4-Imidazol-1-yl-butane-1-sulfonic acid ionic liquid: Synthesis, structural analysis, physical properties and catalytic application as dual solvent-catalyst

Article abstract of DOI:10.1080/10426507.2018.1487426

4-Imidazol-1-yl-butane-1-sulfonic acid (ImBu-SO₃H) has been successfully synthetized and fully characterized by FT-IR and high-resolution NMR spectroscopy (¹H, ¹³C). The “plausible” alternative structures of ImBu-SO₃H were discussed on the basis of its NMR data. The ionic liquid showed interesting dual solvent-catalyst property, which was studied experimentally for the acetylation of a variety of functionalized alcohols, phenols, thiols, amines and α-tocopherol (α-CTP) as the most active form of vitamin E with acetic anhydride and which provided good yields within a short reaction time. ImBu-SO₃H was successfully recycled by product extraction with an average recovered yield of 82% for 5 subsequent runs. The catalytic activity of the recycled ImBu-SO₃H showed almost no loss even after five consecutive runs.

Full text of DOI:10.1080/10426507.2018.1487426

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: http://www.tandfonline.com/loi/gpss20
4-imidazol-1-yl-butane-1-sulfonic acid ionic liquid:
Synthesis, structural analysis, physical properties
and catalytic application as dual solvent-catalyst
Taraneh Mihankhah, Mohd Rafie Johan, Joon Ching Juan & Nader Ghafari
Khaligh
To cite this article: Taraneh Mihankhah, Mohd Rafie Johan, Joon Ching Juan & Nader Ghafari
Khaligh (2018): 4-imidazol-1-yl-butane-1-sulfonic acid ionic liquid: Synthesis, structural analysis,
physical properties and catalytic application as dual solvent-catalyst, Phosphorus, Sulfur, and
Silicon and the Related Elements, DOI: 10.1080/10426507.2018.1487426
To link to this article: https://doi.org/10.1080/10426507.2018.1487426
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Jul 2018.
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4-imidazol-1-yl-butane-1-sulfonic acid ionic liquid: Synthesis, structural analysis,
physical properties and catalytic application as dual solvent-catalyst
Taraneh Mihankhaha, Mohd Rafie Johanb, Juan Joon Chingb, Nader Ghafari Khalighb,*
aFaculty of Engineering, Civil Engineering Department, Kharazmi University, Tehran, Iran
bNanotechnology and Catalysis Research Center, 3rd Floor, Block A, Institute of Postgraduate Studies, University of Malaya, 50603 Kuala Lumpur, Malaysia
4-Imidazol-1-yl-butane-1-sulfonic acid (ImBu-SO3H) has been successfully synthetized and fully characterized by FT-IR and high-resolution NMR
spectroscopy (1H, 13C). The “plausible” alternative structures of ImBu-SO3H were discussed on the basis of its NMR data. The ionic liquid showed interesting
dual solvent-catalyst property, which was studied experimentally for the acetylation of a variety of functionalized alcohols, phenols, thiols, amines and α-
tocopherol (α-CTP) as the most active form of vitamin E with acetic anhydride and which provided good yields within a short reaction time. ImBu-SO3H was
successfully recycled by product extraction with an average recovered yield of 82% for 5 subsequent runs. The catalytic activity of the recycled ImBu-SO3H
showed almost no loss even after five consecutive runs.
Keywords:‎Liquid sulfonic acid catalyst; Dual solvent-catalyst activity; Acetylation; Vitamin E; Tocopherol
Introduction
The development of environmentally benign synthetic routes is strongly required due to the increasing environmental ‎concerns
of conventional chemical processes. Four main approaches have been widely considered for organic syntheses in a ‎sustainable
manner: the use of a green solvent instead of toxic and volatile solvents; performing the reaction under solvent-f‎ree conditions;
loading a catalytic amount of reagent instead of stoichiometric amounts, and utilizing enzymes and ‎organocatalysts.1-3
‎
The esterification of alcohols, phenols, thiols, and amines using acetic anhydride is one of the most important
transformations ‎in organic chemistry.4,5 These functional groups are needed to be ‎protected during the course of various
transformations in the preparation of polyfunctional molecules, such as nucleosides, ‎carbohydrates, steroids and natural
products.6,7 Therefore, a variety of strategies have been reported for the protection of these functional groups, including Lewis
and ‎Brǿnsted acid-base or ionic liquid catalysts in both homogeneous and heterogeneous systems.8-11 However, some of the
reported methods have disadvantages such as drastic ‎reaction conditions, expensive catalysts, long reaction times, limited substrate
scope, and low or moderate yields for some functional groups. Drawbacks such as hygroscopicity and thermal instability of ‎the
catalysts, use of halogen-containing solvents and catalysts, use of catalysts containing metal or transition-metal cation
were ‎observed in the published methods. Several green approaches were reported for the esterification both in terms of catalysts
and ‎solvents, such as the use of lipase/esterase-mediated catalysis in non-aqueous media and using functionalized ionic liquids as
dual solvent-‎catalysts.12-15 Lipase/esterase-mediated esterification has many advantages compared to acid/base catalysis, such as
the ‎mild reaction conditions, high selectivity, formation of less waste, option of solvent-free conditions and recycling of the
catalyst via ‎immobilization of the reactive centre onto a large surface area of a solid carrier.16 On the other hand, the particularly
important drawbacks ‎such as the instability of enzymes during industrial applications should be overcome.12-15 Therefore, the
introduction of the ‎efficient protocol for the protection of functional groups under mild conditions is highly desirable.‎

In recent years, an increasing number of applications of task-specific ionic liquids (TSILs) in organic synthesis have been
published, in which they are used ‎as solvent or catalyst.17,18 TSILs offer many unique properties including polarity, immiscibility
with many organic solvents ‎and possibly simplified separation of the products, low volatility, non flammability, high chemical and
thermal stability, negligible ‎vapor pressure, potential of recycling, and ability to dissolve a wide range of the materials.19 Most of
the ILs reported consist of organic ‎nitrogen-containing heterocyclic cations, such as imidazolium or pyridinium cations, and
inorganic anions.20-22 In general, the presence of ‎halogenated anions in ionic liquids limits their safety; therefore, research on green
ILs is an important topic.23‎
Brønsted acidic ionic liquids (BAILs) are one typical family of TSILs that have been successfully used as dual solvent-
‎catalysts in organic reactions with high conversion rates and selectivity.24-27 Introduction of SO3H-functionalized ‎imidazolium-
based ILs without halogen containing counter anions obviously enhances their safety.24
‎
In general the design and testing of new catalysts is a worthwhile goal and herein, we firstly synthesized 4-Imidazol-1-yl-
‎butane-1-sulfonic acid (ImBuSO3H) and characterized it by FT-IR and one-dimensional NMR spectroscopy (1H, 13C); the ‎detailed
NMR spectra and physical properties of this compound are discussed. To the best of our knowledge, no other
detailed ‎spectroscopic studies on the structure of ImBuSO3H have been published. The “plausible” alternative structures of ImBu-
SO3H are ‎discussed based on the NMR spectra. Also the catalytic activity of this new liquid acid was investigated for the
protection of a variety of alcohols, phenols, t‎hiols and amines using acetic anhydride as well as the production of α-tocopherol
(TCP) acetate (Scheme 1). The extraction of ‎ImBuSO3H was performed by water instead of an organic solvent and the ionic liquid
was reused for five subsequent runs with no loss in ‎catalytic activity.‎
O
S
O
S
O
Ethylbenzene
12 h,90 oC
+
O
HN
N
OH
N
N
O
ImBuSO3H
OAc
R X
H
ImBuSO3H
HOAc
Ac2O
+
+
R X
X = O, S or NH
R = Alkyl, aryl or heteroaryl
Scheme 1 Synthesis od 4-Imidazol-1-yl-butane-1-sulfonic acid (ImBu-SO3H) and its application for the acetylation of alcohols, phenols, amines, and thiols.
Results and Discussion
Synthesis and characterization of the new liquid acid
Imidazole reacted with 1,4-butane sultone in dry ethylbenzene to provide 4-Imidazol-1-yl-butane-1-‎sulfonic acid (ImBuSO3H)
in good yield (84 %). The product was then fully characterized by FTIR and NMR spectroscopy. ‎

Figure 1 FT-IR Spectrum of ImBuSO3H
The spectroscopic characterization of ImBuSO3H was accomplished by FT-IR spectroscopy (Figure 1). The vibrational
bands ‎with wavenumbers greater than 3000 cm−1 correspond to the stretching modes of the CIm-H, O-H and N-H bonds. The
observed ‎red shifting may be due to intramolecular N-H···O and O-H···N interactions in the liquid state, which weakens the O-H
bond ‎due to elongation of the O-H bond distance. The bands at 2925 and 2854 cm−1 are characteristic of C-H aromatic ‎stretching
vibrations. The vibration bands with wavenumbers in the range of 1630-1400 cm−1 represent mainly the C-C and C-N ‎bond
stretching within the imidazole ring and ring deformation modes. Among these vibrations, the bands in the region of 1455-‎1408
cm−1 may be assigned to the C=N functions and the band at 1579 cm−1 should correspond to the C=C stretching vibrations ‎of the
imidazole ring. The band typical for the C=N vibration of the central imidazole ring is located at 1548 cm−1.28-30
‎
The asymmetric and symmetric stretching and bending for S-O vibrations of the sulfonic acid group in ionic liquids were
observed ‎as strong bands at 1280-1116 and 587 cm−1.31 By comparison with S-OH bending frequencies in sulfuric acid and
other ‎sulfonic acids, the band at 1048 cm−1 was assigned to S-OH.32 The broad and strong band in the range of 3400-3200 ‎cm−1
arises from the hydroxyl group in ImBuSO3H.‎

Figure 2 1H and 13C NMR spectra of ImBuSO3H

1H NMR spectra of ImBuSO3H in DMSO-d6 gave sharp signals (Figure 2). The acidic hydrogen atom gave a broadened singlet
at 14.34 ppm, whose chemical shift indicates that the acidic hydrogen is not involved in strong N–H···N hydrogen bonds in
DMSO-d6. ImBuSO3H ‎contains a total of three aromatic protons attached to the imidazole ring and 8 aliphatic protons, which gave
a set of 3 well-resolved ‎signals in the range of 7.69 ppm to 9.24 ppm and a set of 4 well-resolved signals in the range of 4.22 - 1.51
ppm, respectively. ‎Three peaks appear at low field (9.08 - 9.24 ppm) and can be assigned to imidazole ring hydrogen viz. H-a. The
signals of the protons ‎H-b and H-c of the imidazole ring were observed at 7.69 ppm and 7.80 ppm as a singlet and a doublet with a
coupling constant of ‎1.8 Hz, respectively. The signal at (4.23 - 4.18 ppm) and can be assigned to the NCH2 protons since ‎their
3
multiplicities correspond to two triplets at 4.22 ppm and at 4.19 ppm with a same coupling constant J = 7.2 ‎Hz. Another signal
was observed at 2.52 - 2.48 ppm and can be assigned to the SCH2 protons since their multiplicities ‎correspond to two triplets at
3
1
2.51 ppm and 2.50 ppm with a same coupling constant J = 7.2 Hz. The ‎remaining two H NMR signals corresponding to the
remaining four protons display multiplet patterns, as expected for the ‎protons at the 2- and 3-position of the butane chain. The
presence of different structures was illustrated also from 13C NMR ‎experiment (Figure 2, Scheme 2), which displays one signal for
each of the 7 carbon atoms in the plausible structures (zwitterion ‎and molecule) of ImBuSO3H with chemical shifts ranging from
119.8 to 136.5 ppm and 22.2 to 50.9 for the imidazole ring and the b‎ utane chain, respectively. This confirms the presence of two
structures in liquid and indicates the zwitterion and molecular s‎tructure. The butane chain carbon atoms gave signals with chemical
shifts of 50.9 and 40.9 (C-1); 49.1 and 48.7 (C-4); 29.1 ‎and 22.2 (C-2 or C-3); and 29.0 and 22.16 (C-2 or C-3) ppm. The signals
corresponding to the CH imidazole ring carbon atoms can ‎be divided into three sections, which can be assigned to the C-a (134.8-
136.5 ppm), C-b and C-c (119.8-122.9 ppm) sets of carbon ‎atoms. An important result of the NMR spectroscopic analysis is that
1
there are three signals in the H NMR spectrum (9.25, 9.16 and 9.09 ‎ppm) and in the 13C NMR spectrum (136.5, 135.7 and 134.8
ppm) for C-a, which appear at low field as compared to the ‎remaining protons and carbon atoms of the imidazole ring. Also there
are two signals for H-b and H-c at 7.80 ppm as a doublet with a ‎coupling constant of 1.8 Hz and at 7.65 as a doublet with a
coupling constant of 1.2 Hz. In the 13C ‎NMR spectrum two signals appear for C-b and C-c at 122.9 and 120.4, and at 122.5 and
119.8 ppm, respectively. Fortunately, the NMR analysis of several ‎samples of ImBuSO3H provided additional information on the
molecular conformation of the title compound, which helped to ‎accomplish the structural characterization of the liquid.‎
O
S
O
S
O
S
N
OH
N
O
N
O
N
O
HN
O
N
H
O
Scheme 2 The equilibrium between the “plausible” alternative structures of 4-Imidazol-1-yl-butane-1-sulfonic acid (ImBu-‎SO3H).‎
Water is readily absorbed by hydrophilic ILs from the atmosphere during storage. Therefore, it is very important to know
the ‎exactly amount of water in the used ILs. A vacuum oven was used to dry the ILs before evaluation of their water
content. ‎Water content in the ILs was determined by Karl Fisher (KF) titration, using a Metrohm 831 KF coulometer in conditions
of ‎ambient humidity and room temperature. The conditions of temperature, pressure and drying time were 100 °C, 80 mbar, and
12 ‎h, respectively. The water content of ImBuSO3H was 0.11 ± 0.03 wt. %. The 0.01 molar solutions of ImBuSO3H were
prepared ‎from deionized water and the pH values were measured with a pH meter F-71, LAQUA-HORIBA Scientific at 27 ± 1 °C.

The ‎pH of 0.01 M aqueous solution of ImBuSO3H was 2.9 ± 0.1. The standard deviation was obtained from three
replicate ‎determinations on the three different days. ImBuSO3H is soluble in DMSO, DMF, water, methanol, and ethanol. It is
immiscible ‎with diethyl ether, ethyl acetate, and CH2Cl2. ‎
‎
and ‎environmentally benign methods for organic transformations.33,34 BAILs bearing an alkane-sulfonic acid group attached to ‎an
imidazolium or pyridinium cation play an important role for the esterification process due to the fact, that they possess
simultaneously the ‎proton acidity and the characteristic properties of an ionic liquid.35
‎
In order to optimize the reaction conditions, different parameters viz. the reaction time, the molar ratio of acetic anhydride ‎to 4-
chlorobenzyl alcohol, the amount of ImBuSO3H and the temperature were investigated (Table 1). The statistical analyses of ‎the 4-
chlorobenzyl acetate yield were the average of three experiments and the standard deviations (SD) were ‎calculated from three runs.‎
Due to the presence of the mass transfer limitations, the esterification reaction of ‎4-chlorobenzyl alcohol and Ac2O was carried
out slowly at the first ‎minutes in presence of ImBuSO3H. The acetylation conversion increases significantly during 2 - 5 min and
after 5 min it ‎increases slightly (monitored by GC-MS). It was proposed that the mass transfer rate was limited due to the viscosity
of ‎ImBuSO3H, therefore we mixed and stirred Ac2O and ImBuSO3H for 5 - 10 min before adding 4-chlorobenzyl alcohol to the
mixture. The viscosity of ‎ImBuSO3H was significantly reduced by this procedure.‎
The results showed that the yield was depended on the reaction time and the mole ratio of the reactants. As shown in Table 1,
the ‎highest yield was observed at 5 min and the conversion was slightly increased after 5 min. The yield of 4-chlorobenzyl acetate
increased when ‎the molar ratio of Ac2O to 4-chlorobenzyl alcohol was raised to 2 : 1. A higher molar ratio had no significant
effect on the yield of the desired product. The higher molar ratio of Ac2O to 4-chlorobenzyl alcohol can interfere with the
separation of the product.‎
Then, the acetylation of 4-chlorobenzyl alcohol was studied in the presence of different amounts of ImBuSO3H (Table 1). The
conversion ‎increased with increasing of the amount of ImBuSO3H up to 2 mL; nonetheless, a low yield was observed at loading
less than 1 ‎mL even after 1 h incubation at 50 °C in the dark and under the nitrogen atmosphere. The results showed a significant
reduction ‎in the yield when ImBuSO3H was loaded over 2 mL in optimum molar ratio of 2 : 1 within 30 min. It seems that the high
viscosity of ‎ImBuSO3H in a higher loading can cause limiting the mass transfer rate.‎
The temperature plays an important role in the esterification reaction because a higher temperature can decrease the ‎viscosity
of ImBuSO3H and result in a better mass transfer and higher yield at a shorter reaction time. As shown in Table 1, the ‎highest yield
was observed at 50 °C and the conversion was slightly increased at higher temperatures. An incomplete acetylation ‎and low yield
was observed at temperatures below 50 °C. It seems that ImBuSO3H can serve as a dehydrating agent to facilitate t‎he formation of
4-chlorobenzyl actate.3‎6,37

Table 1 Screening results of the different parameters for the acetylation of 4-chlorobenzyl alcohol in the presence of ImBuSO3H.
Parameter
Parameter value
Yielda (%)
23.2
61.4
62.1
62.4
74.6
92.2
92.5
92.6
68.6
92.5
82.9
38.5
78.8
92.5
92.6
SD
0.9
1.8
0.9
1.2
0.9
1.3
1.7
1.2
0.8
1.5
1.7
0.8
1.2
0.7
1.6
Reaction time (min)b
2
5
8
10
1:1
2:1
3:1
5:1
1
The mole ratio of Ac2O to 1ac
ImBuSO3H loading (mL)d
Reaction temperature (°C)e
2
3
r.t.
40
50
60
a Yield was determined through HPLC analysis, using an external standard.
b Reaction conditions: 4-chlorobenzyl alcohol (2 mmol), Ac2O (2 mmol), amount of ImBuSO3H (2 mL), temperature (50 °C).
c Reaction conditions: 4-chlorobenzyl alcohol (2 mmol), amount of ImBuSO3H (2 mL), temperature (50 °C), reaction time (5 min).
d Reaction conditions: 4-chlorobenzyl alcohol (2 mmol), Ac2O (4 mmol), temperature (50 °C), reaction time (5 min).
e Reaction condition: 4-chlorobenzyl alcohol (2 mmol), Ac2O (4 mmol), amount of ImBuSO3H (2 mL), reaction time (5 min).
As shown in Table 1, the highest yield (92.5 %) was obtained with an optimum molar ratio of Ac2O to 4-chlorobenzyl alcohol
(2 : 1) at 50 °C within 5 min in the presence of 2 mL of ImBuSO3H. This demonstrates that ImBuSO3H containing a butane-
sulfonic acid group attached to an imidazole ring can serve as an effective catalyst for the protection of 4-chlorobenzyl alcohol. In
the same way alcohols, phenols, thiols and amines bearing a variety of substituents transformed to the respective esters and amides
using acetic anhydride at 50 °C and the generality and broad substrate scope of acetylation of alcohols and phenols using
ImBuSO3H is demonstrated as shown in Table 2. The reaction afforded the corresponding esters in 88 – 92 % isolated yield and
conversions of 94 – 100 % using 2 equiv. of Ac2O at 50 °C within 5 - 35 min. The compounds bearing both electron-withdrawing
and electron-donating substituents smoothly transformed to give the corresponding esters in excellent yields under the optimized
reaction conditions. Substrates bearing the methoxy (MeO-) substituent efficiently gave the respective products in 90 - 92 % yield
after 5 - 7 min (Table 2, entry 6 and 7). The methoxy group often underwent cleavage in the presence of strong acids or certain
Lewis acids.
Table 2. Screening results of the different parameters for the acetylation of alcohols, phenols, thiols, and amines in the presence of
ImBuSO3H.a

Entry
Substrate
R
Product
Time (min)
Yield (%)b
OH
OAc
R
R
1
2
4-Cl
H
5
5
92.5
92
90
91
90
92
90
88
85
88
3
2-Cl
7
4
4-Me
2-Me
4-MeO
2-MeO
4-NO2
2-NO2
3-NO2
5
5
7
6
5
7
7
8
10
10
10
9
10
OH
OH
OAc
11
12
10
94
OAc
10
92
OH
OH
OAc
OAc
13
10
91
14
15
25
20
86
90
H
H
OH
OAc
OH
OAc
16
17
40
10
87
96
OH
OAc
OH
OH
OAc
OAc
18
15
94c

OH
OAc
OH
OH
OAc
OAc
19
20
92c
20
21
20
15
90
90
OH
OAc
OH
OAc
OH
OAc
22
25
90d
OH
OH
OAc
OAc
OH
OAc
23
24
30
22
92c
OH
OAc
OH
OAc
90c
NH2
NHAc
R
R
R
25
26
27
28
H
2
3
3
5
96
90
94
85
2-Me
4-Br
4-NO2
NH2
NHAc
29
5
91
OH
OAc
N
H
N
30
31
12
8
90c
89c
Ac
NH2
NHAc
OH
SH
OAc
SAc
32
33
15
10
90
93
SH
SAc

SH
OH
SAc
OAc
34
35
20
15
90c
88
O
O
SH
SAc
a Reaction conditions: Substrate (2 mmol), Ac2O (4 mmol), amount of ImBuSO3H (2 mL), 50 °C.
b Isolated yield.
c Ac2O, 4.0 equiv.
d Ac2O, 6.0 equiv.
The ortho-substituted, sterically hindered and electron deficient alcohols (Table 2, entries 3,5,7,9, and 13-16) were smoothly
acetylated in good yield; the secondary and tertiary alcohols did not experience any competitive dehydration under the optimized
reaction conditions (Table 3, entries 11-16). The enantioselectivity with retention of the configuration at the chiral center was
proved by acetylation of two optically active compounds viz. (−)-menthol ([α]D = −50 ± 1 °, c = 10 % ethanol, ≥ 99 % e.e.) and
(+)-borneol ([α]D = +37 ± 2 °, c = 5 in ethanol , 99 % e.e.) (Table 2, entries 13 and 15). The enantiopure form of (−)-menthyl
acetate ([α]D = − 80 °, in benzene, 97 % e.e.) and (+)-bornyl acetate ([α]D = +41 °, neat, 96 % e.e.) were obtained in 91 % and 90
% yield, respectively. The optical rotation of the products was determined and compared with those reported from Sigma-Aldrich.
Retention of configuration in these compounds is a result of the chiral center in the substrates not participating in the
transformation.
The superiority of this strategy was further established by the fact that direct acetylation of amines and thiols with 2.0 equiv.
Ac2O was carried out within 4 - 20 min in 85 - 96 % yields under same optimized reaction conditions (Table 2, entries 25-35); the
same or different functional groups could be simultaneously acetylated during the reaction (Table 2, entries 18,19,22-24,
30,31,34). Heteroaryl thiols such as furylmercaptane were acetylated in 88 % yield within 15 min under the optimized reaction
conditions (Table 2, entry 35).
There is no intrachemoselectivity for acetylation of primary and secondary alcohol (Table 2, entry 23), phenol and primary
alcohol (Table 2, entry 24), secondary amine and primary alcohol (Table 2, entry 30), phenol and aniline (Table 2, entry 31), as
well as phenol and thiophenol (Table 2, entry 34) for the present protocol under the optimized reaction conditions. However, we
observed complete or moderate interchemoselectivity for the acetylation of aniline, benzyl alcohol, phenol, thiophenol and benzyl
thiol (Table 3). The results showed that aniline could be acetylated selectively in the presence of benzyl alcohol, phenol,
thiophenol or benzyl thiol (Table 3, entries 1-4) and almost all of the other substrates were recovered after completion of the
transformation. Also, benzyl alcohol was acetylated in the presence of phenol, thiophenol, and benzyl thiol in 88 : 12, 94 : 6, and
72 : 28 % selectivity, respectively (Table 3, entries 5,8, and 9). Phenol was acetylated in the presence of thiophenol and benzyl
thiol in 81 : 19 and 74 : 26 % selectivity, respectively (Table 3, entries 6 and 7). Also, benzyl thiol was acetylated in the presence
of thiophenol in 68 : 32% selectivity (Table 3, entry 10).
Table 3 Interchemoselectiveity of the present strategy for the acetylation of some functional groups in the presence of other
functional groups.a

Entry
Two substrates
Product(s)
Selectivity (%)b
100
NH2
NHAc
1
OH
OAc
0
NH2
NHAc
100
OH
OAc
2
0
NH2
SH
NHAc
SAc
100
3
0
NH2
NHAc
100
4
SH
SAc
0
OH
OAc
12
5
OH
OAc
88
81
OH
OAc
6
SH
SAc
19
74
OH
OAc
7
26

SH
OH
SAc
OAc
94
8
SH
SAc
6
OH
SH
OAc
SAc
72
9
28
32
SH
SAc
10
SH
SAc
68
a Reaction conditions: Substrates (2 mmol), Ac2O (2 mmol), amount of ImBuSO3H (2 mL), 50 °C, 5 min.
b Based on GC-MS analysis.
Finally, in order to investigate the possible use of the methodology for macro scale and industrial application, the acetylation of α-
tocopherol (α-TCP) was studied. The esterification of vitamins has attracted significant attention in the hydrolase community, due to the
ability of lipases to catalyze the acylation in non-conventional media. Vitamin E is a major natural antioxidant and an essential component of
biological membranes. Vitamin E derivatives have biological activities and have been used as highly selective anticancer agents,38-40
efficiently inducing the apoptosis of cancer cells via the mitochondrial route.41,42 Tocopherols (TCPs) show the highest vitamin E activity
among eight isoforms,38 however, they are unstable and their antioxidant value is reduced by light, air or oxidizing compounds. Acetylation
of vitamin E was reported to improve its stability.43 The enzymatic esterification has widely been carried out in ILs as the solvent because the
enzyme activity as the catalyst was unchanged in most ILs over several consecutive cycles44,45. It was recently reported that the undergoing
cause for the lipase-catalyzed synthesis of vitamin E succinate is the catalytic activity of the histidyl residue in the protein. Thus histidine, its
analogue and 3-alkyl-1-methyl-imidazolium ionic liquids were investigated as dual solvent-catalysts for the production of TCP succinate.46
We performed the acetylation of the α-Tocopherol (α-TCP) with 20 mmol of the α-TCP and 40 mmol Ac2O in the presence of 8 mL
ImBuSO3H at 50 °C and 6.9 g (80.2 % yield) was obtained after 30 min incubation in the dark and under the nitrogen atmosphere (Scheme
3).

OH
OAc
ImBuSO3H (8 mL)
Ac2O
+
HOAc
+
R
O
R
O
20 mmol
40 mmol
6.9 g (80.2 % yield)
R =
Scheme 3 Acetylation of α-tocopherol (α-TCP).
The recoverability and reusability of catalysts are very important for academic and industrial applications from the economic
and environmentally benign points of view. The esters are mostly immiscible with the used ImBuSO3H. In the first run, the
reaction mixture indeed separates into two layers. It was proposed that the produced acetic acid may react with ImBuSO3H and the
acetate anion may coordinate to the imidazolium cation and this product may become miscible with the reactants in subsequent
runs (Scheme 4).
O
S
O
S
HOAc
OAc
HO
N
+
HO
N
O
N
O
NH
Scheme 4 Reaction of 4-Imidazol-1-yl-butane-1-sulfonic acid (ImBu-SO3H) and the produced acetic acid.
Hence, the solvent extraction was determined to be the best choice under the conditions of the process. The best choice was the
extraction of the products with Et2O, which allows the dual solvent-catalyst to remain in the flask and to be used again. Then the
combined ethereal solution is concentrated in vacuo to give the products. After removing the product via extraction, ImBuSO3H
was recycled practically in 82 % yield.
As showed in Table 4, ImBuSO3H can be recycled up to four times without any significant loss of activity. The average
recovery of ImBuSO3H was 82 % for the four times recycling process and the average α-TCP acetate yield was 78 % for the four
runs.
Table 4 Recoverability of ImBuSO3H for the esterification of TCP using Ac2O.a
Run
Recovered yield of ImBuSO3H (%)b
Yield of α-TCP acetate (%)c
fresh
82
82
82
82
82
80
80
78
78
75
1
2
3
4
a Reaction conditions: TCP (20 mmol), Ac2O (40 mmol), amount of ImBuSO3H (8 mL), the incubation temperature in the dark and under nitrogen atmosphere (50 °C).
b After each run, fresh and recycled ImBuSO3H were mixed for the preparation of 8 mL of dual solvent-catalyst medium.
c Yield of α-TCP acetate was determined through HPLC analysis, using an external standard.

These results showed an excellent reusability of ImBuSO3H for the esterification of TCP. The fourth recycled ImBuSO3H was
1
investigated by H NMR at 600 MHz in DMSO-d6. The results indicate that the chemical structure of ImBuSO3H was very stable
and showed no significant change under the optimized conditions (Figure 3).
Figure 3 1H NMR spectrum of the fourth recycled ImBuSO3H.
A plausible mechanism of the acetylation of α-TCP is illustrated in Scheme 5. In the first step, two molecules of liquid acid
form intermediate (
I) as an ion pair. Then in the second step, the anion of intermediate (
I) activates the hydroxyl group for the
nucleophilic attack on the acetyl group of the intermediate cation (
I), which affords the desired product and recovers two
molecules of ImBuSO3H. In the final step, three possible structures in the mixture of ImBuSO3H and HOAc can exist together in
equilibrium as a neutral molecule, ion pair, and zwitterion.
Scheme 5 The plausible reaction mechanism for the acetylation of α-TCP in the presence of dual solvent-catalyst ImBuSO3H.

N
O
N
N
N
4
O S
4
H
O
S
O
N
O
O
O
O
step 1)
O
O
+
N
HO3S
H3C
N
O
CH3
4
HO
CH3
CH3
O
HO S
O
(I)
N
4
CH3
CH3
O
O
CH3
O
CH3
O
N
CH3
HO S
O
N
4
H3C
R
2
+
HO S
O
N
N
4
O
O
CH3
step 2)
O
S
O
H
N
O
4
H3C
N
O
R
O
N
CH3
CH3
O
O
CH3
NH
O
O
O
O
O
step 3)
+
O S
O
N
4
NH +
HO S
N
N
HO S
O
4
4
HO
CH3
R =
HO
CH3
O
Ion pair
CH3
zwitterion
CH3
CH3
H3C
Scheme 5 A plausible reaction mechanism for the acetylation of α-TCP in the presence of dual solvent-catalyst ImBuSO3H.
Finally the solvent-catalyst activity of reagents containing a sulfonic group has been explored to catalyze the acetylation of α-TCP
under the optimized reaction conditions (Table 5). The functionalized sulfonic acid reagents were purchased from Sigma-Aldrich or
were prepared according to the procedures described in the literature.21,50,51

Table 5 Comparison of the results obtained for the acetylation of α-TCP in the presence of ImBuSO3H with those using some
functionalized sulfonic reagents.a
Entry
Functionalized sulfonic reagents as solvent-catalyst
Yield (%) Ref.
1
2
3
4
5
6
7
Sulfamic acid
48
52
62
64
80
88
46
91
Sigma-Aldrich (Merck)
Aminomethanesulfonic acid
Sigma-Aldrich (Merck)
Succinimide sulfonic acid
50
4-(Succinimido)-1-butane sulfonic acid
4-(3-Methylimidazolium)butane sulfonate
3-(Imidazolium)propane sulfonate
4-(2,3-diMethylimidazol-1-yl)butane-1-sulfonic acid
4-(Imidazol-1-yl)butane-1-sulfonic acid
51
21
21
21
8
This work
a
Reaction conditions: TCP (2 mmol), Ac2O (4 mmol), amount of solvent-catalyst (2 mL), incubation temperature in the dark and under
nitrogen atmosphere (50 °C), reaction time (5 min).
As shown in Table 5, the solvent-catalytic efficiency of these functionalized sulfonic reagents derived from alkyl amine, succinimide,
and imidazole is influenced by the structure of core and carbon spacer. The best results were obtained with the imidazole moiety and
strong reduction of the catalytic effect was observed with amine and ethane amine. Introduction of a methyl group on the imidazolium cation
at C-2 and N-3 positions resulted in a marked decrease in catalytic activity of the sulfonic-functionalized reagents with respect to its analogue
(Table 4, entries 5,7 and 8). It seems that the presence of hydrogen atoms at C-2 and N-3 in the imidazole-based reagents increases the
catalytic efficiency (Table 4, entries 5-8).
Experimental
General
Unless specified, all chemicals were purchased from Fluka AG, Sigma-Aldrich, Merck, and Synthetic Chemicals Ltd. Reaction
monitoring and purity determination of the products were accomplished by TLC using silica gel SIL G/UV 254 plates or GC-MS
on an Agilent 6890GC/5973MSD instrument under 70 eV conditions. Fourier transform infrared (FTIR) spectra were obtained
using a Perkin-Elmer spectrometer 781 and a Bruker Equinox 55 instrument using KBr pellets for solid samples and neat liquid
samples in the range of 4000–400 cm–1. In all the cases, the NMR spectra were recorded with a Bruker Avance III 600 MHz
instrument.
Synthesis of ImBuSO3H
Imidazole (0.68 g, 10 mmol) was added to 1,4-butane sultone (1.1 mL, 10.7 mmol) in ethylbenzene (5 mL) and the mixture
was stirred continuously for 12 h at 90 °C to obtain ImBuSO3H as a viscous, clear and colorless liquid. The solvent was then
removed by rotary evaporation and the viscous liquid was washed with 3 × 5 mL of diethyl ether to remove unreacted starting
materials. The resulting ImBuSO3H was dried to constant weight in vacuum at 60 °C (1.72 g, yield 84.2 %).

Typical procedure for acetylation of alcohols, phenols, amines, and thiols
In a 25-mL round bottom flask, a mixture of the substrate (2.0 mmol), acetic anhydride (4.0 mmol), and ImBuSO3H (2 mL)
was stirred at 50 °C for an appropriate time. After completion of the reaction (monitored by TLC), the mixture was extracted with
Et2O (5 × 5mL) and the supernatant ethereal solution was decanted off. The dual solvent-catalyst ImBuSO3H was allowed to
remain in the flask and fresh reagents could be added and the reaction could be run again. The combined ethereal solution were
concentrated in vacuo to give the acetylated product identical (IR, 1H and 13C NMR and GC-MS) to an authentic sample.47,48
Acetylation of α-tocopherol (α-TCP)
In a 25-mL round bottom flask, a mixture of α-tocopherol (2.0 mmol), acetic anhydride (4.0 mmol), and ImBuSO3H (2 mL)
was stirred at 50 °C for 30 min in the dark and under the nitrogen atmosphere. The yield and purity of O-acetyl-α-Tocopherol (Ac-
TCP) were determined through GC-MS analysis, using an external standard (Vitamin E acetate, 96 % Sigma-Aldrich). O-acetyl-α-
Tocopherol was identified by comparison of its NMR data with reference compound.49 Ac-TCP yield was calculated according to
Equation (1).
O-Acetyl-α-Tocopherol (Ac-TCP) yield (%) = (Observed Ac-TCP/Theoretical Ac-TCP) × 100
Eq. (1)
Conclusions
In summary, the high potential of 4-imidazol-1-yl-butane-1-sulfonic acid ionic liquid (ImBuSO3H) for the acylation of
alcohols, phenols, amines, and thiols as well as α-tocopherol as the most active form of vitamin E has been presented. This new
liquid acid, easily accessible from imidazole and 1,4-butane sultone, has been used as an efficient dual solvent-catalyst. The
successful use of ImBuSO3H in such transformation broadens the range for other applications of this reagent in other areas of
organic synthesis and our laboratory is studying some reactions in the presence of this new liquid acid.
Acknowledgements
This work was supported by a High Impact Research Grant (No. RP025A/B/C-14AET) for Scientific Research from
University of Malaya, Malaysia. The authors are grateful to staff members in the Analytical and Testing Center of NANOCAT
(University of Malaya) and Kharazmi University for partial support.

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O
S
O
S
O
Ethylbenzene
12 h,90 oC
+
O
HN
N
OH
N
N
O
ImBuSO3H
OAc
R X
H
ImBuSO3H
HOAc
Ac2O
+
+
R X
X = O, S or NH
R = Alkyl, aryl or heteroaryl
OH
OAc
ImBuSO3H (8 mL)
Ac2O
+
HOAc
+
R
O
R
O
20 mmol
40 mmol
6.9 g (80.2 % yield)
R =