Efficient synthesis of 1,3-dialkylimidazolium-based ionic liquids: The modified continuous Radziszewski reaction in a microreactor setup

Article abstract of DOI:10.1021/op100055f

By making use of a modified Radziszewski reaction, it is demonstrated that water-soluble 1,3-dialkylimidazolium-based ionic liquids can be produced in good yields (70-90%) and purities (>95%) starting from readily available, cost-effective monoalkylamines, glyoxal, formaldehyde, and mineral or organic acids. The homosubstituted 1,3-dialkylimidazolium salts feature high thermal stabilities similar to those of their heterosubstituted counterparts, and relatively low viscosities, thus fulfilling the requirements for solvent application. The effect of various parameters has been studied with the goal of improving yields for both the batchwise and continuous synthesis (making use of a microreactor setup), allowing for the production of a wide variety of ionic liquids and the introduction of functionalities. The applicability of these ionic liquids is demonstrated on the example of cellulose dissolution and the dehydration of fructose to 5-hydroxymethylfurfural.

Full text of DOI:10.1021/op100055f

Organic Process Research & Development 2010, 14, 1102–1109
Efficient Synthesis of 1,3-Dialkylimidazolium-Based Ionic Liquids: The Modified
Continuous Radziszewski Reaction in a Microreactor Setup
Johannes Zimmermann, Bernd Ondruschka, and Annegret Stark*
Institute for Technical Chemistry and EnVironmental Chemistry, Friedrich-Schiller UniVersity, 07743 Jena, Germany
Abstract:
demonstrate the applicability of microreaction technology for
the first step of the conventional ionic liquid synthesis (Scheme
1).6-11
By making use of a modified Radziszewski reaction, it is demon-
strated that water-soluble 1,3-dialkylimidazolium-based ionic
liquids can be produced in good yields (70-90%) and purities
(>95%) starting from readily available, cost-effective monoalkyl-
amines, glyoxal, formaldehyde, and mineral or organic acids. The
homosubstituted 1,3-dialkylimidazolium salts feature high thermal
stabilities similar to those of their heterosubstituted counterparts,
and relatively low viscosities, thus fulfilling the requirements for
solvent application. The effect of various parameters has been
studied with the goal of improving yields for both the batchwise
and continuous synthesis (making use of a microreactor setup),
allowing for the production of a wide variety of ionic liquids and
the introduction of functionalities. The applicability of these ionic
liquids is demonstrated on the example of cellulose dissolution and
the dehydration of fructose to 5-hydroxymethylfurfural.
For example, the solvent-free continuous synthesis of 1,3-
dialkylimidazolium-based ionic liquids was performed in a
spinning tube-in-tube reactor,6 which is known to increase the
mixing efficiency by quickly rotating (12000 rpm) a cylinder
inside a stationary shell. Heat transfer is achieved by thermo-
statting both the rotor and stator. Using equimolar amounts of
1-methylimidazole and various alkylating agents at temperatures
between 70 and 180 °C (depending on the reactivity of the
alkylating agent), up to 18.7 kg d-1 of ionic liquid can be
produced at a conversion of 99%. Waterkamp et al. reported
the solvent-free synthesis of [C4MIM]Br at 85 °C in a
microreactor system equipped with a vortex mixer. The excel-
lent heat removal during the exothermic reaction allows for
running the reaction isothermally at a much higher temperature
than the maximum temperature (48 °C) of the batch setup.
Under optimized conditions (85 °C, flow rate: 8 mL min-1,
molar ratio of butyl bromide:1-methylimidazole, 1:1), a 24-
fold increase in space-time yield is obtained (1.27 kg L-1 h-1
vs 0.05 kg L-1 h-1 in a 4-L reactor), with the potential for further
optimization by applying even higher temperatures. This
translates into a production rate of 9.3 kg [C4MIM]Br per day
in >99% purity.7,8
Renken et al. described the use of a microstructured reactor
for the production of 1-ethyl-3-methylimidazolium ethylsulfate
([C2MIM][EtSO4]), with a reactor performance of 15.84 kg L-1
h-1,9 which can be followed by ATR-IR online spectroscopy.10
In a similar fashion, the synthesis of [C2MIM][EtSO4] in a
tubular reactor has been mentioned.11
A summary of the technical setups, optimum temperatures,
and space-time yields (STY) and capacities of these reports is
given in Table 1. Although continuous alkylation methods have
thus been described, this most often employed synthetic strategy
requires the following:
Introduction
The synthesis of ionic liquids is most often carried out by
alkylation of an organic base, e.g., 1-methylimidazole, with an
alkylating agent. Unless this alkylating agent contains the
desired ionic liquid anion (as it may be the case when using,
for example, dialkyl sulfate, dialkyl carbonate, or alkyl trifluo-
romethylsulfonate, to yield the respective ethylsulfate, alkyl-
carbonate or trifluoromethylsulfonate), a haloalkane is used for
alkylation, and a subsequent ion-exchange step is required to
obtain the final ionic liquid (Scheme 1).1,2
A review of the literature3 reveals that very little chemical
engineering data is available on the synthesis of 1,3-dialkyl-
imidazolium-based ionic liquids for large-scale production, with
the exception of the work of Große Bo¨wing et al. who
investigated the production of 1-butyl-3-methylimidazolium
chloride ([C4MIM]Cl) from 1-methylimidazole and butylchlo-
ride in a continuous tube reactor.4 A continuously operated tank
reactor for similar alkylations has been proposed.5 Interestingly,
in the past years, a series of reports has appeared that
* Author to whom correspondence may be sent. E-mail: annegret.stark@uni-
jena.de. Telephone: 0049 3641 948413. Fax: 0049 3641 948402.
(1) Wasserscheid, P.; Welton, T. In Ionic Liquids in Synthesis, 2nd ed.;
Wiley-VCH Verlag GmbH & Co: Weinheim, 2008; Vol. 1, p 721.
(2) Welton, T. Chem. ReV. 1999, 99, 2071.
(6) Gonzalez, M. A.; Ciszewski, J. T. Org. Process Res. DeV. 2009, 13,
64.
(7) Waterkamp, D. A.; Tho¨ming, J.; Heiland, M.; Sauvageau, J. C.;
Schlu¨ter, M.; Beyersdorff, T. Chem.-Ing.-Tech. 2007, 79, 1482.
(8) Waterkamp, D. A.; Heiland, M.; Schlu¨ter, M.; Sauvageau, J. C.;
Beyersdorff, T.; Tho¨ming, J. Green Chem. 2007, 9, 1084.
(9) Renken, A.; Hessel, V.; Lo¨b, P.; Miszczuk, R.; Uerdinen, M.; Kiwi-
Minsker, L. Chem. Eng. Proc. 2007, 46, 840.
(3) Stark, A.; Seddon, K. R. In Kirk-Othmer Encyclopaedia of Chemical
Technology, 5th ed.; John Wiley & Sons, Inc.: Hoboken, NJ, 2007;
Vol. 26, p 836.
(4) Große Bo¨wing, A.; Jess, A.; Wasserscheid, P. Chem. Ing. Tech 2005,
77, 1430.
(5) Stark, A.; Bierbaum, R.; Ondruschka, B. Verfahren zur Herstellung
ionischer Flu¨ssigkeiten. (Friedrich-Schiller University Jena). DE 10
2004 040 016 A1, 2004.
(10) Minnich, C. B.; Ku¨pper, L.; Liauw, M. A.; Greiner, L. Catal. Today
2007, 126, 191.
(11) Etzold, B.; Jess, A. Chem.-Ing.-Tech. 2007, 79, 1301.
1102
•
Vol. 14, No. 5, 2010 / Organic Process Research & Development
10.1021/op100055f  2010 American Chemical Society
Published on Web 08/30/2010

Scheme 1. Conventional method of ionic liquid preparation
Table 1. Reported technical setups, process conditions, and performance of continuous ionic liquid synthesis strategies
STY
capacity
ionic liquid
technical setup
T [°C]
[kg L-1 h-1
]
[kg d-1
]
ref
[C4MIM]Cl
continuous tube reactor (6 m × 3 mm)
75
130
112
85
0.02
0.17
10.0
2.9
4
[C6 MIM]Cl
continuous batch reactor (700 mL)
5
various, e.g. [C4MIM]Br
[C4MIM]Br
[C2MIM][EtSO4]
spinning tube-in-tube microreactor (gap: 0.25 - 0.44 mm)
vortex micromixer (450 µm channel width)
caterpillar micromixer (600 µm × 600 µm)
4.90
3.2
6
7, 8
9
1.27
15.84
9.3
11.9
95
salts of lower melting points and viscosities.18-20 On the one
hand, it was shown21 that heterosubstituted 1,3-dialkylimida-
zolium salts cannot be selectively obtained using two different
amines (e.g. methylamine and n-butylamine) in the modified
Radziszewski reaction, but a statistic mixture results. On the
other hand, relatively little is known to date about the physi-
cochemical properties22-26 and the potential application of
homosubstituted 1,3-dialkylimidazolium salts.
Hence, it is the goal of this contribution to demonstrate that
(i) water-soluble 1,3-dialkylimidazolium-based salts can
be produced in good yields and purities starting from readily
available starting materials;
(ii) the properties of the 1,3-dialkylimidazolium salts
indeed allow for their classification as ionic liquids (i.e.
melting points below 100 °C);
(iii) the novel ionic liquids can be used in a variety of
applications (cellulose dissolution, dehydration of fructose
to 5-hydroxymethylfurfural); and
(i) high temperatures and reaction times for the alkylation,
especially if a chloroalkane is used, leading to high energy
consumption;12,13
(ii) two extraction steps to remove unreacted starting
materials: the first after the alkylation, and the second after
the ion exchange, leading to a high solvent consumption.
Besides the impact on the environment resulting from energy
and solvent consumption,12,13 this synthesis makes use of the
rather costly precursor 1-methylimidazole, leading to prohibi-
tively high ionic liquid prices for technical solvent applications.
Furthermore, it can be noted that the synthetic strategy
depicted in Scheme 1 does not allow for the technical-scale
manufacture of halide-free, water-soluble ionic liquids, since
these ionic liquids cannot be easily purified by aqueous
extraction.
More than 100 years ago, Radziszewski described the
synthesis of lophine from the condensation of benzil, benzal-
dehyde, and ammonia. Lophine is nowadays known as 2,4,5-
triphenyl-1H-imidazole.14 This reaction was revived and modi-
fied by organometallic chemists, in particular in the group of
Arduengo III, who sought after a method to produce 1,3-
disubstituted imidazolium salts as carbene precursors (Scheme
2).15-17
(iv) the technical production is feasible in continuous
mode using a microreaction setup.
Experimental Section
Chemicals. All chemicals (from Sigma-Aldrich: methyl-
amine (40% aq sol.), n-propylamine (>99%), n-butylamine
(>99.9%), nitric acid (70% aq sol.), acetic acid (>99.7%),
tetrafluoroboronic acid (50% aq sol.), formic acid (98%),
glyoxal (40% aq sol.), formaldehyde (36% aq sol., stabilized
with 10% methanol), Avicel (PH-101), fructose (>99%); sulfuric
acid (64% aq sol.) and HCl (Merck, 32% and 37% aq sol.))
Although the method, which allows for the introduction of
alkyl-, aryl-, and other functionalized moieties, was patented, a
systematic optimization to use this strategy for the technical
production of structurally related ionic liquids has not been
published to the best of our knowledge. The obvious difference
between Arduengo’s carbene precursors and conventionally
used ionic liquids is the substitution pattern on the nitrogen
atoms. While the carbene precursors are homosubstituted (i.e.,
bearing the same substituent on both nitrogen atoms), ionic
liquids are in general heterosubstituted (1-alkyl-3-methylimi-
dazolium derivatives, where alkyl > CH3). The influence of this
heterosubstitution has been the focus of many studies, resulting
in the general understanding that asymmetric cations lead to
(18) Larsen, A. S.; Holbrey, J. D.; Tham, F. S.; Reed, C. A. J. Am. Chem.
Soc. 2000, 122, 7264.
(19) Seddon, K. R. J. Chem. Technol. Biotechnol. 1997, 68, 351.
(20) Holbrey, J. D.; Seddon, K. R. J. Chem. Soc., Dalton Trans. 1999,
2133.
(21) de Souza, R. F.; Rech, V.; Dupont, J. AdV. Synth. Catal. 2002, 344,
153.
(22) Bonhoˆte, P.; Dias, A.-P.; Papageorgiou, N.; Kalyanasundaram, K.;
Gra¨tzel, M. Inorg. Chem. 1996, 35, 1168.
(12) Kralisch, D.; Stark, A.; Ko¨rsten, S.; Kreisel, G.; Ondruschka, B. Green
Chem. 2005, 7, 301.
(13) Kralisch, D.; Reinhardt, D.; Kreisel, G. Green Chem. 2007, 9, 1308.
(14) Radziszewski, B. Ber. Dtsch. Chem. Ges. 1882, 15, 1493.
(15) Arduengo, A. J., III. Preparation of 1,3-disubstituted imidazolium salts.
(Du Pont). WO/1991/14678, 1991.
(16) Arduengo, A. J., III. Acc. Chem. Res. 1999, 32, 913.
(17) Arduengo, A. J., III; Krafczyk, R.; Schmutzler, R. Tetrahedron 1999,
55, 14523.
(23) Dzyuba, S. V.; Bartsch, R. A. Chem. Commun. 2001, 1466.
(24) Tome´, L. I. N.; Carvalho, P. J.; Freire, M. G.; Marrucho, I. M.;
Fonseca, I. M. A.; Ferreira, A. G. M.; Co´utinho, J. A. P.; Gardas,
R. L. J. Chem. Eng. Data 2008, 53, 1914.
(25) Domanska, U.; Rekawek, A.; Marciniak, A. J. Chem. Eng. Data 2008,
53, 1126.
(26) Kuhlmann, E.; Himmler, S.; Giebelhaus, H.; Wasserscheid, P. Green
Chem. 2007, 9, 233.
Vol. 14, No. 5, 2010 / Organic Process Research & Development
•
1103

Scheme 2. Modified Radziszewski reaction
Table 2. Variation of reaction times (addition sequence I,
n-butylamine/glyoxal/formaldehyde/tetrafluoroboronic acid )
2:1:1:1, T1 ) T2 < 10 °C, T3 ) 20 °C) in the batch synthesis
of 1,3-dibutylimidazolium tetrafluoroborate
Table 4. Yields obtained by variation of acids (addition
sequences I, II, III: t1 ) t2 ) 30 min, t3 ) 6 h, T1 ) T2 < 10
°C, T3 ) 20 °C, addition sequence IV: t1 ) 30 min, t2 ) 6 h,
T1 < 10 °C, T2 ) 20 °C; n-butylamine/glyoxal/formaldehyde/
acid ) 2:1:1:1.2) in the batch synthesis of
entry
t1 [min]
t2 [min]
t3 [h]
yield [%]
1,3-dibutylimidazolium-based ionic liquids
1
15
30
60
120
30
30
30
30
30
30
30
30
30
30
30
30
30
30
15
60
120
30
30
30
30
30
30
30
6
6
43
46
40
37
44
39
38
25
32
34
38
40
46
59
addition sequence
2
3
6
acid
I
II
III
IV
4
6
HBF4
HCl
HOAc
59
60
79
53
72
80
65
60
5
6
67a
81
63a
86
6
6
7
6
8
1
a The solution of HCl and formaldehyde should be freshly prepared and
9
2
handled in
a fume-hood, as bis(chloromethyl)ether may form, which is
carcinogenic.
10
11
12
13
14
3
4
5
Geschwenda, Germany), and pressure sensors (Profimess,
Bremerhaven, Germany, PU-02), for timely detection of clog-
ging. The components are connected Via 1/16 in. PFA tubing
(i.d. 1.016 mm). For mixing units, a glass X-mixer (MR-Lab,
Little Things Factory)29 was used. The residence time units
(RTUs) and flow rates were altered as summarized in Table 5.
For HPLC analysis, samples were drawn at the exit of the
setup (0.25 mL, diluted to 25 mL with eluent) at the times
6
20
Table 3. Variation of reactant ratios (addition sequence I, t1
) t2 ) 30 min, t3 ) 6 h, T1 ) T2 < 10 °C, T3 ) 20 °C) in the
batch synthesis of 1,3-dibutylimidazolium tetrafluoroborate
yield
[%]
entry
C4H9NH2
HCHO
C4H9NH2
HBF4
glyoxal
1
2
3
4
5
6
1
1
1
1
1
1.2
1
1
1
1.2
1
1
1
1
1
1
1.2
1
1
1
1
1
1.2
1
46
59
61
48
47
20
1
1.2
1.4
1
1
1
indicated (Table 5), and analyzed (Vide infra). For H NMR
analysis, the product was extracted with ethyl acetate until the
extractant phase was colorless. Volatiles were removed on a
rotary evaporator, and the product was further dried in Vacuo
(80 °C, 12 h, 5 mbar).
1
have been used as received. The content of formaldehyde was
determined following standardized procedures.27
1
The product purity was determined by H NMR and/or
HPLC (Vide infra),28 which was >95% in all cases.
Analytics. Yields were determined using a [C4C4IM]Br
standard made by conventional synthesis (alkylation of 1-bu-
tylimidazole) on a Jasco HPLC equipped with a Prontosil NC-
04 (250 mm × 4 mm), 120-5-C18H 5 µm column from
Bischoff Chromatography, using isocratic 70% aqueous
Na2HPO4 (0.065 M, pH ) 5)/30% acetonitrile as eluent.
Detection was achieved with an UV-diode array detector at 208
nm.
Batch Experiments. Batch experiments were conducted on
a 0.05 molar scale in 250-mL, three-necked, round-bottomed
flasks equipped with a dropping funnel, thermometer, reflux
condenser, and a magnetic stirrer bar. Exothermic reactions were
controlled by immersing the flask in a stirred ice bath while
adding each reactant dropwise. The respective reaction times,
reactant ratios, temperatures, and addition sequences are detailed
in Tables 2-4.
The workup of the products was achieved by extraction with
diethyl ether until the extractant phase was colorless. The water
of the aqueous phase was removed on a rotary evaporator and
the product further dried in Vacuo (80 °C, 12 h, 5 mbar). The
1H NMR spectra were recorded on a Bruker 200 MHz at
room-temperature using deuterated DMSO as solvent. Yields
were obtained by addition of a standard of approximately
equimolar amounts of toluene to which peak integrals were
related.
1
product purity was determined by H NMR and/or HPLC28
(Vide infra), which was >70% in all cases.
1
Yields determined by HPLC and H NMR agreed within
Continuous Experiments. The multipurpose microreaction
setup (Figure 1), designed and built at the TU Ilmenau (Prof.
Ko¨hler/Dr. Groß) has been used for the continuous experiments.
This LABVIEW-controlled setup features a Cetoni syringe
pump with six independent axes (Cetoni GmbH, Korbussen,
Germany), PT-1000 temperature sensors (Umweltsensortechnik,
5%. Residual traces of water were analyzed with a Karl Fischer
Mettler DL37 Coulometer, using Hydranal-Coulomat A and C
(both from Riedel-de Hae¨n). The measurements were performed
in duplicate and agreed within 5%.
As a further indication of the purity, the pH values in 0.1 M
aqueous solution were measured. These pH values ranged
between 5.2-5.3, 2.2-2.9, and 4.5-5.7 for the acetate, chloride,
(27) EN ISO 14184-1: Determination of formaldehyde - Part 1: Free and
hydrolyzed formaldehyde (water extraction method); International
Organization for Standardization, 1998.
(28) Stark, A.; Behrend, P.; Braun, O.; Mu¨ller, A.; Ranke, J.; Ondruschka,
B.; Jastorff, B. Green Chem. 2008, 10, 1152.
(29) Mikromischer-Typ-*-X, internal volume 0.06 mL; Little Things Factory;
http://www.ltf-gmbh.de/de/Mikroverfahrenstechnik/Standardkomponenten/ (last
accessed 07.01.10).
1104
•
Vol. 14, No. 5, 2010 / Organic Process Research & Development

Figure 1. Multipurpose microreaction setup used in the present study, and the X-mixer from the Little Things Factory.29
Table 5. Reaction parametersa for the continuous synthesis of [C4C4IM]Cl (entries 1-6)b and [C4C4IM][OAc] (entries 7-9)
RTU [m]
flow rate [mL min-1
]
residence time [min]
entry L1 L2 C4H9NH2 HCHO + HCl glyoxal total
τ1
τ
yield [%]c capacity [kg d-1
]
STY [kg L-1 h-1
]
total
1
2
3
4
5
6
2.5 7.0
2.5 7.0
2.5 7.0
7.0 30.0
7.0 30.0
7.0 30.0
0.20
0.40
1.00
0.34
0.17
0.09
0.20
0.39
0.98
0.30
0.15
0.08
0.12 0.51
0.23 1.02
0.58 2.56
0.20 0.84
0.10 0.42
0.05 0.22
5.07
2.57
15.10
7.55
5
10
12
45
55
69
0.01
0.06
0.17
0.22
0.13
0.09
0.08
0.31
0.92
0.30
0.18
0.12
1.02
3.01
8.87
17.73
33.38
35.71
71.42
136.35
C4H9NH2 HCHO + HOAc glyoxal total
7
8
9
5.0 15.0
7.0 30.0
7.0 30.0
0.35
0.35
0.18
0.25
0.25
0.13
0.20 0.80
0.20 0.80
0.10 0.41
6.76
9.46
18.31
20.27
37.50
73.16
50
74
91
0.27
0.40
0.25
0.70
0.56
0.35
a c(C4H9NH2) ) 10.08 mol L-1, c(HCHO, 37% aq sol.) ) 13.34 mol L-1, for entries 1-3; (HCl, 32% aq sol.) ) 10.18 mol L-1, for entries 4-6: (HCl, 37% aq sol.) )
12.03 mol L-1, c(HOAc, > 99%) ) 17.49 mol L-1, c(glyoxal, 40% aq sol.) ) 8.75 mol L-1 b The solution of HCl and formaldehyde should be freshly prepared and handled
.
in a fume-hood, as bis(chloromethyl)ether may form, which is carcinogenic. c Except for entries 6 and 9, yields increased with time by further reaction in the collecting
vessel.
and formate samples, respectively, indicating that traces of acid
are present in all cases.
Results and Discussion
Initial experiments showed that water-insoluble 1,3-dibu-
tylimidazolium tetrafluoroborate ([C4C4IM][BF4]) can be ob-
tained by reacting stoichiometric amounts of n-butylamine,
glyoxal, formaldehyde, and tetrafluoroboronic acid. Although
water-insoluble ionic liquids were not the primary goal of the
study, this example was initially chosen as it allows for aqueous
extraction, and hence a larger variability of the process
parameters in the optimization experiments. In order to elucidate
the effect of the relative reactant ratios, various experiments
were carried out using addition sequence I (Scheme 3), in which
in reaction step 1, equimolar amounts of n-butylamine and
formaldehyde are allowed to react at temperature T1 for a
reaction time t1, before a premixed solution of equimolar
amounts of n-butylamine and HBF4 is added in reaction step
2. The resulting mixture is allowed to react at temperature T2
for a reaction time t2. Finally, glyoxal is added and the mixture
reacted (T3, t3) in reaction step 3.
Preliminary experiments indicated that reaction steps 1 and
2 were very sensitive to heating (both are exothermic reactions),
with low selectivities at higher temperatures. Hence, these two
steps were kept <10 °C throughout the study, while the less
sensitive step 3 was run isothermally at room-temperature.
Reaction Times. First, the influence of the reaction times
was investigated in batch experiments on a 0.05 molar scale.
The successive variation of the reaction times showed that
an extension of t1 and t2 beyond 30 min does not improve yields,
Ionic Liquid Specifications. Physicochemical Properties.
Thermogravimetric analyses were conducted on a DTG-60 from
Shimadzu Corporation, using a platinum pan under inert
conditions (nitrogen), at a heating rate of 10 °C min-1. As
reference, R-alumina Al2O3 was used. The midpoint was
obtained by integration of the decomposition curve.
Kinematic viscosities were measured using an Ubbelohde
viscometer (K ) 0.5007) connected to drying tubes filled with
anhydrous calcium sulfate to exclude moisture, equipped with
a pump and a cryostat to control temperature.
The purities of the materials investigated by TGA and
viscometry are given in Table 6 and in the Supporting
Information.
Cellulose Dissolution. Avicel was dissolved by incremental
addition in the ionic liquid at 100 °C while stirring, until further
addition of cellulose rendered the solution visually opaque.
Dehydration of Fructose. Fructose (8.6 wt %) was dissolved
in either 3.0 g of [C4MIM][CH3SO3] or [C4C4IM]Cl. The
reaction (80 °C) was followed by taking samples at the
appropriate times and analyzing after dilution with acetonitrile/
water (80:20). HPLC was used for analysis (5-hydroxymeth-
ylfurfural: UV-DAD, 283 nm, fructose: light scattering detector)
equipped with a Prontosil 120-5-Amino 0.5 µm column from
Bischoff Chromatography using an isocratic acetonitrile/water
eluent (80:20).
Vol. 14, No. 5, 2010 / Organic Process Research & Development
•
1105

Table 6. Yields, purities, decomposition temperatures at midpoint, kinematic viscosities, and water content of some
homosubstituted 1,3-dialkylimidazolium salts prepared by the modified Radziszewski reaction
kinetic viscosity ln(ν) [mm2 s-1
]
c
ionic liquid
yielda [%]
purity [%]
dec. temp. [°C]b,c
25 °C
50 °C
80 °C
water contentd [wt %]
[C1C1IM][OAc]
[C3C3IM][OAc]
[C4C4IM][OAc]
[C1C1IM][NO3]
[C3C3IM][NO3]
[C4C4IM][NO3]
[C1C1IM][HCO2]
[C3C3IM][HCO2]
[C4C4IM][HCO2]
[C1C1IM][HSO4]
[C3C3IM][HSO4]
[C4C4IM][HSO4]
[C4C4IM]Br
85
84
86
85
78
79
95
91
94
70
75
73
76
63
65
nd
nd
nd
95
98
>95
95
>95
95
93
93
271.5
273.6
275.2
321.9
313.3
321.5
250.8
253.1
254.1
383.8
387.5
384.0
310.1
280.3
440.7
nd
nd
nd
nd
1.46
1.17
0.75
0.37
0.32
0.22
0.90
1.30
1.09
1.00
0.32
0.22
1.95
1.30
0.87
0.11
0.05
0.08
6.12
6.53
nd
4.55
4.95
nd
3.27
3.62
nd
6.37
6.74
nd
4.92
5.13
nd
4.07
4.30
nd
6.95
7.29
nd
nd
nd
3.41
3.94
4.35
3.68
3.80
nd
3.00
3.21
nd
5.32
5.59
nd
nd
nd
2.42
2.88
3.22
5.41
5.58
nd
>95
>95
94
nd
>95
nd
79
nd
[C4C4IM]Cl
78
nd
[C4C4IM][BF4]
[C4MIM][BF4]e
[C6MIM][BF4]e
[C8MIM][BF4]e
>95
>98
>98
>98
nd
4.52
5.17
5.64
nd
nd
a Isolated yield. b Midpoint decomposition temperature determined by TGA, Pt cup, N2, rate: 10 °C min-1
.
c For graphic presentation of the decomposition temperatures
and kinematic viscosities, see Supporting Information. d Determined by automated Karl Fischer titration. e Prepared by conventional alkylation.22 nd ) not determined.
Scheme 3. Sequence of addition of reactants
sponding chloride and acetate, since these water-soluble ionic
liquids were the goal of the study.
Surprisingly, a tremendous increase in yield to 80% resulted
if acetic acid was used instead of tetrafluoroboronic acid
employing addition sequence I, while the same yield (60%) was
obtained with HCl (Scheme 3 and Table 4).
Sequence of Reactant Addition. Finally, the effect of the
sequence of reactant addition was investigated for the three acids
(Table 4). Addition sequence II is the one described for the
preparation of carbene precursors.15-17,30,31
Interestingly, this sequence gives slightly lower yields for
the tetrafluoroborate analogue, while the yield of the chloride
improves to about 70%, and that of the acetate remains the same
when compared to addition sequence I. Addition sequence III
improves the yields slightly for the tetrafluoroborate and the
chloride, but not for the acetate. Addition sequence IV was
investigated as it reduces the number of addition steps to two,
which would facilitate the handling of chemicals (number of
pumps) in a continuous setup. This method provides yields for
the tetrafluoroborate and chloride comparable to those of
Addition Sequence I, and slightly higher for the acetate.
Addition Sequence IV was thus adapted for the continuous
synthesis using a microreactor setup.
and for t3, 6 h is sufficient, although this part of the reaction is
most sluggish (Table 2). It should be noted here that it is not
possible to reduce t1 and t2 < 15 min in batch mode on this
scale with T < 10 °C, due to the exothermic nature of these
reactions.
Variation of Reactants. The synthesis was carried out using
various primary amines, and mineral or organic acids, with
glyoxal and formaldehyde, clearly showing the applicability of
the method (see Supporting Information). Yields vary between
60 to 95%. Although a clear trend can not be derived, it appears
as if the acidity of the acid played a role with regard to the
yields, with less acidic ones giving higher yields. This may be
due to the protonation of the amine in the case of strong acids,
leading to unproductive ammonium-based intermediates during
the reaction.
Relative Reactant Ratios. Second, the relative ratio of
reactants was investigated. As displayed in Table 3, under
constant reaction conditions, stoichiometric amounts of the
reactants gives a yield of 46%. An increase of the acid ratio to
1.2 leads to an enhancement of the yield to 59%. Further
increasing the acid ratio did not improve the yield further (entry
3).
Increasing the ratio of either the formaldehyde, glyoxal, or
n-butylamine did not further the yield (entries 4-6). Hence,
for the remainder of the study, a stoichiometric composition
with a 1.2-fold excess of the acid was adapted.
(30) Ren, R. X.; Koch, V. R. One-step process for the preparation of halide-
free hydrophobic salts. (Covalent Associates). WO 02/094883, 2002.
(31) Herrmann, W. A.; Goossen, L. J.; Artus, G. R. J.; Ko¨cher, C.
Organometallics 1997, 16, 2472.
Variation of Acid. Third, the reaction conditions giving
highest yields were transposed to the synthesis of the corre-
1106
•
Vol. 14, No. 5, 2010 / Organic Process Research & Development

Figure 2. Flow scheme of the microreaction setup.
Transfer to Continuous Production in a Microreactor
Setup. Water-soluble ionic liquids ([C4C4IM][OAc] and
[C4C4IM]Cl) were synthesized with the modified Radziszewski
reaction in a continuous procedure in a multipurpose microre-
action device (Figure 1) applying addition sequence IV.
Different total flow rates of reactants from 0.2-2.6 mL
min-1 were chosen to ascertain the reaction stoichiometry of
sequence IV, and total lengths of residence time units (RTUs)
from 9.5 to 37 m were applied to determine the conditions
giving highest yields.
Due to the exotherms occurring during reaction step 1, the
microreactor, mounted in a special metal frame construction
(Figure 1), was cooled in a water bath at 10 °C. It was found
that heating of the second RTU to 40 °C had no significant
influence on product yield and purity. Hence, the reaction step
2 was carried out at ambient temperatures. Figure 2 shows the
flow scheme of the microreaction setup:
First, n-butylamine is reacted with a premixed solution of
formaldehyde and acid (HX ) HCl, HOAc) for selected
residence times τ1. After the pass through an X-mixer (MRLab,
LTF)29 and a RTU of length L1 the reaction mixture is brought
in contact with glyoxal in a second X-mixer and reacted in a
second RTU (L2) for τ2. The pressure at the beginning and the
end of the device is monitored with the pressure senors P1 and
P2. The temperature in the RTUs is measured with the
temperature sensors T1 and T2.
× 10-3 m. Considering the minimum reaction time t3 of 6 h in
the batch reaction, a minimum length of the RTU L2 of 222 m,
444 m, and 1110 m at the flow rates applied in entries 1-3
would be required (eq 1). Therefore, longer RTUs of 37 m in
total and decreased total flow rates of 0.8, 0.4, and 0.2 mL min-1
were operated (entries 4-6).
In the case of the synthesis of [C4C4IM]Cl, an increase in
yield up to 70% was achieved (Table 5, entry 6), resulting in a
STY of 0.12 kg L-1 h-1 and a capacity of 0.09 kg d-1.
The reaction parameters were adapted for the synthesis of
1,3-dibutylimidazolium acetate. Interestingly, a tremendous
increase to 91% yield within a residence time of only 73 min
was obtained, resulting in a STY of 0.35 kg L-1 h-1 and a
capacity of 0.25 kg d-1 (Table 5, entry 9).
In comparison to the modified Radziszewski reaction in
batch mode, the results clearly show the potential of microre-
action technology in terms of process intensification:32,33 the
reaction times are reduced by factor 3 and 6 for chloride- and
acetate-based ionic liquids, respectively, while the yields in-
crease slightly (compare Tables 4 and 5). Both improvements
are a result of improved mixing and heat transfer in micromix-
ers, which allows for faster reactant combination in exothermic
reactions, while reducing side-product formation.
Direct comparison to the conventional synthesis (Table 1)
is not possible owing to both, unlike reactivities of the systems
and the fact that the products are different (homo- vs. hetero-
substituted cations). However, in general the performance of
the combination of the Radziszewski reaction with microreac-
tion technology in terms of STY lies between conventional and
microreaction processing strategies by the conventional syn-
thesis route.
Table 5 shows the reaction parameters as well as residence
times and space-time yields for the ionic liquids [C4C4IM]Cl
and [C4C4IM][OAc].
Initially, the synthesis of [C4C4IM]Cl was carried out using
short RTUs (9.5 m in total) and different flow rates to determine
suitable residence times for the reaction. Here, the residence
time τhydr was not sufficient to give high yields of the desired
reaction product (entries 1-3, Table 5).
Physicochemical Properties of Homosubstituted 1,3-
Dialkylimidazolium Salts. Series of homologues of homosub-
stituted 1,3-dialkylimidazolium salts have been prepared (see
Supporting Information) and their physicochemical properties
investigated. It was found that all 1,3-dimethylimidazolium-
based salts (hydrogensulfate, nitrate, acetate, formate, tetrafluo-
V
b
V
τhydr
)
(1)
-1
b
where V is the reactants’ flow rate [mL min ] and V is the
inner volume of the device of length L with diameter ) 1.016
(32) Hessel, V.; Lo¨we, H. Chem.-Ing.-Tech. 2004, 76, 535.
(33) Pohar, A.; Plazl, I. Chem. Biochem. Eng. 2009, 23, 537.
Vol. 14, No. 5, 2010 / Organic Process Research & Development
•
1107

Figure 3. Comparison of performance of [C4MIM][CH3SO3] and [C4C4IM]Cl in the synthesis of 5-hydroxymethylfurfural from
fructose (8.6 wt %) as function of time, at 80 °C, under otherwise identical conditions.
roborate, chloride) were solid at room-temperature. Increasing
the alkyl chain length to n-propyl or n-butyl gave room-
temperature liquids.
similar thermal stabilities as their heterosubstituted counter-
parts.39 Although conclusions about long-term stability should
only be drawn from isothermal measurements, their relatively
high thermal stability renders these ionic liquids applicable as
solvents for organic reactions.
Application as Solvents. 1,3-Dibutylimidazolium acetate
was tested in cellulose dissolution, a process of wide recent
interest.40-42 The solubility of the microcrystalline cellulose
Avicel (DP ) approximately 300) was about 9 wt %, which is
in good agreement with conventional ionic liquids,40-42 thus
indicating the potential of these ionic liquids in cellulose
processing.
The dehydration of fructose to 5-hydroxymethylfurfural (a
compound presently promoted as platform chemical from
renewable resources) is well-known to proceed efficiently in
ionic liquids.43-48 Figure 3 shows that the performances of both
heterosubstituted 1-butyl-3-methylimidazolium methanosul-
fonate ([C4MIM][CH3SO3]) and the homosubstituted [C4C4-
IM]Cl in the conversion of fructose (8.6 wt %, 80 °C) to
5-hydroxymethylfurfural are identical under otherwise similar
conditions. These preliminary findings show the potential of
homosubstituted ionic liquids to substitute for the more expen-
sive heterosubstituted ones, e.g. in the processing and conversion
of renewable resources.
The viscosity (Table 6) decreases with increasing temper-
ature, as is the case for heterosubstituted salts.34 Furthermore,
n-propyl derivatives have lower viscosities than n-butyl deriva-
tives, independent of the anion chosen. With regard to the
influence of the anion, the viscosity decreases according to
[HSO4]- > [NO3]- > [OAc]- > [CHO2]-. In comparison to the
three heterosubstituted (conventional) ionic liquids presented
in Table 6, the novel ionic liquids feature surprisingly low
viscosities, even if they comprise highly coordinating anions
(compare e.g. tetrafluoroborate vs formate).
The thermal stability of the materials was investigated by
thermogravimetric analysis (Table 6). Interestingly, the decom-
position temperature is independent of the alkyl chain length
of the cation but decreases with increasing nucleophilicity of
the anion. This clearly indicates that the decomposition mech-
anism involves nucleophilic attack of the anion on the alkyl
substituent, known as Hofmann degradation or reversed Men-
schutkin reaction,35 as previously observed for 1-alkylpyri-
dinium36 and tetraalkylammonium salts.37,38
Furthermore, the consistency of decomposition temperatures
is a reflection of the purity of the materials obtained. In general,
these homosubstituted 1,3-dialkylimidazolium salts feature
(39) Huddleston, J. G.; Visser, A. E.; Reichert, W. M.; Willauer, H. D.;
Broker, G. A.; Rogers, R. D. Green Chem. 2001, 3, 156.
(40) Swatloski, R. P.; Spear, S. K.; Holbrey, J. D.; Rogers, R. D. J. Am.
Chem. Soc. 2002, 124, 4974.
(34) Seddon, K. R.; Stark, A.; Torres, M. J. Clean SolVents: AlternatiVe
Media for Chemical Reactions and Processing; Abraham, M. A.,
Moens, L., Eds.; ACS Symposium Series 819; American Chemical
Society: Washington, D.C., 2002; p 34.
(41) Fukaya, Y.; Sugimoto, A.; Ohno, H. Biomacromolecules 2006, 7, 3295.
(42) Heinze, T.; Dorn, S.; Scho¨bitz, M.; Liebert, T.; Ko¨hler, S.; Meister,
F. Macromol. Symp. 2008, 262, 8.
(35) Menschutkin, N. Z. Phys. Chem. 1890, 5, 589.
(36) Tissot, P. In Molten Salt Techniques; Lovering, D. G., Gale, R. J.,
Eds.; Plenum Press: New York, 1983; Vol. 1, p 137.
(37) Blaschette, A.; Wieland, E.; Seurig, G.; Koch, D.; Safari, F. Z. Anorg.
Allg. Chem. 1983, 506, 75.
(43) Zhao, H.; Holladay, J. E.; Brown, H.; Zhang, Z. C. Science 2007,
316, 1597.
(44) Hu, S.; Zhang, S. Z.; Zhou, Y.; Han, B.; Fan, H.; Li, W.; Song, J.;
Xie, Y. Green Chem. 2008, 10, 1280.
(38) Gordon, J. E. J. Org. Chem. 1965, 30, 2760.
(45) Lansalot-Matras, C.; Moreau, C. Catal. Commun. 2003, 4, 517.
1108
•
Vol. 14, No. 5, 2010 / Organic Process Research & Development

Conclusions
This study has demonstrated that homosubstituted 1,3-
The applicability of homosubstituted 1,3-dialkylimidazolium-
based ionic liquids as solvents has been demonstrated on two
presently heavily investigated processes: the dissolution of
cellulose and the dehydration of fructose to 5-hydroxmethyl-
furfural. In such applications, the ionic liquid solvent cost is
paramount for the transferral of novel technologies to industrial
production.
Furthermore, by structural alteration of the starting material,
especially the amines (amino acids), chiral centers and other
functionalities can be introduced, further enhancing the pos-
sibility of using ionic liquids as designer solvents on technical
scale.
dialkylimidazolium-based ionic liquids can be prepared continu-
ously in high yields (70-90%) using readily available starting
materials. The purities (>95%) compare well with many ionic
liquid products commercially available presently and may be
improved further in future. Therefore, the continuous process
shows potential for further scale-up. Additionally, the modified
Radziszewski reaction is atom-efficient, with water being the
only byproduct.
It appears reasonable to argue that this synthetic strategy
reduces the energy and solvent requirement of the preparation
of 1,3-dialkylimidazolium-based ionic liquids compared to those
prepared by the conventional method,1,2,12,13 and detailed energy
measurements will be reported in due course.
This synthetic strategy allows for the cost-efficient technical
production of water-soluble ionic liquids. The chemical costs
(Germany, Sigma-Aldrich catalogue, July 2009, 1 kg-scale)
amount to between 75 and 85 € kg-1 for the [C4C4IM]-based
ionic liquids presented herein. On the same scale and at 95%
yield, the chemical cost for 1 kg of [C4mim]Cl is about the
same (83 € kg-1). Although this appears to be similar, several
aspects need to be considered; first, bulk chemicals (as required
in the Radziszewski reaction) are proportionally cheaper on large
scale than the more highly specialized ones (e.g., 1-methylimi-
dazole), and thus the chemical costs will deviate considerably
on ton scale. Second, [C4mim]Cl is only an intermediate in the
conventional synthesis, and further costs will have to be added
for ion exchange. Contrary to this, with the Radziszewski
reaction, the acid component can be simply varied, and the ionic
liquid with the desired anion is directly produced. Finally, as
pointed out above, energy savings can be expected.
From a technical perspective, the application of a microre-
action setup allows for a quick changeover to other ionic liquid
products, resulting in a reduction of setup time and enabling
on-demand synthesis of various products in the same apparatus.
Acknowledgment
We thank M. Sellin, M. Stru¨mpel, J. Lifka, A. Rehberg, C.
Palik, B. Fa¨hndrich, W. Fa¨hndrich, and N. Blaubach for
continuous support in the laboratory, and the “Middle-German
Cluster of Microreaction Teaching Experiments” (D. Kralisch,
G. Kreisel; ITUC, FSU Jena E. Dietzsch, E. Klemm; TU
Chemnitz. A. Groß, M. Ko¨hler, S. Schneider, TU Ilmenau) for
the cooperation in the design and manufacture of the microre-
actor setup. For financial support, the authors thank the Federal
Ministry of Education and Research (BMBF), the Foundation
for Technology, Innovation and Research Thuringia, Germany
(STIFT), and the German Federal Environmental Foundation
(DBU). A.S. is indebted to the German Research Foundation
(DFG) for financial support within the Priority Programme Ionic
Liquids (1191).
Using this approach, it is also possible to produce halide-
free ionic liquids, an aspect relevant to catalysis and reactor
corrosion.
Supporting Information Available
Data of various other ionic liquids prepared by the modified
Radziszewski reaction, graphic presentation of the decomposi-
tion temperatures and kinematic viscosities. This information
is available free of charge via the Internet at http://pubs.acs.org/.
(46) Yong, G.; Zhang, Y.; Ying, J. Y. Angew. Chem., Int. Ed. 2008, 47,
9345.
(47) Stark, A.; Lifka, J.; Ondruschka, B. Process for the continuous
preparation of 5-hydroxymethylfurfural using ionic liquids. (Friedrich-
Schiller University, Jena, Germany). DE 10 2008 009 933, 2008.
(48) Stark, A.; Ondruschka, B. In Handbook of Green Chemistry; Wass-
erscheid, P., Stark, A., Eds.; Wiley-VCH: Weinheim, 2010; Vol. 6, p
85.
Received for review February 23, 2010.
OP100055F
Vol. 14, No. 5, 2010 / Organic Process Research & Development
•
1109