Functional ionic liquid from biorenewable materials: synthesis and application as a catalyst in direct aldol reactions

Article abstract of DOI:10.1016/j.tetlet.2007.06.051

A new room temperature ionic liquid (IL) (2-hydroxyethyl)-trimethyl-ammonium (S)-2-pyrrolidinecarboxylic acid salt ([Choline][Pro]) has been synthesized from biorenewable and nontoxic raw materials (choline chloride and l(-)-proline) in a simple and relative green route. The IL has been demonstrated to be the efficient catalyst of the direct aldol reactions between ketones and aromatic aldehydes in water at room temperature. The aldol products can be obtained with good yields and the IL in aqueous phase can be separated easily and reused.

Full text of DOI:10.1016/j.tetlet.2007.06.051

Tetrahedron Letters 48 (2007) 5613–5617
Functional ionic liquid from biorenewable materials: synthesis
and application as a catalyst in direct aldol reactions
Suqin Hu, Tao Jiang, Zhaofu Zhang, Anlian Zhu, Buxing Han,*
Jinliang Song, Ye Xie and Wenjing Li
Beijing National Laboratory for Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100080, China
Received 14 March 2007; revised 11 June 2007; accepted 12 June 2007
Available online 15 June 2007
Abstract—A new room temperature ionic liquid (IL) (2-hydroxyethyl)-trimethyl-ammonium (S)-2-pyrrolidinecarboxylic acid salt
([Choline][Pro]) has been synthesized from biorenewable and nontoxic raw materials (choline chloride and L(ꢀ)-proline) in a simple
and relative green route. The IL has been demonstrated to be the efficient catalyst of the direct aldol reactions between ketones and
aromatic aldehydes in water at room temperature. The aldol products can be obtained with good yields and the IL in aqueous phase
can be separated easily and reused.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
tion of CO2, and SO2.9,10 Employment of the ILs with
metal ion-ligating groups in extraction of metal ion
and organometal catalysis has been studied.11,4a Utili-
zation of the ILs with organocatalyst fragments in small
organic molecular catalysis has also been investigated.12
Green chemistry that possesses the spirit of sustainable
development was booming in the 1990s,1 and has
attracted more and more interest in the 21st century.
Large amounts of organic solvents are used in chemical
processes, many of which are volatile, flammable, and
toxic. The use of non-hazardous and renewable materi-
als is one of the most important goals of green chemis-
try.2 Room temperature ionic liquids (ILs), which are
organic salts with a melting point lower than 100 ꢁC,
have attracted much attention in recent years.3 ILs have
some unusual properties, such as negligible vapor pres-
sure, nonflammability, high thermal stability, wide
liquid temperature range, and strong solvent power for
both organic and inorganic substances. In addition,
the structure of ILs can be designed and modified to
achieve desired properties. Recently, some functional
(or task-specific) ILs have been synthesized and applied
in different fields.4 For example, ILs with acidic groups
have been used in Fischer esterification, alcohol dehyd-
rodimerization, pinacol rearrangement,5 and Mannich
reactions.6 The ILs with basic groups have been utilized
in Markovnikov addition,7 Michael addition,8 absorp-
With the increasing concerns about the environmental
protection, synthesis of ILs from renewable raw materi-
als through a green chemistry procedure is desirable.
Some ILs have been synthesized using renewable mate-
rials.13 Many kinds of natural products have the poten-
tial to be converted into ILs through relative green
methods such as simple ion exchange and acid–base
reactions directly.14 Among the biorenewable materials,
choline chloride and proline are very attractive in the
synthesis of ILs. Choline based-ILs (including eutectic
liquids) have been used not only as solvents or catalysts
in organic synthesis,15 but also as solvents and templates
in preparation of novel polymorphous materials.15a,16
As a commonly used organocatalyst, the catalytic
performance of proline in ILs has been studied for dif-
ferent reactions.17 ILs functionalized by proline have
been synthesized and applied to catalyze organic reac-
tions. For example, the nitrogen atom of proline was
transformed into several kinds of ammoniums that
acted as cations of ILs;14b,c The carboxyl group of pro-
line was converted into anions of ILs;14a,d The proline
moiety was covalently linked with the imidazolium cat-
ion of ILs, and these ILs were used as organocatalysts in
Michael additions12a and aldol reactions.18
Keywords: Ionic liquid; Green chemistry; Choline; Proline; Aldol
reaction.
*
Corresponding author. Fax: +86 10 62562821; e-mail: Hanbx@
iccas.ac.cn
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.06.051

5614
S. Hu et al. / Tetrahedron Letters 48 (2007) 5613–5617
In this Letter, we report a new IL (2-hydroxyethyl)-tri-
methyl-ammonium (S)-2-pyrrolidinecarboxylic acid salt
([Choline][Pro]) 1 that is composed of choline cations
and proline anions, which can be synthesized simply
by ion exchange and neutralization. The feature of this
IL is that both cation and anion are from renewable
materials. Our further study has demonstrated that the
IL 1 is a very efficient catalyst for direct aldol reactions,
and can be reused easily in aqueous solution.
OH O OH
OH O
O
O
1
+
RCHO
+
R
+
R
R
R1 R2
3a-j
R
R1 R2
2a-j
R1 R2
4a-j
R1 R2
a:
b:
c:
R= p-nitrophenyl, R1 = H, R2= H
R= m-nitrophenyl,
R= phenyl,
R = H
R1 = H,
2
R1 = H, R2= H
R= 3, 4-methylenedioxyphenyl,
d:
e:
f:
R =H
2
R1 = H,
R= p-methoxyphenyl,
R= p-methylphenyl,
R= p-nitrophenyl,
R= p-nitrophenyl,
R= p-nitrophenyl,
R= p-nitrophenyl,
R1 = H,
R1 = H,
R1 =
R1 =
R1 = H,
R1 = CH3,
R2= H
R2= H
g:
CH2CH2CH2
R2= H
,
,
h:
R2= H
CH2CH2
i:
j:
CH3
R2=
R2= H
2. Results and discussion
Scheme 2. The aldol reactions catalyzed by [Choline][Pro] 1.
The route to prepare the new IL (2-hydroxyethyl)-tri-
methyl-ammonium (S)-2-pyrrolidinecarboxylic acid salt
([Choline][Pro]) 1 is shown in Scheme 1, which is similar
to that used to synthesize imidazolium-based IL with
amino acids.14a Choline chloride was first converted to
choline hydroxide aqueous solution through the column
of 717 anion-exchange resin. The aqueous solution was
neutralized with L(ꢀ)-proline to obtain the IL [Cho-
line][Pro] 1 that is a light-yellow oil at room tempera-
ture.19 The total yield of 1 is 95.0% and the density is
1.13 g/cm3 at 25.0 ꢁC. The thermal stability of 1 was
studied using thermogravimetric analysis (TGA, NET-
ZSCH STA 409 PC/PG) in N2 at a heating rate of
10 ꢁC /min, which shows that the decomposition tem-
perature (Tdec) of 1 is 159.7 ꢁC.
when 30 mol % of 1 was used, the reaction could be fin-
ished in 1 min. The aldol products were the normal
product 2a and the second aldol product 3a (Scheme
2), and there was no dehydrated product 4a detected
by isolation or direct 1H NMR spectroscopy of the
crude products. When the amount of 1 was reduced
from 30 mol % to 5 mol %, the total yield of the aldol
products 2a and 3a decreased from 84.4% to 75.6%
and the reaction took 3 h to complete (Table 1, entries
2 and 3). In the solvent-free condition the ratio of 2a
and 3a was about 1:1. The proposed mechanism of
forming 3a is shown in Scheme 3, which is similar to
the one described by Peng and Jiang.21 Intermediate 5
could be converted in two ways: one would form prod-
uct 2 and another would form intermediate 6 that could
undergo the second aldol condensation to provide prod-
uct 3.
The aldol reaction as a useful C–C bond-forming reac-
tion catalyzed by organocatalysts had been studied
extensively.20 We first applied [Choline][Pro] 1 to cata-
lyze the direct aldol reaction of acetone with p-nitro-
benzaldehyde, and the results are shown in Table 1.
When 1 was used as the catalyst in solvent-free condi-
tions at room temperature, the reaction was completed
in a very short time (Table 1, entries 1–3). Especially,
RCHO
HN
N
-H2O
N
H
H
H
O
+
R
H
O
O
H
O
O
O
O
O
O
N
N
H
O
N
H
O
N
R
R
H
anion exchange
.
.
OH
Cl
N
N
1
R
HO
HO
O
resin
i
O
O
N
H
O
OH O
Choline Chloride
Choline Hydroxide
+H2O
5
2
.
N
COOH
N
COO
HO
N
the second
aldol reaction
H
N
H
R
R
H
ii
[Choline][Pro] 1
O
OH
OH O OH
O
RCHO
N
H
O
3
6
Scheme 1. Schematic illustration of the synthesis of IL [Choline][Pro]
1. Reagents and conditions: (i) 717 anion-exchange resin, water as
eluent, rt; (ii) L(ꢀ)-proline (1.05 equiv), rt, 48 h (95% yield of two
steps).
Scheme 3. The proposed mechanism of the aldol reaction catalyzed by
[Choline][Pro] 1 in solvent-free condition.
Table 1. Direct aldol reaction of 4-nitrobenzaldehyde and acetone at room temperature
Entry
IL (mmol)
4-Nitrobenzaldehyde (mmol)
Acetone (mmol)
Water (mL)
Time (min)
Yielda (%)
2a
3a
2a + 3a
1
2
3
4
5
6
7
0.3
0.3
0.05
0.3
0.1
1
1
1
1
1
1
1
2
10
10
10
10
10
5
—
—
—
1
1
1
10
1
180
5
10
15
20
53.3
40.8
36.4
90.2
89.7
90.2
82.2
29.0
43.6
29.2
7.6
9.9
9.2
82.3
84.4
75.6
97.8
99.6
99.4
95.7
0.05
0.05
1
13.5
a Isolated yield.

S. Hu et al. / Tetrahedron Letters 48 (2007) 5613–5617
5615
In order to improve the yield and selectivity of 2a, the
reaction was conducted in water.22 One of the reasons
was that water was required in the step from intermedi-
ate 5 to product 2. The concentration of water, which
was just produced by the reaction between acetone and
1 in solvent-free conditions (Scheme 3) was much lower
than the concentration of water, which was used as the
solvent. Therefore, the rate of converting 5 to 2 should
be increased in water. As expected, the yield of 2a was in-
creased to 90.2%, and the total yield of 2a and 3a reached
99.6% when water was used as solvent (Table 1, entries 4
and 5). The reaction was still fast, although it was slower
than that under the solvent-free condition. Decreasing
the amount of 1 from 30 mol % to 5 mol % slowed down
the reaction rate considerably (Table 1, entries 4–6), and
the reaction could be finished with similar yields within
15 min instead of 5 min, which indicated that the IL 1
was very efficient for the reaction. Moreover, increasing
the equivalents of acetone (Table 1, entries 6 and 7)
improved the reaction rate and chemoselectivity.
Figure 1. The photographs of the model reaction in water (Table 1,
entry 4) at different stages. From left to right: aqueous solution of
[Choline][Pro] and acetone; the powder of 4-nitrobenzaldehyde added
into the aqueous solution; the oil phase of products appeared under the
aqueous phase after the reaction.
Table 2. The recycling of [Choline][Pro] aqueous solution in direct
aldol reaction of 4-nitrobenzaldehyde with acetone
Runs
Time (min)
Yield (%)
2a
3a
2a + 3a
1a,b
2c
5
5
5
6
90.2
90.2
91.9
89.4
7.6
5.3
4.8
7.3
97.8
95.5
96.7
96.7
In addition, the phase states at different reaction stages
were observed carefully and the pictures are shown in
Figure 1. There were two phases, the oily product phase
and aqueous phase, in the system after the reaction was
completed. Therefore, using water as the solvent made
the separation easier. More importantly, IL can be recy-
cled more easily because IL existed in the aqueous
phase. In this work we tested the reusability of the aque-
ous phase that contained the IL. The aqueous solution
was used directly for the next run after separation and
extraction of the products, and the results are listed in
3c
4c
a The condition of the first run was the same as that for entry 4 in Table
1.
b Isolated yield.
c Determined by 1H NMR without isolation.
Table 2. There was no obvious decrease in yields after
the aqueous phase was recycled three times.
Table 3. Direct aldol reactions of aromatic aldehydes and ketones
Entry
Ketone
Aldehyde
Products
Time
Yielda (%)
2 (anti:syn)
3
4
2 + 3 + 4
CHO
O
1
2
3
4
5
6
7
8
9
2a, 3a
2b, 3b
2c, 4c
2d, 4d
2e, 4e
2f, 4f
2g
15 min
10 min
12 h
90.2
9.2
—
99.4
O2N
O2N
CHO
O
O
O
O
O
88.9
11.0
—
—
—
—
—
—
—
—
99.9
88.4
65.6b
62.5c
93.4
97.9
97.8
99.0
CHO
80.4
8.0
CHO
O
O
5.5 h
24 h
55.1
10.5
26.5
23.4
—
CHO
36.0
MeO
Me
CHO
CHO
21 h
70.0
4 h
97.9(2:1)
97.8(1:2)
60.4/38.6e
O
O2N
O2N
CHO
CHO
2h
1.5 h
0.5 h
—
Od
O
2i/2j
—
O2N
The reaction conditions: [Choine][Pro] 1 (0.05 mmol), ketone (10 mmol), aldehyde (1 mmol), water (1 mL), and room temperature.
a Entries 1–5 are isolated yields, entries 5–9 are determined by 1H NMR spectroscopy without isolation.
b 30.6% piperonaldehhyde was recycled.
c 37.3% p-methoxybenzaldehyde was recycled.
d 2 mmol cyclopentanone was used.
e The yield of 2i is 60.4%, the yield of 2j is 38.6%.

5616
S. Hu et al. / Tetrahedron Letters 48 (2007) 5613–5617
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and solvent-free cases.
´
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Direct aldol reactions of different aromatic aldehydes
and ketones catalyzed by 1 in water were also studied,
and the results are summarized in Table 3. The results
indicated that not only reactive aromatic aldehydes bear-
ing electron-withdrawing groups but also benzaldehyde,
p-methylbenzaldehyde, piperonaldehyde, and p-meth-
oxybenzaldehyde could reach good to moderate yields.
For the reactions with reactive aromatic aldehydes,
almost 100% conversion of the aromatic aldehydes was
achieved in 10–240 min and the dehydrated products
were not detected by isolation or 1H NMR spectroscopy
of the crude products (Table 3, entries 1, 2, 7, 8, and 9).
When the direct aldol reaction was conducted with less
reactive aromatic aldehydes, there were no second aldol
products, but dehydrated products 4 were obtained
(Table 3, entries 3–6). For the reactions of benzaldehyde
and p-methylbenzaldehyde, the total yields were good and
the reaction rates were relatively fast (Table 3, entries 3
and 4). In addition, when cyclohexanone, cyclopenta-
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3. Conclusions
A new functional IL [Choline][Pro] 1 has been synthe-
sized from choline chloride and L(ꢀ)-proline, which is
a successful example of preparing IL completely from
biorenewable nontoxic raw materials through a simple
and green route. The IL can be used to catalyze direct
aldol reactions between a variety of ketones and aro-
matic aldehydes efficiently in water. The aldol reactions
catalyzed by this IL can be finished in a very short time
with good yields, and there is no dehydrated product
produced in most cases. The reaction mixtures separate
into an aqueous phase and an organic phase after reac-
tion. After simple separation and extraction, the IL-con-
taining aqueous phase can be reused without any
obvious decrease in activity. We expect that this green
IL would have the potential for other applications.
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Acknowledgment
This work was financially supported by the National Nat-
ural Science Foundation of China (20533010, 20332030).
Supplementary data
´
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(f) Abello, S.; Medina, F.; Rodrıguez, X.; Cesteros, Y.;
Salagre, P.; Sueiras, J. E.; Tichit, D.; Coq, B. Chem.
Commun. 2004, 1096–1097.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2007.06.051.
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19. Procedures to prepare ionic liquid (2-hydroxyethyl)-tri-
methyl-ammonium (S)-2-pyrrolidinecarboxylic acid salt
[Choline][Pro] (1): Choline chloride (5.02 g, 36.0 mmol)
was converted into choline hydroxide aqueous solution
though the column of 717 anion-exchange resin. In this
step, the eluate was collected until its pH value was 9,
using water as the eluent. Then L(ꢀ)-proline (4.35 g,
37.8 mmol) was added into the above aqueous solution.
The mixture was stirred at room temperature for 48 h, and
then water was removed under vacuum at 50 ꢁC to obtain
a light-yellow oil. Acetonitrile (10 mL) and methanol
(10 mL) were added into the oil to precipitate the excess
proline. The mixture was filtered to remove the excess
proline. The filtrate was evaporated to remove the solvent
to give a light-yellow liquid. The obtained product was
dried under vacuum for 2 days at 60 ꢁC. The total yield
was 95.0%. 1H NMR (300 MHz, D2O) d (ppm): 1.64–1.69
(m, 3H), 2.01–2.05 (m, 1H), 2.67–2.75 (m, 1H), 2.94–3.00
(m, 1H), 3.10 (s, 9H), 3.40–3.47 (m, 3H), 3.95 (d,
21. Ji, C. Y.; Peng, Y. G.; Huang, C. Z.; Wang, N.; Jiang, Y.
Z. Synlett 2005, 986–990.
22. General procedures of conducting direct aldol reactions: The
desired amounts of IL [Choline][Pro] and ketone (10 mmol)
were dissolved in water (1 mL), and aromatic aldehyde
(1 mmol) was added into the aqueous solution. The
reaction mixture was stirred at room temperature until
that the TLC showed that the aldehyde disappeared
completely. An oil phase appeared under the aqueous
layer. The oil phase was separated directly from the
aqueous phase. Then the aqueous phase was extracted with
ethyl acetate (2 · 2 mL). The extract was combined with the
oil phase, and dried with anhydrous magnesium sulfate.
The crude product was obtained after removing the solvent
under vacuum. The product was identified by 1H NMR.