Eco-efficiency and scalable synthesis of bisamides in deep eutectic solvent

Article abstract of DOI:10.1016/j.molliq.2015.02.033

Solvents define a major part of the environmental performance of processes in chemical industry and also impact on cost, safety and health issues. In order to minimize the environmental impact resulting from the use of volatile organic solvents in chemica

Full text of DOI:10.1016/j.molliq.2015.02.033

Journal of Molecular Liquids 206 (2015) 268–271
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Journal of Molecular Liquids
journal homepage: www.elsevier.com/locate/molliq
Eco-efficiency and scalable synthesis of bisamides in deep
eutectic solvent
⁎
Najmedin Azizi , Masoumeh Alipour
Department of Green Chemistry, Chemistry & Chemical Engineering Research Center of Iran, P.O. Box 14335-186, Tehran, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
Solvents define a major part of the environmental performance of processes in chemical industry and also impact
on cost, safety and health issues. In order to minimize the environmental impact resulting from the use of volatile
organic solvents in chemical production, a deep eutectic solvent (DES) consisting of choline chloride and urea
(1:2 molar ratio) was prepared and used as the co-solvent for the preparation of gem-bisamides starting from
aldehydes. The deep eutectic solvent fulfills the triple role of being a solvent, as a catalyst and as reagents, and
provides a green, safe and cost-effective access to various gem-bisamides without a tedious work-up. The desired
compounds were obtained in a few min (15–120 min) with moderate to good yields (52–90%) and amenable to
large scale production without significant loss in its efficiency.
Received 21 October 2014
Received in revised form 21 January 2015
Accepted 24 February 2015
Available online 26 February 2015
Keywords:
Deep eutectic solvent
Green chemistry
Bisamide
© 2015 Elsevier B.V. All rights reserved.
Urea
Aldehyde
1. Introduction
only for intriguing biological activities and their versatile role in the
treatment of high blood pressure, but also for particular importance as
Due to their toxicity and flammability common organic solvents
were used in industries and laboratories and it is necessary to design
and elaborate new processes in order to avoid waste and to substitute
benign chemicals for toxic hazardous solvents. In this regard, the devel-
opment of a cleaner process is more attractive in green chemistry [1–3].
Among the several principles of green chemistry, the reduction of vola-
tile organic solvents and catalysts from the reaction medium or in the
work-up procedure is of utmost importance. The use of a huge amount
of volatile organic solvents required to conduct a chemical process cre-
ates adverse effects on organisms. The search for a safer solvent and cat-
alyst alternative is thus holding a key role in the green chemistry. Deep
eutectic solvents (DESs) that mix quaternary ammonium salts such as
choline chloride and hydrogen bond donor's compounds have attracted
much attention due to their significant advantages [4–10]. DESs have a
promising alternative to ionic liquids and conventional organic solvent
because they are easier to prepare from biodegradable, renewable and
natural starting materials with high purity at a low cost. After the first
report by Abbott and co-workers in 2003, the number of papers on
the use of DESs in chemistry and biology has significantly increased
over the past few years [11–19].
key synthons in the organic synthesis [20–22]. Therefore, many synthet-
ic methods for Gem-bisamides were achieved via condensation reaction
between aldehyde and amide in the presence of catalyst or activator
[23–30]. Although these methodologies are useful tools and serve as
the synthetic requirements for simple gem-bisamides, most of them
suffer from limitation such as expensive catalyst, harmful organic sol-
vent, and harsh reaction conditions and prolong reaction times. Further-
more, despite the efficiency of the used catalyst in this reaction,
insolubility of bisamides in the common organic solvents, separation
of products from the catalyst was difficult and this leads to the tedious
work-up in most cases. Thus, the development of a catalyst free method
for the synthesis of bisamides was the major goal of our research.
2. Experimental section
2.1. Materials and instrumentation
All chemicals, solvents and DES components were commercially
available. All products were confirmed by 1HNMR, FT-IR spectroscopy
and mass spectrometry. 1H NMR spectra were recorded on 500 and
300 MHz 1H NMR, 13C NMR 125.7 and 75 MHz NMR spectrometer
using DMSO-d6 as a solvent and chemical shifts have been expressed
in (ppm) downfield from TMS. Water and ethanol were distilled before
used. Melting points were recorded on Buchi 535 melting point appara-
tus and are uncorrected. FT-IR spectra were determined on a Bruker
Vector-22 infrared spectrometer using KBr disks. 1H NMR spectra
were recorded at r.t. on a FT-NMR Bruker Ultra Shield TM (500 and
The development of environmentally benign procedures to access
functional amide derivatives has infused continuing interest, as such
compounds have been used widely in the construction of natural prod-
ucts and pharmaceutical compounds. Gem-bisamides are important not
⁎
Corresponding author.
http://dx.doi.org/10.1016/j.molliq.2015.02.033
0167-7322/© 2015 Elsevier B.V. All rights reserved.

N. Azizi, M. Alipour / Journal of Molecular Liquids 206 (2015) 268–271
269
Table 1
300 MHz). EI-MS data was collected on an Agilent Technologies 5973
Mass Selective Detector (MS model).
Optimization of reaction condition.
2.2. DES preparation
Choline chloride-urea deep eutectic solvent was prepared according
to the literature [5]. Urea (200 mmol) and choline chloride (100 mmol)
were mixed, stirred and heated at 60 °C for 50 min until a clear liquid
appeared. The obtained deep eutectic solvent was used without any fur-
ther purification (Fig. 1).
Entry Solvent (mL)
Temp. (°C) Reaction time (min) Yield (%)a,b
1
2
3
4
5
6
7
8
DES (0.5 mL)
DES (0.5 mL)
DES (0.5 mL)
DES (0.5 mL)
DES (0.5 mL)
DES (0.5 mL)
DES (0.5 mL)
DES (0.1 mL)
DES (0.2 mL)
DES (1.0 mL)
DES (2.0 mL)
DES (5.0 mL)
DES (5.0 mL)
Water (1.0 mL)
rt
720
90
41
58
62
82
82
86
80
72
72
80
80
84
78
10
40
48
32
45
20
40
60
40
80
15
100
120
140
80
15
15
15
10
2.3. General procedure
A dried test tube, equipped with a magnetic stir bar, was charged
with an aldehyde (1.0 mmol), and DES (0.5 mL contain 4.67 mmol
urea) and the mixture was heated at 80 °C until the reaction was com-
plete (monitored visually, the reaction mixture was solidified). After
this time, water was added and the residue collected by filtration. The
resulting solid was washed with water and recrystallized from ethanol
to give pure products. All compounds were characterized by melting
found to be identical with the ones described in literature.
9
80
10
10
11
12
13c
14
15
16
17
18
19
80
30
80
30
80
80
80
15
100
600
600
600
600
600
600
Ethyl acetate (1.0 mL) 100
DMF (1.0 mL)
CH3CN (1.0 mL)
Toluene (1.0 mL)
THF (1.0 mL)
100
100
100
100
3. Results and discussion
a
DES: urea-choline chloride based deep eutectic solvent.
Isolated yields.
Reaction was carried out in 10 mmol scale.
b
c
In our research on organic transformation in green reaction media,
we recently reported that a one-pot three component reaction acceler-
ated in water and deep eutectic solvent [31–36]. In our continued work,
we became interested in exploring the reaction of aldehydes with DES
as a solvent, as a reagent and as a catalyst.
After optimization of the reaction conditions, we carried out the gen-
erality and synthetic scope of this condensation reaction with various
electronically divergent aldehydes (Table 2). The presence of an
electron-withdrawing group in the aromatic ring can influence reactiv-
ity of aldehydes and higher yield of the products was obtained in short
reaction times. On the other hand, the presence of electron-donating
groups exerts the reverse effects. The bromo-, chloro-, methyl- and
methoxy-substituted benzaldehydes were successfully converted and
gave the corresponding products in 58–90%. Several heterocyclic
aldehydes such as 2-furaldehyde, thiophene-2-carbaldehyde and
pyridine-3-carbaldehyde were applied as substrates because of the
important biological topics of heterocycles, the corresponding
bisamides were synthesized in good yields and short reaction times.
On the other hand, for the first time we have shown that aliphatic
aldehydes (entry 19), still displayed good reactivity and clean reactions
under this standard condition.
In an initial endeavor, the reaction of benzaldehyde with urea–cho-
line chloride based DES was studied as a model reaction to determine
the temperature and reaction times required to complete the transfor-
mation (Table 1). Low yields were observed at room temperature after
prolong reaction time (41% after 12 h) (Table 1, entry 1). It was ob-
served that the mixture which was initially in a partial semiliquid
state, solidified during increasing the temperature to 80 °C to a light
white solid mass for 15 min and thin layer chromatography (TLC) indi-
cated the complete conversion to the desired product. Further increas-
ing the temperature to 140 °C did not change the time and yields of
products. Further studies were conducted to optimize the volume of
the DESs, and 0.5 mL urea-choline chloride gave higher yields at a
short reaction time. Under optimized temperature, we also carried out
the model reaction in various solvents including H2O, THF, CH3CN,
ethyl acetate, toluene and DMF. All of these solvents turned out to be
less efficient than DES in promoting the reaction (Table 1, entries 14–
19). Most importantly, the reaction setup is very simple and easy.
Mixing of aldehydes and DES and heating of reaction mixture at 80 °C
gave the solid mass at a short reaction time, that was washed with
water to remove DES and recrystallized from ethanol to give pure
gem-bisamides with simple work-up.
In order to show the practical applicability of this green procedure,
the model reaction was carried out in a scale of 10 mmol (Fig. 2). The re-
action was completed in 15 min with 78% isolated yield after simple
work-up (Table 1, entry 13). After completion of the reaction, the mix-
ture was cooled to room temperature and the product was filtered and
washed with water and purified with recrystallized from hot ethanol.
Fig. 1. Deep eutectic solvent preparation from urea and ChCl.

270
N. Azizi, M. Alipour / Journal of Molecular Liquids 206 (2015) 268–271
Table 2
Synthesis of various gem-bisamides from aldehydes and DES.
Entry
1
Aldehyde
Yield (%)
82
Time (min)
15
M.P. (°C)
205–207
2
86
15
202–205
3
4
90
76
20
30
198–201
188–191
5
85
20
188–190
6
7
8
9
74
80
71
62
40
30
45
30
189–191
222–225
218–222
199–201
10
78
30
198–200
11
12
54
61
120
120
199–202
153–156
13
14
64
65
90
210–213
173–175
120
15
16
52
56
60
60
179–181
188–190
17
18
60
56
15
40
203–206
196–199
19
58
90
188–191

N. Azizi, M. Alipour / Journal of Molecular Liquids 206 (2015) 268–271
271
Fig. 2. Large-scale synthesis of substituted bisamides.
[9] A. Hayyan, M.A. Hashim, M. Hayyan, F.S. Mjalli, I.M. AlNashef, J. Clean. Prod. 65
(2014) 246–251.
4. Conclusion
[10] A.P. Abbott, R.C. Harris, K.S. Ryder, C. D'Agostino, L.F. Gladden, M.D. Mantle, Green
Chem. 13 (2011) 82–90.
[11] S.B. Phadtare, K.J. Jarag, G.S. Shankarling, Dyes Pigments 97 (2013) 105–112.
[12] B.S. Singh, H.R. Lobo, D.V. Pinjari, K.J. Jarag, A.B. Pandit, G.S. Shankarling, Ultrason.
Sonochem. 20 (2013) 633–639.
[13] F.S. Mjalli, J. Naser, B. Jibril, V. Alizadeh, Z. Gano, J. Chem. Eng. Data 59 (2014)
2242–2251.
[14] J. Parnica, M. Antalik, J. Mol. Liq. 197 (2014) 23–26.
[15] J. Ru, Y. Hua, J. Li, C. Xu, Y. Li, D. Wang, C. Qi, Y. Jie, J. Mol. Liq. 199 (2014) 208–214.
[16] A. Paiva, R. Craveiro, I. Aroso, M. Martins, R.L. Reis, A.R.C. Duarte, ACS Sustain. Chem.
Eng. 2 (2014) 1063–1071.
In summary, we have demonstrated for the first time, a unique prop-
erty of DES as a solvent, reagent and catalyst for the clean and efficient
synthesis of bis-amide derivatives due to high concentration of urea
present in the reaction medium. Remarkable advantages of this green
procedure include the use of biodegradable DES, short reaction times,
and a simple separation and purification. Further investigations of or-
ganic reactions in DESs are now underway in our laboratory.
[17] F. Monte, D. Carriazo, M.C. Serrano, M.C. Gutiérrez, M.L. Ferrer, ChemSusChem 7
(2014) 999–1009.
Acknowledgments
[18] W. Ailing, Z. Xueliang, Z. Zhuangzhi, L. Changping, Z. Xuefang, Prog. Chem. 26 (2014)
784–795.
[19] P. Li, F. Ma, P. Wang, Z. Zhang, Chin. J. Chem. 31 (2013) 757–763.
[20] E.E. Magat, B.F. Faris, J.E. Reith, L.F. Salisbury, J. Am. Chem. Soc. 73 (1951)
1028–1035.
Partial financial support of this work by the Chemistry and Chemical
Engineering Research Center of Iran is gratefully appreciated.
Appendix A. Supplementary data
[21] T.A. Ebel, A.A. Harwood, A.M. Burkman, J. Med. Chem. 10 (1967) 946–952.
[22] C. Vanier, A. Wagner, C. Mioskowski, Chem. Eur. J. 7 (2001) 2318–2325.
[23] Y. Zhang, Z. Zhong, Y. Han, R. Han, X. Cheng, Tetrahedron 69 (2013) 11080–11083.
[24] F. Tamaddon, H. Kargar-Shooroki, A.A. Jafari, J. Mol. Catal. A Chem. 369 (2013)
66–71.
[25] A.A. Bakibaev, Russ. J. Org. Chem. 30 (1994) 1773–1775.
[26] V.K. Singh, H. Sharma, S.K. Singh, L. Gangwar, Chem. Biol. Drug Des. 82 (2013)
119–124.
Supplementary data to this article can be found online at http://dx.
doi.org/10.1016/j.molliq.2015.02.033.
References
[27] B.F. Mirjalili, M.A. Mirhoseini, J. Chem. Sci. 3 (2013) 1481–1486.
[28] A. Bayer, M.E. Maier, Tetrahedron 60 (2014) 6665–6672.
[29] Q. Wang, L. Sun, Y. Jiang, C. Li, Beilstein J. Org. Chem. 4 (2008) 51–59.
[30] M. Anary-Abbasinejad, M. Mosslemin, A. Hassanabadi, S.T. Safa, Synth. Commun. 40
(2010) 2209–2215.
[31] N. Azizi, E. Batebi, Catal. Sci. Technol. 2 (2012) 2445–2448.
[32] N. Azizi, E. Batebi, S. Bagherpour, H. Ghafuri, RSC Adv. 2 (2012) 2289–2293.
[33] N. Azizi, E. Gholibeglo, RSC Adv. 2 (2012) 7413–7416.
[34] N. Azizi, F. Ebrahimi, E. Aakbari, F. Aryanasab, M.R. Saidi, Synlett (2007) 2797–2800.
[35] N. Azizi, A. Khajeh-Amiri, H. Ghafuri, M. Bolourtchian, M.R. Saidi, Synlett (2009)
2245–2248.
[1] M. Lancaster, Green Chemistry: An Introductory Text, Royal Society of Chemistry,
Cambridge, 2002.
[2] A.S. Matlack, Introduction to Green Chemistry, Marcel Dekker, New York, 2001.
[3] P.T. Anastas, J.C. Warner, Green Chemistry: Theory and Practice, Oxford University
Press, Oxford, 1998.
[4] A.P. Abbott, G. Capper, D.L. Davies, R.K. Rasheed, V. Tambyrajah, Chem. Commun. 7
(2003) 70–71.
[5] Q. Zhang, K.D.O. Vigier, S. Royer, F. Jérôme, Chem. Soc. Rev. 41 (2012) 7108–7146.
[6] P. Wang, F.-P. Ma, Z.-H. Zhang, J. Mol. Liq. 198 (2014) 259–262.
[7] A. Hayyan, F.S. Mjalli, M.A. Hashim, M. Hayyan, I.M. AlNashef, S.M. Al-Zahrani, M.A.
Al-Saadi, Bioresour. Technol. 102 (2011) 9564–9570.
[36] N. Azizi, Z. Manocheri, Res. Chem. Intermed. 38 (2012) 1495–1500.
[8] A. Hayyan, F.S. Mjalli, I.M. AlNashef, T. Al-Wahaibi, Y.M. Al-Wahaibi, M.A. Hashim,
Thermochim. Acta 541 (2012) 70–75.