Electrocatalytic carboxylation of 2-amino-5-bromopyridine with CO 2 in ionic liquid 1-butyl-3-methyllimidazoliumtetrafluoborate to 6-aminonicotinic acid

Article abstract of DOI:10.1016/j.electacta.2010.05.010

A new electrochemical procedure for the electrocatalytic carboxylation of 2-amino-5-bromopyridine with CO₂ in ionic liquid, 1-butyl-3-methyllimidazolium tetrafluoborate (BMIMBF₄), to 6-aminonicotinic acid was investigated for the first time. The experiments were carried out in three electrodes undivided cell under mild conditions, and the use of volatile and toxic solvents and catalysts, as well as any other additional supporting electrolytes, was avoided. The electrochemical reduction behavior of 2-amino-5-bromopyridine in BMIMBF₄ had been studied by cyclic voltammetry with a reduction peak at-1.6V (vs. Ag). 6-Aminonicotinic acid was obtained in 75% yield and 100% selectivity, under the optimized condition. Moreover, the ionic liquid was successfully recycled.

Full text of DOI:10.1016/j.electacta.2010.05.010

Electrochimica Acta 55 (2010) 5741–5745
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Electrochimica Acta
journal homepage: www.elsevier.com/locate/electacta
Electrocatalytic carboxylation of 2-amino-5-bromopyridine with CO in ionic
2
liquid 1-butyl-3-methyllimidazoliumtetrafluoborate to 6-aminonicotinic acid
∗
Qiuju Feng, Kelong Huang , Suqin Liu, Xuanyun Wang
College of Chemistry & Chemical Engineering, Central South University, Changsha 410083, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
A new electrochemical procedure for the electrocatalytic carboxylation of 2-amino-5-bromopyridine
with CO2 in ionic liquid, 1-butyl-3-methyllimidazolium tetrafluoborate (BMIMBF4), to 6-aminonicotinic
acid was investigated for the first time. The experiments were carried out in three electrodes undivided
cell under mild conditions, and the use of volatile and toxic solvents and catalysts, as well as any other
additional supporting electrolytes, was avoided. The electrochemical reduction behavior of 2-amino-5-
bromopyridine in BMIMBF4 had been studied by cyclic voltammetry with a reduction peak at −1.6 V (vs.
Ag). 6-Aminonicotinic acid was obtained in 75% yield and 100% selectivity, under the optimized condition.
Moreover, the ionic liquid was successfully recycled.
Received 26 January 2010
Received in revised form 3 May 2010
Accepted 3 May 2010
Available online 11 May 2010
Keywords:
Ionic liquid
CO2
Halopyridine
Aminonicotinic acid
Electrocarboxylation
©
2010 Elsevier Ltd. All rights reserved.
1
. Introduction
liquids have been the green reaction media in organic synthetic
processes as the substitutes for conventional toxic and volatile sol-
vents and supporting electrolytes, due to their low vapour pressure,
high ionic conductivity and wide electrochemical potential win-
dow, solvating ability and ability to act as catalysts [17–21].
To our best knowledge, chemical fixation of CO2 with 2-amino-
5-bromopyridine (2-ABP) in ionic liquids has not been reported.
Herein, we reported the study of the reactivity of 2-ABP in CO2-
saturated ionic liquid BMIMBF4 (Scheme 1). The aim of this
investigation was to set-up an alternative methodology for electro-
catalytic carboxylation of 2-ABP with CO2 in BMIMBF4 to 6-ANA.
The electrolyses were carried out in BMIMBF4 under mild condi-
tions without supporting electrolyte and catalysts.
The synthesis of 6-aminonicotinic acid (6-ANA) arouses a strong
interest in many researchers, due to its biochemical properties as
protein synthesis inhibitor, vitamin B3 antagonist and modulating
agent in chemotherapy treatment for some types of cancer [1–4].
Conventional synthesis has certain drawbacks, such as the use of
hazardous chemicals including cyanide and ammonia gas, the high
reaction temperatures, and the poor yields [5–7].
It is well known that electrocarboxylation of organic halides on
silver (Ag) electrode is a powerful pathway for the production of
carboxylic acids [8–12]. Recently, efforts have been directed toward
the use of CO , as a possible raw material in the synthesis of 6-ANA.
2
Direct incorporation of CO2 into 2-amino-5-halopyridine, to yield
6
-ANA had been established [13,14]. Nevertheless, the use of toxic
organic solvents (CH CN, DMF, etc.) and large amounts of support-
3
ing electrolytes, makes it more complex to recover the solvents. In
addition, with the growing demand of environmental friendly tech-
nologies, the effort should be devoted to avoid the use of volatile
and damaging solvents and supporting electrolytes.
2. Experimental
2.1. Chemicals and apparatus
Ionic liquids, the molten salts with melting points close to
room temperature, are obtained by combination of large organic
cations (N,N-dialkylimidazolium, pyridinium, phosphonium, qua-
The ionic liquid BMIMBF4 (with a purity of more than 99%) was
dried under vacuum at 120 C, until cyclic voltammogram result
◦
indicated that there was no detectable water. The purity of CO2
and argon (Ar) was 99.99%. Unless otherwise noted, other reagents
and solvents were used as received from commercial suppliers.
HNMR spectra were obtained with a Varian INOVA-300 spec-
trometer using tetramethylsilane (TMS) as internal standard and
−
−
ternaryammoniums, etc.) with a variety of anions (AlCl , PF6
,
4
−
−
−
BF4 , CF SO , (CF SO ) N , etc.) [15,16]. In recent years, ionic
3
3
3
3 2
∗ Corresponding author. Tel.: +86 731 8887 9850; fax: +86 731 8887 9850.
E-mail address: huangkelong@yahoo.com.cn (K. Huang).
deuterated chloroform (CDCl ) as solvent. Liquid chromatograph
mass spectra (LC–MS) were recorded with an Agilent 1100 series.
3
0
013-4686/$ – see front matter © 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.electacta.2010.05.010

5
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Q. Feng et al. / Electrochimica Acta 55 (2010) 5741–5745
Scheme 1.
2.2. Typical electrolyse procedure
aminepyridin carbanion [8,25,26]. Another irreversible reduction
peak appears at −1.9 V, which is attributed to the reduction of CO .
2
The potentiostatic electrolyses were performed in a standard
It is noteworthy that Ep of 2-ABP is about 0.3 V more positive than
three electrode undivided cylindrical glass cell equipped with a
that of CO , which provides a possible potential window to per-
2
gas inlet and outlet. The sacrificial magnesium rod (Mg, d = 0.5 cm)
anode was placed down the middle of a ringed Ag (area = 3 cm )
form the electrocarboxylation of 2-ABP without any interference
from reduction of CO2.
2
cathode. The reference electrode was Ag wire. Prior to every exper-
iment, BMIMBF4 (2 mL) with definite concentration of 2-ABP was
3.2. Influence of reaction conditions
bubbled with CO for 30 min after bubbling Ar gas for 30 min. After
2
that the gas through the cell was closed and a constant potential
applied. Until 2.0 F charge passed, the electrolyse was interrupted.
In order to optimize experimental conditions, the influence of
temperature, working potential, concentrations, passed charge and
electrode material on the yield was investigated. The results are
summarized in Table 1. The yields are based on the starting material
Then K CO (1-fold molar) and PhCH Br (2-fold molar) were added,
2
3
2
◦
stirred at 55 C for 12 h. In this experiment PhCH Br was used
2
as esterification agent. Then the reaction mixture was extracted
with diethyl ether (3× 5 mL), and the combined organic layers
were dried over anhydrous MgSO4 for 12 h. After filtration, the
solvent was evaporated to yield the benzyl 6-aminopyridine-3-
carboxylate. Finally, at room temperature, 6-ANA was obtained by
hydrogenation of the ester in methanol (10 mL) with the catalyst
of 10% Pd/C (200 mg) overnight [22,23]. The product was purified
through silica gel column with petroleum ether/ethyl acetate (1:1
by volume) as eluents.
2
-ABP. The selectivity of the product is 100% in all our experiments.
3.2.1. Influence of temperature
The viscosity of ionic liquids is very high, which affect on the
rate of mass transport within solution, so the temperature effect
of on the reaction yield was investigated firstly [17]. Electrolyses
were carried out under constant potential at 25 C, 50 C, 75 C. The
obtained results are given in Table 1 (entries 1–3). With increasing
the temperature, the yield of 6-ANA was increased from 41% to 56%.
◦
◦
◦
◦
◦
However, the yield was hardly changed from 50 C to 75 C.
LC–MS [M−H]: 137
It is well known that the viscosity of BMIMBF displays an essen-
4
HNMR (CDCl ): ı 6.26 (d, 1H, J = 8.4 Hz), 7.36 (brs, 2H, −NH ), 8.0
tial Arrhenius behavior [17,27]. Increasing temperature leads to a
decrease of viscosity and an increase of conductivity, which is help-
ful to this reaction. But increasing temperature is unfavorable to the
electrocarboxylation, since it also leads to a decrease of the solubil-
ity of CO2 in BMIMBF4 [20,28]. Therefore, the optimal temperature
3
2
(
dd, 1H, J = 8.3 Hz,), 8.79 (d, 1H, J = 2.1 Hz), 11.64 (brs, 1H, −COOH)
3
. Results and discussion
◦
is 50 C due to the above two factors.
3
.1. Cyclic voltammogram behavior of 2-ABP in BMIMBF4
Cyclic voltammogram behavior of 2-ABP on Ag electrode
2
−1
area = 0.3 cm ) at the scan rate of 10 mV s in BMIMBF was mea-
4
(
◦
2
sured in an undivided cell at 50 C with platinum (Pt, area = 1 cm )
as the counter electrode. The references electrode was Ag wire. All
potentials are given with respect to this reference electrode. Fig. 1
shows the typical curves.
As can be seen from Fig. 1a, in neat BMIMBF4 there is no reduc-
tion peak in the sweeping region −1.1 V to −2.7 V. It also can be
observed that the cathodic current starts to increase at around
−
2.2 V, which is due to the polarization of the BMIMBF4 [24]. As
shown in Fig. 1b, in CO -saturated BMIMBF , a single irreversible
2
4
reduction peak is observed at −2.0 V, which is attributed to the
•
−
−1
)
reduction of CO2 to CO2 . After addition of 2-ABP (20 mmol L
to neat BMIMBF , the cathodic current starts to increase at around
4
−
1.5 V (Fig. 1c), and a distinct reduction peak appears at about
1.8 V.
Bubbling CO2 to the solution of BMIMBF4 containing 2-ABP
−
strongly modifies the voltammetric behavior. As shown in Fig. 1d,
after saturating with CO , a significant positive shift of peak poten-
2
Fig. 1. Cyclic voltammograms recorded with Ag electrode: (a) neat BMIMBF4; (b)
BMIMBF4 saturated with CO2; (c) BMIMBF4 containing 20 mmol L 2-ABP; (d) as
(c) saturated with CO2.
tial (Ep) from −1.8 V to −1.6 V is observed, which indicates a
−1
rapid chemical reaction between CO2 and the electrogenerated 2-

Q. Feng et al. / Electrochimica Acta 55 (2010) 5741–5745
5743
Table 1
Electrocatalytic carboxylation of 2-ABP with CO2 under various conditions.
◦
−1
−1
Q (F mol )
Entry
T ( C)
E vs. Ag (V)
c (mol L
)
Electrode
Conversion (%)
Yield (%)
1
2
3
4
5
6
7
8
9
25
50
75
50
50
50
50
50
50
50
50
50
50
50
50
50
50
−1.9
−1.9
−1.9
0
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.01
0.05
0.075
0.01
0.01
0.01
0.01
0.01
0.01
0.05
2.0
2.0
2.0
0
Ag/Mg
Ag/Mg
Ag/Mg
Ag/Mg
Ag/Mg
Ag/Mg
Ag/Mg
Ag/Mg
Ag/Mg
Ag/Mg
Ag/Mg
Ag/Mg
Ag/Mg
Cu/Mg
SS/Mg
Ni/Mg
Ag/Al
43
59
57
0
41
55
56
0
−1.7
−1.8
−2.0
−1.9
−1.9
−1.9
−1.9
−1.9
−1.9
−1.9
−1.9
−1.9
−1.9
2.0
2.0
2.0
2.0
2.0
2.0
4.0
8.0
12.0
2.0
2.0
2.0
2.0
42
55
47
78
67
60
43
32
25
55
52
52
73
41
53
45
75
65
58
39
31
23
54
50
49
72
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
3
.2.2. Influence of working potential
As shown in Fig. 1d, the potential of 2-ABP reduction peak was at
1.6 V, and −1.7 V, −1.8 V, −1.9 V and −2.0 V were chosen as oper-
remaining unchanged. Table 1 (entries 12 and 14–17) shows that
Ag cathode gives 6-ANA in good yield (75%, entry 8), while Cu cath-
ode only affords the product in low yield (54%, entry 14). The result
of Ni cathode is almost the same as that of SS cathode (entries 15
and 16).
−
ating potential for the electrosynthesis. The results are summarized
in Table 1 (entries 2 and 4–7). No reaction could be observed
without the voltage application (entry 4). The yields of product
increased from 41% to 56% with the potential became negative from
The excellent result of Ag cathode may be associated with its
electrocatalytic activation toward organic halides. Organic halides
(RX) can adhere to Ag electrode surface. Then the RX is activated
and the reaction reaches the transition state where an activated
complex interacting with the Ag electrode surface is formed. In the
activated complex, the C–X bond has been considerably weakened
because of the X· · ·Ag and R· · ·Ag interactions [29,30].
−
1.7 V to −1.9 V, and the maximum yield was 56% at −1.9 V. While
when potential was more negative than −1.9 V, the yield of product
decreased.
The curve in Fig. 1 indicated that the current increased with
increasing the potential from −1.5 V to −1.9 V. Also the larger the
current between anode and the cathode is, the more electrogener-
ated intermediate is produced, which leads to the increasing yield
Also, the effect of sacrificed anode was studied, and the results
suggested that no obvious difference was observed between Mg
and Al (entry 17). It indicates that the property of the sacrificed
anode has less impact on the reaction.
[
18,28]. But when potential was more negative than −1.9 V, CO
2
reduction competes with the 2-ABP reduction, some of the applied
energy is consumed by CO reduction instead of the reduction of 2-
ABP, which resulted in lower yield. Therefore, in these electrolyses,
In conclusion, according to our results, the optimized condition
2
−
for the electrosynthesis of 6-ANA in BMIMBF required 0.01 mol L
4
1
the optimized potential is −1.9 V.
of 2-ABP using Ag as cathode and Mg as the anode with a potential
of −1.9 V at 50 C with a charge passed of 2.0 F.
◦
3.2.3. Influence of substrate concentrations and charge passed
The effect of substrate concentrations on electrochemical syn-
3.3. Recycle of ionic liquid
thesis of 6-ANA was also investigated. Experimental results are
presented in Table 1 (entries 2 and 8–10). Obviously, the concen-
trations influenced the yield of 6-ANA dramatically. The reaction
yield decreases from 75% to 55% with increasing the 2-ABP con-
centrations. Electrolyses conducted at high concentrations are not
very successful. When the electrolyse was conducted at high con-
centrations, the product of Mg carboxylate started to deposit at
the cathode, which leads to the dramatic decrease of the cur-
rent between anode and cathode [12,18]. The less concentrated
solutions allowed the electrolyse to proceed at a constant volt-
age without any deposit at the cathode to give a good yield. These
results are quite consistent with the previous study, showing that
concentration is a key role in the reduction of organic halides
Following extraction by ether, dichloromethane (CH Cl , 20 mL)
2
2
was added to BMIMBF . And the mixture was filtered to eliminate
4
K CO . Then the solvent was washed with 1 mL deionized water six
2
3
times. The obtained aqueous solution was tested with silver nitrate
until no precipitate formed, indicating that no chloride was present.
Then organic layer containing BMIMBF was evaporated to remove
4
the CH Cl . And the obtained BMIMBF was dried under vacuum.
2
2
4
The recycled BMIMBF4 can be used three cycles without activity
loss.
3.4. Mechanism of electrosynthesis of 6-ANA in BMIMBF4
[
12].
Several electrolyses were carried out using different numbers of
Based on our experimental results and other people’s study
[18,26,31], the proposed pathway is outlined in Fig. 2. Initially 2-
ABP molecule approaches and contacts Ag electrode surface by
weak adsorption. Then the 2-ABP molecule is activated and the
reaction reaches the transition state A where an activated complex
interacting is formed. In this transition state, C–Br bond has been
considerably weakened because of the Br· · ·Ag and C· · ·Ag interac-
tions. Then electrons transfer from the Ag electrode to 2-ABP, which
leads to 2-aminepyridin carbanion B [30].
charge per mole of 2-ABP supplied to electrodes (Q). As shown in
Table 1 (entries 2 and 11–13), the yield of 6-ANA decreases with
the increasing Q. The maximum yield is achieved at 2.0 F of 2-ABP.
3
.2.4. Influence of electrode material
During electrolyses, the reduction of 2-ABP takes place on sur-
face of electrode. Thus, the choice of electrode materials is of quite
importance. For comparison, the reaction was investigated using
Ag, copper (Cu), nickel (Ni) and stainless steel (SS) as cathode, Mg
and aluminium (Al) as anode under other experimental conditions
As previously reported, there was a weak Lewis acid–base inter-
−
action between CO2 and BF4 anion, so that CO2 molecule can
couple with BMIMBF4 to give C as shown in Fig. 2 [32,33]. At

5
744
Q. Feng et al. / Electrochimica Acta 55 (2010) 5741–5745
Fig. 2. Electrochemical reduction mechanism of 2-ABP with CO2 to 6-ANA in BMIMBF4.
the cathode, two-electron reduction of 2-ABP generates anion B. B
Acknowledgement
attacks the carbon atom of the carbonyl group to afford carboxylate
+
anion, which captured by Mg2 ions to form the stable Mg carboxy-
We thank the National Natural Science Foundation, China, for
the financial support (No. 20976197).
lates D [18,31]. Finally, treatment of the metal carboxylates with
method above gives 6-ANA. In practice, the formation process of
6
-ANA is very complicated, which involves electrochemical reac-
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