Alkaloid induced enantioselective electroreduction of acetophenone

Article abstract of DOI:10.1016/j.electacta.2013.06.082

The feasibility of the enantioselective electroreduction of pro-chiral acetophenone was investigated at the silver cathode in an undivided cell for the first time. Electroreduction of acetophenone in the presence of cinchonidine (CD) yielded two main products: the optically active alcohol, and the dimer product pinacol with no optical rotation. The influence of water in the co-solvent (MeCN/H₂O), supporting electrolyte, electrode material, current density, and the alkaloid type on the enantiomeric excesses (ee) and yield was investigated. Under the optimized conditions, the alcohol was obtained with a 21.6% ee and a 3.6% yield, whereas, an 83.2% yield and a 5.5 dl/meso ratio were obtained for pinacol. The electrochemical behavior of the samples was also studied through cyclic voltammetry (CV). Finally, we proposed a possible induction mechanism based on the results of the electrolysis and CV.

Full text of DOI:10.1016/j.electacta.2013.06.082

Electrochimica Acta 107 (2013) 320–326
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Electrochimica Acta
journal homepage: www.elsevier.com/locate/electacta
Alkaloid induced enantioselective electroreduction of acetophenone
Bao-Li Chen, Yan Xiao, Xiao-Ming Xu, Heng-Pan Yang, Huan Wang∗, Jia-Xing Lu∗∗
Shanghai Key Laboratory of Green Chemistry and Chemical Processes, Department of Chemistry, East China Normal University, Shanghai 200062, China
a r t i c l e i n f o
a b s t r a c t
Article history:
The feasibility of the enantioselective electroreduction of pro-chiral acetophenone was investigated at the
silver cathode in an undivided cell for the first time. Electroreduction of acetophenone in the presence of
cinchonidine (CD) yielded two main products: the optically active alcohol, and the dimer product pinacol
with no optical rotation. The influence of water in the co-solvent (MeCN/H2O), supporting electrolyte,
electrode material, current density, and the alkaloid type on the enantiomeric excesses (ee) and yield was
investigated. Under the optimized conditions, the alcohol was obtained with a 21.6% ee and a 3.6% yield,
whereas, an 83.2% yield and a 5.5 dl/meso ratio were obtained for pinacol. The electrochemical behavior of
the samples was also studied through cyclic voltammetry (CV). Finally, we proposed a possible induction
mechanism based on the results of the electrolysis and CV.
Received 29 December 2012
Received in revised form 18 June 2013
Accepted 18 June 2013
Available online 26 June 2013
Keywords:
Alkaloid
Cinchonidine
Enantioselective
Electroreduction
Acetophenone
© 2013 Elsevier Ltd. All rights reserved.
1. Introduction
Asymmetric electrochemical reduction has developed since the
1960s. Furthermore, this method has considerably progressed in
Asymmetric synthesis by diastereoselective reduction, which
change intrinsic optical substrate conformation by diastereoselec-
tive reduction due to the presence of a prochiral and a chiral center
in the substrate, has attracted increasing attention in the last few
decades. Chiral drugs have caused great concerns from scientists
because of the dependence of their pharmacologic activity on struc-
ture, wherein only one isomer is effective and the other one is inert
or even has opposite effects. Thus, methods for the enantioselective
preparation of chiral products are urgently needed to synthesize
biologically active compounds for pharmaceutical and agrochemi-
cal use [1]. Organic asymmetric reduction and catalysis are efficient
methods for producing chiral compounds and they have made great
progress during the last few decades [2–12]. However, these pro-
cedures have disadvantages, such as the use of toxic transition
metal compounds, costly chiral ligands and high-pressure con-
ditions. Consequently, electrochemical techniques [13–15] which
deals with a clean reagent, the electron [16], becomes a viable alter-
native because of its mild and safe conditions. The electrochemical
methods are useful tools because they are the only pathway for
some organic transformations [17]. In addition, electrochemical
reactions generate highly energetic intermediates in a facile and
precise way by controlling the electrode potential [18].
both theory and application in the past 20 years. The pioneering
work has been performed in field of enantioselective electro-
chemical reduction of organic compounds, especially those that
contain activating bonds, such as C X, C C and C O [1,19–27]. A
number of methods for creating a chiral environment have been
reported for electrochemical enantioselective synthesis, such as
the use of chiral solvents [28,29], chiral supporting electrolytes
[29–31], intrinsic optical substrate conformation [17,32,33], chi-
ral electrodes [22–24,34–36], and chiral catalytic systems [37].
Recently, we successfully synthesized the pharmaceutically active
intermediates 2-hydroxy-2-phenylpropionic acid (atrolactic acid)
and ␣-ethyl-␣-hydroxy-4-methylbenzeneacetic acid through the
asymmetric electrochemical carboxylation of pro-chiral ketone in
the presence of a chiral alkaloid inducer [38,39]. The electrore-
duction of ketone in the presence of hydrogen source yields two
main products: alcohol and pinacol, as shown in Scheme 1. The
alcohol is produced through the use of two-electron reduction and
the pinacol is produced through the use of one-electron reduction.
Optically active alcohol can be obtained if the ketone is reduced
in a chiral environment; otherwise, only the racemic alcohol is
produced.
The electrochemical asymmetric reduction of pro-chiral ketones
to alcohols has been observed in many systems [24]. Vago [25]
reported the enantioselective electrocatalytic hydrogenation of
ethyl pyruvate on carbon-supported Pd electrodes modified with
cinchonidine (CD) to yield ethyl lactate with 13% enantiomeric
excesses (ee). On one hand, acetophenone is one of the simplest aro-
matic ketones. On the other hand, one of its products, chiral alcohol,
∗
Corresponding author. Tel.: +86 21 52134935.
Corresponding author. Tel.: +86 21 62233491.
∗∗
E-mail addresses: hwang@chem.ecnu.edu.cn (H. Wang), jxlu@chem.ecnu.edu.cn
(J.-X. Lu).
0013-4686/$ – see front matter © 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.electacta.2013.06.082

B.-L. Chen et al. / Electrochimica Acta 107 (2013) 320–326
321
with a UV (RS Variable Wavelength) detector and a chiralcel OD-H
column [DAICEL Chiral technologies (China) CO., Ltd.]. GC–MS spec-
tra was obtained on a 5973N spectrometer which was connected
with a HP 6890 gas chromatograph.
2.2. Electroanalytical procedure
The electroanalytical experiments were carried out in ace-
tonitrile (MeCN) or co-solvent (MeCN–H2O, MeCN–EtOH,
MeCN–HOAc) with 0.1 M tetraethylammonium tetrafluorobo-
rate (TEABF4) as the supporting electrolyte in an undivided glass
cell equipped with a gas inlet and outlet, a glassy carbon (GC) elec-
trode (d = 2 mm) as the working electrode, a platinum spiral (Pt) as
the counter electrode and a Ag/AgI/0.1 M TBAI in DMF as the ref-
erence electrode. All experiments were performed at 25 ◦C under
an atmospheric pressure. In addition, the oxygen was removed by
continuous bubbling with nitrogen before the experiment.
Scheme 1.
is a very useful chiral building block for the production of pharma-
ceuticals, agrochemicals, and natural products. In 1998, Moutet [26]
studied the asymmetric induction of acetophenone on a chiral poly
[2,2ꢀ-bipyridyl rhodium (III) complex] film electrode with 12% ee;
however, the electrode preparation process is complex. In addition,
the induction of several alkaloids during ketone electroreduction
on a mercury cathode has been reported in preliminary studies,
with particular reference to the catalytic concentrations of certain
alkaloids that are strongly adsorbed onto the cathode and provided
a chiral environment [20,23] with the highest ee of 14.9%. How-
ever, toxic Hg electrode, which contradicts the principles of green
chemistry, was used. In the current study, we established a novel
method for the enantioselective electroreduction of pro-chiral ace-
tophenone that uses nontoxic electrode materials and four different
alkaloids [cinchonidine (CD), cinchonine (CN), quinidine (QD) and
quinine (QN)] under mild conditions (Scheme 2).
2.3. General electrolysis procedure
The galvanostatic electrolysis was carried out in a mixture of
substrate acetophenone (0.1 M), supporting electrolyte (0.1 M) and
1 mM alkaloid in 10 ml co-solvent bubbled with N2 to remove the
oxygen in an undivided glass cell, equipped with a sacrificial mag-
nesium rod (Mg) anode and a cathode such as Ag (9.8 cm2), Cu
(10.6 cm2), C (3.8 cm2), Zn (10.6 cm2), Ti (10.4 cm2), Pt (4.0 cm2), Ni
(8.0 cm2), 316 stainless steel (Ss) (10.7 cm2). The electrolyte solu-
tion was continuously stirred during electrolysis. At the end of each
set of experiment, the co-solvent was distilled off in vacuo. The
residue was hydrolyzed and extracted three times with diethyl
ether. In addition, the organic layers were washed with satu-
rated brine, dried over anhydrous MgSO4, eventually, evaporated in
vacuo. After isolation and identification, the product yields, based
on the starting material, were determined by high performance liq-
uid chromatography (HPLC), also for the enatiomeric excesses (ee)
of the alcohol and the dl/meso ratio of pinacol. The ee of optically
active alcohol is defined as follows:
2. Experimental
2.1. Chemicals and instruments
[R] − [S]
ee =
× 100%
[R]+[S]
All reagents were used as received. Cyclic voltammograms were
measured with CHI 600c electrochemical Station (Shanghai Chen-
hua Instruments Company). The galvanostatic electrolysis was
done with a dc regulated power supply HY12001 E (Hangzhou
Huayi Electronics Industry Co., Ltd.). The product yields and the ee
value were determined by a high performance liquid chromatog-
raphy (HPLC) instrument (DIONEX Ultimate 3000 pump) equipped
3. Results and discussion
3.1. Electroanalytical results
The cyclic voltammograms of acetophenone using a glass car-
bon (GC) electrode at different scan rates in MeCN are shown in
Fig. 1. Two successive one-electron reduction peaks at −1.68 V
and −2.15 V, which correspond to the two-electron transfer of the
ketone group (C O) of acetophenone [40], were observed at a scan
rate of 0.1 V s−1 (Fig. 1, curve a). When the scan rate was increased,
the two reduction peaks became more negative, with the peak cur-
rent increasing concomitantly (Fig. 1, curves a–e). The first peak
current varied linearly with v1/2 (Fig. 1, inset), which confirms
the diffusion control for the electrochemical reduction process
[41,42]. Meanwhile, the ratio of the two peak current (I pc2/I pc1)
decreased with increasing scan rate (Table 1). This behavior indi-
cates that the intermediate reducted at the second peak come from
a slow reaction following the first electron transfer (Scheme 3).
In addition, the experimental result suggests that producing alco-
hol from acetophenone consists of an ECEC mechanism [38,43] (E:
electron transfer, C: chemistry), not an EECC mechanism.
To study the cyclic voltammograms of acetophenone in the pres-
ence of water, the aprotic MeCN solution (Fig. 2A) was replaced with
the protic co-solvent (MeCN/H2O) at a 9/1 volume ratio (Fig. 2B).
The voltammetric behavior (Fig. 2) was strongly modified by the
Scheme 2.

322
B.-L. Chen et al. / Electrochimica Acta 107 (2013) 320–326
The second peak mainly disappeared because it was concealed by
the current for the reduction of the protic co-solvent. To deter-
mine the number of electrons transferred in the reduction peak of
curve c in Fig. 2B, potential controlled electrolysis experiment was
carried out at −1.35 V. The electrolysis was interrupted after the
current dropped to ca. 6% of its initial value, which corresponded to
total conversion of the acetophenone. Reduction of acetophenone
consumes ca. 1e−/molecule of acetophenone. After electrolysis, the
sample was analyzed using GC–MS, which indicated that only the
dimerization product pinacol was obtained, and no alcohol was
detected. The result further illustrates that the peak (curve c in
Fig. 2B) is a one-electron reduction of acetophenone into pinacol.
The positive shift in the reduction potential for the peak I (curve c in
Fig. 2A and B) of acetophenone caused by the addition of water into
the solvents may be ascribed to both the protonation and hydrogen-
bonding effects of H2O [42,44,45]. In addition, the peak potential
of the peak I exhibited a positive shift (curve c in Fig. 2B) and the
minimal increase in the acetophenone reduction peak current in
the present of H2O are consistent with the ECEC mechanism [38] of
the acetophenone reduction, which can be caused by subsequent
chemical reactions between the anion radicals and a proton source.
To further study the effect of alkaloid on the voltammetric
behavior of acetophenone, 0.1 mM CD was added into the apro-
tic electrolyte (Fig. 2A) and protic co-solvent (MeCN/H2O = 9/1)
(Fig. 2B), respectively. As shown in curves c and d in Fig. 2A, the
two reduction peak currents both increased slightly, with the first
reduction peak potential shifting to a more positive value, which (i)
indicates the strong interaction between CD and the 1-(1-phenyl-
1-hydroxy)-ethyl anion; (ii) most probably because acetophenone
is activated by a hydrogen bond from the protonated alkaloid or
the HO-group of the alkaloid to yield after a proton and elec-
tron transfer the 1-(1-phenyl-1-hydroxy)-ethyl radical. No obvious
peak was detected in the potential region when 0.1 mM CD was
added into the MeCN–0.1 M TEABF4 system, which demonstrated
that the increase of the peak current does not correspond to the
direct reduction of CD (Fig. 2A, curve b). Moreover, CD favored
acetophenone reduction. Fig. 2B plots the change after adding
0.1 mM of CD to the protic co-solvent system. The reduction peak
potential slightly shifted to a more positive region, and the peak
current increased minimally (Fig. 2B, curves c and d). Similar to
curve b in Fig. 2A, no obvious peak was observed in the poten-
tial region when only 0.1 mM CD was in the protic co-solvent
(MeCN/H2O = 9/1)–0.1 M TEABF4, demonstrating that the increase
in peak current did not correspond to the direct reduction of CD
(Fig. 2B, curve b). Therefore, the protonated CD can act as proton
donor, which favored the reduction of acetophenone [1].
Fig. 1. Cyclic voltammograms of 10 mM acetophenone in MeCN–0.1 M TEABF4 at
different scan rates: (a) 0.1 V s−1, (b) 0.2 V s−1, (c) 0.3 V s−1, (d) 0.4 V s−1, (e) 0.5 V s−1
,
T = 25 ◦C. Inset: variation of the first peak current (I pc1) of 10 mM acetophenone vs.
square root of scan rate (v1/2).
Table 1
Effect of scan rate to the ratio of the two reduction peak (I pc2/I pc1).a
v (V s−1
)
I pc1(mA)
I pc1 (mA)
I pc2/I pc1
0.1
0.2
0.3
0.4
0.5
0.151364
0.206789
0.243745
0.278821
0.306317
0.0311085
0.0393741
0.0496153
0.0496153
0.0526049
0.205521
0.190407
0.180566
0.177947
0.171734
a
Experiment condition as Fig. 1.
Scheme 3.
water content in the solvent, which may be attributed to the abun-
dant proton source in the system after the addition of water. As
shown in Fig. 2B curve c, when water was added, the first cathodic
peak (peak I in Fig. 2A, curve c) shifted to a more positive potential
region with a minimal increase in the peak current, whereas the
second peak (peak II in Fig. 2A curve c) disappeared completely.
d
0.3
0.2
0.1
0.0
c
A
3.2. Preparative electrolysis
I
b
a
II
MeCN
The preparative electrolysis (Scheme 2) was carried out in
co-solvent (MeCN/H2O = 9/1)–0.1 M TEABF4 containing 0.1 M ace-
tophenone and 1 mM CD in an undivided cell equipped with a
Mg rod anode and a Ag cathode at 25 ◦C. After 2 F mol−1 charge
was passed, the current was switched off. The electrolyte was then
extracted with ethyl ether. The yield and the dl/meso ratio of pina-
col with three stereoisomers (Scheme 2) were both detected by
HPLC analysis. Two products, optically active alcohol (2) and dimer
product pinacol (3) with no optical rotation, were obtained with
3.6% yield and 83.2% yield, respectively (Table 2, entry 2). In the
presence of CD, the R enantiomer was more abundant than the S
enantiomer with 21.6% ee for alcohol, whereas the pinacol exhib-
ited no optical rotation. The peak areas in the HPLC suggest the pres-
ence of equal amounts of the two enantiomers; that is, the pinacol is
optically inactive. To optimize the synthesis condition, the effect of
water in the co-solvent, supporting electrolyte, electrode material,
current density, and alkaloid type were investigated systematically.
-1.0
-1.2
-1.4
-1.6
-1.8
-2.0
-2.2
-2.4
d
c
0.3
0.2
0.1
0.0
B
MeCN/H2O = 9/1
b
a
E vs. (Ag/AgI) / V -2.0
-1.0
-1.2
-1.4
-1.6
-1.8
-2.2
-2.4
Fig. 2. Cyclic voltammograms recorded at GC electrode at 25 ◦C with the scan rate of
0.1 V s−1: (a) blank cyclic voltammetry in solvent–0.1 M TEABF4, (b) as (a) +0.1 mM
CD, (c) as (a) +10 mM acetophenone, (d) as (c) +0.1 mM CD. (A) The solvent is 10 ml
MeCN. (B) The solvent is 10 ml co-solvent (MeCN/H2O = 9/1, volume ratio).

B.-L. Chen et al. / Electrochimica Acta 107 (2013) 320–326
323
Table 2
Effect of water content in the co-solvent and supporting electrolyte on the enantioselective electroreduction of acetophenone.a
Entry
MeCN/H2O volume ratio
Supporting electrolyte
Alcohol yieldb (%)
Pinacol yieldb (%)
eeb (R-%)
Pinacol dl/mesob
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
9.5/0.5
9/1
8.5/.5
8/2
7.5/2.5
7/3
6/4
TEAI
TEAI
TEAI
TEAI
TEAI
TEAI
TEAI
TEAI
TEAI
TEAI
TEABr
TEACl
TEABF4
TBAI
TBABr
KCl
0.9
3.6
6.7
10.1
16.1
16.8
28.7
45.2
1.9
0.9
1.5
1.2
2.5
88.0
83.2
55.2
51.5
62.5
43.8
38.6
14.7
43.7
34.5
65.9
87.5
79.8
88.0
81.3
7.8
39.4
21.6
6.8
2.0
1.2
6.7
5.5
4.9
4.2
4.0
3.6
3.1
2.8
2.0
1.2
6.2
6.3
5.4
5.6
6.0
3.3
2.7
4.9
1.0
0.5
5/5
trace
25.6
5.7
22.3
30.2
15.2
6.7
46.5
4.5
8.9
9/1c
9/1d
9/1
9/1
9/1
9/1
9/1
9/1
9/1
9/1
3.2
0.9
3.9
1.1
NaCl
KClO4
2.3
13.7
3.2
8.4
a
Cathode: silver. Anode: Mg. Acetophenone concentration: 0.1 M. Charge passed: 2 F mol−1. CD concentration: 1 mM. Supporting electrolyte concentration: 0.1 M. Current
density: 3 mA cm−2. Temperature: 25 ◦C.
b
The yield based on the starting materiel, enantioselectivity of alcohol and the ratio of dl/meso of pinacol were determined by HPLC analysis.
MeCN/EtOH.
MeCN/HOAc.
c
d
3.2.1. Effect of water in the co-solvent and effect of the electrolyte
The effect of water amount of the co-solvent on enantioselec-
tive electroreduction was first investigated. In our study, the best
result was achieved with 21.6% ee and 3.6% chemical yield for alco-
hol. For pinacol, a chemical yield of 83.2% and a dl/meso ratio of 5.5
were found (Table 2, entry 2). As shown in Table 2 (entries 1–8),
with the decreasing MeCN/H2O volume ratio in the co-solvent, (i)
the alcohol yield increased whereas the pinacol yield decreased.
This result is due to the increase of the water amount as pro-
ton donor. The ratio of alcohol to pinacol should depend on the
competing dimerization and reduction of the intermediate car-
bonyl radical [phenyl(CH3)(OH)C•] [44]. A rich proton source is
more conducive to the reduction of the intermediate carbonyl rad-
ical, because the resulting anion is faster protonated. Competing
with the dimerization, the radical was reduced to 1-(1-phenyl-1-
hydroxy)-ethyl anion, which is protonated though intermolecular
proton transfer, water, and/or CD. These results are probable but
not experimentally well supported for the moment. (ii) The ratio
of the dl to meso decreases with decreasing pH [46,47]. The pH
of the electrolyte increases near the cathode during electrolysis
because of hydrogen evolution. At a higher water content, the
increase should be lower, and then caused the decrease in the
dl/meso ratio. Third, the ee value of the alcohol decreased. The H2O,
not the protonated alkaloid, probably acted as the proton donor
when the amount of water was higher. For the ee and chemical
yield of alcohol, the MeCN/H2O = 9/1 volume ratio was used for
the next optimization. In addition, replacing the H2O in the co-
solvent with other proton donors such as ethanol (EtOH) and acetic
acid (HOAc) (Table 2, entries 9 and 10) did not improve the prod-
uct yield (alcohol and pinacol) and the enantioselectivity except
for the enantioselectivity in the MeCN/EtOH co-solvent. The result
is consistent with the acetophenone voltammograms obtained
using the MeCN/EtOH, MeCN/HOAc (Fig. 3), and MeCN/H2O co-
solvents (Fig. 2B). Figs. 2B and 3A indicate that the voltammetric
curve of acetophenone in the MeCN/EtOH co-solvent is similar to
that obtained using the MeCN/H2O co-solvent, except the reduc-
tion peak potentials in MeCN/EtOH co-solvent were more negative
than these in the MeCN/H2O co-solvent. Thus, the yield using the
MeCN/EtOH co-solvent (Table 2, entry 9) was lower than that
using the MeCN/H2O co-solvent (Table 2, entry 2). Fig. 3B shows
a reduction current in MeCN/HOAc already at −0.8 V whilst in
MeCN/EtOH the current starts at about −1.45 V. This result indicates
that in MeCN/HOAc the current is mainly used for the reduction
of the solvent, which explains the low yield in this solvent. In
summary, the best co-solvent was MeCN/H2O at a 9/1 volume
ratio.
Table 2 (entries 2, 11–18) shows that with the regard to the
chemical yield the best supporting electrolytes were tetraalkylam-
monium salts. The use of alkali salts as the supporting electrolyte
(entries 16–18) decreased the alcohol and pinacol yields. The result
could be attributed to the ability of the tetraalkylammonium cation
to stabilize the acetophenone radical anion by forming an ion pair as
has been assumed in related reaction [48–50]. As shown in Table 2
(entries 2, 11, 12), the alcohol yield decreased in dependence on
the anion in the following order: I−1 > Br−1 > Cl−1 under the same
electrolytic conditions. However, the origin of the effect is unclear
at this stage. In addition, the ammonium salt anions affected the
enantioselectivity of alcohol. As shown in Table 2 (entries 2, 11–12),
in the same TEA+ case, the ee value of alcohol increased in the
following order: I−1 < Br−1 < Cl−1. Also this effect remains unclear.
0.6
0.5
0.4
0.3
0.2
0.1
0.0
d
c
b
A
MeCN/EtOH = 9/1
a
-1.0
-1.2
-1.4
-1.6
-1.8
-2.0
1.6
1.2
0.8
0.4
0.0
d
B
MeCN/HOAc = 9/1
a
-0.2
-0.4
-0.6
-0.8
-1.0
-1.2
-1.4
E vs. (Ag/AgI) / V
Fig. 3. Cyclic voltammograms recorded at GC electrode at 25 ◦C with the scan rate
of 0.1 V s−1: (a) blank cyclic voltammogram in co-solvent–0.1 M TEABF4, (b) as (a)
+0.1 mM CD, (c) as (a) +10 mM acetophenone, (d) as (c) +0.1 mM CD. (A) Co-solvent
MeCN/EtOH = 9/1, volume ratio. (B) Co-solvent MeCN/HOAc = 9/1, volume ratio.

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B.-L. Chen et al. / Electrochimica Acta 107 (2013) 320–326
Table 3
Effect of electrode material and current density on the enantioselective electroreduction of acetophenone.a
Entry
Electrode materials
Current density (mA cm−2
)
Alcohol yieldb (%)
Pinacol yieldb (%)
eeb (R-%)
Pinacol dl/mesob
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Ag
Pt
Ni
Ss
Zn
Ti
Cu
C
Ag
Ag
Ag
Ag
Ag
Ag
3
3
3
3
3
3
3
3
5
4
3.5
2.5
2
3.6
83.2
trace
trace
trace
87.2
88.1
71.5
70.5
85.6
84.5
83.2
65.0
41.4
35.8
21.6
–
–
5.5
–
–
trace
trace
trace
1.3
1.2
0.7
3.8
2.6
2.7
2.8
–
–
32.1
53.3
58.6
7.2
9.2
12.6
15.8
7.9
6.9
3.6
5.9
5.6
5.6
6.3
5.7
5.6
5.6
5.4
5.5
4.8
4.2
3.1
2.1
1
a
Solvent: co-solvent (MeCN/H2O = 9/1, volume ratio). Anode: Mg. Acetophenone concentration: 0.1 M. Charge passed: 2 F mol−1. CD concentration: 1 mM. Supporting
electrolyte: 0.1 M TEAI. Temperature: 25 ◦C.
b
The yield based on the starting materiel, enantioselectivity of alcohol and the ratio of dl/meso of pinacol were determined by HPLC analysis.
3.2.2. Effect of electrode material and current density
The current density also affected the reaction. Table 3 (entries 1,
9–14) shows the chemical yield and enantioselectivity under var-
ious current densities. At a current density of 3 mA cm−2, a high
ee value and chemical yield was achieved. Higher or lower cur-
rent densities resulted in lower ee values, although higher yields
were obtained at 2.5 mA cm−2. On the one hand, higher current
densities accelerate the electron transfer rate between the elec-
trode and the substrate [38]. Possibly the high concentration of
generated radical anions (see Scheme 4) depletes the electrode
surface from the alkaloid and the enantioselective protonation of
the 1-(1-hydroxy-phenethyl)-anion (see Scheme 4) competes with
the non-enantioselective protonation by water. On the other hand,
The nature of the cathode material strongly affected the yield
and ee value of the electroreductive reaction. The most effective
cathode with regard to the enantioselectivity was the Ag elec-
trode with a 21.6% ee and a 3.6% alcohol yield (Table 3, entry 1).
Possibly the Ag electrode adsorbs the alkaloid similar as the Hg
electrode [20,21,23] to create a chiral environment that eventu-
ally caused chiral induction. With Pt, Ni, and Ss cathodes (Table 3,
entries 2–4) no desired reduction product was obtained, whereas
a large number of unreacted substrate was detected. The result
is consistent with the voltammetric behavior of acetophenone in
the co-solvent at the Pt, Ni, and Ss cathodes (curves f, b, and e in
Fig. 4): no reduction peak for the acetophenone, but high reduc-
tion currents for the hydrogen evolution due to the more anodic
hydrogen evolution potential of these cathodes. Bubbles that cor-
responded to hydrogen were clearly observed in the surface of
the three electrodes during electrolysis, but this phenomenon was
not observed for the other materials in Table 3 (entries 1, 5–8).
Table 3 (entries 1–8) also suggests that the total reduction yields
depend on the cathode materials in the following order: Pt (trace,
entry 2), Ni (trace, entry 3) and Ss (trace, entry 4) < Cu (72.2%, entry
7) < C (74.3%, entry 8) < Ag (86.8%, entry 1) < Zn (88.5%, entry 5) < Ti
(89.3%, entry 6). The yield correlates with the reduction potential
of acetophenone at the different electrodes: Cu (−1.50 V, curve d
of Fig. 4) < Ag (−1.47 V, curve a of Fig. 4) < GC (−1.44 V, curve c of
Fig. 4).
1.6
f
1.4
e
1.2
1.0
0.8
0.6
0.4
0.2
0.0
d
c
a
b
-1.0
-1.1
-1.2
-1.3
-1.4
-1.5
-1.6
-1.7
E vs. (Ag/AgI) / V
Fig. 4. Cyclic voltammograms of 10 mM acetophenone in co-solvent
(MeCN/H2O = 9/1, volume ratio)–0.1 M TEABF4with the scan rate of 0.1 V s−1
at different electrodes: (a) Ag, (b) Ni, (c) GC, (d) Cu, (e) Ss, (f) Pt, T = 25 ◦C.
Scheme 4. Mechanism for the alkaloid induced enantioselective electroreduction
of acetophenone.

B.-L. Chen et al. / Electrochimica Acta 107 (2013) 320–326
325
Table 4
Effect of alkaloid types on the enantioselective electroreduction of acetophenone.a
Entry
Alkaloid
Alcohol yieldb (%)
Pinacol yieldb (%)
eeb (R-%)
Pinacol dl/mesob
1
2
3
4
5
CD
QD
QN
CN
–
3.6
4.1
3.3
3.6
2.8
83.2
79.9
85.7
74.3
79.2
21.6
4.7
4.9
4.0
–
5.5
5.5
5.5
5.4
5.4
a
Solvent: co-solvent (MeCN/H2O = 9/1, volume ratio). Cathode: silver. Anode: Mg. Acetophenone concentration: 0.1 M. Charge passed: 2 F mol−1. Alkaloid concentration:
1 mM. Supporting electrolyte: 0.1 M TEAI. Current density: 3 mA cm−2. Temperature: 25 ◦C.
b
The yield based on the starting materiel, enantioselectivity of alcohol and the ratio of dl/meso of pinacol were determined by HPLC analysis.
lower current densities slow the electron transfer rate between the
electrode and the substrate. Under such conditions, the generated
complex (4a) may diffuse or migrate again into the solution, and
consequently decreased the ee value. Moreover, the electrolysis
conducted at low current densities was very inefficient [Table 3,
entries 13, 14]. Unreacted substrate was detected in HPLC after
electrolysis. This is because lower current densities leading to more
positive of electrode potential [51], thereby decreasing the elec-
troreduction yield.
Acknowledgements
This work was financially supported by the Project for
the National Natural Science Foundation of China (20973065,
21173085), “Chen Guang” project supported by Shanghai Munic-
ipal Education Commission and Shanghai Education Development
Foundation, China (10CG26), Specialized Research Fund for the
Doctoral Program of Higher Education (20100076120020), the Fun-
damental Research Funds for the Central Universities, China and
Shanghai Leading Academic Discipline Project, China (B409).
3.2.3. Effect of alkaloid type
Table 4 (entries 1–4) presents the results obtained using dif-
ferent alkaloids (CD, CN, QD, QN, structures shown in Scheme 2).
The best result was obtained using CD as inducer (Table 4, entry 1),
wherein, alcohol was obtained at 21.6% ee with 3.6% yield. When
the inducer CD was replaced with CN, QD, or QN (Table 4, entries
2–4), no substantial change in chemical yield was observed, but
the ee values were lower. Thus, an excess of the R enantiomer was
formed in all cases (when CD was replaced with CN, QD, or QN).
The mechanism of the asymmetric induction is discussed below.
The successful asymmetric induction of alkaloid was attributed to
complexation (4a) formed through the one-electron reduction of
acetophenone (1) and the protonated alkaloid (e.g. CD-H) [1]. In
addition, Table 4 (entries 1–5) revealed that the addition of any of
the alkaloids tested increased the product yield, which is consistent
with the cyclic voltammograms in Fig. 2. Moreover, it also increased
the relative alcohol production during electrolysis [23].
References
[1] N. Schoo, H.J. Schafer, Enantioselective cathodic reduction of 4-substituted
coumarins with alkaloids as catalysts, 1, Liebigs Annalen der Chemie 1993
(1993) 601.
[2] Y. Kawanami, K. Hoshino, W. Tsunoi, Enantioselective reduction of trifluo-
romethyl ketones using an oxazaborolidine catalyst generated in situ from a
chiral lactam alcohol, Tetrahedron: Asymmetry 22 (2011) 1464.
[3] T.D. Nixon, M.K. Whittle, J.M.J. Williams, Ruthenium-catalysed transfer hydro-
genation reactions with dimethylamine borane, Tetrahedron Letters 52 (2011)
6652.
[4] O. Prakash, P. Singh, G. Mukherjee, A.K. Singh, Efficient catalysis of transfer
hydrogenation of ketones and oxidation of alcohols with newly designed half-
sandwich rhodium(III) and iridium(III) complexes of half-pincer chalcogenated
pyridines, Organometallics 31 (2012) 3379.
[5] W.N.O. Wylie, J. Alan, H.M. Robert, Factors favoring efficient bifunctional
catalysis. Study of a ruthenium(II) hydrogenation catalyst containing an N-
heterocyclic carbene with a primary amine donor, Organometallics 31 (2012)
2137.
[6] K.D. Huynh, H. Ibrahim, E. Kolodziej, M. Toffano, V.T. Giang, Synthesis of a new
class of ligands derived from isosorbide and their application to asymmet-
ric reduction of aromatic ketones by transfer hydrogenation, New Journal of
Chemistry 35 (2011) 2622.
[7] S.-W. Wei, R. Messerer, S.B. Tsogoeva, Asymmetric synthesis of ␤-adrenergic
blockers through multistep one-pot transformations involving in situ chiral
organocatalyst formation, Chemistry: A European Journal 17 (2011) 14380.
[8] R. Boshra, A. Doshi, F. Jakle, Allylation of ketones with a ferrocene-based pla-
nar chiral Lewis acid, Angewandte Chemie International Edition in English 47
(2008) 1134.
[9] Y.-H. Li, Y.-G. Zhou, Q.-X. Shi, K.-L. Ding, R. Noyori, C.A. Sandoval, An efficient
diphosphine/hybrid-amine combination for ruthenium (II)-catalyzed asym-
metric hydrogenation of aryl ketones, Advanced Synthesis & Catalysis 353
(2011) 495.
[10] T. Marziatetti, J.L.G. Fierro, P. Reyes, Iridium-supported catalyst for enan-
tioselective hydrogenation of 1-phenyl-1 2-propanedione: the effects of the
addition of promoter and the modifier concentration, Catalysis Today 107–108
(2005) 235.
3.3. Mechanism of the alkaloid-induced enantioselective
electroreduction of acetophenone
Based on the results of the electrolysis and CVs discussed above,
we accordingly propose an induction mechanism (Scheme 4). The
alkaloid is probably adsorbed at the Ag electrode similar to the
adsorption at the mercury cathode as a chiral proton donor after
protonation. In the course of the reduction, at first the radical
anion of acetophenone is formed and protonated by the protonated
alkaloid or water. The resulting 1-(1-hydroxy-phenethyl)-radical
bound to the alkaloid or not the hydroxy anion 4a or being a
free anion 4b can couple to the pinacol (3) and/or be reduced
to the corresponding anions 5a and 5b. 5a can be enantioselec-
tively protonated to the optically active alcohol (2a) in an inter-
or intramolecular reaction, whereas 5b must be protonated to the
racemic alcohol (2a + 2b) in an intermolecular reaction.
[11] C. Li, Chiral synthesis on catalysts immobilized in microporous and mesoporous
materials, Catalysis Reviews 46 (2004) 419.
[12] A.M. Rouhi, Priestley Medalist. Above and beyond organic synthesis, Chemical
& Engineering News 82 (2004) 37.
[13] D.-D. Yuan, C.-H. Yan, B. Lu, H.-X. Wang, C.-M. Zhong, Q.-H. Cai, Electrochemical
activation of carbon dioxide for synthesis of dimethyl carbonate in an ionic
liquid, Electrochimica Acta 54 (2009) 2912.
[14] F.-G. Xu, M. Deng, G.-Y. Li, S.-H. Chen, L. Wang, Electrochemical behavior of
cuprous oxide-reduced graphene oxide nanocomposites and their application
in nonenzymatic hydrogen peroxide sensing, Electrochimica Acta 88 (2013) 59.
[15] L.A. Estudillo-Wong, G. Santillan-Diaz, E.M. Arce-Estrada, N. Alonso-Vante, A.
4. Conclusions
In summary, an electrochemical enantioselective reduction of
acetophenone in the presence of alkaloids has been established at
the Ag electrode. Thereby optically active 1-phenyl-1-ethanol and
optically inactive pinacol is obtained. Under the optimized condi-
tion, the enantiomeric excess of alcohol was 21.6% ee and the yield
3.6%; additionally, the pinacol was obtained in 83.2% yield with a
5.5 dl/meso ratio.
z
Manzo-Robledo, Electroreduction of NOx species in alkaline medium on Pt
nanoparticles, Electrochimica Acta 88 (2013) 358.
[16] M. Orsini, M. Feroci, G. Sotgiu, A. Inesi, Stereoselective electrochemical car-
boxylation: 2-phenylsuccinates from chiral cinnamic acid derivatives, Organic
& Biomolecular Chemistry 3 (2005) 1202.
[17] M. Feroci, M. Orsini, L. Palombi, G. Sotgiu, M. Colapietro, A. Inesi, Diastere-
oselective electrochemical carboxylation of chiral a-bromocarboxylic acid

326
B.-L. Chen et al. / Electrochimica Acta 107 (2013) 320–326
derivatives: an easy access to unsymmetrical alkylmalonic ester derivatives,
Journal of Organic Chemistry 69 (2004) 487.
[18] C. Amatore, Basic Concepts, in: H. Lund, O. Hammerich (Eds.), Organic Electro-
chemistry, Marcel Dekker, Inc., New York, 2001, p. 53, Ch. 1.
[19] R. Hazard, S. Jaouannet, A. Tallec, Stereochemistry of electroreductions of bro-
mocyclopropanes, Tetrahedron 38 (1982) 93.
[20] L. Horner, D. Degner, Asymmetrische induction bei der reduction von acetophe-
non an der quecksilberkathode mit chiralen leitsalzen, Tetrahedron Letters 56
(1968) 5889.
[35] A.M. Abeysekera, J. Grimshaw, S.D. Perera, Electroactive poly(amino acids). Part
3. Ferrocene-doped poly(l-Iysine) as an electroactive layer on platinum, Journal
of the Chemical Society, Perkin Transactions 2 (1990) 1797.
[36] T. Nonaka, S. Abe, T. Fuchigami, Electro-organic reactions on organic electrodes.
Part 2. Electrochemical asymmetric reduction of citraconic and mesaconic acids
on optically-active poly(amino acid)-coated electrodes, Bulletin of the Chemi-
cal Society of Japan 56 (1983) 2778.
[37] P. Tascedda, E. Dunach, Electrosynthesis of cyclic carbamates from aziridines
and carbon dioxide, Chemical Communications 6 (2000) 449.
[21] A.K. Yadav, M. Manju, P.R. Chhinpa, Enantioselective cathodic reduction of some
prochiral ketones in the presence of (−)-N,Nꢀ-dimethylquininium tetrafluoro-
borate at mercury cathode, Tetrahedron: Asymmetry 14 (2003) 1079.
[22] M. Schwientek, S. Pleus, C.H. Hamann, Enantioselective electrodes: stereose-
lective electroreduction of 4-methylbenzophenone and acetophenone, Journal
of Electroanalytical Chemistry 461 (1999) 94.
[23] E. Kariv, H.A. Terni, E. Gileadi, The role of quinidine in induction of asymmetric
synthesis at mercury cathodes, Electrochimica Acta 18 (1973) 433.
[24] J. Kopilov, E. Kariv, L.L. Miller, Asymmetric, cathodic reduction of
acetylpyridines, Journal of the American Chemical Society 99 (1977)
3450.
[38] K. Zhang, H. Wang, S.-F. Zhao, D.-F. Niu, J.-X. Lu, Asymmetric electrochemical
carboxylation of prochiral acetophenone: an efficient route to optically active
atrolactic acid via selective fixation of carbon dioxide, Journal of Electroanalyt-
ical Chemistry 630 (2009) 35.
[39] S.-F. Zhao, M.-X. Zhu, K. Zhang, H. Wang, J.-X. Lu, Alkaloid induced asymmet-
ric electrocarboxylation of 4-methylpropiophenone, Tetrahedron Letters 52
(2011) 2702.
[40] P. Zuman, D. Barnes, A.R. Keyjharova, Polarographic reductions of some car-
bonyl compounds, Discussions of the Faraday Society 45 (1968) 202.
[41] Electroanalytical Method, in: A.J. Bard, M. Stratmann (Eds.), Encyclopedia of
Electrochemistry, Vol. 3, Instrumentation and Electroanalytical Chemistry, P.R.
Unwin, Wiley-VCH, Weinheim, 2003, p. 86, Ch. 2.
[42] S.-H. Wang, P.-S. Singh, D.-H. Evans, Concerted proton-electron trans-
fer: effect of hydroxylic additives on the reduction of benzophenone
4-cyanobenzophenone, and 4,4ꢀ-dicyanobenzophenone, Journal of Physical
Chemistry C 113 (2009) 16686.
[43] S.-F. Zhao, L.-X. Wu, H. Wang, J.-X. Lu, A.M. Bond, J. Zhang, A unique proton
coupled electron transfer pathway for electrochemical reduction of acetophe-
none in the ionic liquid [BMIM][BF4] under a carbon dioxide atmosphere, Green
Chemistry 13 (2011) 3461.
[44] J.M. Saveant, Electrochemical concerted proton and electron transfers. further
insights in the reduction mechanism of superoxide ion in the presence of water
and other weak acids, Journal of Physical Chemistry C 111 (2007) 2819.
[45] S.-F. Zhao, J.-X. Lu, A.M. Bond, J. Zhang, Remarkable sensitivity of the elec-
trochemical reduction of benzophenone to proton availability in ionic liquids,
Chemistry: A European Journal 18 (2012) 5290.
[25] M. Vago, F.J. Williams, E.J. Calvo, Enantioselective electrocatalytic hydrogena-
tion of ethyl pyruvate on carbon supported Pd electrodes, Electrochemistry
Communications 9 (2007) 2725.
[26] J.C. Moutet, D.T. Carole, S. Menage, S. Tingry, A chiral poly(2,2ꢀ-bipyridyl
rhodium(III)complex) film electrode for asymmetric induction in electrosyn-
thesis, Advanced Materials 10 (1998) 665.
[27] D. Seebach, H.A. Oei, Zum Mechanismus der elektrochemischen
Pinakolisierung. Die erste asymmetrische Elektrosynthese in chiralem
Medium, Angewandte Chemie International Edition in English 87 (1975) 629.
[28] D. Seebach, H.A. Oei, Mechanism of Electrochemical Pinacolization. The First
Asymmetric Synthesis in a Chiral Medium, Angewandte Chemie International
Edition in English 14 (1975) 634.
[29] L. Horner, D. Degner, Studien zum vorgang der wasserstoffübertragung-
33. Zur kenntnis des aufbaus der elektrochemischen doppelschicht. Die
asymmetrische elektrochemische reduktion einiger alkyl-phenyl-ketone in
gegenwart optisch aktiver leitsalze, Electrochimica Acta 19 (1974) 611.
[30] D. Brown, L. Homer, Studien zum Vorgang der Wasserstoffübertragung 41.
Elektroreduktion von Acetophenon unter Mitwirkung optisch aktiver Leitsalze,
Liebigs Annalen der Chemie 1977 (1977) 77.
[46] J.H. Stocker, R.M. Jenevein, Quantitative studies in stereochemistry C. Electro-
chemistry. 1. The ratio of diastereomeric pinacols formed in the electrolytic
bimolecular reduction of acetophenone-7-Cl4, Journal of Organic Chemistry 33
(1968) 294.
[31] L. Horner, W. Brich, Studien zum vorgang der wasserstoffübertragung, 49:
zur frage der auslösung einer optischen induktion durch anwendung optisch
aktiver ephedrinderivate und optisch aktiver kronenether als leitsalze bei der
elektroreduktion von acetophenon, Chemische Berichte 111 (1978) 574.
[32] M. Feroci, A. Inesi, M. Orsini, L. Palombi, Electrochemical carboxylation
of N-(2-bromopropionyl)-4R-phenyloxazolidin-2-one: an efficient route to
unsymmetrical methylmalonic ester derivatives, Organic Letters 4 (2002) 2617.
[33] C. Schuster, M. Knollmueller, P. Gaertner, Chiral linker. Part 4: diastereoselec-
tive addition of RZnX to a-keto esters using m-hydrobenzoin derived chiral
auxiliaries in solution and on solid support and their application in the stereo-
selective synthesis of frontalin, Tetrahedron: Asymmetry 17 (2006) 2430.
[34] B.F. Watking, J.R. Behling, E. Kariv, L.L. Miller, Chiral electrode, Journal of the
American Chemical Society 97 (1975) 3549.
[47] V.J. Puglisi, G.L. Clapper, D.H. Evans, Stereochemistry of the electrolytic reduc-
tive coupling of benzaldehyde, Analytical Chemistry 41 (1969) 279.
[48] N. Kise, S. Iitaka, K. Iwasaki, N. Ueda, Stereoselective hydrocoupling of cin-
namic acid esters by electroreduction: application to asymmetric synthesis of
hydrodimers, Journal of Organic Chemistry 67 (2002) 8305.
[49] M. Feroci, A. Inesi, L. Rossi, The reaction of amines with an electrogenerated
base, Tetrahedron Letters 41 (2000) 963.
[50] D.-F. Niu, L.-P. Xiao, A.-J. Zhang, G.-R. Zhang, Q.-Y. Tan, J.-X. Lu, Electrocatalytic
carboxylation of aliphatic halides at silver cathode in acetonitrile, Tetrahedron
64 (2008) 10517.
[51] K. Zhang, H. Wang, L.-X. Wu, J.-B. Zhang, J.-X. Lu, Efficient electrocarboxylation
of p-methylpropiophenone in the presence of carbon dioxide, Chinese Journal
of Chemistry 28 (2010) 509.