Ionic liquids on demand in continuous flow

Article abstract of DOI:10.1021/op900069a

We report on the development of an alternative protocol for the facile, solvent-free synthesis of various novel imidazolium-based ionic liquids (ILs) that affords highly pure products without the necessity of subsequent purification steps. The continuous

Full text of DOI:10.1021/op900069a

Organic Process Research & Development 2009, 13, 961–964
Ionic Liquids on Demand in Continuous Flow
Daniel Wilms, Johannes Klos, Andreas F. M. Kilbinger, Holger Lo¨we,* and Holger Frey*
Institut fu¨r Organische Chemie, Johannes Gutenberg-UniVersita¨t Mainz, Duesbergweg 10-14, D-55099 Mainz, Germany
Abstract:
in recent years. Due to their inherent nonvolatility, ionic liquids
cannot be conveniently distilled prior to use as solvents or
reactants. However, very high purity of these compounds is
essential for their practical use, which often requires tedious
subsequent purification steps, leading to high cost and limited
potential for industrial application.
We report on the development of an alternative protocol for the
facile, solvent-free synthesis of various novel imidazolium-based
ionic liquids (ILs) that affords highly pure products without the
necessity of subsequent purification steps. The continuous ap-
proach is based on the combination of HPLC pumps with a
micromixer and a capillary residence tube. Our system provides
a high degree of control over the alkylation reactions due to a
high surface-to-volume ratio and superior heat and mass transport.
Within the scope of our studies, we focused on ionic liquids
containing differently substituted phenyl rings and characterized
these compounds with respect to further use for direct application
or subsequent reaction sequences. Scale-up can conveniently be
achieved by operating several reactors with high continuous
throughput in parallel.
Microstructured reactors have recently attracted increasing
interest due to significant benefits originating in very short
diffusion pathways and large interfacial contact areas per unit
volume (10 000-50 000 m2/m3)9 that result in superior heat and
mass transfer compared to conventional lab reactors. Conse-
quently, higher yields and selectivities as well as improved
product qualities have been achieved by transferring chemical
reactions (especially those that are highly exothermic or
endothermic) from classical batch reactors to microstructured
devices.9-14 Higher throughput of products is often conveniently
accessible by running several microreactors in a parallel setup.
Thus continuous reaction platforms based on micromixing of
reactants offer intriguing potential for the preparation of ionic
liquids. Waterkamp et al. described the preparation of 1-butyl-
3-methylimidazolium bromide in a microstructured reactor and
carried out an elegant process intensification study.15 In another
interesting study, Renken et al. reported on the high reactor
performance of a microstructured device in the case of a
continuously synthesized imidazolium ethylsulfate.16 Here we
present the development of a simple but highly versatile
approach for the synthesis of a variety of high purity ionic
liquids in a continuous flow reactor equipped with a micromixer,
circumventing any additional purification steps.
Introduction
Ionic liquids are generally understood as fluids that solely
consist of ions yet differ from conventional molten salts in a
variety of properties.1 While the latter mostly exhibit high
melting points, viscosity, and corrosiveness, the former species
are usually liquid below 100 °C and nonvolatile and exhibit an
almost negligible vapor pressure. Numerous ionic liquids have
been synthesized in the past;2-5 however this class of com-
pounds only attracted broad attention when hydrolysis-stable
compounds with strongly expanded potential for practical
applications were introduced in the early 1990s.6 Within the
past 15 years, a wide variety of ionic liquids has been prepared,
characterized with respect to both physical and chemical
properties, and increasingly used as an alternative to classic
organic solvents, as they often show high dissolving power for
otherwise sparingly soluble compounds.1,7,8 The first step in the
synthesis of ionic liquids usually involves formation of the
cation by quarternization of an amine or phosphane. Variation
of the alkylating agent leads to salts with different anions,
typically halide ions. The demand for ionic liquids for a variety
of synthetic and analytical purposes has been steadily growing
Experimental Section
Materials. All chemicals were purchased from Acros
Organics and used as received. Deuterated DMSO-d6 was
purchased from Deutero GmbH and used as received.
Instrumentation. 1H and 13C NMR spectra were recorded
at 300 and 75 MHz, respectively, on a Bruker AC and are
referenced internally to residual proton signals of the deuterated
solvent.
(9) Hessel, V.; Lo¨we, H.; Mu¨ller, A.; Kolb, G. Chemical Micro Process
Engineering; Wiley-VCH: Weinheim, 2005.
* To whom correspondence should be addressed. E-mail: hfrey@uni-mainz.de.
(1) Wasserscheid, P.; Keim, W. Angew. Chem., Int. Ed. 2000, 39, 3773.
(2) Wasserscheid, P.; Welton, T. Ionic Liquids in Synthesis; Wiley-VCH:
Weinheim, 2003.
(10) Ehrfeld, W.; Hessel, V.; Lo¨we, H. Microreactors: New Technology
for Modern Chemistry; Wiley-VCH: Weinheim, 2000.
(11) Thayer, A. M. Chem. Eng. News 2005, 83, 43.
(12) Geyer, K.; Code´e, J. D. C.; Seeberger, P. H. Chem.sEur. J. 2006,
12, 8434.
(3) Sugden, S.; Wilkins, H. J. Chem. Soc. 1929, 1291.
(4) Chum, H. L.; Koch, V. R.; Miller, L. L.; Osteryoung, R. A. J. Am.
Chem. Soc. 1975, 97, 3264.
(13) Ja¨hnisch, K.; Hessel, V.; Lo¨we, H.; Baerns, M. Angew. Chem., Int.
Ed. 2004, 43, 406.
(5) Wilkes, J. S.; Levisky, J. A.; Wilson, R. A.; Hussey, C. L. Inorg.
Chem. 1982, 1263.
(14) Kockmann, N.; Brand, O.; Fedder, G. K. Micro Process Engineering:
Fundamentals, DeVices, Fabrication, and Applications; Wiley-VCH:
Weinheim, 2006.
(15) Waterkamp, D. A.; Heiland, M.; Schlu¨ter, M.; Sauvageau, J. C.;
Beyersdorff, T.; Tho¨ming, J. Green Chem. 2007, 9, 1084.
(16) Renken, A.; Hessel, V.; Lo¨b, P.; Miszczuk, R.; Uerdingen, M.; Kiwi-
Minsker, L. Chem. Eng. Proc. 2007, 46, 840.
(6) Wilkes, J. S.; Zaworotko, M. J. J. Chem. Soc., Chem. Commun. 1992,
965.
(7) Welton, T. Chem. ReV. 1999, 99, 2071.
(8) Holbrey, J. D.; Seddon, K. R. Clean Products and Processes 1999, 1,
223.
10.1021/op900069a CCC: $40.75  2009 American Chemical Society
Published on Web 06/17/2009
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Figure 1. Mixing principle and setup of the slit-interdigital mixer. The inner volume of the micromixer is 8 µL. Mixing takes place
by very fast diffusion between the thin reactant layers formed by the parallel microchannel alignment.
DSC curves were recorded on a Perkin-Elmer DSC 7 and a
Perkin-Elmer Thermal Analysis Controller TAC 7/DX.
X-ray structure determination was collected on a Bruker
AXS Smart CCD diffractometer with graphite monochromated
Mo KR radiation (λ ) 0.710 69 Å).
Synthesis of Ionic Liquids in Batch. In a typical experi-
ment, a 100 mL two-necked glass flask equipped with a
mechanical stirrer was charged with 17.78 mL (20.8 g, 0.126
mol) of 1-bromohexane and 10 mL (10.35 g, 0.126 mol) of
1-methylimidazole and immediately immersed into an oil bath
pretempered to the desired temperature. After stirring for 10
min, small samples were removed, cooled down to 0 °C, and
dissolved in DMSO-d6 for NMR characterization.
Figure 2. Illustration of the experimental setup for the synthesis
of ionic liquids in continuous flow.
Synthesis of Ionic Liquids in Continuous Flow. All
reactions were carried out in a continuous flow reaction setup
provided by the Institut fu¨r Mikrotechnik Mainz (IMM). It
consists of a tempered oil bath hosting the micromixing device
(stainless steel interdigital SIMM-V2 mixer with an internal
volume of 8 µL and channel widths of 45 µm) that is equipped
with two reactant inlets and one outlet. In a typical experiment,
alkyl bromide and imidazole were separately pumped into the
mixing chamber. After mixing, the reaction mixture is directly
guided into the respective capillary residence tube with a
diameter of 500 µm (Volume ) 10 or 30 mL). The rear end of
the tubular delay tube leads to the reactor outlet. Flow rates are
controlled via HPLC pumps (Knauer WellChrom K-501, inert
10 mL pump heads with ceramic inlays).
1
Figure 3. H NMR spectrum of 3-hexyl-1-methylimidazolium
bromide (IL-1).
zole with 1-bromohexane and exhibits very low viscosity at
elevated temperatures. Hence, it was considered a suitable
reaction product for an initial test run of the applied setup, which
included two HPLC pumps separately introducing the liquid
reactants to the preheated micromixer. There, the fluids are
combined to form a homogeneous solution that is passed
through a residence tube of variable length before the reaction
product is recovered at the outlet of the device (Figure 2).
The reaction time can be varied by simply adjusting the flow
rate and/or elongation or shortening of the residence tube.
Compound IL-1 was obtained as a slightly yellow liquid. The
highly efficient mixing process permits working at a temperature
of 140 °C without noticeable hotspot formation. These reaction
conditions accounted for very short reaction times of 5-10 min,
Results and Discussion
All syntheses presented in this paper were carried out in a
reactor equipped with a stainless steel slit-interdigital mixer
provided by the Institut fu¨r Mikrotechnik Mainz (IMM). The
layout of the micromixer allows mixing processes to take place
within several milliseconds due to the combination of the regular
flow pattern created by multilamination with geometric focusing
(Figure 1).
Residence times are very short as the inner volume of the
mixer is extremely small (∼8 µL). High pressure stability of
the setup (up to 100 bar) permits continuous flow at viscosities
of up to 10 000 mPas. To determine the applicability of the
continuous reactor setup for the intended synthesis of ionic
liquids, a compound well established in conventional batch
synthesis (3-hexyl-1-methylimidazolium bromide IL-1) was
targeted. It can be obtained from alkylation of 1-methylimdida-
1
depending on the specific system and the flow rates. The H
NMR spectrum of IL-1 is shown in Figure 3. It indicates a
remarkably high quality of the crude ionic liquid recovered
directly from the outlet of the microreactor setup without the
necessity for further purification steps.
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Scheme 1. Synthesis of phenylalkyl imidazolium bromides
In addition, analysis by HPLC showed less than 1% of
impurities (mostly unreacted starting materials). In the conven-
tional batch synthesis, the reaction proceeds explosively at
temperatures higher than 100 °C and thus has to be carried out
at milder conditions. Lower temperatures however involve the
drawback of significantly slower kinetics. High conversions
cannot be achieved within reaction times in a range comparable
to the continuous flow approach. For instance, after 10 min at
60 °C, a conversion of only 5% was observed in the batch
experiment, whereas the continuous flow setup permits working
safely at high temperatures without thermal overrun and
subsequent loss of control over the reaction. NMR spectra and
conversion data for the samples obtained by the standard batch
approach can be found in the Supporting Information. Encour-
aged by the promising initial results obtained by applying the
continuous setup we directed our efforts towards the synthesis
of entirely new ionic liquids that had not been reported
previously. These were prepared by alkylation of alkylimida-
zoles with phenylalkyl bromides in the microstructured reactor.
The novel compounds represented an interesting class of ILs
for probing and establishing the versatility of our continuous
flow process. Scheme 1 depicts the pathway to four different
novel ionic liquids that we prepared in the microstructured
reaction device described above.
slow crystallization, a behaviour that is not observed for the
nonsubsituted derivative IL-3. Thermal analysis (DSC) of the
ionic liquids obtained from the microreactor showed generally
low glass transition temperatures below 0 °C (Table 1) and a
clear trend in the phenyl-substituted series IL-2-IL-5. The
presence of an additional nitro group leads to a strong increase
of the Tg. Compound IL-1 exhibits the lowest transition
temperature, attributed to the disorder associated with the
flexible alkyl substituent. While IL-3 is liquid at room tem-
perature, all other species, exhibiting the typical characteristics
of ionic liquids, should be employed at temperatures above 50
°C where they form viscous liquids.
Ionic liquids IL-1-IL-5 represent typical examples for
expedient, easily accessible ionic liquids that exhibit high
dissolving power for polar organic compounds. Another inter-
esting ionic liquid prepared within the scope of our initial
investigations was a structure containing a vinyl instead of a
methyl group (Scheme 2). This was achieved by reaction of
vinyl imidazole with 1-bromohexane.
To prevent thermal polymerization of the vinyl function, this
compound was prepared at a reduced temperature of 110 °C
using a delay loop with an increased inner volume of 30 mL.
Incorporation of a vinyl group into an ionic liquid offers great
potential for structural diversification, as the respective com-
All compounds were obtained as slightly yellow or orange
liquids at high throughputs between 100 and 200 mL/h at
analogous conditions to the preparation of IL-1. The respective
1H NMR spectra of compounds IL-2-IL-5, measured directly
after recovery from the continuous reaction device (see Figure
4 and Supporting Information), indicate complete reactant
conversion as well as the absence of any undesired side
products, which are frequently observed in conventional batch
syntheses for ionic liquids.
It should be noted that compound IL-2 differs from the ionic
liquid IL-3 by just one methylene group. However, IL-2 does
not remain liquid at room temperature but turns into a tough
yellow solid after several hours that can be recrystallized from
acetone to form colorless needles. The crystal structure of
recrystallized IL-2 was characterized by X-ray crystallography
and is shown in Figure 5.
The additional methylene group incorporated into compound
IL-3 is sufficient to prevent formation of a highly ordered crystal
lattice at room temperature. The ionic liquids possessing a nitro
group on the phenyl subsituent remained liquid at room
temperature for prolonged periods but started crystallizing after
several weeks. Nitro groups introduce an additional polar moiety
capable of intermolecular interaction that apparently promotes
1
Figure 4. H NMR spectra of novel nitrophenyl substituted
ionic liquids IL-4 (top) and IL-5 (bottom).
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Figure 5. Single crystal X-ray structure of 1-methyl-3-phenethyl-imidazolium bromide IL-2.
Table 1. Glass temperatures of ionic liquids synthesized in
microstructured reactor. The remarkably versatile approach
based on micromixing of the reactants permitted the first
preparation of imidazolium-type ILs bearing additional aromatic
units. A wide variety of further novel ionic liquids are
conveniently accessible by this procedure under facile control
of the reaction parameters. Our approach avoids time-consuming
purification steps while meeting the strict demands for highly
pure reaction products and simultaneously bearing the possibility
to prepare large scales of the desired compounds “on demand”.
Further work will involve counterion variation as well as
detailed kinetic studies. This will finally lead to the rapid
synthesis of tailor-made products for a steadily growing demand
for ionic liquids.
the microstructured reaction device
ionic liquid
IL-1 IL-2 IL-3 IL-4 IL-5 IL-6
-68.6 -47.3 -39.1 -8.9 -6.3 -65.6
Tg/°C
crystallization at no
room temperature
yes
no
yes
yes
no
Scheme 2. Synthesis of 3-hexyl-1-vinylimidazolium bromide
pounds can be derivatized by subsequent reaction sequences
such as olefin cross metathesis, radical polymerization, hydrosi-
lylation, and other olefin addition reactions. It is important to
point out the versatility of the process described. Reaction
temperatures and residence times can be individually chosen
without having to change the experimental setup. A crucial
advantage of the described approach is the possibility to prepare
large product amounts with little experimental effort. Scale-up
can be achieved by simply operating several continuous flow
reactors in parallel. While in a typical experiment using a single
microstructured reactor, up to 200 mL of high purity ionic liquid
can be prepared; the employment of additional similar devices
and parallel operation provides convenient access to multiki-
logram per hour scales without having to resort to a more
complex system.
Acknowledgment
We thank the Institut fu¨r Mikrotechnik Mainz for continuous
technical support. Dr. Dieter Schollmeyer is acknowledged for
X-ray single crystal measurements. H.F. acknowledges continu-
ous support by the Fonds der Chemischen Industrie. D.W. is
grateful for a fellowship from the Fonds der Chemischen
Industrie and further support provided by POLYMAT. J.K. and
A.F.M.K. are grateful to the IRTG for financial support.
Supporting Information Available
Additional NMR characterization data and illustrations of
the experimental setup. This material is available free of charge
via the Internet at http://pubs.acs.org.
Conclusion
Received for review March 24, 2009.
OP900069A
In conclusion, we have developed a quick and facile
continuous flow process for the synthesis of ionic liquids in a
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