Choline chloride based deep eutectic solvent as an efficient solvent for the benzylation of phenols

Article abstract of DOI:10.1016/j.tetlet.2014.11.053

Deep eutectic solvents (such as the combination of urea and choline chloride) are found to be promising solvent and phase-transfer-media for benzylation of phenol. These methods avoided the complexity of multiple alkylations giving selectively O-alkylated aromatic products. Good to excellent yields of the corresponding benzyl phenyl ether were obtained. The non-toxic, biodegradable, inexpensive, and recyclable nature of DES make this protocol green and cost-effective.

Full text of DOI:10.1016/j.tetlet.2014.11.053

Accepted Manuscript
Choline chloride based deep eutectic solvent as an efficient solvent for the ben-
zylation of phenols
Abhilash S. Singh, Suresh S. Shendage, Jayashree M. Nagarkar
PII:
S0040-4039(14)01946-7
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.11.053
TETL 45437
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
2 October 2014
10 November 2014
13 November 2014
Please cite this article as: Singh, A.S., Shendage, S.S., Nagarkar, J.M., Choline chloride based deep eutectic solvent
as an efficient solvent for the benzylation of phenols, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/
j.tetlet.2014.11.053
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Choline chloride based deep eutectic solvent
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Abhilash S.Singh, Suresh S. Shendage, Jayashree M. Nagarkar*

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Choline chloride based deep eutectic solvent as an efficient solvent for the
benzylation of phenols
Abhilash S Singha , Suresh S Shendagea and Jayashree M Nagarkara
aDepartment of Chemistry, Institute of Chemical Technology (Deemed), N. M. Parekh Marg, Matunga, Mumbai – 400 019, India.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Deep eutectic solvents (such as the combination of urea and choline chloride) are found to be
promising solvent and phase-transfer-media for benzylation of phenol. These methods avoided
the complexity of multiple alkylations giving selectively O-alkylated aromatic products. Good to
excellent yields of the corresponding benzyl phenyl ether were obtained. The non-toxic,
biodegradable, inexpensive and recyclable nature of DES makes this protocol green and cost-
effective.
Available online
Keywords:
Benzylation
Phenols
2009 Elsevier Ltd. All rights reserved.
O-alkylation
Deep eutectic solvent
Benzylation of phenol is an important synthesis reaction and
was first published in 1974 by McKillop using dichloromethane
as a solvent.1 These aromatic ethers are widely used in perfume,
flavor, agriculture, and pharmaceutical industries. A variety of
procedures have been developed in which various catalysts have
been utilized some of these includes the use of crown ethers,2
phase-transfer catalysis (PTC),3 other methodologies includes use
of ionic liquids,4 microwave method etc.5 However, most of the
commonly used methods require costly alkali metal hydrides and
phase-transfer catalysis conditions. Besides these the other
reported methods for benzylation of phenols were carried out in
volatile, toxic and flammable organic solvents such as
acetonitrile, dichloromethane, 2-methyltetrahydrofuran and
alcohols. The other polar aprotic solvents such as DMSO and
DMF were also employed. However, extensive C-alkylation
takes place in the presence of water and trifluoroethanol.6-7
Hence, these factors greatly limit the scope of selective
procedures for O-alkylation of aromatic phenols.
a greener solvent called DES (Deep Eutectic Solvents) was
introduced. DES is similar to ILs which forms a eutectic by
mixing two components with a melting point much lower than
either of the individual components. DES is mainly prepared by
mixing ammonium salt such as choline chloride with the
hydrogen-bond donor like urea, or Lewis acids.10 DES possesses
properties such as nontoxicity, biodegradability, low price and
easy availability. DES is widely used in electrochemical
applications and is devoted as promising solvents for catalysis.11
They have also received substantial attention in the area of
enzymatic synthesis as enzymes are highly stable and more active
in DES compared to other solvents.12 At the same time, there has
been relatively little work explored on the ability of DES to serve
as catalyst and solvents in the field of synthetic organic
chemistry.13 With our continued interest in the synthesis and
application of DES,14 herein we wish to report benzylation of
phenols using deep eutectic solvent of choline chloride and urea.
Initially the reaction of benzyl bromide and phenol was
selected as model reaction. The reactions were carried at different
temperatures and the best yield was obtained at 80°C (Table 1,
entries 1-4). It was found that the reaction proceeded smoothly in
ChCl:urea based DES to afford the anticipated product in 96%
yield after 2 h (Table 1, entry 3). Lower yield was obtained in
other biodegradable media such as ChCl:glycerol and
ChCl:ZnCl2 (Table 1, entry 5-6). The reaction was also
investigated in the presence of various inorganic bases such as
NaOH, K2CO3 and K3PO4 (Table 1, entries 7-9). Among all the
bases, the KOH gave the highest yield of the desired product. No
benzylation of phenol was observed when the reaction was
However, in most of the above described protocols it is very
difficult to separate the catalyst and product from the reaction
mixture. Therefore the development of alternative solvents which
is environmentally benign, cheap, inexpensive, easily available
and non-toxic is highly desirable. With the view of green
chemistry concern in synthetic organic chemistry, new ‘‘green
solvents’’ have been introduced.8 In this context, Ionic liquids
(ILs) have appeared as a new class of promising solvents.
However, recent studies have shown that there are several ILs
which have hazardous toxicity and possess very poor
biodegradability.9 To overcome the problem associated with ILs
———
 Corresponding author. Tel.: +0-000-000-0000; fax: +0-000-000-0000; e-mail: author@university.edu

2
Tetrahedron
studied in the absence of DES, demonstrating the necessity of
10
11
12
13
14
15
16
17
18
19
20
94
95
93
92
75
82
81
85
87
90
90
DES under given reaction conditions (Table 1, entry 10).
Table 1. Optimization of reaction conditionsa
Entry
DES
Temp.(°C)
Base
Yieldb (%)
1
ChCl:urea
ChCl:urea
ChCl:urea
ChCl:urea
Chcl:glycerol
ChCl:ZnCl2
ChCl:urea
ChCl:urea
ChCl:urea
-
40
60
80
100
80
80
80
80
80
80
KOH
KOH
KOH
KOH
KOH
KOH
K2CO3
K3PO4
NaOH
KOH
46
75
96
97
84
67
88
84
94
N.R
2
3
4
5
6
7
8
9
10c
aReaction condition: Phenol (1.0 mmol), benzyl bromide (1.2 equiv), DES
(1.0 mL), base (2.0 equiv), 2 h and Temperature (80° C)
bIsolated yields
cWithout DES
Table 2. Benzylation of phenols with benzyl bromide by
using deep eutectic solvent (choline chloride: urea)a
aReaction conditions: phenol (1.0 mmol), benzyl bromide (1.2 equiv), DES
(1.0 mL) and base (2.0 equiv), 2h, Temperature (80° C)
Entry
1
Benzyl
Phenol
Product
Yieldb(%)
96
bIsolated yields
bromide
With the optimized conditions at hand, the DES-catalyzed
reactions were further explored for the substrate scope of
different aromatic phenols and the results were summarized in
table 2.15 Structurally diverse phenols with different functional
groups such as methyl, methoxy, chloro, bromo, tertiary butyl,
acyl, and trifluoromethyl groups underwent benzylation with
various aromatic bromides under mild reaction conditions and the
product were isolated in good to excellent yield. The highest
yield of the desired product was observed for the sterically
hindered substrates (Table 2, entries 2-4). Moderate to good yield
were obtained for electron-donating substituent on the aromatic
ring (Table 2, entries 5-8). The deactivated phenols were found to
be more active for O-alkylation (Table 2, entries 9-13). The
etherification products of naphthol and heterocycle phenol were
also studied and moderate yields was obtained (Table 2, entries
14-15).
2
3
4
5
6
7
8
9
95
90
90
80
84
85
89
95
The study was further continued using different substituents
on the phenyl ring of benzyl bromide. Different functional group
has little effect at the aryl moiety of benzyl bromides. It was
observed that the benzyl bromides bearing electron-withdrawing
groups produced the corresponding products in slightly higher
yields electron-donating groups. Good to excellent yield were
observed for different electronic substituents on benzyl bromide
(Table 2, entries 16-20). Hence an electron-withdrawing group
favours the formation of the benzyl phenyl ethers, in contrast to
those with electron-donating groups.

3
Recyclability of the DES was examined for the benzylation of
phenol using benzyl bromide under optimized reaction
parameters. After completion, the reaction mixture was cooled to
room temperature and water (2mL) was added. The product was
extracted with ethyl acetate and DES was dried was under
vacuum at 80 °C. The reusability of the deep eutectic solvent was
tested for five consecutive cycles but a decrease in the catalytic
activity of DES was observed after the fourth cycle (Table 3).
References and notes
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1379-1382.
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3. (a) Srivastava, P.; Srivastava, R. Tetrahedron Lett. 2007, 48,
4489-4493; (b) Benaglia, M.; Cinquini, M.; Cozzi, F.; Tocco, G.
Tetrahedron Lett. 2002, 43, 3391-3393; (c) Albanese, D.;
Benaglia, M.; Landini, D.; Maia, A.; Lupi, V.; Penso, M. Ind. Eng.
Chem. Res. 2002, 41, 4928-4935; (d) Tamami, B.; Ghasemi, S. J.
Iran. Chern. Soc. 2008, 5, 26-32; (e) Chen, Z. X.; Xu, G. Y.;
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Tian, H.; Yu, A.; Chang, J.; Wu, Y. Tetrahedron 2014, 70, 2669-
2673.
Table 3. Recyclability of DES solventa
Entry
Recycling
Yieldb (%)
1
2
3
4
5
1st
2nd
3rd
4th
5th
94
93
90
88
72
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aReaction condition: Phenol (1.0 mmol), benzyl bromide (1.2 equiv), DES
(1.0 mL), base (2.0 equiv), 2 h and Temperature (80° C)
bIsolated yields
Table 4. Comparison of different methodology for
benzylation of phenols with benzyl bromide
Entry
External Solvent
Catalyst
Time(h)/
Yield
(%)
Reusa Ref.
-bility
Temp.(°C)
1
2
-
DES
2 /(80)
2 /(80)
96

Present
work
-
[bmIm]
OH
92

4b
6. Kornblum, N.; Berrigan, P. J.; Le Noble, W. J. J. Am. Chem. Soc.
1963, 85, 1141-1147.
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Chem. Soc. Rev. 2008, 37, 123-150.
3
4
CS2CO3 CH3CN
5/(80)
1/(30)
92
89


5a
3b
PEG-
DCM
Water
Ammon
ium salt
10. Abbott, A.P, Davies, D. L.; Capper, G.; Rasheed, R. K.;
Tambyrajah, V.; US Patent 7,183, 433, 2007.
5
TBAB
2/(28)
97

3h
11. (a) Jhong, H. R.; Wong, D. S. H.; Wan, C. C.; Wang, Y. Y.; Wei,
T. C.; Electrochem. Commun. 2009, 11, 209-211 (b) Abbott, A.
P.; Capper, G.; McKenzie, K. J.; Ryder, K. S.; J. Electroanal.
Chem. 2007, 599, 288-294.
12. (a) Gorke, J. T.; Srienc, F.; Kazlauskas, R. J. Chem. Commun.
2008, 1235-1237; (b) Zhao, H.; Baker, G. A.; Holmes, S. Org.
Biomol. Chem. 2011, 9, 1908-19016.
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2005, 7, 705-707; (b) Morales, R. C.; Tambyrajah, V; Jenkins, P.
R.; Davies, D. L.; Abbott, A. P. Chem. Commun. 2004, 2, 158-
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462.
The efficacy of the DES for benzylation of phenols with
benzyl bromide was compared with some earlier reported
catalysts as demonstrated in Table 4. Even though TBAB gives
better result at lower temperature it suffers from the drawbacks of
reusability of catalyst and solvent which is desirable from
economic and environmental point of view (Table 4, entry 5).
In conclusion, the greener protocol described in this paper
offer a new scope for benzylation of various aromatic phenols
using the deep eutectic mixture as green catalyst/solvent. The
DES was used as the catalyst and solvent there by giving good to
excellent yield of the desired product. This protocol offers
advantages with regard to high yields of products and the
greenness of procedure as no external hazardous organic solvents
and toxic catalysts was used. The DES is eco-friendly, safe,
biodegradable, non-toxic, inexpensive, easily available and
recyclable solvent. Hence this protocol offers marked
improvements in terms of simplicity, recyclability and procedure
for the preparation of benzyl phenyl ethers.
14. Patil, U. B.; Singh, A. S.; Nagarkar, J. M.; RSC Advances, 2014, 4,
1102-1106.
15. Representative reaction conditions: Phenol (0.5 mmol), benzyl
bromide (1.2 mmol) and KOH (2.0 mmol) was added to the DES
(1mL) and heated at temperature (80° C) for 2hr. After cooling to
room temperature water was added and the product was extracted
with ethyl acetate (1x 3 mL) and analyzed by GC-MS after the
addition of hexamethylbenzene as an internal standard. The
product was purified using column chromatography on silica gel
(hexane/EtOAc :: 99:1). The pure product was characterized by 1H
NMR and 13C NMR.
Acknowledgments
The author gratefully acknowledges the financial assistance
from the Green Tech. U.P.E. Government of India.