Polyelectrolyte Br?nsted acid catalyzed three-component Mannich reactions accelerated by emulsion

Article abstract of DOI:10.1039/c6ra04180a

An effective polyelectrolyte Br?nsted acid (polyacrylic acid) catalyzed three-component Mannich reaction accelerated by emulsion has been developed. The results demonstrated that the polyacrylic acid (PAA) provided the best catalytic activity in water because of the formation of emulsions during the reaction. This newly developed simple catalyst could be recycled at least five times without any loss of activity.

Full text of DOI:10.1039/c6ra04180a

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Polyelectrolyte Brønsted acid catalyzed three-
component Mannich reactions accelerated by
emulsion†
Cite this: RSC Adv., 2016, 6, 39343
Received 16th February 2016
Accepted 11th April 2016
*
Xi Chen,‡ Huaming Sun, Yanlong Luo,‡ Yajun Jian, Ya Wu, Weiqiang Zhang
*
and Ziwei Gao
DOI: 10.1039/c6ra04180a
www.rsc.org/advances
An effective polyelectrolyte Brønsted acid (polyacrylic acid) catalyzed improving the molarity of organic compounds in emulsion
three-component Mannich reaction accelerated by emulsion has droplets. Based on such a great idea, Kobayashi and coworkers13
been developed. The results demonstrated that the polyacrylic acid has successfully applied a surfactant emulsion systems to
(PAA) provided the best catalytic activity in water because of the improve the Mannich reaction in water. However, the huge
formation of emulsions during the reaction. This newly developed surface tension of the catalyst made it difficult to separate the
simple catalyst could be recycled at least five times without any loss of products from the catalyst. Thus, the exploration of an efficient
activity.
approach to form a stable emulsion to promote the organic
reaction in water remains of great signicance. Poly-
electrolytes14 may be good candidates as they are charged
polymers capable of stabilizing colloidal emulsions through
electrostatic interactions. Herein, we report a PAA catalyzed
three-component Mannich reaction in water, with the forma-
tion of stable emulsion droplets, affording a product in good to
excellent yield. Furthermore, the catalyst could be reused at
least ve times without any loss of activity.
To examine the feasibility of our proposal, the Mannich
reaction of benzaldehyde (1.0 mmol), aniline (1.1 mmol) and
cyclohexanone (5.0 mmol) in the presence of catalysts (0.075
mmol) was choosed as a model reaction (Table 1) (see ESI† in
details). The data showed that the polyelectrolytes like PAA
whose main chain contained a constituent carboxylic acid
group could catalyze the reaction with the highest yield of 92%
in water (entry 2). However, this great improvement could not
be simply attributed to the fact that PAA is the Brønsted acid
since the acrylic acid itself only generated the product in 59%
yield (entry 1). Then control experiments were carried out in
other solvents, such as acetonitrile, THF, DMF, DMSO, ethanol,
and methylene dichloride (entry 6–11). To our surprise, the
emulsion was formed in the process of the PAA-catalyzed reac-
tion in water (Fig. 1 and 2). Among all solvents, the yield in
water was also the best. Therefore, the forming of the emulsion
was the key factor causing the yield increase.
The Mannich reaction is one of the most important funda-
mental carbon–carbon bond forming reactions in organic
synthesis,1 since its nal products are important synthetic
building blocks, as well as key intermediates of many valuable
pharmaceuticals.2 Performing organic reactions in water has
attracted much attention due to numerous advantages, such as
water being safe, nontoxic, environmentally friendly, and
cheap.3 In the past decade, impressive efforts have been devoted
to performing Mannich reactions in water utilizing various
catalyst systems with the involvement of Lewis or Brønsted
acids, such as Bi(OTf)3$4H2O,4 scandium tris(dodecyl sulfate),5
HBF4,6 dodecylbenzenesulfonic acid,7–9 acidic ionic liquids,10
SO3H-fuctionalized ionic liquids,11 and amino acids.12 However,
most of these examples suffer from severe drawbacks, such as
being expensive, involving highly toxic catalysts and requiring
complex workup procedures, etc.
One of the major challenges when performing an organic
reaction in water is to solve the issue of immiscibility between
the water phase and a majority of organic substrates. Surfac-
tants, bearing both hydrophobic and hydrophilic moieties in
a single molecule, can trigger the formation of an emulsion
when oil and water coexist, and are usually a good choice for
To better observe the emulsion, photographs and optical
micrographs of the PAA catalyzed Mannich reaction at different
time were recorded. The PAA (0.075 mmol) was stirred in 1 mL
Key Laboratory of Applied Surface and Colloid Chemistry, Ministry of Education,
School of Chemistry & Chemical Engineering, Shaanxi Normal University, Xi'an
710062, P. R. China. E-mail: hmsun@snnu.edu.cn; zwgao@snnu.edu.cn; Fax: +86-
29-81530821
ꢀ
H2O for 10 minutes at 25 C, ketone (5 mmol) was added into
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c6ra04180a
the mixture under vigorous stirring, resulting in an emulsion.
Aldehyde (1 mmol) and aniline (1.1 mmol) was added into the
‡ Xi Chen and Yanlong Luo contributed equally to this article.
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Table 1 Catalyst and solvent screening for the Mannich reactiona
Entry
Catalyst
Solvent
Yieldb (%)
1
2
3
4
Acrylic acid
H2O
H2O
H2O
H2O
59
92
12
9
Polyacrylic acid
Sodium polyacrylate
Polypropylene
5
6
7
8
9
10
11
Polymethyl acrylate
Polyacrylic acid
Polyacrylic acid
Polyacrylic acid
Polyacrylic acid
Polyacrylic acid
Polyacrylic acid
H2O
CH3CN
THF
DMF
DMSO
EtOH
CH2Cl2
11
60
51
30
20
57
53
Fig. 3 The Photographs and optical micrographs of the Mannich
reaction at different time. ((a) Before the reaction; (b) after 2 hours; (c)
after 4 hours; (d) after 6 hours).
a
Reaction conducted with 1.0 mmol of benzaldehyde, 1.1 mmol of
aniline, 5.0 mmol of cyclohexanone and 0.075 mmol of catalysts in
b
1.0 mL solvent, at 25 ꢀC for 6 h. Isolated yield was obtained aer
purication by column chromatography.
Fig. 1 Illustration of the reaction process of PAA catalyzed three-
Fig. 4 Transmission DT for the Mannich reaction catalyzed by PAA in
component Mannich reaction in water.
water before the reaction.
occurring over the sample tube. When changes take place in the
latex, the transmission proles vary with the height of the
sample and with time. According to Fig. 4, we can see the DT
was comparative small at the beginning of test, which indicated
the emulsion was formed rapidly in the presence of PAA in
water. The DT increased with an increasing time in the bottom,
indicated the emulsion is oil/water type.
Fig. 2 Photographs of different solvents for PAA catalyzed Mannich
reaction.
In order to directly quantify the effect of PAA on the emulsion
stability, we used the stability coefficient (TSI—Turbiscan
Stability Index). This parameter takes into account all processes
taking place in the sample (thickness of sediment and clear
emulsion and the reaction mixture was vigorously stirred. As
shown in Fig. 3(a), the emulsion remained stable in water. The
photographs and optical micrographs of PAA catalyzed Man-
nich reaction at 2 h, 4 h and 6 h suggested that the emulsion
particles remained stable during the whole reaction process, as
shown in Fig. 3(b)–(d). The substrates were concentrated in the
emulsion particles, which acted as a hydrophobic reaction
reactor and speeded the organic reactions in water up.
The stability of the emulsion in static state was further tested
by Turbiscan, the results were shown in Fig. 4. The gure
showed the variation of the transmission prole DT vs the
height of the samples as measured for 1.5 h. The interpretation
of the transmission proles was based on the change in the
light transmission caused by the changes in size of the particles
Fig. 5 TSI for the Mannich reaction catalyzed by PAA in water before
the reaction.
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Table 2 The catalytic activity for three-component Mannich reactions
layer, process of particles settling). According to the fact that
small TSI value indicates stability,15 we deduced that the
emulsion could remain stable without any stirring in 1.5 h
(Fig. 5).
in watera
Kinetics studies were further conducted to describe the
highly efficient reaction process of the PAA catalyzed three-
component Mannich reaction (Fig. 6). When the blank test
group (without catalyst) was conducted or sodium polyacrylate
was added, few products could be detected, indicating that
Mannich reaction need add the catalyst. When PAA was added,
the reaction occured, and Fig. 6 showed the conversion of
products varying with time. Aer 6 h, the conversion of products
with PAA reached 92% which was two times more than
comparative experiments with acrylic acid as catalysts. The high
reaction rate of the PAA-catalyzed three-component Mannich
reaction in water could be attributed to the high concentration
of substrates inside the emulsion droplet formed by PAA in
water. In this case, the droplet could act as a hydrophobic
reaction site which enabled the smooth transformation of the
substrate into the product.16
Under the optimized reaction conditions, the possible
substrate range was throughly investigated (Table 2). Various
ketone, aldehydes and aniline-bearing electron-donating or
electron-withdrawing substituents were applied to this protocol
and the desired products were obtained in high to excellent
yields. It was found that the reaction proceeded smoothly with
aromatic aldehydes and aromatic amines bearing either
electron-withdrawing or donating groups. For example, when
the p-substituents of amines were changed from methyl (4b) to
chloro (4c) and nitro-groups (4d), the yields of the condensa-
tions increased from 80% to 84% and 90%, respectively (entry
2–4), which was slightly lower than aromatic aldehydes and
aromatic amines without any substituents (4a) (entry 1). The m-
(4e, 4f), o-(4g) functionalized anilines reacted with benzalde-
hydes and cyclohexanone giving yields from 75 to 78% (entry
5–7). Under similar conditions, changing the substituents of the
aldehydes from methoxy (4h) to bromo (4i) and chloro-groups
Entry
R1
R2
R3, R4
Yieldb (%)
dr
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
o-OCH3Ph
o-BrPh
o-ClPh
p-ClPh
p-NO2Ph
m-NO2Ph
p-ClPh
p-ClPh
p-NO2Ph
Furyl
Furyl
i-Bu
H
(CH2)4
(CH2)4
(CH2)4
(CH2)4
(CH2)4
(CH2)4
(CH2)4
(CH2)4
(CH2)4
(CH2)4
(CH2)4
(CH2)4
(CH2)4
(CH2)4
(CH2)4
(CH2)4
(CH2)4
(CH2)4
(CH2)4
Ph, H
4a, 92
4b, 80
4c, 84
4d, 90
4e, 75
4f, 77
4g, 78
4h, 90
4i, 94
4j, 95
4k, 93
4l, 98
4m, 76
4n, 63
4o, 72
4p, 65
4q, 82
4r, 74
4s, 72
4t, 85
4u, 79
4v, 36
4w, 27
4x, 81
4y, 77
54 : 46
64 : 36
90 : 10
87 : 13
>99 : 1
50 : 50
62 : 38
>99 : 1
>99 : 1
>99 : 1
80 : 20
52 : 48
52 : 48
54 : 46
62 : 38
58 : 42
76 : 24
53 : 47
>99 : 1
n.d.
p-CH3
p-Cl
p-NO2
m-CH3
m-Cl
o-OCH3
H
H
H
H
H
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
H
p-Cl
p-CH3
p-CH3
o-OCH3
H
H
H
p-Cl
H
H
Ph
Ph
Ph
p-CH3OPh
p-CH3OPh
Ph
Ph, H
n.d.
n.d.
n.d.
n.d.
CH3, H
CH3, H
CH3, C2H5
CH3, C2H5
H
H
n.d.
a
Reaction conducted with 1.0 mmol of benzaldehyde, 1.1 mmol of
aniline, 5.0 mmol of ketone and 0.075 mmol of PAA in 1.0 mL H2O, at
b
25 ꢀC, 6–12 h. Isolated yields were obtained aer purication by
column chromatography.
(4j) led to the yields of the condensation reaction increasing b-amino ketones were obtained in excellent yield (98%), which
from 90% to 94% and 95%, respectively (entry 8–10). In the case, was somewhat higher than that of p-chloro aldehydes (4k) ob-
p-nitro aldehydes (4l) and aromatic amines with cyclohexanone, tained at 93% (entry 11 and 12). However, m-nitro aldehydes
(4m) were only obtained in 76% yield with a longer reaction
time (entry 13). p-Functionalized benzaldehydes (4n, 4o, 4p)
reacted with p-functionalized anilines and cyclohexanone with
63%, 72% and 65% yields (entry 14–16).
To broaden the scope of this transformation, heterocycle and
aliphatic aldehydes were examined as Mannich donors. The
reaction with furaldehyde and aniline (4q), o-methoxyaniline
(4r) afforded product yields in the range 74–82%, while iso-
valeraldehyde (4s) converted to the condensation product at
72% yield, a little lower than for furaldehyde (entry 17–19).
Interestingly, a few Mannich reactions resulted in products with
extremely excellent diastereoselectivities17 (entry 7–9 and 11).
To further investigate the scope and limitations of poly-
electrolyte Brønsted acid catalyzed three-component Mannich
reactions accelerated by emulsion, a series of ketones were
screened, and the results were presented in Table 2. When
Fig. 6 Control experiment for the PAA-catalyzed Mannich reaction.
PAA acrylic acid sodium polyacrylate without catalyst.
acetophenones (4t, 4u) were used, the yields of 85% and 79%
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were afforded, respectively (entry 20 and 21). The reaction also resultant cation intermediate reacted with aniline to form an
worked well with cycloalkanones other than cyclohexanone iminium ion with the simultaneous loss a water, followed by an
under the same conditions (Table S4†). The Mannich conden- attack of the enolized ketone to give rise to the Mannich
sation of open chain ketones including acetone and 2-penta- product. Once the product was released, H+ was regenerated for
none with benzaldehydes and aniline or p-methoxyaniline the next cycle.
afforded the products (4v, 4w, 4x and 4y) in 36%, 27%, 81% and
88% yields. The yield with acetone was obviously lower than 2-
pentanone and acetophenone because the emulsion could not
Conclusions
be formed during the reaction (entry 22–25). This results was In conclusion, an effective polyacrylic acid-catalyzed three-
further supported by the optical micrographs (Fig S2–S6†). component Mannich reaction accelerated by emulsion has
Therefore, the reaction worked well with ketones which was been developed. The results demonstrated that the PAA
some extent hydrophobic (see the ESI† 3 in more details).
provided the best catalytic activity because of the formation of
The recovery and reusability of the catalyst were investigated emulsions. Notably, the catalyst could be recovered directly by
in a PAA-catalyzed Mannich reaction of aniline, benzaldehyde simple treatment and still exhibit over 90% yields aer ve
and cyclohexanone (Fig. 7). Aer the completion of the reaction, cycles. The polyelectrolyte catalyst described herein represents
the reaction mixture was treated with chloroform, and the layers an economic and ecological alternative enabling us to avoid the
were separated. The aqueous phase was then directly trans- use of an organic solvent. Further investigations of the appli-
ferred to another ask along with fresh reagents for the next cation of polyelectrolyte catalysts are currently ongoing in our
run. To our delight, the catalytic activity of the catalyst had little laboratory.
change aer ve catalytic cycles. This result suggested the
excellent chemical stability and sustained activity of the PAA
catalyst (see the ESI† 1.3).
Acknowledgements
A plausible mechanism18 for the three-component Mannich We acknowledge the 111 Project (B14041), Innovative Research
reactions catalyzed by PAA is proposed in Fig. 8. The hydro- Team in University of China (IRT1070), the Project Supported by
phobic characteristic of the emulsion particles induced the Natural Science Basic Research Plan in Shaanxi Province of
entry of benzaldehyde, followed by protonation by PAA. The China (Program No. 2015JQ2056), the grant from National
Natural Science Foundation of China (21571121, 21271124, and
21446014), and the Fundamental Research Funds for the
Central Universities (No. GK201302015, No. GK201501005) for
nancial support.
Notes and references
1 A. Michael, W. Bernhard and R. Nikolaus, Angew. Chem., Int.
Ed., 1998, 37, 1044–1070.
2 R. Muller, H. Goesmann and H. Waldmann, Angew. Chem.,
Int. Ed., 1999, 38, 184–187.
3 M. O. Simon and C. J. Li, Chem. Soc. Rev., 2012, 41, 1415–
1427.
4 T. Ollevier, E. Nadeau and A. A. Guay-Begin, Tetrahedron
Lett., 2006, 47, 8351–8354.
5 K. Manabe, Y. Mori, T. Wakabayashi, S. Nagayama and
Fig. 7 Recycling test of polyacrylic acid catalyzed Mannich reaction in
water.
S. Kobayashi, J. Am. Chem. Soc., 2000, 122, 7202–7207.
6 T. Akiyama, J. Takaya and H. Kagoshima, Synlett, 1999, 9,
1426–1428.
7 K. Manabe and S. Kobayashi, Org. Lett., 1999, 1, 1965–1967.
8 K. Manabe, Y. Mori and S. Kobayashi, Synlett, 1999, 9, 1401–
1402.
9 K. Manabe, Y. Mori and S. Kobayashi, Tetrahedron, 2001, 57,
2537–2544.
10 G. Y. Zhao, T. Jiang, H. X. Gao, B. X. Han, J. Huang and
D. H. Sun, Green Chem., 2004, 6, 75–77.
11 T. Chang, L. Q. He, L. Bian, H. Y. Han, M. X. Yuan and
X. R. Gao, RSC Adv., 2014, 4, 727–731.
12 S. Mitsumori, H. L. Zhang, P. H. Y. Cheong, K. N. Houk,
F. Tanaka and C. F. Barbas, J. Am. Chem. Soc., 2006, 128,
1040–1041.
Fig. 8 Proposed mechanism of polyacrylic acid catalyzed Mannich
reaction in water.
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13 K. Manabe, Y. Mori, T. Wakabayashi, S. Nagayama and 16 K. Manabe, Y. Mori, T. Wakabayashi, S. Nagayama and
S. Kobayashi, J. Am. Chem. Soc., 2000, 122, 7202–7207. S. Kobayashi, J. Am. Chem. Soc., 2000, 122, 7202–7207.
14 D. O. Grigoriev, T. Bukreeva, H. Mohwald and 17 (a) S. Shimizu, N. Shimada and Y. Sasaki, Green Chem., 2006,
¨
D. G. Shchukin, Langmuir, 2008, 24, 999–1004.
15 D. D. Kaombe, M. Lenes, K. Toven and W. R. Glomm, Energy
Fuels, 2013, 27, 1446–1452.
8, 608–614; (b) Q. X. Guo, H. Liu, C. Guo, S. W. Luo, Y. Gu and
L. Z. Gong, J. Am. Chem. Soc., 2007, 129, 3790–3791.
18 H. Y. Tan, P. Zhang, L. Wang, D. Yang and K. B. Zhou, Chem.
Commun., 2011, 47, 11903–11905.
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