products.9,10 There have been many
reports on the asymmetric electrosynthesis of chiral alcohols
from aromatic ketones, starting from the perspectives of chiral
media11 and chiral inducers.12,13 In our previous work, chirally
functionalized electrodes, such as alkaloid@metal compo-
sites,14,15 L-cysteine-functionalized CuPt alloy,16 and mino
acid-functionalized multiwalled carbon nanotubes,17,18 have
been prepared, and the ee value has been increased to 40−70%.
Although the performance of the target asymmetric reaction can
be greatly improved by fixing the chiral inducer on the surface of
the electrode, its reactivity is still not comparable to
homogeneous chiral transition metal complexes.
Herein, we wish to report a possible electrochemical route for
the asymmetric hydrogenation of 2,2,2-trifluoroacetophenone
to form optically active α-(trifluoromethyl) benzyl alcohol in the
presence of the chiral RuCl2[(R)-xylbinap][(R)-daipen]-
complex (Scheme S1).
Initially, the influence of the solvent was studied by using
2,2,2-trifluoroacetophenone as the substrate and RuCl2[(R)-
xylbinap][(R)-daipen] as the chiral catalyst in an undivided cell
(Table 1). DMF, commonly used in an electroorganic synthesis
system as an aprotic solvent, was tried first. When alcohols (e.g.,
EtOH, i-PrOH) were added into DMF as the hydrogen donor,
i-PrOH
a
Reaction conditions: undivided cell, Mg anode, Pt cathode, solvent
(20 mL), TEAI (0.1 M), 2,2,2-trifluoroacetophenone (0.1 M),
RuCl2[(R)-xylbinap][(R)-daipen] (3 mM), t-BuOK (6 mM), current
density = 3 mA cm−2, charge = 2 F mol−1, room temperature.
b
c
d
Determined by GC with a chiral column. EtOH (0.2 M). i-PrOH
(0.2 M).
only 16−26% yield of desired product could be obtained (Table
1, entries 1 and 2). By increasing the volume ratio of alcohol to
DMF to 1:1, the product yield also increases (Table 1, entries 3
and 4). More interestingly, when using mixed alcohols to replace
DMF solvent, both yield and ee values have been greatly
improved. As shown in Table 1, entry 5, (R)-α-(trifluoromethyl)
benzyl alcohol with 96% yield and 94% ee was obtained in a
EtOH/i-PrOH (1:1) mixed solvent, which is better than
previous electrosynthesis reports and is comparable to
Special Issue: Electrochemistry in Synthetic Organic
Chemistry
Received: April 30, 2021
https://doi.org/10.1021/acs.joc.1c01030
© XXXX American Chemical Society
J. Org. Chem. XXXX, XXX, XXX−XXX
A

The Journal of Organic Chemistry
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Note
homogeneous catalytic systems (Table S1). Pure EtOH and i-
PrOH were also usable solvents, although the reactivity was
lower than that in the mixed alcohols (Table 1, entries 6 and 7).
In addition to the solvent, the electrode material is also an
important factor affecting electroorganic synthesis reactions.
Here, conventional metal and nonmetal materials are tested for
the enantioselective electroreduction of 2,2,2-trifluoroacetophe-
none (Table 2). Although a moderate yield can be obtained on a
very high at room temperature and normal pressure. As shown in
Figure 1, the ee value is higher than 90% when the charge
amount is larger than 0.25 F mol−1. However, unexpectedly, as
the charge amount decreases, the product yield does not
decrease linearly. The yield when the charge amount is 1 F mol−1
is almost the same as that when the charge amount is 2 F mol−1.
Even when the charge amount is only 0.5 F mol−1, which is a
quarter of the theoretical amount, the yield is as high as 93%
(isolated yield: 88%), and the corresponding current efficiency is
372%. A further decrease in charge amount will bring the current
efficiency close to 600%. These results are completely
inconsistent with the traditional electroreduction of aromatic
ketones, which requires two electrons. Meanwhile, a control
experiment without electricity was carried out. After stirring the
solution for 9 h (similar to the electrolysis time for charge
amount of 2 F mol−1) under room temperature and normal
pressure, the yield of the desired product was only 5%. It shows
that electrolysis is essential for this reaction process.
Table 2. Influence of Cathode on the Enantioselective
Electroreduction of 2,2,2-Trifluoroacetophenone with a Ru
a
Catalyst
b
b
entry
cathode
yield (%)
R ee (%)
1
2
3
4
GC
Ni
Cu
Pt
55
85
88
96
90
93
91
94
a
Reaction conditions: undivided cell, Mg anode, solvent (EtOH/i-
Is it possible that some intermediate generated by electrolysis
will trigger the target reaction? In other words, is it possible that
the electrogenerated intermediate can stably exist in the solution
and can catalyze the reaction under room temperature and
normal pressure? Therefore, a series of control experiments were
carried out. After electrolysis for a certain charge amount, the
current was disconnected, but the solution was continuously
stirred for the same time as previous electrolysis. For instance,
after electrolysis for a charge amount of 0.25 F mol−1
(corresponding to electrolysis for 67 min), the solution was
continuously stirred for another 67 min. Therefore, the total
reaction time is equivalent to that of the experiment, which is
electrolyzed for a charge amount of 0.5 F mol−1. As previously
guessed, if the electrogenerated intermediate can continuously
catalyze the target reaction, the reaction will continue for a
period of time even if the current is disconnected. However,
surprisingly, as shown in Figure 1, the continued stirring after
electrolysis had almost no effect on the yield. The yield depends
only on the electrolysis process.
PrOH = 1:1, 20 mL), TEAI (0.1 M), 2,2,2-trifluoroacetophenone (0.1
M), RuCl2[(R)-xylbinap][(R)-daipen] (3 mM), t-BuOK (6 mM),
current density = 3 mA cm−2, charge = 2 F mol−1, room temperature.
b
Determined by GC with a chiral column.
GC electrode (Table 2, entry 1), it is still significantly lower than
those on metal electrodes. The order of metal electrodes in the
reactivity was Pt > Cu ≈ Ni (Table 2, entries 2−4). On the other
hand, there is almost no difference in the enantioselectivity of
the products on the tested electrodes. Therefore, it is inferred
that, in the asymmetric electroreduction of the substrate
participated by the Ru complex, the cathode material only
affects the yield of the product but hardly affects the optical
activity.
Then, the influence of charge amount was investigated.
Generally, the electroreduction of aromatic ketones involves two
electrons and two protons. In other words, the theoretical
amount of electricity for electroreduction of aromatic ketones is
2 F mol−1. As mentioned earlier, the product yield is 96%, which
is very close to 100%, when the charge amount is 2 F mol−1. It
indicates that the efficiency of this electrosynthesis process is
In order to further understand the reaction system, cyclic
voltammograms (CVs) have been carried out. Due to the serious
Figure 1. Influence of the charge amount on the enantioselective electroreduction of 2,2,2-trifluoroacetophenone. Red: electrolysis only (E). Blue:
stirring for a certain time after electrolysis (E&S).
B
https://doi.org/10.1021/acs.joc.1c01030
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Note
Figure 2. CVs recorded in DMF containing 0.1 M TEAI: (a) blank CV in DFM−0.1 M TEAI, (b) a + 50 mM 2,2,2-trifluoroacetophenon, (c) b + 1.5
mM Ru catalyst.
polarization of the EtOH/i-PrOH (1:1) mixed solvent, the
electrochemical behavior of the substrate and RuCl2[(R)-
xylbinap][(R)-daipen] is mostly obscured (Figure S1). There-
fore, the electrochemical behavior of each component in the
reaction system was studied in DMF. As shown in Figure 2,
curve b, two reduction peaks at −0.71 V and −1.20 V could be
observed for 2,2,2-trifluoroacetophenone, corresponding to the
two single-electron reduction of CO bond. With the addition
of RuCl2[(R)-xylbinap][(R)-daipen] (Figure 2, curve c), no
new peak appeared, indicating the Ru complex itself is difficult to
be reduced or oxidized in the scanning potential range. In
previous studies,1,2 it is reported that the oxidation state of the
metal does not change during the catalytic reaction. This is
completely different from our previous study about asymmetric
electrocarboxylation of organic halides catalyzed by electro-
generated chiral [CoI(salen)]− complex.19
From the above electrochemical behavior, it can be shown
that the Ru complex does not affect the process of electron
transfer to the substrate. However, this does not seem to explain
the experimental fact that only one-fourth of the theoretical
charge amount can make the substrate close to complete
conversion. It has been reported20 that the activation barrier
could be lower ca. 10 kcal/mol by an oriented external electric
field (OEEF), according to the DFT calculation. So judiciously
applied OEEFs could manipulate the kinetics and improve the
thermodynamics of chemical reactions. For example,21 CH3−X
bond activation in alkyl halides could be achieved with a
palladium catalyst under room temperature conditions in the
presence of an oriented external electric field. Moreover, the
approximately linear relationship of the equilibrium of
intermediate to other species with the applied bias voltage has
been found.22 On the basis of these reports, we speculate that
during our electrolysis process, the current past the cell forms a
certain electric field, which may greatly reduce the activation
energy of the target reaction and make the reaction proceed
quickly under room temperature and normal pressure. The
specific reaction mechanism needs further investigation.
α-(Trifluoromethyl) benzyl alcohol with 96% yield, and 94% ee
was obtained at room temperature and normal pressure.
Detailed mechanistic studies to the role of electrolysis and the
origin of the enantioselectivity are ongoing.
EXPERIMENTAL SECTION
■
General Procedure for the Electrolysis. A typical galvanostatic
electrolysis was carried out in a mixture of 2,2,2-trifluoroacetophenon
(2 mmol, 348 mg), RuCl2[(R)-xylbinap][(R)-daipen] (0.06 mmol,
73.3 mg), t-BuOK (0.12 mmol, 13.5 mg), TEAI (2 mmol, 514 mg), and
EtOH/i-PrOH (20 mL, v/v = 1:1) in a one-chamber electrolytic cell
with a sacrificial Mg anode and Pt cathode with a direct-current-
regulated power supply (HY3002D, HYelec, China). The product yield
and enantiomeric excess (ee) value (eq S1) were measured with
Shimadzu GC-2010 equipped with a Stabilwax column (30 m × 0.32
mm i.d., 0.5 μm film thickness). A total of 60 μL of as-prepared L-
cysteine-CuPt colloids was coated on carbon paper (2 × 2 cm) and used
as a cathode.
Cyclic Voltammetry. Cyclic voltammograms were analyzed on a
CHI 600c electrochemical station (Shanghai Chenhua Instruments
Company). A three-electrode cell equipped a glassy carbon (GC, d = 2
mm) as a working electrode, a Pt gauze (1.5 cm × 1.5 cm) as a counter
electrode, and Ag/AgI/0.1 M TEAI in MeCN as the reference
electrode. All electrochemical measurements were performed at a scan
rate of 0.1 V s−1 in a N2-saturated solution.
Characterization Data for Product. α-(Trifluoromethyl) benzyl
alcohol. Eluent: ethyl acetate/petroleum ether = 1:10 v/v. Light yellow
oil (310 mg, 88%). 1H NMR (500 MHz, DMSO-d6, δ ppm): 7.50−7.48
(m, 2H), 7.42−7.38 (m, 3H), 6.82−6.80 (m, 1H), 5.17−5.13 (m, 1H).
13C{1H} NMR (125 MHz, DMSO-d6, δ ppm): 135.9, 128.8, 128.2,
127.6, 125.1 (q, J = 280 Hz), 70.4 (q, J = 30 Hz).
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c01030.
Equation, formula, cyclic voltammetry studies, and NMR
spectra (PDF)
In summary, we have realized the electrochemically promoted
hydrogen transfer reaction of 2,2,2-trifluoroacetophenone. (R)-
C
https://doi.org/10.1021/acs.joc.1c01030
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The Journal of Organic Chemistry
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AUTHOR INFORMATION
■
Corresponding Authors
Huan Wang − Shanghai Key Laboratory of Green Chemistry
and Chemical Processes, School of Chemistry and Molecular
Engineering, East China Normal University, Shanghai
200062, China; orcid.org/0000-0002-6759-3475;
Phone: +86-21-52134935; Email: hwang@
chem.ecnu.edu.cn
Jia-Xing Lu − Shanghai Key Laboratory of Green Chemistry and
Chemical Processes, School of Chemistry and Molecular
Engineering, East China Normal University, Shanghai
200062, China; orcid.org/0000-0001-9239-9888;
Phone: +86-21-62233491; Email: jxlu@chem.ecnu.edu.cn
Authors
Ying-Na Yue − Shanghai Key Laboratory of Green Chemistry
and Chemical Processes, School of Chemistry and Molecular
Engineering, East China Normal University, Shanghai
200062, China
Rui Xiong − Shanghai Key Laboratory of Green Chemistry and
Chemical Processes, School of Chemistry and Molecular
Engineering, East China Normal University, Shanghai
200062, China
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Yu-Ting Liu − Shanghai Key Laboratory of Green Chemistry
and Chemical Processes, School of Chemistry and Molecular
Engineering, East China Normal University, Shanghai
200062, China
Li-Rong Yang − Shanghai Key Laboratory of Green Chemistry
and Chemical Processes, School of Chemistry and Molecular
Engineering, East China Normal University, Shanghai
200062, China
Ying Wang − Shanghai Key Laboratory of Green Chemistry and
Chemical Processes, School of Chemistry and Molecular
Engineering, East China Normal University, Shanghai
200062, China
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Complete contact information is available at:
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(17) Yue, Y.-N.; Meng, W.-J.; Liu, L.; Hu, Q.-L.; Wang, H.; Lu, J.-X.
Amino acid-functionalized multi-walled carbon nanotubes: A metal-
free chiral catalyst for the asymmetric electroreduction of aromatic
ketones. Electrochim. Acta 2018, 260, 606−613.
Notes
The authors declare no competing financial interest.
(18) Yue, Y.-N.; Zeng, S.; Wang, H.; Wang, S.; Wang, H.; Lu, J. X.
One-Pot Synthesis of d-Phenylalanine-Functionalized Multiwalled
Carbon Nanotubes: A Metal-Free Chiral Material for the Asymmetric
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Asymmetric electrocarboxylation of 1-phenylethyl chloride catalyzed
by electrogenerated chiral [COI(salen)](−) complex. Electrochem.
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ACKNOWLEDGMENTS
■
Financial support from the National Natural Science Founda-
tion of China (21773071 and 22072046) is gratefully acknowl-
edged.
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