Knoevenagel condensation catalyzed by novel Nmm-based ionic liquids in water

Article abstract of DOI:10.1016/j.tetlet.2017.05.006

A series of novel N-methyl morpholine (Nmm) based ionic liquids with 1,2-propanediol group were synthesized and used as catalysts for Knoevenagel condensation at room temperature in water. Under the effect of the catalyst, various aldehydes or aliphatic ketones could react with a wide range of activated methylene compounds well, including malononitrile, alkyl cyanoacetate, cyanoacetamide, β-diketone, barbituric acid, 2-arylacetonitrile and thiazolidinedione. Furthermore, most of the products could be separated just by filtrating and washing with water. Additionally, the catalyst is recyclable and applicable for the large-scale synthesis.

Full text of DOI:10.1016/j.tetlet.2017.05.006

Accepted Manuscript
Knoevenagel condensation catalyzed by novel Nmm-based ionic liquids in wa-
ter
Hao Xu, Liyang Pan, Xiaomin Fang, Baoying Liu, Wenkai Zhang, Minghua Lu,
Yuanqing Xu, Tao Ding, Haibo Chang
PII:
S0040-4039(17)30576-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.05.006
TETL 48899
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
20 March 2017
25 April 2017
4 May 2017
Please cite this article as: Xu, H., Pan, L., Fang, X., Liu, B., Zhang, W., Lu, M., Xu, Y., Ding, T., Chang, H.,
Knoevenagel condensation catalyzed by novel Nmm-based ionic liquids in water, Tetrahedron Letters (2017), doi:
http://dx.doi.org/10.1016/j.tetlet.2017.05.006
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Knoevenagel condensation catalyzed by novel Nmm-based ionic
liquids in water
Hao Xu, Liyang Pan, Xiaomin Fang, Baoying Liu, Wenkai Zhang, Minghua Lu, Yuanqing Xu,* Tao
Ding,* Haibo Chang
Henan Engineering Laboratory of Flame-retardant and Functional Materials, College of Chemistry and
Chemical Engineering, Henan University, Kaifeng 475004, P. R. China.
E-mail : 18937822307@163.com; dingtao@henu.edu.cn
ABSTRACT: A series of novel N-methyl morpholine (Nmm) based ionic liquids with 1,2-propanediol
group were synthesized and used as catalysts for Knoevenagel condensation at room temperature in
water. Under the effect of the catalyst, various aldehydes or aliphatic ketones could react with a wide
range of activated methylene compounds well, including malononitrile, alkyl cyanoacetate,
cyanoacetamide, β-diketone, barbituric acid, 2-arylacetonitrile and thiazolidinedione. Furthermore, most
of the products could be separated just by filtrating and washing with water. Additionally, the catalyst is
recyclable and applicable for the large-scale synthesis.

INTRODUCTION
Ionic liquids (ILs) were introduced as environmentally benign reaction media and widely applied in
the field of organic synthesis,1,2 electrochemistry3 and materials chemistry,4,5 as a alternative procedure
to avoid the use of harmful organic reagents and solvents. In recent years, many functional ILs have also
been synthesized and developed further as catalysts, playing a remarkable role in various reactions like
Knoevenagel condensation,6 Henry reaction,7 Mannich reaction,8 Friedel-Crafts alkylation.9 Meanwhile
it has been found that cations and anions of ILs have synergetic effect in catalyzing these organic
reactions.10,11 Therefore, It is necessary to explore well-designed, cheap and easily available IL catalysts
for organic synthesis.
Knoevenagel condensation between activated methylene compounds and aldehydes is one of the most
important carbon-carbon double bond forming reactions, through losing a molecule of H2O in the
presence of catalysts such as solid bases,12,13 amino acids,14,15 lewis acids,16,17 organometallic
compounds.18,19 The reaction usually takes long time to perform in organic solvent under heating or
other special conditions.
“the best solvent is no solvent and if a solvent is needed it should preferably be water” stated by R. A.
Sheldon.20 Water represents a green solvent because it is cheap, readily available, non-flammable and
non-toxic. However, Knoevenagel dehydration condensation in water is still a fundamental challenge
because the large excess of water pushes the equilibrium in favor of the hydrated compounds.21 A few
examples of this reaction, conducted in water, were reported by employing a wide array of catalysts
such as KI3,22 ionic liquids,6,23 organometallic cage24 and calcium vanadate apatite.25 In most cases, the
range of activated methylene compounds was limited to malononitrile and alkyl cyanoacetate, and the
range of carbonyl compounds was limited to aromatic aldehydes in water. Up to now, the poor tolerance
2

for substrates is still the main hurdle with the Knoevenagel condensation in water, and there is a need to
improve the reaction based on green and sustainable chemistry.
In this manuscript, a serial of basic ionic liquids based on N-methyl morpholine (Nmm) and 3-chloro-
1,2-propanediol were synthesized as catalysts in Knoevenagel condensation. These catalysts are
compatible with various carbonyl compounds including aromatic/aliphatic/heterocyclic/α,β-unsaturated
aldehydes and aliphatic ketones, meanwhile they are also tolerant of various activated methylene
compounds such as malononitrile, alkyl cyanoacetate, cyanoacetamide, β-diketone, barbituric acid, 2-
arylnitrile and thiazolidinedione. Most of the products could be obtained at room temperature in water
with excellent yield and selectivity, and the separation is simple just by filtrating and washing with
water when the products are solid. Moreover, the catalysts are recyclable and applicable for the large-
scale synthesis. Additionally, as far as I know the application of morpholine-based ionic liquids in
Knoevenagel condensation has not been reported before.
RESULTS AND DISCUSSION
Five new Nmm-based ionic liquids were synthesized (Scheme 1); the preparation of [Nmm-
PDO][OH], [Nmm-PDO][OAc], [Nmm-PDO][BF4], [Nmm-PDO][Gly] and [Nbmm][OAc] were
described in detail in the Supplementary Material.
Scheme 1. Synthesis of the [Nmm-PDO][X] and [Nbmm][OAc] Ionic Liquids
At first, the condensation of benzaldehyde with malononitrile was chosen as the model reaction to
3

optimize conditions including catalysts, reaction time and catalyst dosage. As shown in Table 1, Five
Nmm-based IL catalysts were tested by using water as the solvent at room temperature for 7 min (Table
1, entries 1-4), and [Nmm-PDO][OAc] showed the highest activity (entry 2). The reaction could not be
carried out successfully in the absence of IL catalysts, even reaction time was prolonged to 10 h (entry
6). For comparison, we used [Nbmm][OAc] as the catalyst, and the target product 3a was only obtained
in 66% yield (entry 5); although the anion is also the acetate ion in [Nmm-PDO][OAc], the yield of 3a
was 99% while using [Nmm-PDO][OAc] as the catalyst (entry 2); the results implied hydrogen bonding
interaction existed between the carbonyl group of the aldehyde and the hydroxyl groups in the cation of
[Nmm-PDO][OAc], and the hydrogen bonding interaction increased the electrophilicity of the carbon
atom in the carbonyl group (see reaction mechanism in Scheme 2). When reacted under solvent-free
condition, the reaction mixture precipitated as soon as the catalyst was added, and it could not be stirred
so well that the yield is not so high (entry 7). When using water as solvent, product 3a solidified and
dissolved out of the reaction solution in several minutes (entry 2); and the pure product was isolated just
by filtrating and washing with water. We also investigated the effect of catalyst dosage on the model
reaction. When decreasing the dosage of the catalyst [Nmm-PDO][OAc], product 3a could be generated
in high yield as well, but more time needed to complete the reaction (entry 8-10); even we reduced the
amount of [Nmm-PDO][OAc] to 0.2 mol%, 3a was also provided with 73 % yield after 24 h.
Table 1. Knoevenagel condensation of benzaldehyde (1a) with malononitrile (2a) catalyzed by Nmm-base ionic
liquids: Optimization of conditions.a
Entry
Cat.
Slovent
H2O
H2O
Time(min)
Yieldb(%)
1
2
3
[Nmm-PDO][OH]
[Nmm-PDO][OAc]
[Nmm-PDO][BF4]
7
7
7
97
99
73
H2O
4

4
5
[Nmm-PDO][Gly]
[Nbmm][OAc]
Catalyst free
[Nmm-PDO][OAc]
[Nmm-PDO][OAc]
[Nmm-PDO][OAc]
[Nmm-PDO][OAc]
H2O
H2O
H2O
neat
H2O
H2O
H2O
7
7
90
66
6
7
8c
9d
10e
600
20
35
90
1440
trace
82
96
95
73
a Reaction conditions: benzaldehyde (0.5 mmol, 51 µL), malononitrile (0.5 mmol, 33 mg), catalyst (10 mol%), solvent
(1 mL), room temperature. b Isolated yield. c Catalyst 5 mol%. d Catalyst 1 mol%. e Catalyst 0.2 mol%.
The scope of Nmm-based ionic liquid-catalyzed Knoevenagel condensation was investigated under
the optimized condition (10 mol% [Nmm-PDO][OAc] as the catalyst, water as solvent, room
temperature); and most of the substrates could provide good to excellent yields as shown in Table 2.
Under the optimized condtion, aromatic/aliphatic/heteroaryl/α,β-unsaturated aldehydes as well as
aliphatic ketones were completely tolerated in this reaction. Compared to various aldehydes, the
condensations of aliphatic ketone with activated methylene compound need more time (entries 16-17,
24), because steric hindrance by the substrates could decrease the reaction rate. Moreover the reaction
rate of aliphatic aldehydes were slower than aromatic aldehydes (entry 15). Furthermore, the position of
the substituents on the aryl group (ortho vs meta vs para) affected the yield of 3, and the para-
substituted substrates with least steric hindrance gave higher yields (compare entries 4-8).
we also extended the scope of substrates from malononitrile to a wide range of activated methylene
compounds, including alkyl cyanoacetates, cyanoacetamide, β-diketone, benzothiazole-2-acetonitrile,
barbituric acid, 2,4-thiazolidinedione. Compared to malononitrile, other activated methylene compounds
needed more time to perform the Knoevenagel condensation with aldehydes or aliphatic ketones (Table
2, entries 18-37). Because the methylene group of malononitrile is more activated than other activated
methylene compounds due to the stronger electron-withdrawing ability of the CN group. When we used
water as solvent, 2,4-thiazolidinedione did not work under standard condition; this result caused by poor
solubility of 2,4-thiazolidinedione in water possibly; fortunately, it also afforded the corresponding
target compounds in the excellent yields when [Nmm-PDO][Gly] was used as the catalyst and the
5

o
temperature was raised to 60 C under solvent-free condition (entries 36-37). To sum up, the Nmm-
based ionic liquid-catalyzed Knoevenagel condensation above could tolerate various aromatic
aldehydes, aliphatic ketones and diversified activated methylene compounds including alkyl
cyanoacetates, cyanoacetamide, β-diketone, benzothiazole-2-acetonitrile, 2,4-thiazolidinedione,
barbituric acid. In addition, compared with the reported melting point and NMR data, the reaction is
highly stereoseletive when using Nmm-based ionic liquids as catalysts; the structure of new compounds
3u, 3v, 3a’ was also confirmed by X-ray crystallography (Figure S1-S3 in Supporting Information).
Table 2. Knoevenagel condensations catalyzed by [MML-PDO][OAc]a
Entry
t/min
7
Yield b/%
1
2
3
1
2
3
4
99
8
8
8
98
99
99
2a
2a
2a
5
10
92
2a
6

6
7
7
7
97
95
2a
2a
8
8
91
2a
9
8
8
7
96
99
99
2a
2a
2a
10
11
12
13
14
8
98
97
97
2a
2a
2a
10
12
CN
CN
15c
16
240
840
93
93
2a
3o
2a
7

17
2a
840
90
18
19
1b
1c
600
600
96
96
2b
20
21
1d
1j
2b
2b
600
600
98
96
22
23
24
1l
2b
600
96
600
97
90
1m
1p
2b
2b
1200
25
26
600
600
96
95
1a
1m
2c
27
600
95
1c
8

28
29
600
93
57
1a
1a
1200
30
31
1200
55
98
1k
1a
2f
1200
1200
1200
32
33
95
94
1b
1k
2g
2g
34
35
1200
1200
94
94
1b
1k
2h
36c,d
600
600
96
95
1b
1d
2i
2i
37c,d
9

a
Reaction conditions: carbonyl compound (0.5 mmol), activated methylene compound (0.5 mmol), catalyst [Nmm-
b
d
PDO][OAc] (10 mol%), water (1 mL), room temperature. Isolated yield. c Catalyst [Nmm-PDO][Gly] (10 mol%).
Solvent-free at 60 oC
The model reaction of benzaldehyde with malononitrile was chosen to examin the catalyst’s
recyclability and applicability in the large-scale synthesis. After completion of the reaction, product 3a
was filtered from the reaction mixture, the residual water solution of ionic liquid was evaporated under
vacuum and reused for six runs without further processing; the result showed that the catalyst still
maintaining a high catalytic activity even in the sixth run (See supporting information, Table S1). In
addition, the scaled-up experiment was performed on a one-mol scale, and 143 g of 3a were prepared in
93 % yield. This result demonstrated that the catalyst [Nmm-PDO][OAc] was efficient for large-scale
production as well.
A possible mechanism for the [Nmm-PDO][OAc] catalyzed Knoevenagel condensation is proposed
in Scheme 2 according to the results above (herein, reaction of benzaldehyde 1a with ethyl cyanoacetate
2c is chosen as the example). At first, the acetate anion of the IL removes a proton (H+) from the
methylene of ethyl cyanoacetates to form carbanion A. At the same time, the hydroxyl groups of the IL
and the carbonyl group of benzaldehyde can form hydrogen-bonding interactions which making
benzaldehyde more vulnerable by A.23 Then A attack on the electron-deficient carbonyl carbon of
benzaldehyde leading to the Knoevenagel product 3y via the intermediates B and C.
Scheme 2. Possible Mechanism for the Knoevenagel condensations catalyzed by [MML-PDO][OAc] between
methyl cyanoacetate and benzaldehyde
10

O
O
O
OH O
C2H5
N
O
H
C2H5
Knoevenagel reaction
AcOH
AcO
O
O
CH3
O
nucleophic addition
CN
H
CN
AcO
O
C
B
H
1a
-H2O
H
O
C
H
O
C
H
O
NC
CH3
NC
C2H5
C2H5
O
O
O
2c
AcOH
CN
A
Product 3y
To verify the proposed mechanism, we compared the FTIR spectrum of benzaldehyde with
benzaldehyde-[Nmm-PDO][OAc] mixture, and the results were shown in Figure 1. It was found that the
absorption peak of carbonyl group in benzaldehyde was at 1703 cm-1, while it was red-shifted to 1573
cm-1 in mixture. Furthermore, we also compared the 13C NMR spectrum of benzaldehyde with
benzaldehyde-[Nmm-PDO][OAc] mixture (Figure S4,S5 in the ESI); the chemical shift of carbonyl
group in benzaldehyde was 193.13, while it was 193.37 in mixture. These results implied the existence
of the hydrogen bonding interactions between the carbonyl group of the aldehyde and the hydroxyl
groups in [Nmm-PDO][OAc]. In addition, to verify the synergistic action of acetate anion and hydroxyl
groups in the [Nmm-PDO][OAc], the catalyst of [Nmm-PDO][OAc] was replaced with alcohol-NaOAc
binary system or NaOAc; and alcohol-NaOAc binary system showed higher catalytic activity than
NaOAc under standard conditions; this result indicated the synergistic action of acetate anion and
hydroxyl groups was exist in the catalytic system.
11

Benzaldehyde
Benzaldehyde+[Nmm-PDO][OH]
1703
1573
4000 30002000
1500
1000
500
Wavenumbers (cm-1)
Figure 1. FTIR comparison of benzaldehyde and benzaldehyde-[Nmm-PDO][OH] mixture
Additionally, Thermal gravimetric analysis (TGA) of the [Nmm-PDO][OAc] and [Nmm-PDO][Gly]
o
o
were also studied at the range of 25-600 C, with a temperature ramp rate of 10 C/min under nitrogen
atmosphere (Figure S6,S7). As TG and DTG diagram indicates, [Nmm-PDO][OAc] showed a stable
structure up to 197 oC (initial thermal-decomposition temperature), and [Nmm-PDO][Gly] up to 195 oC.
CONCLUSION
We have developed readily available and eco-friendly Nmm-based ILs as the efficient and recyclable
catalysts for the Knoevenagel condensations of various aldehydes, aliphatic ketones with a wide range
of activated methylene compounds. All the substrates containing activated methylene group except
thiazolidinedione were performed well at room temperature in water, including malononitrile, alkyl
cyanoacetates, cyanoacetamide, β-diketone, barbituric acid and benzothiazole-2-acetonitrile. And the
thiazolidinedione could also afford the corresponding products when using [Nmm-PDO][Gly] as the
catalyst at 60 oC under solvent-free condition. Additionally, the catalyst is recyclable and applicable for
12

the large-scale synthesis. All the results thus represent a practical and green catalyst for the Knoevenagel
condensations in water.
ACKNOWLEDGEMENTS
This work was supported by National Natural Science Foundation of China (Grant No. 21502042,
51403051, 21477033, 21204018), Scientific Research Key Project Fund of Henan Provincial Education
Department (Grant No. 15A150041, 16A150003), Scientific Research Fund of Henan University (No.
2013YBZR008).
A. SUPPLEMENTARY DATA
The supplementary material contains general experimental procedures, characterization data, and 1H,
13C NMR spectra of these synthesized compounds. Supplementary data associated with this article can
be found, in the online version, at http://dx.doi.org
REFERENCES
1. Hallett, J. P.; Welton, T. Chem. Rev. 2011, 111, 3508-3576.
2. Santner, S.; Heine, J.; Dehnen, S. Angew. Chem. Int. Ed. 2016, 55, 876-893.
3. Jain, R.; Jadon, N.; Singh, K. J. Electrochem. Soc. 2016, 163, H159-H170.
4. Eshetu, G. G.; Armand, M.; Ohno, H.; Scrosati, B.; Passerini, S. Energ. Environ. Sci. 2016, 9, 49-61.
5. Marr, P. C.; Marr, A. C. Green Chem. 2016, 18, 105-128.
6. Xu, D. -Z.; Liu, Y. -J.; Shi, S.; Wang, Y. -M. Green Chem. 2010, 12, 514-517.
7. Grosseheilmann, J.; Bandomir, J.; Kragl, U. Chem. Eur. J. 2015, 21, 18957-18960.
8. Feng, L. -C.; Sun, Y. -W.; Tang, W. -J.; Xu, L. -J.; Lam, K. -L.; Zhou, Z. -Y.; Chan, A. S. C. Green
Chem. 2010, 12, 949-952.
9. Taheri, A.; Lai, B. -B.; Cheng, C.; Gu, Y. -L. Green Chem. 2015, 17, 812-816.
13

10. Wang, M. -Y.; Song, Q. -W.; Ma, R.; Xie, J. -N.; He, L. -N. Green Chem. 2016, 18, 282-287.
11. Saptal, V. B.; Bhanage, B. M. ChemCatChem 2016, 8, 244-250.
12. Wang, Y. -X.; Wang, L. -J.; Liu, C. -P.; Wang, R. -H. ChemCatChem 2015, 7, 1559-1565.
13. Fujita, S.; Katagiri, A.; Watanabe, H.; Asano, S.; Yoshida, H.; Arai, M. ChemCatChem 2015, 7,
2965-2970.
14. Rahmati, A.; Vakili, K. Amino Acids, 2010, 39, 911-916.
15. Lee, A.; Michrowska, A.; Sulzer-Mosse, S.; List, B. Angew. Chem., Int. Ed. 2011, 50, 1707-1710.
16. Dandia, A.; Parewa, V.; Jain, A. K.; Rathore, K. S. Green Chem. 2011, 13, 2135-2145.
17. Parvanak B. K.; Ghasemi, P. Catal. Commun. 2013, 37, 50-54.
18. Fildes, D.; Caignaert, V.; Villemin, D.; Jaffres, P. -A. Green Chem. 2001, 3, 52-56.
19. Yamashita, K.; Tanaka, T.; Hayashi, M. Tetrahedron 2005, 61, 7981-7985.
20. Lindstrom, U. M. Chem. Rev. 2002, 102, 2751-2771.
21. Li, C.-J.; Chen, L. Chem. Soc. Rev. 2006, 35, 68-82.
22. Thakur, A. J.; Prajapati, D.; Gogoi, B. J.; Sandhu, J. S. Potassium triiodide. Chem. Lett. 2003, 32,
258-259.
23. Ying, A. -G.; Ni, Y. -X.; Xu, S. -L; Liu, S.; Yang, J. -G.; Li, R. -R. Ind. Eng. Chem. Res. 2014, 53,
5678.
24. Takashi M.; Yuki N.; Makoto F. J. Am. Chem. Soc. 2012, 134, 162-164.
25. Takayoshi H.; Satoko K.; Kohsuke M.; Tomoo M.; Kohki E.; Koichiro J.; Kiyotomi K. J. Org.
Chem. 2006, 71, 7455-7462.
14

(1) The Knoevenagel condensations catalyzed by the novel Nmm-based ionic liquids show higher
tolerance for diverse substrates.
(2) The purification is easy and applicable for the large-scale synthesis.
(3) The catalyst is recyclable.
15