Triethylamine: A potential N-base surrogate for pyridine in Knoevenagel condensation of aromatic aldehydes and malonic acid

Article abstract of DOI:10.1039/c5nj03125g

Cinnamic acids are intermediates with significant potential for synthesis of several industrially important chemicals. Classically, cinnamic acids are produced through Knoevenagel condensation of aromatic aldehydes and malonic acid in the presence of an organocatalyst and large amounts of carcinogenic pyridine. An alternative pyridine free reaction scheme for Knoevenagel condensation of malonic acid and aromatic aldehydes was investigated by replacing pyridine with an aliphatic tertiary amine surrogate in toluene as the reaction medium. Of the three aliphatic tertiary amines used, namely, triethyl amine (TEA), trioctyl amine (TOA) and tributyl amine (TBA), only TEA afforded cinnamic acids in comparable yields to those obtained with pyridine. Validation through a computational analysis is attempted to provide an explanation for the observed role of TEA as an aliphatic N-base instead of TBA and TOA. The use of TEA as a mild base in place of pyridine can be seen as playing the dual role of a base catalyst as well as a phase transfer agent evidenced by the in-process ATR-FITR spectroscopy. Use of the TEA-toluene system in place of pyridine can be seen as resulting in a process that affords ease of handling, separation and recycling of the solvent and the catalyst.

Full text of DOI:10.1039/c5nj03125g

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Triethylamine: A Potential N-Base Surrogate for Pyridine in
Knoevenagel Condensation of Aromatic Aldehyde and Malonic
Acid
Received 00th January 20xx,
Accepted 00th January 20xx
a
a
a, b*
DOI: 10.1039/x0xx00000x
Hitesh. S. Pawar , Adhirath. S. Wagh and Arvind. M. Lali
www.rsc.org/
Cinnamic acids are intermediates with significant potential for synthesis of several industrially important chemicals.
Classically,cinnamic acids are produced through Knoevenagel condensation of aromatic aldehydes and malonic acid in
presence of an organocatalyst and large presence of carcinogenic pyridine.An alternative pyridine free reaction scheme for
Knoevenagel condensation of malonic acid and aromatic aldehydes was investigated replacing pyridine with an aliphatic
tertiary amine surrogate in toluene as reaction medium. Of the three aliphatic tertiary amines used namely, triethyl amine
(TEA), trioctyl amine (TOA) and tributyl amine (TBA), only TEA afforded pyridine comparable yields of cinnamic acids.
Validation thourgh a computational analysis is attempted to provide an explanation for the observed role of TEA as
aliphatic N-base instead of TBA and TOA. The use of TEA as a mild base in place of pyridine can be seen as playing a dual
role of a base catalyst as well as a phase transfer agent evidenced by the in-process ATR-FITR spectroscopy. Use of TEA-
toluene system in place of pyridine can be seen resulting in a process that affords ease of handling, separation and
recycling of the solvent and the catalyst.
[
11]
base
. Use of piperidine as organo-catalyst with pyridine
Introduction
doubling as a solvent as well as a base is the most frequently
used process strategy in conducting the Knoevenagel
Carbon-carbon double bond synthesis of α, β-unsaturated
carbonyl compounds by employing Knoevenagel condensation
is a widely used method in organic synthesis and allows
[12]
condensation
.
[1]
production of variety of cinnamic acids . Synthesis of
cinnamic acids via Knoevenagel condensation has received
significant attention in both academia and industry on account
of the broad spectrum of applications in cosmetics, flavors,
perfumery products, pharmaceuticals, agrochemicals, and
[
2]-[6]
pharmaceuticals intermediates production sectors
. Several
ester derivatives of cinnamic acids have proven significant for
[7]
their antitumor, anti-inflammatory, and sunscreen actions
Fig.1). Conventionally, cinnamic acids and their derivatives are
(
synthesized by condensation of aromatic aldehydes and active
methylene compounds in the presence of organic and/or
[8],[9]
inorganic base
. The condensation of aromatic aldehyde
Fig.1Several significant pharmaceutically active cinnamic acid esters derivatives
and malonic acid in the presence of a base is the well-known
[10]
Knoevenagel condensation reaction
. Usually, ammonia,
primary or secondary amines and their salts are employed as Reports however continue to be published as chemists
attempt to improve the strategy to render it less energy
[13]
intensive, green, safe and rapid. Mcnulty et al
compared
condensation of malonic acid and aromatic aldehydes in the
presence of pyridine and piperidine using ultrasound and
[14]
conventional heating. Kappe et al
reported use of silicon
carbide vessel for microwave assisted condensation of malonic
[
acid and aromatic aldehyde. In another report Kappe et al
15]
suggested use of microwave reactors as well as silicon carbide
autoclave for synthesis of cinnamic acids in presence of
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ARTICLE
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piperidine in ethanol. In spite of these advancements replace
of pyridine is of crucial importance due to its unpleasant
effects.
Results and discussion
Dual role of Triethylamine
Use of pyridine is not convenient from many angles like Knoevenagel condensation traditionally uses pyridine as a
environmental and safety due to its carcinogenic effect, solvent as well as a base in presence of catalytic amounts of
[
16],
[26],[27]
hazardous nature and complexity in handling at bulk scale
piperidine
Thus, attempts have also been directed towards reaction as a base as well as a neat solvent has been reported
devising pyridine free protocols for synthesis of cinnamic acids. to facilitatein situ decarboxylation of the dicarboxylic acid
. In addition, use of pyridine in Knoevenagel
[17],[18]
.
[28]
[29]
Several metal salts as base catalysts have been explored for
.Sakai et al
reported use of ammonium decarboxylation of dicarboxylic acid in presence of In (III)
acetate as a base for microwave assisted synthesis of cinnamic catalyst. In present study we have explored use of TEA as
have recently reported incomplete
[19]
this purpose. Kumar et al
[20]
acids, and later, the same group
reported bismuth chloride potential N-base surrogate for pyridine free formation of
as an efficient non-toxic catalyst for production of cinnamic cinnamic acid. Thus, pyridine free model reaction using
acids under solvent free and microwave heating conditions. benzaldehyde and malonic acid was conducted in toluene as
[
21]
Valizadeh et al
catalyst under microwave assisted heating. Gupta et al
reported ammonium chloride as a base reaction medium using three different tertiary amines (TEA,
[22]
TOA and TBA) in presence of catalytic amounts of piperidine.
The results are shown in Table 1.
reported tetrabutylammoniumbromide (TBAB) and K CO
2
3
under microwave irradiation. However, while use of heavy
metals for synthesis of pharmaceuticals, food and cosmetic
Table1. Influence of different tertiary amines on yield.
a
[23],[24]
Sr.No
Reaction system
Yield
%)
Time
(h)
3
Reference
products is not encouraged
and use of metal free bases
(
continue to attract attention, use of microwave for synthesis
1
2
3
TEA: Piperidine
TOA: Piperidine
90
n.d.
n.d.
99
This work
This work
This work
13
[25]
continues to face scalability issues. Zhang et al reported β-
alanine and 1, 8-diazabicyclo [5.4.0] Andes-7-ENE (DBU) as an
efficient catalytic system for Knoevenagel condensation of
benzaldehyde and malonic acid. The use of non-complex,
non-expensive and metal free base catalyst would be adding
a significant contribution for development of techno-
commercial and eco-friendly process for production of
cinnamic acids.
5
TBA: Piperidine
5
b
4
Pyridine: Piperidine
Pyridine: Piperidine
Pyridine: Piperidine
3
c
5
97
0.03
24
26
6
75-85
37
Reaction conditions: Benzaldehyde (4.7 mmole), Malonic acid (4.7 mmole),
a
Amine (6.7 mmole), Piperidine (0.8 mmole) Toluene (5 ml), reflux; isolated
b
c
yield; Ultrasound assisted; Microwave assisted.
In the present work an attempt is made to conduct pyridine
free Knoevenagel condensation reaction of aromatic It was found that of the tested amines in combination with
aldehydes and malonic acid using TEA in toluene instead of catalytic amount of piperidine only the use of TEA afforded a
pyridine as the base (Scheme 1). Replacement of pyridine with yield of cinnamic acid comparable to those obtained with the
TEA is proposed as advantageous because of three reasons (a) conventional processes using pyridine. The results obtained
pyridine has one of the lowest known LDLo at 500 ppm; (b) indicated a significant trend. Malonic acid is not soluble in
pyridine has a narcotic and carcinogenic effect its vapors toluene and did not show any reaction by itself and also with
concentrations of above 3600 ppm pose a health risk; and (c) it TBA and TOA. Of the tested aliphatic N-base TEA alone was
has several toxic effects with
a
maximum allowable found to favor the reaction indicating that it not only helped
concentration in air being 5ppm. TEA was considered as solubilize the acid but also helped shifting reaction equilibrium
relatively safer base as compared to pyridine especially in through formation of a toluene soluble complex (Scheme 2).
higher boiling solvent like toluene besides expected to behave Absence of any reaction in TBA and TOA indicated that
as a phase transfer agent aiding dissolution of malonic acid in increasing carbon chain length on tertiary amine hindered
toluene, and also as a base in the presence of catalytic amount soluble complex for further condensation thereby not being
of piperidine. The condensation of benzaldehyde and malonic able to catalyze the reaction. Computational analysis on
acid was studied as a model reaction for process optimization Discovery Studio 3.5 software was used to explore the energy
and then extended to other derivatives of benzaldehyde to minimized conformations of respective amine and malonic
obtain respective cinnamic acids.
acid ion pair complexes under CHARMm force field. The
analysis clearly brought out the relative hindrance of –CH
2
proton of malonic acid for the formation of carbanion for
further condensation with aromatic aldehyde (Fig.2). The
energy minimized structure of –CH
was found to be sterically hindered by C
TBA and C and C protons of TOA. Whereas in case of TEA
2
proton of malonic acid
2
,C , and C protons of
3
4
7
8
such hindrance was absent due to shorter carbon chain.
Scheme 1.General reaction scheme for pyridine free synthesis of cinnamic acid
2
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The possible mechanism involving the dual role of TEA as a
phase transfer catalyst as well as a base is depicted in Scheme
2. It can be speculated that formation of cinnamic acid
occurred in three steps: a) Phase transfer with carbanion
formation; b) Condensation; and c) Elimination. Formation of
malonic acid and TEA complex was confirmed by ATR-FTIR
spectroscopy (Fig. 3). The ATR-FTIR spectra overlay of malonic
acid, the intermediate (malonic acid-TEA complex) and TEA
clearly indicates the diminishing of broad characteristic peak (-
-1
COOH) around 3000 cm in FTIR spectrum of the intermediate.
The condensation step with decarboxylation was monitored by
on FTIR analysis of intermediate and reaction mass after
completion of reaction (Fig.4).The FTIR overlay of intermediate
and reaction mixture indicates the presence of characteristic
-1
peak for α, β-unsaturated carboxylic acid at 3500cm .
Fig.3ATR -FTIR of overlay of malonic acid, malonic acid TEA complex and TEA, A:
Malonic acid, B: Malonic acid–TEA complex, C: TEA.
Fig 2.Energy minimized conformations of malonic acid complex with A) TEA B)
TBA C) TOA showing the steric hindrance of malonic acid.
Fig.4 ATR-FTIR overlay of malonic acid-TEA complex and malonic acid (A: reaction mass,
B malonic acid-TEA complex)
Influence of molar ratio of TEA and Piperidine
Optimization around stoichiometric molar ratios of involved
reactants plays a crucial role for developing economical as well
[
30],[31]
as environmentally safer process
. However, optimal
[32]
concentration of a catalyst often defies stoichiometry . In
the present protocol, piperidine played the role of a base
Scheme 2 Possible mechanism for pyridine free Knoevenagel condensation via phase
transfer catalysis by using TEA.
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catalyst while TEA played the dual role of a catalyst as well as a aldehyde. Such a stability of malonic acid carbanion was not
base promoter. In order to optimize the molar ratio of TEA and probably possible in toluene. Further, toluene also provides a
piperidine, the model reaction between benzaldehyde and medium since TEA and its quaternary ammonium salt with
malonic acid was conducted in presence of different molar malonic acid are both soluble in toluene and thus nucleophilic
ratios. The results are shown (Table 2).
addition on the partly soluble aldehyde can be expected to
In order to optimize the molar ratios, the molar ratio of TEA to take place effectively with elimination of water that could be
benzaldehyde was varied from 0.5 to 1.5 with constant molar distilled off as azeotrop with toluene. Since totally solvent free
ratio of piperidine (0.18), and the molar ratio of piperidine to reactions offer advantages and are preferred as green and
[35],[36]
benzaldehyde was varied from 0 to 0.36 with constant molar techno-economically processes
the Knoevenagel
ratio of TEA (1.3). In absence of piperidine there is no condensation under investigation was also studied under
formation of cinnamic acid. Thus it was notated that the solvent free reaction condition with TEA acting as reaction
addition of catalytic amount of piperidine significantly medium. It was found that solvent free reaction conditions
improves the yield. The addition of piperidine promotes the also gave good yield of cinnamic acid comparable with yield
condensation step during formation of cinnamic acid (Scheme obtained in toluene (90%).
2). In case of TEA concentration it was found that increasing
TEA concentration initially increased the yield of cinnamic acid
but then decreased remarkably after an optimum. The same
case was seen to happen with concentration piperidine as well
since the optimal ratio of TEA and piperidine significantly
improves the cinnamic acid yield. The decrease in yield of
cinnamic acid at higher concentrations of both TEA and
piperidine may be attributed to highly basic conditions that
favor double decarboxylation of cinnamic acid. This is in line
with the reported observations with respect to piperidine
[
12]
concentrations used in pyridine
.
Table 2. Influence of molar ratio of TEA and Piperidine.
a
Sr.No
Catalyst used
Molar ratio
Yield (%)
0
.5
21.28
34.04
90.32
53.19
0
Fig 5. Influence of solvent on percentage yield of cinnamic acid in presence of
pyridine free condition.
1
1
TEA
1
1
.3
.5
0
Use of different Substrates
2
Piperidine
0.09
21.28
In order to explore the scope of the present approach of using
TEA in place of pyridine, various derivatives of aromatic
aldehydes wi.th different electron donating and withdrawing
0
0
.18
.36
90.32
55.32
a
Isolated yield. Reaction condition: Benzaldehyde (4.7 mmole), Malonic acid (5.2 substituents were screened under at the benzaldehyde
mmole), Toluene (5 mL) reflux for 2h.
optimized reaction conditions. The results on the influence of
various substituents on the yield and purity of respective
cinnamic acid are summarized in Table 3. It was found that of
Influence of solvent
Use of a base miscible benign solvent in place of neat pyridine the tested aromatic aldehydes, aldehydes having electron
or TEA was considered useful for reducing volatility of the donating as well as withdrawing substituent provided good to
reaction mixture and rendering the system safer to excellent isolated yields of the respective cinnamic acids.
[
33],[34]
handle
polar solvent toluene; moderately
. In order to investigate the role of solvent, non- The structural confirmations of all the synthesized derivatives
polar solvent of cinnamic acid were performed by using ATR FT-IR
tetrahydrofuran (THF); polar solvent methanol; and polar (Attenuated total reflection Fourier transform spectroscopy),
1
aprotic solvent acetonitrile (ACN) were selected. The influence high resolution LC-MS, and H-NMR analysis. It was found that
the all the compounds matched well to their respective
of solvent choice on the yield of cinnamic acid is seen in Fig. 5.
It was found that of the tested solvents, the best yield of characteristic spectral data. In order to confirm the purity of
cinnamic acid was obtained in toluene. THF, ACN and synthesized cinnamic acids, all the isolated but unpurified
methanol did not give significant reaction possibly due to the products were analyzed for their HPLC purity and all showed
higher stability of carbanion of malonic acid in these solvents excellent HPLC peak purities (Table. 3). Thus, the present
through hydrogen bonding thus resulting in suppression of the methodology was seen to provide cinnamic acids in high yields
next condensation step (Scheme 2) and preventing and purities without formation of side products.
nucleophilic attack by malonic acid on carbonyl carbon of
4
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Table 3. Substrate study for pyridine free Knoevenagel reaction for synthesis of cinnamic acids
ARTICLE
a
b
c
Yield (%)
HPLC Purity (%)
Sr.no
Substrate
Product
9
0
1
96
2
3
8
8
8
9
99
100
8
7
7
7
4
5
99
100
8
0
6
100
8
8
4
9
7
8
100
98
a
c
b
Reaction conditions: aldehyde (1eq), malonic acid (1eq), TEA (1.3eq), piperidine (0.18eq), reaction time 2h, reflux temperature. Isolated yield,
HPLC area% purity.
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Product characterization
An NMR spectrum of the obtained product in DMSO-d
Conclusions
6
was
A new strategy for synthesis of cinnamic acids was successfully
investigated using a pyridine free Knoevenagel condensation in
the presence of triethlyamine, as neat solvent or in combine
action with toluene with catalytic amounts of piperidine. To
the best of our knowledge this is the first report on exploring
triethlyamine as a base in place of pyridine for condensation of
aromatic aldehyde and malonic acid. The in situ FTIR analysis
was performed to investigate the reaction mechanism. It was
found that the triethlyamine also plays a dual role of a base as
well as a solubilizing agent for promoting the reaction both in
toluene and TEA itself. The investigated methodology provides
acceptable yields of the different cinnamic acids synthesized
while being carried out in toluene as well as under solvent free
conditions with low formation of by-products.
obtained on a Bruker Advance 400 spectrometer (1H: 400
MHz, at 300 K). The spectrum was referenced against the NMR
obtained internal standard and chemical shift are reported in
ppm. The functional group characterization was done on a
Shimadzu IR Prestige-21 instrument equipped with ATR-FTIR.
The mass of obtained products was confirmed by high
resolution mass spectrometer having Agilent Tripal-Quard LC
MS 6520 coupled with Agilent 1200 HPLC. The FTIR, HR-LCMS
1
and HNMR characterization of all synthesized cinnamic acids
(Table.3) was as,
Compound 3a: Cinnamic acid
-1
-1
FTIR (cm ): 2968, 2829, 1668 and 1624. HR LC-MS (cm ):
1
1
47.5000, 103.7000. H-NMR: 7.97 (d, 2H), 7.68 (m, 2H), 7.50
d, 2H), 6.63 (d, 1H).
Compound 3b: 4-Hydroxy cinnamic acid
(
Experimental
-1
-1
All the chemicals and reagents were used are of synthetic
grade chemicals and obtained from commercial suppliers and
used without further purification. The solvents used for the
reactions are of commercial grade pure solvents. Solvents used
for HPLC analysis is of HPLC grade solvents. The entire samples
before the HPLC analysis were diluted at appropriate
concentrations and filtered through 0.2 micron PTFE filter
paper before HPLC analysis. The structural characterization of
FTIR (cm ): 3352, 2823, 1664 and 1625. HR LC-MS (cm ):
1
1
2
63.500, 110.800. H-NMR: 9.80 (s, 1H), 7.76 (m, 1H), 7.48 (d,
H), 6.99 (d, 2H), 6.39 (d, 1H).
Compound 3c: 4-Methoxy cinnamic acid
-1
FTIR (cm ): 2935, 2841, 1672, 1624 and 1311. HR LC-MS (m/z):
1
1
1
77.5000, 133.7000, 118.7000. H-NMR: 7.60 (d, 2H), 7.50 (d,
H), 6.93 (d, 2H), 6.34 (d, 1H), 3.73 (s, 3H), 12.18 (s, 1H).
Compound 3d: 4-Hydroxy, 3-methoxy cinnamic acid
-1
synthesized
compounds
was
obtained
after
the
FTIR (cm ): 3427, 2968, 2837, 1685, 1614 and 1377. HR LC-MS
1
recrystallization.
(
m/z):190.7000, 146.7000. H-NMR: 7.70 (d, 1H), 7.48 (s, 1H),
.45 (d, 1H), 7.16 (d, 1H), 6.44 (d, 1H), 3.93 (s, 3H).
Compound 3e: 4-Hydroxy, 3, 5-dimethoxy cinnamic acid
7
General process for preparation of cinnamic acid
-1
In a four necked round bottom flask with reflux condenser, FTIR (cm ): 3429, 2968, 2841, 1687, 1618 and 1377. HR LC-MS
thermometer, and addition funnel, toluene (5mL), malonic (m/z): 223.6000. H-NMR: 7.87 (d, 1H), 7.58 (s, 2H), 6.26 (d,
1
acid (4.7mmole), and triethlyamine (6.1mmole) were mixed 1H), 3.96 (s, 6H).
for 3-4min. Aromatic aldehyde (4.7mmole) and piperidine (0.8 Compound 3f: 4-N, N-dimethyl amino cinnamic acid
-1
mmole) were added slowly with vigorous stirring. Then the FTIR (cm ): 2897, 2816, 1664, 1587, 1365 and 1186. HR LC-MS
reaction mixture was heated for 2-3h at reflux temperature. (m/z): 193.5000, 178.5000, 149.7000, 134.7000.H-NMR: 7.87
The reaction was continuously monitored after every half hour (d, 2H), 6.79 (d, 2H), 7.72 (d, 1H), 6.32 (d, 1H), 3.2 (s, 6H).
by TLC. After the complete consumption of aryl aldehyde, the Compound 3g: 4-Nitro cinnamic acid
-1
resulting reaction mixture was taken for vacuum distillation to FTIR (cm ): 2939, 2835, 1631, 1616, 1516, 1423 and 1219. HR
1
remove triethlyamine and solvent. The resulting viscous liquid LC-MS (m/z): 192.6000, 148.7000. H-NMR: 8.20 (d, 2H), 7.95
was cooled at room temperature. Then 5mL of 5 % (d, 2H), 7.66 (d, 1H), 6.72 (d, 1H).
bicarbonate was added slowly through addition funnel and Compound 3h: 2-chloro cinnamic acid
-1
stirred for 10min. The resulting reaction solution was washed FTIR (cm ): 2964, 2829, 1676, 1616, 1544, 1417 and 1276. HR
1
by 10ml of ethyl acetate and aqueous layer was collected. The LC-MS (m/z): 182.3000, 180.3000. H-NMR: 7.51 (d, 1H), 6.58
resulting aqueous layer was cooled at 0ºC and then acidic pH (d, 1H), 7.44 (m, 2H), 7.89 (m, 2H).
of aqueous layer was adjusted by means of con HCl. The
resulting solid was filtered, suck dried on suction pump and Acknowledgements
then dried at 60ºC in vacuum oven.
The authors are graceful for the financial support from the
Department of Biotechnology (DBT), Ministry of Science and
HPLC analysis
Technology India.
The HPLC analysis of all synthesized product were performed
on Agilent 1200 HPLC system coupled with UV detector. The
Notes and references
Agilent C18 column was used as stationary phase. The
1
L. F. Tietze, U. Beifuss, The Knoevenagel reaction In
Comprehensive Organic Synthesis; Trost, B. M., Ed.;
Pergamon Press: Oxford, UK, 1991.
methanol water (30: 70) mobile phase was used for elution at
0ºC column temperature. All the samples were dissolved in
mobile phase at appropriate dilution before HPLC analysis.
4
6
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2
3
H. M. Cho, M. Ueda, M. Tamaoka, K. Hamaguchi, Y. Aisaka, T. 37 Y. Qian, H.-J. Zhang, H. Zhang, C. Xu, J. Zhao and H.-L. Zhu,
Bioorg. Med. Chem. 2010, 18, 4991–4996.
Kiso, R. Inoue, T. Ogino, T. Tatsuoka, T. Ishihara, I. Noguchi, S.
Morita, J. Med. Chem. 1991,34, 1503-1505.
J. Nokami, K. Kataoka, K. Shiraishi, M.O safune, I. Hussain,
and S. Sumida, J. Org. Chem. 2001, 66, 1228-1232.
G. Kwak, M. Fujiki, Macromolecules. 2004, 37, 2021-2025.
4
5
H. V.Chavan, B. P. Bandgar, ACS Sustain. Chem. Eng.2013,
29-936.
P. De, G.Y. Koumba, P. Constant, F. Bedos-Belval, H. Duran,
1,
9
6
N. Saffon, M. Daffe, M. Baltas, J. Med. Chem. 2011,54, 1449-
1
461.
P. Sharma, J. Chem. Pharm. Res.2011,
T. Jackson, J.H Clark, D.J. Macquarrie, and J.H. Brophy, Green
Chem. 2004, , 193-195
R.K Hangarge, D.V. Jarikote, and M.S. Shingare, Green Chem,
002, , 266-268.
7
8
3, 403-423.
6
9
2
4
1
1
0 E. Knoevenagel, Chem. Ber. 1894, 27, 2345.
1 O. Tanaka, O, H. Hiramatsu and K. Fujiwara, Bull. Chem. Soc.
Jpn.61, 7, 1988, 2473-2479.
2 V. Aldabalde, Open J. Phys. Chem.2011, 01, 85–93.
3 J. Mcnulty, I.J.A Steere, S. Wolf, 1998,39, 8013-8016.
4 B. Gutmann, D. Obermayer, B. Reichart, B. Prekodravac, M.
Irfan, J.M. Kremsner, O.C. Kappe, Chemistry.2010,16, 12182–
1
1
1
1
2194.
5 D. Obermayer, M. Damm, O.C Kappe, Chemistry.2013,19
5827-15830.
6 U.S. EPA. Health and Environmental Effects Profile for
Pyridine. U.S. Environmental Protection Agency 1986,
Washington, D.C., EPA/600/X-86/168 (NTIS PB89123384).
7 G. Aylward, SI Chemical Data 6th Ed;ISBN 978-0-470-81638-
1
1
,
1
1
1
7
, John Wiley and Sons, 2008.
8 K. Alfonsi, J. Colberg, P. J. Dunn, T. Fevig, S. Jennings, T. A.
Johnson, H. P. Kleine, C. Knight, M. A. Nagy, A. Perry and M.
Stefaniak, Green Chem. 2008, 10, 31–36.
1
9 H. M. SawpathKumar. V Subbareddy. Anjaneyulu, J. S. Yadav,
Synth. Commun.1998, 28, 3811–3815.
2
2
0 D. Kumar, J. Sandhu, Synth. Commun.2010, 40, 1915–1919.
1 H. Valizadeh, M. Mamaghani, A. Badrian, Synth.
Commun.2005, 35, 785–790.
2
2
2 M. Gupta, B. P Wakhloo, ARKIVOC, 2007,
3 P.I. Dalko, L. Moisan, Angew. Chem. Int. Ed. Engl.2004, 43,
138–5175.
4 G. R. Krishnan, K. Sreekumar, European J. Org. Chem.2008,
, 4763–4768.
5 L. Zhu, N. Lei, Z. Miao, C. Sheng, C. Zhuang, J. Yao, W. Zhang,
Chinese J. Chem.2012, 30, 139-143.
6 A.K Mitra, N. Karchaudhuri, Synth. Commun. 1999, 29, 573-
i, 94–98.
5
2
2
2
2
2
2
3
2
8
5
81.
7 C.J. Simpson, M.J Fitzhenry, and N.P.J. Stamford,Tet. Lett.
005, 46, 6893- 6896.
2
8 M. Kidwai, N.K. Mishra, Green Chemistry - Environmentally
Benign Approaches; ISBN 978-953-51-0334-9, InTech 2012.
9 Y. Ogiwara, K. Takahashi, T. Kitazawa, N. Sakai, J. Org.
Chem.2015, 80, 3101–3110.
0 Y. Ikushima, M. Arai, Stoichiometric Organic Reactions, in
Chemical Synthesis Using Supercritical Fluids; Wiley-VCH
Verlag GmbH, Weinheim, Germany. 1999.
3
3
1 K.V. Narayanan, Lakshmikutty, B. Sticheomitry and Process
Calculations; PHI Learning Pvt. Ltd., 2006.
2 C.H. Bartholomew, R. J. Farrauto, Fundamentals of Industrial
Catalytic Processes; John Wiley & Sons, 2011.
3 R.A. Sheldon, Green Chem.2005,7,267-278.
4 P. Anastas, J.C. Warner, Green Chemistry: Theory and
practice; Oxford University Press, Oxford, 1998.
5 C. Villa, E. Mariani, A. Loupy, C. Grippo, G.C Grossi, A.
Bargagna, Green Chem. 2003, 5, 623-626.
6 M.A.P. Martins, C. P. Frizzo, D.N. Moreira, L. Buriol, and P.
Machado, Chem. Rev. 2009, 109, 3885-4531.
3
3
3
3
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New Journal of Chemistry
Page 8 of 8
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DOI: 10.1039/C5NJ03125G
Graphical Abstract
Triethylamine: A Potential N-Base Surrogate for Pyridine in
Knoevenagel Condensation of Aromatic Aldehyde and Malonic Acid
a
a
a,b
Hitesh S. Pawar , Adhirath S. Wagh and Arvind M. Lali*
a
DBT-ICT Centre for Energy Biosciences, Institute of Chemical Technology, N.P.Marg Matunga (w), Matunga, Mumbai, India.Fax: 91 22 3361
020; Tel: 91 22 3361 1111(Extn. 2301);E-mail: hiteshudct@gmail.com
1
a,b*
Department of Chemical engineering, Institute of Chemical Technology, N.P.Marg Matunga (w), Matunga, Mumbai, India. Fax: 91 22 3361
020; Tel: 91. E-mail: arvindmlali@gmail.com
1
•
TOC entry
•
TEXT entry
Triethyl amine was successfully examined as potent N-base surrogate for Knoevenagel condensation to
produce cinnamic acids without compromising product yield.