Choline chloride based eutectic solvents: Magical catalytic system for carbon-carbon bond formation in the rapid synthesis of β-hydroxy functionalized derivatives

Article abstract of DOI:10.1016/j.catcom.2012.03.021

Significant β-hydroxy functionalized derivatives including nitroaldols, β-hydroxy nitriles and β-hydroxy carboxylic acids were successfully prepared, for the first time, by catalytic use of deep eutectic solvents (DES). This paper explores the versatility

Full text of DOI:10.1016/j.catcom.2012.03.021

Catalysis Communications 24 (2012) 70–74
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Catalysis Communications
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Short Communication
Choline chloride based eutectic solvents: Magical catalytic system for carbon–carbon
bond formation in the rapid synthesis of β-hydroxy functionalized derivatives
⁎
Balvant Shyam Singh, Hyacintha Rennet Lobo, Ganapati Subray Shankarling
Department of Dyestuff Technology, Institute of Chemical Technology, N. P. Marg, Matunga, Mumbai, 400019, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Significant β-hydroxy functionalized derivatives including nitroaldols, β-hydroxy nitriles and β-hydroxy carbox-
ylic acids were successfully prepared, for the first time, by catalytic use of deep eutectic solvents (DES). This paper
explores the versatility and effectiveness of DES as catalyst in three different carbon–carbon bond formation reac-
tions. The uniqueness of this catalyst lies in its simplicity since it avoids expensive catalysts and multi-step synthe-
sis as reported in literature. The compounds, which are potent intermediates for innumerable useful products,
were synthesized in excellent yields within very short reaction times. The catalyst prepared from choline chloride
and urea, is biodegradable, non-toxic, cost-effective and recyclable.
Received 29 December 2011
Received in revised form 27 February 2012
Accepted 14 March 2012
Available online 24 March 2012
Keywords:
Nitroaldol
β-Hydroxynitriles
β-Hydroxycarboxylic acid
Deep eutectic solvent
© 2012 Elsevier B.V. All rights reserved.
1. Introduction
these systems with milder one that will not only be environmentally
benign but would be as effective as the above stated reagents.
β-Hydroxy functionalized derivatives prepared by classical carbon–
carbon bond forming reaction could be versatile intermediates for the
preparation of variety of compounds like nitroalkenes, 2-aminoalcohols,
2-nitroketones [1], etc. A short diagrammatic summary is shown in Fig. 1.
One of the extremely significant β-hydroxy functionalized com-
pound includes nitroaldol or β-hydroxy nitroalkanols that have found
increasing applications in pharmaceutical industries [2], synthesis of
natural products [3], synthesis of biological compounds including fungi-
cides, insecticides [4,5] certain antibiotics [6], polyaminoalcohols and
polyhydroxylated amides [7].
Nitroaldols can be extensively prepared by Henry reaction in pres-
ence of bases [4] such as sodium methoxide, sodium hydroxide,
triethylamine, LDA and butyl lithium. However, the basic reagents
often lead to side reactions such as aldol condensation, Cannizzaro
reaction and elimination. Apart from bases, some other reports ex-
plain use of lanthanide [8] and rhodium based metal complexes [9],
enzymatic catalysts [10], chloroaluminate ionic liquids as reaction
media [11], microwave technique [12] etc. These methods either in-
volve difficult catalyst preparation, longer reaction time, expensive
catalysts or higher equivalents of nitroalkylating agent.
Deep eutectic mixtures belong to an interesting set of eutectics
which have been recently explored in important organic reac-
tions [13,14]. Deep eutectic solvents (DES) are a special type of
ionic solvent composed of quaternary salt like choline chloride
(CHCl) and neutral molecules like urea, glycerol, etc. The melting
point of such mixtures is much lower than either of the individual
components [15]. Although they are somewhat similar in features to
conventional ionic liquids, but their advantages can be justified through
the major differences that lie between them. These eutectics are cost-
effective, non-toxic and easy to store than the most ionic liquids
owing to the fact that choline is a naturally occurring bio-compatible
compound and choline chloride is also commercially produced on a
large scale as a chicken feed additive.
In addition to being eco-friendly, another advantage of using deep
eutectic of choline chloride and urea is the ability of the urea component
to catalyze nitroaldol reactions via hydrogen bond catalysis [16]. Several
urea [17] and thiourea [18] based catalyst have been investigated in the
past for such reactions owing to their efficient hydrogen bonding ac-
tivity. However, we have limited our reaction to urea based DES since
choline chloride:thiourea based DES (freezing point 69 °C) is not liquid
[19] at our reaction temperature (room temperature).
Also, the toxic reagents, harsh bases, volatile organic solvents have
negative effects on the environment. Hence, it is important to replace
Therefore, we explored the catalytic activity of deep eutectic solvent
(CHCl:Urea) in methanol media for rapid and eco-friendly synthesis of
nitroaldol compounds. Its catalytic role is observed from the fact that
the reaction does not initiate at all in methanol but rapidly progresses
once DES catalyst is added to it.
⁎
Corresponding author at: Department of Dyestuff Technology, Institute of Chemical
Technology, N. P. Marg, Matunga, Mumbai, 400019, India. Tel.: +91 22 33612708;
fax: +91 22 33611020.
E-mail addresses: gsshankarling@gmail.com, gs.shankarling@ictmumbai.edu.in
(G.S. Shankarling).
We further extended the methodology towards synthesis of other
important β-hydroxy derivatives like β-hydroxynitriles and
1566-7367/$ – see front matter © 2012 Elsevier B.V. All rights reserved.
doi:10.1016/j.catcom.2012.03.021

B.S. Singh et al. / Catalysis Communications 24 (2012) 70–74
71
NO2
Table 1
Optimization of catalyst/organic solvent in nitroaldol reaction.a
O
R
NO2
Sr. no.
1.
Catalyst
Organic solvent
Yieldsb (%)
R
–
Hexane
–
10% DES
–
Hexane
Toluene
Toluene
Methanol
Methanol
Methanol
Methanol
Methanol
30
–
OH
NH2
2.
3.
NO
2
10% DES
–
55
–
R
R
10% DES
15% DES
20% DES
25% DES
70
80
95
94
O
4.
5.
6.
R
OH
a
Reaction conditions: 4-Nitrobenzaldehyde (1.0 eq) and nitromethane (5.0 eq), 20%
DES in MeOH (10 vol), room temperature, reaction time=8 min.
R
b
Isolated yields.
Fig. 1. Versatile applications of nitroaldol compounds in organic synthesis.
2. Experimental
2.1. General
β-hydroxy carboxylic acids. Such molecules are important building
blocks in most natural product synthesis [20] especially because
groups like nitrile and acids provide rapid access to much useful
functionalities and also nitriles are much stable towards handling
[21].
FT-IR spectrums were recorded on a Bomem Hartmann and Braun
MB-Series FT-IR spectrometer. 1H NMR spectrums were recorded on
Varian 300 MHz mercury plus spectrometer. Mass spectral data were
obtained with a micromass-Q-TOF (YA105) spectrometer. Common re-
agent grade chemicals were procured from M/s S.D. Fine Chemical Ltd.
India and were used without further purification.
Conventionally, β-hydroxynitriles are synthesized by deproton-
ation of α proton of acetonitrile or benzyl nitrile with equivalent
amount of strong alkali metal base [22]. Some other reports show
catalytic use of quaternary ammonium salts like TBAF [23] or use
modified form of acetonitrile like trimethylsilylacetonitrile in pres-
ence of Lewis base catalysts [24]. However, these methods suffer
from demerits like either low yield [22], requirement of harshly
basic conditions, multi-step procedures, side reactions like oxida-
tion of aldehydes to acids [23], etc. β-Hydroxy carboxylic acids are
also difficult to prepare directly via aldol condensation owing to dif-
ficult deprotonation of α proton due to carboxylic acid group. Some
reports suggest use of Mukaiyama aldol reactions [25] but cannot
prepare β-hydroxy carboxylic derivatives, of reactants like 4-
nitrobenzaldehyde by direct aldol reaction with acetic acid. We
have devised a method by which such derivatives are prepared via
catalytic application of deep eutectic solvents not only in single
step but also without use of complicated procedures or reagents
and in an environmentally benign manner.
Spectral data for representative compounds:
2-Nitro-1-(4-nitrophenyl)ethanol (3b). IR(KBr): νmax cm−1 3508,
2921, 2851, 1552, 1515, 1416, 1379,1347, 1080, and 855 cm−1; 1H
NMR (300 MHz; CDCl3; Me4Si) δppm 8.31–8.27 (m, 2H), 7.65–
7.63 (m, 2H), 5.62 (m, 1H), 4.65–4.55 (m, 2H), 3.09 (d, 1H); 13C
NMR (100 MHz, CDCl3) 148.0, 145.0, 126.9, 124.1, 80.6, and 69.9;
m/z (EI) 213.1(M+1); C8H7N2O5 calculated m/z: 212.04.
3-Hydroxy-3-(3′-nitrophenyl)propanenitrile (5). IR(KBr): νmax
;
cm−1 3504, 2251, 1665, 1598, 1547, 1381, 1104, 855 cm−1 1H
NMR (300 MHz; CDCl3; Me4Si) δppm 8.30–8.20 (m, 2H), 7.76–
7.60 (m, 2H), 5.18 (s, 1H), 3.09 (s, 1H), 2.81–2.83 (m, 2H); 13C
NMR (300 MHz, CDCl3) 148.4, 143.4, 130.7, 129.1, 123.5, 120.2,
116.7, 69.9, 29.2; m/z (EI) 193.1(M+1); C8H7N2O5 calculated m/z:
192.04.
3-Hydroxy-3-(4-nitrophenyl)propanoic acid (7). IR(KBr): νmax
cm−1 3457, 3307, 1650, 1639, 1599, 1550, 1346,1275, 1107,
854 cm−1 1H NMR (300 MHz; CDCl3; Me4Si) δppm 11.2 (s, IH)
;
Hence, our present study highlights the first catalytic use of deep
eutectics in successful synthesis of β-hydroxy functionalized deriv-
atives. In addition, optimization and recycling studies are also
discussed.
8.30–8.25 (m, 2H), 7.75–7.60 (m, 2H), 5.31 (m, 1H), 2.81 (m,
Scheme 1. Synthesis of β-hydroxy derivatives using deep eutectic solvent as a catalyst.

72
B.S. Singh et al. / Catalysis Communications 24 (2012) 70–74
Table 2
Nitroaldol reaction of nitromethane with functionalized aromatic aldehydes catalyzed by deep eutectic solvents in methanol.
Entry
no.
Reactants
Productsa
Reaction
time
(min)
Yieldb
(%)
Physical constants
Found
Literature
3a
3b
30
83
B.P.: 140
142–143 [27]
CHO
OH
NO2
5
95
86
83–85 [28]
75–77 [28]
OH
CHO
NO2
O2N
O2N
3c
7
93
74–76
OH
CHO
NO2
NO2
O
NO2
3 d
3e
8
89
86
B.P.: 128
130–131 [29]
35–37 [28]
OH
CHO
O
NO2
12
40
CHO
OH
NO2
Cl
Cl
3f
9
90
88
66
68 [30]
N
NO2
N
CHO
OH
OH
3 g
10
120
116–117 [31]
CHO
NO2
N
N
3 h
35
60
78
69
62
59–61 [32]
HO
CHO
NO2
3i
112
110–111 [33]
OH
CHO
NO2
H3C
N
H3C
N
CH3
CH3
a
Reaction conditions: Aromatic aldehyde (1.0 eq) and nitromethane (5.0 eq), 20% DES in MeOH (10 vol), room temperature.
Isolated yields.
b
2H), 2.74 (m, 1H); 13C NMR (300 MHz, CDCl3) 171.3, 151.1, 147.3,
127.0, 123.3, 68.2, 43.4; m/z (EI) 212.1(M+1); C8H7N2O5 calcu-
lated m/z: 211.04.
used for reactions without any purification. This method gives deep
eutectic solvent with 100% atom economy without any other by-
product formation (Scheme 1).
2.2. Preparation of deep eutectic solvent (DES)
2.3. Typical experimental procedure
In this study, deep eutectic solvents (DES) were synthesized
according to the procedures reported in the literature [26].
2.3.1. Deep eutectic solvent catalyzed reaction for synthesis of nitroaldol
derivatives
The preparation involved reaction of choline chloride (1 mol) with
urea (2 mol) at 74 °C till a clear solution was obtained which was
Aromatic aldehyde (1.0 eq) and nitromethane (5.0 eq) were
mixed together in a 50 mL round bottom flask. This was followed by

B.S. Singh et al. / Catalysis Communications 24 (2012) 70–74
73
Table 3
Optimization for quantity of DES catalyst in synthesis of β-hydroxynitriles and β-hydroxy carboxylic acids.
Compd.
no.
Reactant
Product
Catalyst
Solvent
Yieldsc
(%)
Melting point
Found
Literature
5a
–
Methanol
Methanol
Methanol
Methanol
Methanol
–
90
86–89 [34]
OH
CHO
10% DES
20% DES
30% DES
40% DES
80
85
95
94
CN
NO2
NO2
7b
–
Methanol
Methanol
Methanol
Methanol
Methanol
–
108–110
112–114 [34]
CHO
OH
10% DES
20% DES
30% DES
40% DES
77
83
90
91
COOH
O2N
O2N
a
Reaction conditions: 3-Nitrobenzaldehyde (1.0 eq) and acetonitrile (5.0 eq), DES in MeOH (10 vol), room temperature, reaction time=2 h.
Reaction conditions: 4-Nitrobenzaldehyde (1.0 eq) and acetic acid (3.0 eq), DES in MeOH (10 vol), room temperature, reaction time=3 h.
Isolated yields.
b
c
addition of catalytic system containing 20% DES catalyst in methanol.
DES. However, the progress in reaction was observed soon after addition
of DES. This highlights the catalytic effect of DES in this reaction. Also, the
catalytic system of DES–methanol gave best results. Hence, the reaction
was also checked to know the optimum amount of DES required for the
reaction. It was found that 20% DES in methanol is the most effective
combination.
The reaction mixture was then stirred at room temperature for an ap-
propriate time (Table 2). The progress of the reaction was monitored
by TLC. The reaction mixture was then extracted with ethyl acetate
and the DES layer was separated off. The ethyl acetate layer was
washed with water and concentrated. The residue was chromato-
graphed on silica gel column (hexane: ethyl acetate=9:1) to afford
pure nitroaldol derivatives.
3.2. Nitroaldol reaction of nitromethane with functionalized aromatic
aldehydes
2.3.2. Deep eutectic solvent catalyzed reaction for synthesis of
β-hydroxynitriles [3-hydroxy-3-(3-nitrophenyl)propanenitrile]
3-Nitrobenzaldehyde (1.0 eq) and acetonitrile (5.0 eq) were
mixed together in a 50 mL round bottom flask. This was followed by ad-
dition of catalytic system containing DES catalyst (quantity optimized in
Table 3) in methanol. The reaction mixture was stirred at room temper-
ature for 2 h. The progress of the reaction was monitored by TLC. The re-
action mixture was then extracted with ethyl acetate and the DES layer
was separated off. The ethyl acetate layer was washed with water and
concentrated. The residue was chromatographed on silica gel column
(hexane: ethyl acetate=8:2), to afford pure β-hydroxynitrile
derivative.
Various functionalized aromatic aldehydes including heterocylcic
systems were reacted with nitromethane in the presence of DES–
methanol mixture as summarized in Table 2. The reaction proceeded
very fast in cases of electron deactivating groups. However, electron
activating systems gave results not so fast but within 1 h. The method
gave extremely interesting results in terms of yield as well as time as
compared to many of the reported methods that proceeded in
24–50 h. One more interesting aspect is that this method used only
5 eq of nitromethane as against conventional methods that use
more 20–30 eq of nitromethane.
3.3. Extension of the methodology towards synthesis of other β-hydroxy
2.3.3. Deep eutectic solvent catalyzed reaction for synthesis of β-hydroxy
carboxylic acids [3-hydroxy-3-(4-nitrophenyl)propanoic acid]
4-Nitrobenzaldehyde (1.0 eq) and acetic acid (3.0 eq) were mixed
together in a 50 mL round bottom flask. This was followed by addition
of catalytic system containing DES catalyst (quantity optimized in
Table 3) in methanol. The reaction mixture was stirred at room tem-
perature for 3 h. The completion of the reaction was monitored by
TLC. Water was added to the reaction mass which resulted in forma-
tion of precipitate. The precipitate was filtered off and the filtrate was
subjected to evaporation of water/methanol under vacuum to obtain
DES. The solid product was chromatographed on silica gel column (hex-
ane: ethyl acetate=8:2 to 5:5), to afford pure β-hydroxy carboxylic
derivative.
derivatives
To explore the versatility of the DES catalyst towards other impor-
tant β-hydroxy compounds, we performed the reaction of nitrobenzal-
dehyde with acetonitrile or acetic acid to obtain β-hydroxynitriles and
β-hydroxy carboxylic acids (Table 3). To our surprise, we got extremely
3. Results and discussion
3.1. Influence of catalyst and solvent on nitroaldol reaction
In order to understand the importance of deep eutectic solvent in
nitroaldol reaction, the optimization studies were performed as depicted
in Table 1. For this purpose, the reaction of 4-nitrobenzaldehyde with ni-
tromethane was taken as standard. Initially, the reaction was conducted
in the presence and the absence of DES in different organic solvents. It
was observed that the reaction does not proceed at all in absence of
Fig. 2. Recyclability tests of DES catalyst in reaction of 4-nitrobenzaldehyde with
nitromethane.

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B.S. Singh et al. / Catalysis Communications 24 (2012) 70–74
Scheme 2. Proposed mechanism for nitroaldol reaction in DES-catalyzed medium.
better results in both the cases than reported literature that use multi-
step synthesis and expensive reagents. Once again, the quantity of
DES was optimized to know the effective quantity.
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4. Conclusion
In summary, we have developed a simple, green and efficient cat-
alytic system using deep eutectic mixtures for rapid synthesis of
nitroaldol compounds. The reaction gave excellent yields in very
short reaction times. The reaction was also extended towards synthe-
sis of β-hydroxynitriles and β-hydroxy carboxylic acids that showed a
marked improvement over reported methods. To the best of our
knowledge, this is the first report of a catalyst that can effectively cata-
lyze these three important C\C bond formation reactions. In addition to
having good catalytic potency, the DES catalyst could also be easily
recycled and reused at least up to four runs without any considerable
loss in yields.
Acknowledgments
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Authors are thankful to UGC-CAS for providing financial assistance
and to the Institute of Chemical Technology, SAIF IIT-Bombay for re-
cording IR, 1H NMR,13C NMR and Mass spectra.