Alkaloid-induced asymmetric hydrogenation on a Cu nanoparticle cathode by electrochemical conditions

Article abstract of DOI:10.1016/j.elecom.2015.03.006

Copper nanoparticles were prepared in an aqueous solution, compacted into a coin, and used as a cathode for asymmetric hydrogenation by the electrochemical method for the first time. A good ee value and excellent yield were obtained under mild conditions. Electrochemical conditions were crucial for alkaloid adsorption on metallic Cu, which is a key process of asymmetric induction. Furthermore, the ee value was linear with an adsorption amount.

Full text of DOI:10.1016/j.elecom.2015.03.006

Alkaloid-induced asymmetric hydrogenation on a Cu nanoparticle cathode by
electrochemical conditions
Heng-Pan Yang, Huan Wang, Jia-Xing Lu
PII:
DOI:
Reference:
S1388-2481(15)00074-0
doi: 10.1016/j.elecom.2015.03.006
ELECOM 5406
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Electrochemistry Communications
Received date:
Revised date:
Accepted date:
17 February 2015
5 March 2015
10 March 2015
Please cite this article as: Heng-Pan Yang, Huan Wang, Jia-Xing Lu, Alkaloid-induced
asymmetric hydrogenation on a Cu nanoparticle cathode by electrochemical conditions,
Electrochemistry Communications (2015), doi: 10.1016/j.elecom.2015.03.006
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ACCEPTED MANUSCRIPT
Alkaloid-induced asymmetric hydrogenation on a Cu
nanoparticle cathode by electrochemical conditions

Heng-Pan Yang, Huan Wang, Jia-Xing Lu
Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of
Chemistry and Molecular Engineering, East China Normal University, Shanghai
2
00062, China
Abstract: Copper nanoparticles were prepared in an aqueous solution, compacted
into a coin, and used as cathode for asymmetric hydrogenation by the electrochemical
method for the first time. A good ee value and excellent yield were obtained under
mild conditions. Electrochemical conditions were crucial for alkaloid adsorption on
metallic Cu, which is a key process of asymmetric induction. Furthermore, the ee
value was linear with an adsorption amount.
Keywords: Copper nanoparticles; Asymmetric hydrogenation; Electrochemical
conditions; Alkaloids; Adsorption
1
. Introduction
Asymmetric synthesis is a fundamental part of the pharmaceutical and
agrochemical industries [1]. Asymmetric hydrogenation occupies a particularly
important position in asymmetric synthesis, which provides an effective route for
chiral compounds，but a majority of these reactions are homogeneously catalyzed by
transition metal complexes such as Rh, Ir, and Ru catalysts, which are always
expensive and hardly recyclable [2–9]. Heterogeneous catalysts have clear advantages
compared with homogeneous catalysts. However, successful heterogeneous
asymmetric catalysts are currently confined to several specific metals.
One of the most effective and well-document heterogeneous asymmetric catalysts
are Pt/Al O (or Pd) modified with alkaloids, which is used for the asymmetric
2
3
hydrogenation of α-ketoesters, despite the use of noble metals [10–14]. Since the
original discovery of this catalytic system, its mechanism has been studied thoroughly

Corresponding Author: Prof. Jia-Xing Lu (Tel: +8621-62233491, E-mail: jxlu@chem.ecnu.edu.cn)
1

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with both theoretical and experimental methods. Alkaloids can be adsorbed on the
supported metal and quinoline moiety of alkaloids that lie parallel to the metal surface
through a π-electron interaction, which is important for the formation of a preferential
enantiomer [15–18].
Because of its rarities and large potential application in extensive fields, to explore
a novel heterogeneous catalyst for asymmetric hydrogenation has both commercial
and academic value. Metallic Ag or Cu, which are abundant and relatively cheap, can
be alternative heterogeneous asymmetric catalysts; these metals are types of
face-centered cubic metals，just like Pt and Pd. However, to the best of our knowledge,
there is no report on the application of metallic Ag or Cu in heterogeneously
asymmetric hydrogenation as active substance. No proof also exists on alkaloid
adsorption on metallic Ag or Cu surface by typical methods.
In our previous research, alkaloids were electrosorbed on metallic Ag for
heterogeneously asymmetric hydrogenation by electrocatalysis; moderate to suitable
ee values were obtained under mild conditions [19–21]. For metallic Cu, the
cinchonidine (CD) adsorption on the Cu (111) electrode surface was investigated by
in-situ scanning tunneling microscopy (STM) in an aqueous solution by the
electrochemical method, but not involving any actual catalysis [22]. We further
explored the application of metallic Cu in asymmetric hydrogenation by the
electrochemical method under the guidelines of this strategy.
2
. Experimental
2
.1. Apparatus and reagents
All reagents were used as received.
Galvanostatic electrohydrogenation and electrosorption of alkaloids were
performed with a direct-current-regulated power supply (HY3002D, HYelec®, China).
The product yield, ee value, and adsorption amount were determined with a
high-performance liquid chromatography (HPLC) instrument (DIONEX Ultimate
3
000 pump) equipped with a UV (RS variable wavelength) detector and a chiralcel
OD-H column (DAICEL Chiral technologies Co., Ltd., China). The microstructure
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and morphology were analyzed with a Hitachi S-4800 field-emission scanning
electron microscope. X-ray diffraction (XRD) patterns were recorded with an Ultima
IV x-ray powder diffractometer with Cu Kα radiation (k = 1.5406 Å).
2
.2. General procedure
The synthesis of Cu (Pt) NPs was performed as follows. 5 g of CuSO ·5H O (2.07 g
4
2
H PtCl ·6H O) was dissolved in 100 mL deionized water. 8 mL of ethylene glycol
2
6
2
was then added into the solution. After 10 min of stirring, 50 mL of hydrazine hydrate
solution (10%) was slowly added. The mixture was then stirred at 25 °C for 4 h. Cu
(Pt) was precipitated immediately. The precipitate was filtered, washed with 10 mL
water and 10 mL anhydrous ethanol for 4 times each, and dried for 12 h under
vacuum.
The electrohydrogenation procedure is as follows. Cu NP powder was pressed into a
coin and used as a cathode. Typical galvanostatic electrohydrogenation was conducted
in a mixture of 50 mM substrate, certain concentration of alkaloid and 0.1 M
tetraethylammonium iodide (TEAI) in a 20 mL co-solvent (MeCN/H O = 9/1) in an
2
undivided glass cell with a Cu NP cathode and sacrificial magnesium (Mg) anode.
3
. Results and discussion
First, Cu NPs and Pt NPs were characterized by multiple methods. The typical
diffraction peaks of Cu (Fig. 1D, a) and Pt (Fig. 1D, c) were observed in the XRD
patterns, and no trace of metal oxides was noted. The SEM pattern shows that Cu NPs
have nanostructures (Fig. 1A) that were aggregated from Cu nanograins in the ~20 nm
size range, similar to Pt NPs (Fig. 1B).
As previously mentioned, alkaloid adsorption on metallic Pt is a key step for chiral
induction in a typical system. Can this adsorption be possible on metallic Cu similar
to a Pt–alkaloid system? Contrastive experiments were performed to explore this
scenario. Alkaloid adsorptions on both Pt NPs and Cu NPs were conducted in a
mixture of 0.1 M TEAI and 1.5 mM CD in 20 mL MeCN under N atmosphere for 30
2
mins. The alkaloid adsorption amount was calculated from the alkaloid concentration
differences before and after the addition of 0.5 g Pt NPs or Cu NPs, which was
˗
1
detected by HPLC. The concentration differences show that 168 μg g CD was
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adsorbed on Pt NPs, but the CD concentration remained unchanged after the addition
of Cu NPs. This phenomenon indicates that the CD cannot be adsorbed on Cu NPs as
Pt NPs by the typical method. Thus, electrochemical conditions were introduced to
the asymmetric hydrogenation on metallic Cu and were demonstrated to be very
efficient in our work.
Typical asymmetric hydrogenation was conducted in a mixture of 50 mM substrate
and certain CD concentration as a chiral inducer in an undivided glass cell with a Cu
NP cathode and Mg anode. Methyl benzoylformate (1a) was selected as the model
substrate to optimize the reaction conditions. The influence of alkaloid concentration,
electric charge, current density, and cathode was investigated (Table 1). Optically
active methyl mandelate (2a) was obtained with a 40% ee and a 95% yield (Table 1
entry 2) under optimized conditions. Certain ee values and yield could also be
achieved with other alkaloids (Table l), such as cinchonine (CN), quinine (QD), and
quinidine (QN) (Table 1 entries 12–14).
Encouraged by the suitable results achieved with 1a, the preparative scope of
substrates was further studied under the reaction conditions in Table 1, entry 2. The
results summarized in Table 2 show that moderate or good yields and ee values could
be obtained with substituted ketones, including both electron withdrawing and
electron-donating groups. Therefore, Cu NPs electrosorbed with alkaloids could be
effective in the heterogeneous asymmetric hydrogenation of carbonyl with a wide
range of substrates.
Given that alkaloids could not be adsorbed on the Cu surface by the typical method,
investigating alkaloid behavior on the Cu surface under electrochemical conditions is
necessary to understand the mechanism of this system. CD adsorption on the Cu (111)
electrode surface was confirmed qualitatively by in-situ STM [22], which was
performed in an aqueous solution unlike the actual reaction condition. In our work,
we investigated the adsorption of alkaloids on Cu electrode quantitatively, which was
performed under actual catalytic condition except for the absence of substrates. We
detected the alkaloid concentration before and after adsorption by HPLC [21]. The
concentration differences show that the adsorption amounts were 28, 10, 14, 18, 23,
˗2
and 28 μg cm under the conditions listed in Table 1 (entries 2, 7, 8, 9, 10, and 11,
respectively) in the absence of substrates. It is quantitative evidence that CD can be
adsorbed on the Cu NP surface under actual reaction conditions, and the adsorption
−
2
amount is in the μg cm levels. An interesting phenomenon was observed under the
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conditions of Table 1 entries 2, 7, 8, 9, 10, and 11, wherein the ee values of 40%, 14%,
2
1%, 27%, 32%, and 39%, respectively, increased with the adsorption amount. We
plot the ee value versus the adsorption amount to further understand the relationship
between the adsorption amount and ee value (Fig. 2A). A straight line could be
achieved; thus, we can infer that the alkaloid adsorption was in favor of chiral
induction and the ee value was linear with an adsorption amount.
Moreover, 50 mM 1a was added for asymmetric hydrogenation after CD adsorption;
9
3% yield and 61% ee value were obtained (Table 1, entry 15). Compared with the 1a
added with CD (Table 1, entry 2), the yield was similar but the ee value was clearly
higher. With a pre-adsorbed Cu NP electrode, a similar yield but much higher ee value
could also be achieved with other alkaloids (Table 1, entries 16–18). In summary,
alkaloids could be adsorbed on the Cu NP surface and the adsorbed alkaloids
contributed to the formation of a preferential enantiomer.
The major disadvantage of homogeneous asymmetric hydrogenation involves the
utilization of valuable and hardly recyclable transition metal complexes. By contrast,
cheap alkaloids were used as chiral inducers in our catalytic system. Unlike a typical
Pt/Al O (or Pd) system, the Cu NPs used in our system were non-noble, abundant,
2
3
and easily prepared. Furthermore, the Cu NP cathode has remarkable stability and
reusability, can be easily cleaned after the previous run, and then reused for the next
catalytic procedure. It was tested for recycle times under the reaction conditions of
Table 1, entry 2. The yields and ee values of 2a can be maintained at approximately
9
4% and 60% for 10 times (Fig. 2B). The Cu NP electrode stability was characterized
by XRD before (Fig. 1D, a) and after (Fig. 1D, b) hydrogenation for 10 times. The
XRD patterns show that the Cu NP electrode is stable and its components do not
change. Cu NPs can also maintain its nanostructures and size range after recycling
(Fig. 1C). Therefore, the Cu NP electrode we prepared is stable and reusable.
Moreover, water was employed as a hydrogen source in our system without
high-pressure and high-temperature hydrogen in a typical Pt/Al O (or Pd) system. All
2
3
procedures can be performed under mild conditions.
4
. Conclusions
Alkaloids cannot be adsorbed on metallic Cu, such as metallic Pt, by the typical
method, which is important for chiral induction. Metallic Cu was successfully
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introduced to heterogeneous asymmetric hydrogenation for the first time by
electrochemical conditions. Furthermore, alkaloid adsorption on the metallic Cu
surface was quantitatively investigated by HPLC under actual catalytic conditions and
the ee value was linear with an adsorption amount. Unlike noble metallic Pt, metallic
Cu is abundant, relatively cheap, and highly reusable. Metallic Cu could be an
alternative option for heterogeneous asymmetric hydrogenation.
Acknowledgements
Financial support from National Natural Science Foundation of China (21173085,
2
1203066, 21373090, 21473060) is gratefully acknowledged.
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1
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A
B
8

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C
D
Fig. 1 Characterization of metal NPs. FE-SEM patterns of Cu NPs before using (A),
Pt NPs (B), and Cu NPs after using for 10 times (C); D: XRD patterns of Cu NPs
before using (a), after using for 10 times (b) and Pt NPs (c).
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A
B
Fig. 2 ee value of 2a versus CD adsorption amount (A); Reuse of Cu NPs electrode,
reaction conditions as Table 1 entry 2 (B).
10

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a
Table 1 Asymmetric hydrogenation of 1a on various reaction conditions .
b
b
Entry
C
CD (mM)
Yield (%)
R-ee (%)
c
1
1.5
1.5
1.5
1.5
1.5
1.5
0.5
0.75
1.0
1.25
2.0
93
95
57
11
95
94
92
92
93
91
90
94
90
87
93
92
86
85
38
40
2
d
3
29
e
4
24
f
5
36
g
6
39
7
8
9
14
21
27
1
0
1
32
1
39
h
1
1
1
1
1
1
1
2
3
4
5
6
7
8
1.5
38(S)
33
i
1.5
j
1.5
31(S)
61
k
1.5
l
1.5
63(S)
52
m
1.5
n
1.5
50(S)
a
Cathode: Cu NPs, anode: Mg, 20 mL co-solvent (MeCN/H O=9/1), 0.05 M 1a, supporting
2
-2
-1 b
electrolyte: 0.1 M TEAI, current density: 10 mA cm , charge: 3 F mol . Determined by HPLC
c
-2
d
-2 e
with a chiral column. current density: 5 mA cm , current density: 15 mA cm , current density:
-2
f
-1
g
-1
h
i
j
2
0 mA cm , charge: 4 F mol , charge: 5 F mol , Alkaloid: CN. Alkaloid: QD. Alkaloid:
11

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k
l
m
n
QN. Alkaloid: CD, pre-adsorbed. Alkaloid: CN, pre-adsorbed. Alkaloid: QD, pre-adsorbed.
Alkaloid: QN, pre-adsorbed.
a
Table 2 Asymmetric hydrogenation of several substrates on Cu NPs electrode .
b
b
Entry
Substrate
Product
Yield (%) R-ee (%)
1
86
88
4
33
36
16
20
1
b
2b
2c
2d
2e
2f
2
3
4
5
1
c
1d
7
1
e
6
28
1
f
6
89
47
1g
2g
a
Cathode: Cu NPs, anode: Mg, 20 mL co-solvent (MeCN/H O=9/1), 0.05 M substrate, 0.1 M
2
-
2
b
TEAI, 1.5 mM CD, current density: 10 mA cm , charge: 300 C. Determined by HPLC with a
chiral column.
12

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Graphical Abstract
13

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Highlights




Metallic Cu was used for heterogeneous asymmetric hydrogenation for the
first time.
All the preparation of Cu NPs and catalysis procedure were performed under
mild conditions.
Electrochemical conditions were crucial for alkaloid adsorption on metallic
Cu and the ee value was proved to be linear with an adsorption amount.
Cu NPs are much more abundant, relatively cheap, and remarkable reusable.
14