Knoevenagel condensation in aqueous micellar media using EDAHS as a new Bronsted acidic ionic liquid

Article abstract of DOI:10.1007/s13738-014-0440-8

The Knoevenagel condensation between aromatic aldehydes and malononitrile, barbituric acid or 1,3-dimethylbarbituric acid with ethane-1,2-diammonium hydrogen sulfate (EDAHS) in aqueous micellar media, using sodium dodecyl sulfate is described. EDAHS was found to be a highly active and stable Bronsted acidic ionic liquid catalyst under the reaction conditions. Graphical Abstract: [Figure not available: see fulltext.].

Full text of DOI:10.1007/s13738-014-0440-8

J IRAN CHEM SOC
DOI 10.1007/s13738-014-0440-8
ORIGINAL PAPER
Knoevenagel condensation in aqueous micellar media using
EDAHS as a new Bronsted acidic ionic liquid
•
Kiumars Bahrami Mohammad M. Khodaei
•
•
Nasrin Babajani Fardin Naali
Received: 31 October 2013 / Accepted: 18 February 2014
Ó Iranian Chemical Society 2014
Abstract The Knoevenagel condensation between aro-
matic aldehydes and malononitrile, barbituric acid or 1,3-
dimethylbarbituric acid with ethane-1,2-diammonium
hydrogen sulfate (EDAHS) in aqueous micellar media,
using sodium dodecyl sulfate is described. EDAHS was
found to be a highly active and stable Bronsted acidic ionic
liquid catalyst under the reaction conditions.
a new path for the Knoevenagel condensation. Although
other methods are available for this transformation [13–
23], attention is moving toward newer and more selective
methods for this purpose.
Much work has shown that this condensation is strongly
solvent-dependent and benzene, ethanol, and DMF are
commonly used. However, toxic reagents, harsh reaction
conditions, long reaction time, low yield, and difficult
work-up have always posed problems. In addition to, the
use of solvents in large scale for the Knoevenagel con-
densation has led to environmental problems. In view of
these limitations, the introduction of efficient and new
methods based on green methodology is still in demand.
An area of recent intense synthetic attempt is the use of
approaches that are beneficial to industry as well as to the
environment. Since green chemistry is mainly concerned
with the reduction of chemical hazards and pollution [24],
a plausible convention is to use safer solvents that present
significantly less threat to ecosystems. Thus, the use of
water as solvent in chemical reactions has demonstrated an
alternative to organic solvents because water is the most
environmentally acceptable, safe and inexpensive solvent
[25]. However, organic reactions in water are often limited
in scope due to poor solubility of the organic compounds.
A possible way to improve the solubility of substrates is the
use of surface-active compounds that can form micelles
[26–29]. On the basis of previous reports [30], it is likely
that micelles act as nanoreactors to bring the reactants
together to provide a confined reaction environment.
Ionic liquids have attracted considerable interest as
environmentally benign reaction media due to their specific
properties such as high thermal and chemical stability, no
measurable vapor pressure, no flammability, friction
reduction, anti-wearing performance, and high loading
capacity [31–34].
Keywords Knoevenagel reaction Á Aqueous micellar
media Á Bronsted acidic ionic liquid Á Nanoreactors
Introduction
The Knoevenagel reaction is an important and widely
employed method for carbon–carbon bond formation in
organic synthesis [1–3]. It is widely used in the synthesis of
important intermediates or end-products for perfumes,
pharmaceuticals, calcium antagonists, and polymers [4–6].
Traditionally, the Knoevenagel reaction is catalyzed in
the presence of base catalyst [1, 7, 8], Lewis acids [9], and
zeolites [10]. The use of ionic liquids [11, 12] is applied as
Electronic supplementary material The online version of this
article (doi:10.1007/s13738-014-0440-8) contains supplementary
material, which is available to authorized users.
K. Bahrami (&) Á M. M. Khodaei Á N. Babajani Á F. Naali
Department of Organic Chemistry, Faculty of Chemistry,
Razi University, 67149-67346 Kermanshah, Iran
e-mail: kbahrami2@hotmail.com
123

J IRAN CHEM SOC
Table 1 Optimization of the reaction conditions
CN
Ar
CN
CN
CN
NC
CHO
2
+
NC
CN
CN
4 a-j
Ar CHO
or
or
+
Entry
EDAHS (mmol)
Yield %a
1
O
N
O
O
Ar
1
2
3
4
5
0.0
Trace
40
X
N
X
0.05
0.075
0.1
O
O
N
N
80
O
X = H, Me
X
X
4 k-p
94
3
0.2
94
Reaction conditions: the reactions were performed with benzaldehyde
(1 mmol), malononitrile (1 mmol), and SDS (1 CMC, 5 mL) in the
presence of EDAHS (0.1 mmol) for 6 min at 25 °C
Scheme 1 Reagents and conditions: EDAHS (0.1 mmol), SDS (1
CMC, 5 mL), H2O, 25 °C
a
Isolated yields
Results and discussion
chains can dissolve the organic substrate. Thus, there was
no requirement to employ water-soluble compounds
(Fig. 1).
As part of our ongoing efforts to develop environmentally
benign processes [20], and in continuation of our research
program to develop selective and efficient methods in
organic synthesis [35–40], herein, we describe an eco-
friendly and economical approach to the Knoevenagel
condensation reaction catalyzed by ethane-1,2-diammo-
nium hydrogen sulfate (EDAHS) as a new Bronsted acidic
ionic liquid (Scheme 1). The reactions were completed at
room temperature with excellent yields of desired products.
Sodium dodecyl sulfate (SDS) was selected because it
forms micelles in water, can solubilize organic substrates
that are otherwise insoluble in water. We envisioned that
the SDS surfactant micelles (SDS micelle diameter about
4 nm [41]) could act as nanoreactors to induce better sol-
ubilization of aldehydes and active methylene compounds
and ultimately allow these compounds to interact more
intimately with the EDAHS. The nonpolar alkyl chains
remain in a nonpolar environment and the hydrocarbon
Our investigations on the Knoevenagel condensation
reaction of malononitrile with aryl aldehydes began with
the optimization of reaction conditions. Initially, the reac-
tion of 1 mmol of benzaldehyde with 1 mmol of malono-
nitrile in the presence of SDS micellar solution (1 CMC,
5 mL) was tested in the absence of EDAHS at room tem-
perature. The reactants remained unchanged even after 3 h
stirring. Upon addition of 0.05, 0.75 and 0.1 mmol of
EDAHS, condensation occurred and the reaction led to
desired product straightaway in 40, 80, and 94 %, respec-
tively. Further increase in the reaction temperature and the
amount of EDAHS did result in no decrease in the reaction
time or in no increase in the yield (Table 1, entry 4). Also,
using 2 mmol of benzaldehyde (and 1 mmol of malono-
nitrile) showed no change in the final product yield and
again, 2-benzylidenemalononitrile was obtained as a final
Fig. 1 Micelle-promoted the
Knoevenagel reaction in water
in the presence of EDAHS
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
EDAHS
H2O
H2O
H2O
H2O
+ H2O
H2O
H2O
H2O
H2O
H2O
H2O
= 2-Arylidenemalononitrile
= 5-Arylidenebarbituric acid derivatives
= Aryl aldehyde derivatives
= Malononitrile
= Barbituric acid derivatives
EDAHS = Ethane-1,2-diaminium hydrogensulfate
=
OSO3Na
123

J IRAN CHEM SOC
Table 2 EDAHS catalyzed the Knoevenagel condensation in aqueous micellar media
Entry
Aryl aldehyde
Active methylene
compound
Time
(min)
Product
Yield
(%)a
Mp (oC)
[Ref]
1
C6H5-CHO
NC(CH2)2CN
NC(CH2)2CN
6
8
94
79–81 [42]
CN
NC
4a
2
4-ClC6H4-CHO
94
162–164 [42]
l
C
CN
NC
4b
3
4
2-ClC6H4-CHO
NC(CH2)2CN
NC(CH2)2CN
12
6
93
95
95–97 [43]
CN
l
C N
C
4c
3-O2NC6H4-CHO
99–101 [44]
CN
NC
O2N
Me
4d
5
6
4-MeC6H4-CHO
4-HOC6H4-CHO
NC(CH2)2CN
NC(CH2)2CN
8
3
88
93
136–138 [45]
186–187 [42]
CN
NC
4e
HO
CN
NC
4f
7
8
9
4-MeOC6H4-CHO
4-Me2NC6H4-CHO
2-furfuryl-CHO
NC(CH2)2CN
NC(CH2)2CN
NC(CH2)2CN
12
5
90
90
92
110–112 [43]
179–181 [46]
68-69 [43]
MeO
N
C
N
C
4g
Me2N
CN
NC
4h
12
O
CN
NC
4i
10
11
12
C6H5CH = CH-CHO
C6H5CH2CH2-CHO
C6H5-CHO
NC(CH2)2CN
NC(CH2)2CN
5
9
7
85
89
92
124–126 [42]
124–126 [46]
260–261 [42]
N
C
CN
4i
CN
CN
4j
O
O
NH
O
NH
O
NH
O
O
HN
13
4k
123

J IRAN CHEM SOC
Table 2 continued
Entry
Aryl aldehyde
Active methylene
compound
Time
(min)
Product
Yield
(%)a
Mp (oC)
[Ref]
13
4-ClC6H4-CHO
6
80
295–297 [45]
O
O
NH
O
l
C
NH
O
NH
O
HN
HN
O
4l
14
4-MeC6H4-CHO
10
85
274–276 [45]
O
O
NH
O
NH
O
Me
NH
O
O
4m
15
16
C6H5-CHO
10
94
96
160–162 [42]
158–160 [42]
O
N
O
N
O
N
O
N
O
4n
O
4-ClC6H4-CHO
6
O
O
N
O
N
l
C
N
O
O
N
N
O
4o
4p
17
18
4-HOC6H4-CHO
8
O
90
296–298 [42]
O
N
O
N
HO
N
O
O
O
C6H5CO-CH3
NC(CH2)2CN
60
no reaction
–
The products were characterized by comparison of their spectroscopic and physical data with authentic samples synthesized by reported
procedures
a
Yields refer to pure isolated products
product. Thus, under these optimized conditions, various
structurally diverse aromatic aldehydes were reacted with
malononitrile, and the corresponding results are listed in
Table 2. As shown, the aryl aldehydes bearing electron-
releasing and electron-withdrawing groups undergo this
reaction with equal efficiency. For example, 2-(4-hydrox-
ybenzylidene)malononitrile (Table 2, entry 6) is produced
in 95 % yield, and 2-(3-nitrobenzylidene)malononitrile in
98 % yield (Table 2, entry 4).
cinnamaldehyde (Table 2, entry 10), also undergoes clean
condensation without changing of the double bond.
To demonstrate the efficiency and applicability of the
EDAHS further, the Knoevenagel condensation of barbi-
turic acids and various aromatic aldehydes was also
investigated (Scheme 1). The same reaction conditions
were applied via the condensation of aldehyde (1 mmol)
and barbituric acid derivative (1 mmol) in SDS micellar
solution (1 CMC, 5 mL) in the presence of EDAHS
(0.1 mmol). The reactions were completed within
6–10 min with excellent product yields (Table 2, entries
12–17).
Acid-sensitive aryl aldehyde such as 2-furancarboxal-
dehyde worked well without the formation of any side
products, which are normally observed either in the pre-
sence of protic or Lewis acids (Table 2, entry 9). Inter-
estingly, the presence of ether (Table 2, entry 7) and amine
(Table 2, entry 8) groups did not interfere with the con-
densation process of the aryl aldehydes, and desired pro-
ducts were obtained in excellent yields. Acid-labile
However, as can be seen from the data in Table 2, the
chemoselectivity of this process is similar to that of the
synthesis of 2-arylidenemalononitrile and the nature of
substituent on the aromatic ring does not affect on the yield
of the Knoevenagel condensation. However, the reaction
123

J IRAN CHEM SOC
that the acidic part of EDAHS (ammonium moiety) prot-
onates the oxygen of carbonyl group of aryl aldehyde and
this makes the carbonyl group more electrophilic. On the
other side, the anionic part of EDAHS (hydrogen sulfate
anion) is basic and deprotonates acidic position of a
methylene compounds and causes the formation of nucle-
ophile. Subsequently, the nucleophilic addition to the
protonated aryl aldehyde produces an intermediate alcohol.
In the end, protonation of this alcohol followed by elimi-
nation of water gives the desired products.
A comparison of the catalytic efficiency of EDAHS with
selected previously known catalysts is shown in Table 3 to
demonstrate that the present method is indeed superior to
several of the other methods.
Conclusions
In conclusion, EDAHS is introduced as new and chemo-
selective Bronsted acidic ionic liquid catalyst for the
Knoevenagel condensation of aromatic aldehydes with
active methylene compounds in aqueous micellar media,
using SDS. The advantages of the present reaction are the
elimination of the metals and organic solvents, inexpensive
reagents, operational simplicity and excellent yields of
products.
Scheme 2 Plausible catalytic pathway for the EDAHS-mediated
Knoevenagel condensation
Table 3 Comparison of some of the results obtained with this work
and the some reported systems
Substrate Conditions (Ref.)
Time
Yield %
4a
this work
6 min
2.5 h
24 h
94
Experimental
HAP–Cs2CO3/H2O/reflux [44]
[Promim]CF3COOa/80°C [46]
77
98
Materials and techniques
potassium sorbate/solvent-free/
r.t.[43]
5 min
97.9
Melting points were taken with an Electrothermal 9100
1
4e
4f
this work
8 min
88
apparatus and left uncorrected. H and 13C NMR spectra
Na2S/Al2O3/CH2Cl2/reflux [47]
this work
55 min 96
were recorded with a Bruker DRX-300 Avance spectrom-
eter at 400/300 and 100/75 MHz. All the chemicals were
purchased from Fluka, Merck, and Aldrich, and used
without purification.
3 min
93
HAP–Cs2CO3/H2O/reflux [44]
3.5 h
68
potassium sorbate/solvent-free/
r.t.[43]
36 min 97.7
4g
this work
[Promim]CF3COOa/80°C [46]
12 min 90
Preparations of EDAHS
24 h
92
potassium sorbate/solvent-free/r.t.
[43]
TEBAb/H2O/70°C [45]
this work
7 min
99.6
Ethylene diamine (6.67 mL, 0.1 mol) was placed in a two-
necked flask equipped with a reflux condenser and a
dropping funnel. The flask was fixed in an ice bath. Under
vigorous stirring with a magnetic stirring bar (10.7 mL,
0.2 mol) of 98 % H2SO4 was added dropwise to the flask in
about 20 min to afford a brown powder as the product
5 h
90
80
84
4l
6 min
2 h
TEBA/H2O/70°C [45]
a
Ionic liquid-supported proline
b
Triethylbenzylammonium chloride
1
(94 % yield), m.p. 85–89 °C. H NMR (D2O, 400 MHz)
spectrum of EDAHS shows signal at 3.08 ppm (s, 4 H,
–CH2–N); 13C NMR (D2O, 100 MHz) spectrum shows a
signal at 36.4 ppm. Anal. Calc. for C2H12N2O8S2: 256; C
9.37, H 4.72, N 10.93, S 25.03. Found: C 9.30, H 4.80, N
10.85, S 25.25.
failed to proceed with ketones under the same reaction
conditions (Table 2, entry 18).
The proposed mechanism for the Knoevenagel conden-
sation is depicted in Scheme 2. It is reasonable to assume
123

J IRAN CHEM SOC
16. J.M. Khurana, K. Vij, Tetrahedron Lett. 52, 3666 (2011)
17. F.X.L. Xamena, F.G. Cirujano, A. Corma, Microporous Meso-
porous Mater. 157, 112 (2012)
General procedure for the Knoevenagel condensation
of active methylene compounds with aryl aldehydes
18. K.M. Parida, S. Mallick, P.C. Sahoo, S.K. Rana, Appl. Catal.
A Gen. 381, 226 (2010)
19. A. Modak, J. Mondal, A. Bhaumik, Appl. Catal. A Gen. 459, 41
(2013)
20. B.A. Robichaud, K.G. Liu, Tetrahedron Lett. 52, 6935 (2011)
21. S. Ghosh, J. Das, S. Chattopadhyay, Tetrahedron Lett. 52, 2869
(2011)
22. Y. Zhang, Y. Zhao, C. Xia, J. Mol. Catal. A Chem. 306, 107
(2009)
23. J. Xu, K. Shen, B. Xue, Y.-X. Li, J. Mol. Catal. A Chem. 372, 105
(2013)
24. C. Pellerin, Chemistry goes green. Ejournal USA Global Issues.
(2005)
25. C.-J. Li, Chem. Rev. 93, 2023 (1993)
26. J.H. Fendler, E.J. Fendler, Catalysis in micellar and macromo-
lecular systems (Academic Press, London, 1975)
27. Mixed Surfactant Systems, ed. by P. M. Holland, D. N. Rubingh
(American Chemical Society, Washington, 1992)
28. Structure and Reactivity in Aqueous Solution, ed. by C.
J. Cramer, D. G. Truhlar (American Chemical Society, Wash-
ington, 1994)
To a micellar solution of SDS (5 mL, 1 CMC = 8.1 9
10-3 M in H2O), a mixture of aryl aldehyde (1 mmol) and
active methylene compound (1 mmol) was added. Then
EDAHS (0.026 g, 0.1 mmol) was added and the resulting
mixture was stirred at room temperature for the indicated
reaction time (Table 2). After the reaction was over as
monitored on TLC, The organic material was extracted
with ethyl acetate and the surfactant was precipitated by
the slow addition of CaCl2 to the vigorously stirred mixture
of the micellar solution and ethyl acetate. Upon the evap-
oration of solvent, the crude product was recrystallized
from ethanol and identified by comparison of spectral and
physical data with those described in the literature. Spectral
data for the selected compound follows.
2-(Furan-2-ylmethylene)malononitrile (Table 2, entry 9)
29. Surfactant-Enhanced Subsurface Remediation, ed. by D.
A. Sabatini, R. C. Knox, J. H. Harwell (American Chemical
Society, Washington, 1994)
1H NMR (300 MHz, CDCl3): dH (ppm): 6.73 (1H, t,
J = 1.8 Hz), 7.37 (1H, d, J = 3.6 Hz), 7.52 (1H, d,
J = 4.5 Hz), 7.82 (s, 1H); 13C NMR (75 MHz, CDCl3): dC
(ppm): 112.5, 113.8, 114.4, 123.4, 143.0, 148.1, 149.5.
´
30. D.M. Vriezema, M.C. Aragones, J.A.A.W. Elemans, J.J.L.M.
Cornelissen, A.E. Rowan, R. Nolte, J.M. Chem. Rev. 105, 1445
(2005)
31. L. Chen, M. Zheng, Y. Zhou, H. Liu, H. Jiang, Synth. Commun.
38, 239 (2008)
Acknowledgments We are thankful to the Razi University
Research Council for partial support of this work.
32. J.C. Legeay, J.Y. Goujon, J.J. Vanden Eynde, L. Toupet, J.P.
Bazureau, J. Comb. Chem. 8, 829 (2006)
33. M.A. Zolfigol, A. Khazaei, A.R. Moosavi-Zare, A. Zare, H.G.
Kruger, Z. Asgari, V. Khakyzadeh, M. Kazem-Rostami, J. Org.
Chem. 77, 3640 (2012)
34. M. Ali Zolfigol, V. Khakyzadeh, A.R. Moosavi-Zare, A. Zare,
S.B. Azimi, Z. Asgari, A. Hasaninejad, C. R. Chimie. 15, 719
(2012)
35. K. Bahrami, M.M. Khodaei, A. Nejati, Green Chem. 12, 1237
(2010)
36. M.M. Khodaei, K. Bahrami, A. Farrokhi, Synth. Commun. 40,
1492 (2010)
References
1. G. Jones, Organic reaction, vol. 15 (Wiley, New York, 1967),
p. 204
2. F. Texier-Boullet, A. Foucaud, Tetrahedron Lett. 23, 4927 (1982)
3. S. Chalais, P. Laszlo, A. Mathy, Tetrahedron Lett. 26, 4453
(1985)
4. F. Liang, Y.J. Pu, T. Kurata, J. Kido, H. Nishide, Polymer 46,
3767 (2005)
37. K. Bahrami, M.M. Khodaei, F. Naali, J. Org. Chem. 73, 6835
(2008)
5. G. Kwak, M. Fujiki, Macromolecules 37, 2021 (2004)
6. S.M. Lai, C.P. Ng, R. Martin-Arnada, K.L. Yeung, Microporous
Mesoporous Mater. 66, 239 (2003)
7. M.M. Heravi, F. Derikvand, M. Haghighi, Kh Bakhtiari, Lett.
Org. Chem. 3, 297 (2006)
8. J. March, Advanced organic chemistry: reactions, mechanisms,
and structure, 4th edn. (Wiley, New York, 1992)
9. D. Prajapati, K.C. Lekhok, J.S. Sandhu, A.C. Ghosh, J. Chem.
Soc. Perkin Trans. 1, 959 (1996)
10. T.I. Reddy, R.S. Verma, Tetrahedron Lett. 38, 1721 (1997)
11. J.R. Harjani, S.J. Nara, M.M. Salunkhe, Tetrahedron Lett. 43,
1127 (2002)
38. K. Bahrami, M.M. Khodaei, M. Soheilizad, J. Org. Chem. 74,
9287 (2009)
39. K. Bahrami, M.M. Khodaei, M. Sheikh Arabi, J. Org. Chem. 75,
6208 (2010)
40. K. Bahrami, M.M. Khodaei, P. Fattahpour, Catal Sci. Technol. 1,
389 (2011)
41. P.A. Hassan, S.R. Raghavan, E.W. Kaler, Langmuir 18, 2543
(2002)
42. M.L. Deb, P.J. Bhuyan, Tetrahedron Lett. 46, 6453 (2005)
43. Q. Liu, H. Ai, Z. Li, Ultrason. Sonochem. 18, 477 (2011)
44. M. Gupta, R. Gupta, M. Anand, Beilstein J. Org. Chem. 5, 1
(2009)
12. F.A. Khan, J. Dash, R. Satapathy, S.K. Upadhyaya, Tetrahedron
Lett. 45, 3055 (2004)
45. D.Q. Shi, J. Chen, Q.Y. Zhuang, X.S. Wang, H.W. Hu, Chin.
Chem. Lett. 14, 1242 (2003)
13. Z. Wenfei, L. Jinhua, L. Yanqiu, S. Shoufei, R. Xiaoqian, J. Min,
Chin J. Catal. 34, 559 (2013)
46. C. Zhuo, D. Xian, W. Jian-Wei, X. Hui, ISRN Org. Chem. 2011,
1 (2011)
14. A. Rostami, B. Atashkar, H. Gholami, Catal. Commu. 37, 69
(2013)
15. W. Hu, Z. Guan, X. Deng, Y.-H. He, Biochimie 94, 656 (2012)
47. M.M. Heravi, K. Bakhtiari, S. Taheri, H.A. Oskooie, J. Chin.
Chem. Soc. 54, 1557 (2007)
123