Improved methods for the synthesis and isolation of imidazolium based ionic salts

Article abstract of DOI:10.1016/j.tetlet.2014.09.116

Solvent-free reactions were used for the synthesis of a series of imidazolium-based ionic salts: 3,3′-[pyridine-2,6-diylbis(methylene)]bis(1-R-1H-imidazol-3-ium)chloride; (R = methyl, ethyl, butyl, isobutyl, hexyl, and benzyl). A simple and effective filtration process was used to isolate all the products in high purity and with yields ≥93% within a 24 h period. The highly pure ionic compounds which are precursors to N-heterocyclic carbene ligands used in catalysis were fully characterized as gray-white hygroscopic salts.

Full text of DOI:10.1016/j.tetlet.2014.09.116

Tetrahedron Letters xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Improved methods for the synthesis and isolation of imidazolium
based ionic salts
⇑
Halliru Ibrahim, Muhammad Dabai Bala
School of Chemistry and Physics, University of KwaZulu-Natal, Private Bag X54001, Durban 4000, South Africa
a r t i c l e i n f o
a b s t r a c t
Solvent-free reactions were used for the synthesis of a series of imidazolium-based ionic salts: 3,30-[pyr-
idine-2,6-diylbis(methylene)]bis(1-R-1H-imidazol-3-ium)chloride; (R = methyl, ethyl, butyl, isobutyl,
hexyl, and benzyl). A simple and effective filtration process was used to isolate all the products in high
purity and with yields P93% within a 24 h period. The highly pure ionic compounds which are precursors
to N-heterocyclic carbene ligands used in catalysis were fully characterized as gray-white hygroscopic
salts.
Article history:
Received 27 March 2014
Revised 3 September 2014
Accepted 24 September 2014
Available online xxxx
Keywords:
Ó 2014 Elsevier Ltd. All rights reserved.
Green chemistry
Silica gel filtration
Ionic salt
N-Heterocyclic carbene
The isolation of the first stable carbene by Arduengo1 paved the
way to the use of ionic imidazolium salts as cheap and affordable
sources of N-heterocyclic carbene (NHC) ligands, and when appro-
priately constituted, they also serve as convenient sources of ionic
liquid (IL) solvents. On the one hand, the detailed spectroscopic
and structural studies of NHC ligands supported by their excellent
coordinating ability2 have made them credible alternatives to
phosphines in organometallic chemistry and catalysis3 while on
the other hand, the unique physical and chemical properties of IL
solvents, which include low melting points (usually below
100 °C) accompanied by high thermal stability, wide electrochem-
ical windows, negligible vapor pressures, high viscosity, non-vola-
tility and non-flammability distinguish them from traditional
organic solvents.4 In metal-free catalysis,5 imidazolium salts have
created a niche as highly effective catalysts and initiators in the
synthesis of quinoxaline derivatives6 and in the hydrogenation of
ketones to alcohols,7 while they also effect C-metalation of nicotin-
amide groups on hydride ion uptake.8 In addition, they exhibit bio-
logical and antimicrobial activities.9 More importantly, when
coupled to metal ions, their complexes have found use as catalysts
in a wide range of applications such as C–S coupling,10 hydroviny-
lation,11 olefin metathesis,12 hydrogenation of ketones to alco-
hols,13 oxidation of alcohols to ketones,14 hydrosilation of amides
to amines and nitriles,15 and in Heck reactions.16 This wide diver-
sity of features which includes their ability to be functionalized,
immobilized, made hydrophilic, chiral, or chelating has influenced
their applications and those of the metal complexes generated
from them.17 Of particular interest to catalysis is the pincer form
of the NHC ligand characterized by multiple binding to metal cen-
tres and the ability to stabilize various stages of active species in a
catalytic cycle. In this study, various pincer imidazolium salts with
potential to serve as sources of pincer NHC ligands are reported.
The novelty of our study is not in the nature of the salts (a few vari-
ants of which are known), but in the simple and effective technique
used for their synthesis and isolation in excellent yields. We report
herein a simple and quick throughput technique for the isolation of
high purity NHC precursors that will be, we suggest, universally
applicable to a wide variety of salt formulations.
Typically, the synthesis of pincer CNC ligands (Scheme 1) has
been achieved through the use of organic solvents such as
N-methyl-2-pyrrolidone, 1,4-dioxane or tetrahydrofuran (THF),11
which are highly detrimental to the environment. In addition, it
has been well established18 that with such synthetic routes the
reactions progress rather slowly, often over several days and
at high temperatures. There is also the potential for side reac-
tions that often result in diminished yields and contaminated
products requiring even more post-reaction treatment for their
purification.
The common practice still employed by many researchers today
for the synthesis of NHC ligand salt precursors is the quaterniza-
tion (functionalization) of an imidazole N-position with suitable
alkyl/aryl halides in an appropriate solvent; usually an aprotic sol-
vent. A reaction conducted by this route usually takes several days
⇑
Corresponding author. Fax: +27 31 260 3091.
E-mail address: bala@ukzn.ac.za (M.D. Bala).
http://dx.doi.org/10.1016/j.tetlet.2014.09.116
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Ibrahim, H.; Bala, M. D. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.09.116

2
H. Ibrahim, M.D. Bala / Tetrahedron Letters xxx (2014) xxx–xxx
procedures, where compounds 9, 11, 12, and 13 have not been pre-
viously reported.
The starting materials, N-substituted imidazoles 1–5 were syn-
thesized at room temperature by adaptation of the method of
Starikova et al.,20 while benzyl imidazole 6 was synthesized by a
modification of the method of Corberán et al.21 In the synthesis
of the imidazolium pincer compound, all the salts were isolated
within 24 h as pure, hygroscopic materials. The pure ionic salts
were characterized by NMR, IR, and high resolution MS. As the salts
are highly hygroscopic and quickly absorbed varying amounts of
water, it was impossible to obtain consistent CHN analysis data,
but the neat NMR spectra and HRMS analyses confirmed isolation
of high purity compounds.
N
N
Cl
Cl
7
Cl
Cl
N
N
N
solvent-free
heat, 60 oC, N2, 16 h
N
R
N
N
R
R
1: R= -CH3
: R= -CH2CH3
2
8
:
R= -CH3
9: R= -CH2CH3
3: R= -(CH2)3CH3
4: R= -CH2CH(CH3)2
10: R= -(CH2)3CH3
11
12
: R= -CH2CH(CH3)2
5
: R= -(CH2)5CH3
: R= -(CH2)5CH3
The reactants [N-substituted imidazoles 1–6 and 2,6-bis(chlo-
romethyl)pyridine (7), in 2:1 mole ratio] were mixed neat at room
temperature.22 With gentle stirring, the reaction flask was gradu-
ally brought to 60 °C over about 20 min, and by this time the con-
tents of the reaction flask had melted to a colorless liquid which
was kept at the same temperature for a further 16 h. With the
exception of 13, a change in color from colorless to gray or the for-
mation of a very viscous crude product indicated completion of the
reaction. In the synthesis of 13 however, progress and reaction
completion was observed as a gradual change in color from light
yellow to gray. It is important at this stage to emphasize that if
not for the continued sublimation of 7, up to 100% conversion
and yield was possible via this method. This could have meant
no further purification was necessary, but as shown in Table 1 yield
of 95% was the highest isolated in this study. After analysis of the
crude product using thin-layer chromatography (TLC) with 100%
ethyl acetate as the mobile phase, we observed the unreacted
N-substituted imidazole 1–6 with Rf values that varied from 0.48
to 0.75, while traces of unreacted 7 moved with the solvent front.
Most importantly, the salt products 8–13 were immobilized onto
the TLC plate and only became mobile (Rf value = 0.20) when the
solvent system was switched to 100% methanol. Based on this
observation, we attempted separating the residual unreacted start-
ing materials from the product by direct extraction with the ethyl
acetate, but realized that some of the salt products were also
extracted along with the starting materials, which led to dimin-
ished isolated yields. Hence we used a short plug (about 3 cm
thick) of silica in a glass column to temporarily immobilize the
product, thereby enabling removal of unreacted starting materials
with ethyl acetate. We believe the basic salts were immobilized on
to the acidic silica via the imidazolium nitrogen in products 8–13
and depending on the solvent system, the temporary immobiliza-
tion can be weakened and eventually the salts were obtained in
pure form as methanol eluents. Essentially this is a quick through-
put column filtration system based on solvents that are environ-
mentally friendlier than in any system used prior to this. The
salts so obtained needed no further purification (confirmed by
NMR) before further applications such as use as an IL or as a source
of an NHC ligand. However when required, recrystallization from a
dichloromethane/hexane mixed solvent system yielded hygro-
scopic crystals of 8–13. After several attempts at adopting pub-
lished methods, it is worth noting that this new isolation method
is now standard in our laboratories and has been adapted to the
synthesis of a wide variety of substituted imidazolium salts,
including those based on the triazole moiety, with appreciable
success.
6: R= -CH2C6H5 (rt-100 oC, 24 h)
13: R= -CH2C6H5
Scheme 1. Synthetic route to compounds 8–13.
and only proceeds under high temperatures (solvent reflux). Exam-
ples include reports by Nielsen,16 Serra11 and Crabtree.18
Essentially, there are two main issues that we addressed:
(i) Using a high yielding and efficient synthetic procedure as an
improvement over currently available methods.
(ii) Developing a simple, non-complicated means of isolating
the products in pure form.
In this Letter, we have addressed the points raised above by
using a solvent-free technique for the synthesis of several pincer
NHC salts and utilizing the acidic nature of silica to temporarily
adsorb the salts 8–13, thereby resulting in a simple but effective
purification protocol. The method allows for the synthesis (and
high isolated yields) of NHC ligand precursor salts with a chelating
CNC donor architecture built around a lutidine backbone. It must
be noted at this stage that ours is not the first attempt at utilizing
solvent-free techniques for the synthesis of ionic liquids and salts.
In fact, Youngs and co-workers19 have applied this method to
obtain pincer NHC ligands, which were later complexed to silver
and transmetalated to rhodium and palladium. However, our
approach is a significant improvement over previously reported
methods in terms of quick throughput, isolated yields, and the pur-
ity of products. The major point of divergence is that most previous
methods eventually relied on slow precipitation of the final prod-
uct from an organic solvent which can often take days to achieve;
an example is acetone over 48 h in Youngs’ method. This method-
ology leads to lower yields as compared to the modified strategy
we have developed which reduced significantly the total reaction
time to just 16–24 h. Table 1 shows a comparison with reported
Table 1
Comparison of the isolated yields for compounds 8–13
Compound
Our work
Other studies for comparison
Conditions
Yield (%)
Conditions
Yield (%)
8
9
10
11
12
13
SF
SF
SF
SF
SF
SF
95
94
94
94
80a
94
RD11
NC
85
—
85
—
—
—
SFY19
NC
NC
NC
Characteristic signals of the imidazolium salts were observed in
the NMR spectra of the salts,2b,21 within the ranges 9–9.9 and 153–
160 ppm for 1H and 13C NMR data, respectively. The downfield sin-
glet in the 1H NMR and the far downfield imidazolium NCHN (C2)
carbon peaks suggest formation of the salts. The ATR-FTIR spectra
identified all the expected functional groups, that is, aryl C@C, CAN
and CAH sp3 stretching vibrations,21 while further analysis by
NC = new compound, not previously reported.
RD = 1,4-dioxane as the reaction solvent; 100 °C, 12 h, precipitated from MeOH/
Et2O, 0–5 d.
SF = solvent-free, 60 °C, 16 h, purified via trapping with silica, obtained as the MeOH
eluent.
SFY = solvent-free, 60 °C, precipitated from acetone, 2 d.
a
Reactants 5 and 7 were used in a 3:1 mole ratio.
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H. Ibrahim, M.D. Bala / Tetrahedron Letters xxx (2014) xxx–xxx
3
high-resolution MS confirmed formation of the salts in pure form.
References and notes
The HRMS (TOF-MS ES+) of all the salts exhibited peaks due to the
molecular ion with the loss of one chloride ion. The found values
are all within the acceptable limits (0.003 m/z units) of the calcu-
lated values of the parent-derived ion peak. All the solid salts
showed narrow melting point ranges within expected limits of
their molecular composition and were comparable to related pub-
lished data.
Salt 8 was obtained as a white hygroscopic powder, while 9, 10,
11, and 13 were hygroscopic gray-white solids and 12 was a color-
less, hygroscopic, jelly-like substance. With the exception of 12, all
the other salts were obtained in excellent yields higher than 92%.
The lower yield of 12 could be associated with the flexibility of
the longer alkyl side chain, which reduced the rate of coupling of
the N-imidazole 5 with 2,6-bis(chloromethyl)pyridine (7). Many
attempts at the synthesis of 12 based on the default molar ratio
and conditions used for the other salts resulted in low yields being
recorded, but when the ratio of 5 was trebled, the yield almost
doubled to 80%.
In conclusion, we have developed a generic strategy applicable
to the synthesis of a wide variety of imidazolium-based ionic salts
in a safe and controlled manner that is easy to adapt.22 The method
is high yielding and environmentally benign because it is based on
a solvent-free technique. The acidity of silica gel was employed for
trapping the salts and aiding their isolation in high purity within
reasonable time frames. The method reported here significantly
reduces the reaction time, decreases the severity of the reaction
conditions, eliminates the use of eco-unfriendly solvents and
makes viable the preparation of ionic salts in a rapid and reproduc-
ible manner. The synthetic route is not only suitable for the aryl
and alkyl substituted compounds reported herein, but is robust
enough to tolerate a wide variety of functional groups and is
important because the system overcomes all the limitations high-
lighted in previously employed strategies for the synthesis of,
especially, pincer NHC ligand precursors.
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Pombeiro, A. J. L. Chem. Eur. J. 2012, 18, 899–914.
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Imidazole (0.010 mol, 0.680 g) was stirred at room temperature with KOH
(0.015 mol) in DMSO (25 ml) for 2 h. Benzyl bromide (Aldrich, 98% assay,
1.436 g cmꢀ3, 0.010 mol, 1.2 ml) was then added dropwise at 100 °C and the
mixture heated at reflux temperature for 24 h. Chilled distilled H2O was used
to wash and dilute the mixture until neutral. The organic components were
extracted with CH2Cl2/CHCl3 (50/50, 6 ꢁ 10 ml), dried over anhydrous MgSO4,
and concentrated under reduced pressure to yield orange-brown crude
products. Pure N-benzyl imidazole (Rf = 0.48 in EtOAc) was obtained as the
CH2Cl2 (100%) eluent. Yield: yellow viscous oil that dried to give a white solid;
0.948 g, 60%; mp 67–69 °C; dH (400 MHz, DMSO-d6): 5.19 (2H, s, CH2), 6.96
(1H, s), 7.19 (1H, s), 7.27 (2H, d, J = 14.9 Hz), 7.29 (1H, d, J = 1.3 Hz), 7.34 (2H, d,
J = 7.6 Hz), 7.79 ppm (1H, s); dC (400 MHz, DMSO-d6): 49.5, 119.5, 127.4, 127.7,
128.6, 128.7, 137.4, 137.7 ppm; IR (ATR cmꢀ1): 3348 (broad, residual
moisture), 3031 (@CAH), 2929 (sp3 CAH), 1672 (C@N), 1454 (aryl C@C),
1075 (CAN medium), 708 (phenyl moiety); HRMS (TOFMS ES+): m/z C10H11N2
calcd: 159.0922, found: 159.0925.
Acknowledgements
We thank the University of KwaZulu-Natal and the National
Research Foundation (NRF) for financial support.
22.
A typical experimental procedure is described: N-substituted imidazole 1–6
(1 mmol equiv) and 2,6-bis(chloromethyl)pyridine (7) (0.5 mmol equiv for
each compound, mp 73–78 °C; Aldrich) were mixed with gentle stirring
under inert conditions in a 50 ml round-bottom flask. The temperature was
gently raised to 60 °C giving a molten substance that was allowed to continue
stirring for 16 h at 60 °C. The resultant gray or light brown crude solid was
allowed to cool to room temperature and loaded onto a short plug of silica gel.
Unreacted starting materials were eluted with EtOAc while the product salts
were obtained (Rf = 0.20) as MeOH (100%) eluents. The solvent was removed
under reduced pressure to yield the pure imidazolium salt 8–13.
Supplementary data
Supplementary data (experimental procedures and spectro-
scopic characterization) associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.09.
116.
Please cite this article in press as: Ibrahim, H.; Bala, M. D. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.09.116