Preparation of second generation ionic liquids by efficient solvent-free alkylation of N-heterocycles with chloroalkanes

Article abstract of DOI:10.3390/molecules13010149

Non-conventional techniques, such as microwave (MW) and power ultrasound (US) as well as combined MW/US irradiation, have been used to promote one-pot synthesis of second-generation ionic liquids (ILs), cutting down reaction times and improving yields. However, the use of chloroalkanes in the alkylation of N-heterocycles requires more drastic conditions if results are to match those obtained with more reactive alkyl halides. The present paper describes a series of MW- or MW/US-promoted IL preparations starting from chloroalkanes and classic heterocycles (1-methylimidazole, pyridine and 1-methylpyrrolidine). When reactions were carried out under conventional heating in an oil bath they required longer reaction times and gave poorer yields. ¹H-NMR analysis and ion-exchange chromatography showed that the present solventless procedure afforded ILs of satisfactory purity. The observed high yields (usually 70-98% isolated), and short reaction times showed that a straightforward access to ILs can be also achieved with the use of alkyl chlorides, resulting in a considerable reduction of costs.

Full text of DOI:10.3390/molecules13010149

Molecules 2008, 13, 149-156
molecules
ISSN 1420-3049
© 2008 by MDPI
www.mdpi.org/molecules
Full Paper
Preparation of Second Generation Ionic Liquids by Efficient
Solvent-Free Alkylation of N-Heterocycles with Chloroalkanes
Giancarlo Cravotto 1,*, Emanuela Calcio Gaudino 1, Luisa Boffa 1, Jean-Marc Lévêque 2, Julien
Estager 2 and Werner Bonrath 3
1
Dipartimento di Scienza e Tecnologia del Farmaco, Università di Torino, Via Giuria 9, 10125
Torino, Italy; E-mails: emanuela.calcio@unito.it; luisa.boffa@unito.it
2
Laboratoire de Chimie Moléculaire et Environnement, Polytech’Savoie, Université de Savoie,
73376 Le Bourget du Lac Cedex, France; E-mails: jean-marc.leveque@univ-savoie.fr;
julien.estager@univ-savoie.fr
3
DSM Nutritional Products, Research and Development, NRD/CC, Building-214/071, P.O. Box 3255,
CH 4002-Basel, Switzerland; E-mail: werner.bonrath@dsm.com
* Author to whom correspondence should be addressed; E-mail: giancarlo.cravotto@unito.it
Received: 24 December 2007; in revised form: 23 January 2008 / Accepted: 23 January 2008 /
Published: 25 January 2008
Abstract: Non-conventional techniques, such as microwave (MW) and power ultrasound
(US) as well as combined MW/US irradiation, have been used to promote one-pot
synthesis of second-generation ionic liquids (ILs), cutting down reaction times and
improving yields. However, the use of chloroalkanes in the alkylation of N-heterocycles
requires more drastic conditions if results are to match those obtained with more reactive
alkyl halides. The present paper describes a series of MW- or MW/US-promoted IL
preparations starting from chloroalkanes and classic heterocycles (1-methylimidazole,
pyridine and 1-methylpyrrolidine). When reactions were carried out under conventional
heating in an oil bath they required longer reaction times and gave poorer yields. 1H-NMR
analysis and ion-exchange chromatography showed that the present solventless procedure
afforded ILs of satisfactory purity. The observed high yields (usually 70-98% isolated),
and short reaction times showed that a straightforward access to ILs can be also achieved
with the use of alkyl chlorides, resulting in a considerable reduction of costs.
Keywords: Ionic liquids, chloroalkanes, one-pot reaction, microwaves, ultrasound.

Molecules 2008, 13
150
Introduction
The increasing interest in ionic liquids (ILs) is documented by the increasing publication rate of
papers dealing with their applications; this number was roughly about 20 papers per year around 1995,
rising to some 300 papers per year around 2001 [1] and it rose further to 2,500 in 2006. Although
scientific indicators predict a brilliant future for ILs, some major hurdles remian to be addressed before
their industrial use becomes routine, particularly regarding production costs, possible safety hazards,
as well as technical problems to be solved before preparative scale-up can be undertaken.
Second-generation ILs are halogen-free and stable in the presence of air and moisture [2, 3]. They
are usually prepared through two successive steps: 1) the alkylation of a nitrogen-bearing compound
(Menshutkin reaction) to yield first-generation halogenated ILs; 2) the exchange of halide with a
different anion (metathesis). Non-conventional techniques, such as irradiation with microwaves (MW)
[4] and power ultrasound (US) [5], whether used alone or in combination [6, 7], have considerably
improved the synthesis of ILs, cutting down reaction times and improving yields [8-14]. The recent
introduction of efficient, solventless, one-pot synthetic protocols [15-18] should certainly make ILs
cheaper and thus encourage a wider employ of these innovative reaction media. We present here
another significative contribution to this end showing that alkyl iodides and bromides can be
effectively replaced by the corresponding chlorides, which are much cheaper and readily available,
albeit much less reactive.
Results and Discussion
In a recent paper [17] we described the synthesis of 1-octyl-3-methylimidazolium
hexafluorophosphate ([C8mim][PF6]), starting from chlorooctane and working under simultaneous
MW/US irradiation in a cooled reactor. The reaction temperature was 140°C after an initial step (10
min) at 120°C to avoid overshooting the final temperature. The reaction was continued at 140°C for 20
min to afford the IL in nearly quantitative yield (98%, Table 1, entry 1a). It was by means of an
efficient cooling system that we could raise the MW energy input enough to sufficiently increase the
reactivity of the alkyl chloride without causing any attendant decomposition. In the present work we
extended our investigation to several other ILs by changing the heterocycle, the chloroalkane and the
anion source. With the aim to compare the effects of the different energy sources on the kinetics of this
reaction we carried it out at the same temperature under MW irradiation only (Table 1, entry 1b),
under conventional heating plus US irradiation (Table 1, entry 1c) and under conventional heating
alone for up to four hours (Table 1, entries 1d and 1e). Although longer reaction times were required,
even under the last-mentioned conditions good yields were achieved (84%). When the reaction
mixture, being heated in an oil bath, was irradiated with a 20 kHz US probe, the yield rose from 47 to
62% after one hour (Table 1, entry 1c).
We obtained 1-octyl-3-methylimidazolium tetrafluoroborate ([C8mim][BF4]) (95% yield) (Table 1,
entry 2) in 30 min (two irradiation steps). The preparation of 1-octyl-3-methylimidazolium triflate
([C8mim][OTf]) (Table 1, entry 3) and 1-octyl-3-methylimidazolium bis(trifluoromethanesulfon)imide
([C8mim][NTf2]) (Table 1, entry 4) took longer times (yields 65% and 72%, respectively, see Table 1).

Molecules 2008, 13
151
When the state-of-the-art is considered [3], these results represent a significant progress towards an
easier access to ILs.
Table 1. ILs synthesis under simultaneous MW/US irradiation in a cooled reactor or
under conventional heating in an oil bath. Reagents: 1-methylimidazole (1-mim) and
1-chlorooctane.
MW
power
(W)
90
US
power
(W)
40
Anion
source
Irradiation
time (min)
Temperature Yield
Entry
(°C)*
(%)
1a
1b
1c
1d
1e
2
KPF6
**10/20
60
120/140
140
98
88
62
47
84
95
65
72
KPF6
60
-
KPF6
60 (oil bath)
60 (oil bath)
240 (oil bath)
**10/20
-
40
140
KPF6
-
-
140
KPF6
-
-
140
KBF4
KOTf
LiN(Tf)2
75
40
120/140
120/140
120/140
3
**10/45
**10/90
85
45
4
110
45
*Measured by optical-fibre thermometer. **Two temperature steps.
After these outstanding results, we applied the same MW/US procedure to the synthesis of ILs with
1-butyl-3-methylimidazolium and N-octylpyridinium cations. In either case, however, because higher
temperatures were necessary to achieve N-alkylation [180°C for pyridine (pyr) and 140°C for
1-methylimidazole], operative difficulties arose in the use of the combined MW/US reactor. In fact the
reaction temperature could not exceed the boiling points of pyridine and 1-chlorobutane (115°C and
78°C, respectively) because the MW/US combined reactor is an "open vessel" system. Scheme 1
summarizes the overall synthetic strategy.
Scheme 1. General synthetic procedure.
CnH2n+1
N
N
N
N
A
simultaneous MW/US
or
MW closed-vessel
+
+ C H2n+1Cl
n
MA
A
120° - 180°C
N
N
N
CnH2n+1
M = K+, Li+
A
N
-
-
-
A = PF6 , BF4 , OTf-, N(Tf)2
CnH2n+1
n = 4, 8

Molecules 2008, 13
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While the syntheses of 1-butyl-3-methylimidazolium and N-octylpyridinium chlorides, attempted
with this system (at 75°C and 100°C, respectively), were unsuccessful (Table 2, entries 2 and 5),
excellent yields were obtained under MW irradiation in a closed vessel at 180°C (98% C4mimCl and
85% C8PyCl; see Table 2, entries 3 and 6). N-Alkylation of 1-methylpyrrolidine also was strongly
temperature-dependent. The same reaction was carried out under MW irradiation in a closed vessel at
120°C, 160°C and 180°C (two-step temperature increases; Table 2, entries 8, 9 and 10). At 120°C, no
IL was formed, while at 180°C a quantitative yield was obtained. The N-alkylation of 1-methyl-
imidazole, pyridine and 1-methylpyrrolidine was carried out under conventional heating in a closed
vessel (Table 2, entries 1, 4 and 7). Reaction yields were comparable with those obtained under MW
irradiation, while reaction times were considerably longer.
Table 2. N-alkylation of heterocycles under conventional heating, simultaneous MW/US
irradiation or MW in a closed vessel.
Entry Heterocycle*
Alkyl
halide
Irradiation
time (min)
MW
power
(W)
US
power
(W)
Temperature Yield
(°C)
(%)
(1 or 2 steps)
1
2
1-mim
1-mim
1-mim
pyr
1-ClC4
1-ClC4
1-ClC4
1-ClC8
1-ClC8
1-ClC8
1-ClC8
1-ClC8
1-ClC8
1-ClC8
**60/240
-
120***
85
-
30
-
140/180
75
95
<5
98
80
<5
85
88
0
150
3
10/30
**60/240
180
120/180
140/180
100
4
-
-
5
pyr
60***
25
-
6
pyr
10/30
**60/240
10/60
15/50
15/50
85
120/180
140/180
80/120
120/160
120/180
7
1-mpyr
1-mpyr
1-mpyr
1-mpyr
-
-
8
40
-
9
80
-
20
99
10
90
-
*1-mim: 1-methylimidazole; pyr: pyridine; 1-mpyr: methylpyrrolidine.
** Reactions were carried out in a pressure-resistant Pyrex tube, heated in an oil bath.
*** Cooled reactor [8].
Successively we applied the MW procedure (closed vessel) to the one-pot synthesis of several 1-
butyl-3-methylimidazolium and N-octylpyridinium second-generation ILs. The alkyl chloride,
heterocycle and anion source were placed in a pressure-resistant reactor and irradiated with MW under
vigorous magnetic stirring. The reaction temperature was raised up to 180°C after an initial step (10-15
min) at 120°C, which allowed the heterogeneous system to gain a more regular heating ramp. The
reaction was then continued at 180°C for 30-50 min (Table 3).
[C4mim][PF6], [C4mim][BF4] and [C4mim][OTf] (Table 3, entries 1, 2 and 3, respectively) were
obtained in good yields (72-90%), while a slightly lower yield (62%) was found for [C4mim][N(Tf)2]

Molecules 2008, 13
153
(Table 3, entry 4). This result can probably be justified by the lower polarization degree of the N(Tf)2-
anion, hence its lower sensitivity to MW.
Good yields (>60%) were also achieved for [C8Py][PF6], [C8Py][BF4] and [C8Py][OTf] (Table 3,
entries 5, 6 and 7, respectively) while [C8Py][NTf2] (Table 3, entry 8) could not be synthesized in
one-pot with this procedure. Although the peculiar behaviour of the reaction with LiN(Tf)2 had already
been observed [15], we have no explanation for this failure, considering the good results achieved with
1-mim (see Table 1). The low boiling point of 1-methylpyrrolidine (1-mpyr) (80°C) forced us to use
the closed-vessel system exclusively. A comparison of reactions carried out at different temperatures
showed that it was necessary to reach 180°C in order to obtain a quantitative yield for 1-methyl-1-
octylpyrrolidinium chloride (Table 2, entry 10). Yields close to 80% were achieved in less than 1 h for
different 1-methyl-1-octylpyrrolidinium ILs (Table 3, entries 9 -11).
Table 3. MW-assisted one-pot RTIL synthesis (closed vessel)*.
Alkyl
Anion
Irradiation MW power Yield
Entry Heterocycle**
halide source
steps (min)
15/30
10/30
15/40
10/30
15/50
10/40
10/50
15/50
15/35
10/45
10/45
(W)
60
(%)
90
1
2
1-mim
1-mim
1-mim
1-mim
pyr
1-ClC4
1-ClC4
1-ClC4
KPF6
KBF4
KOTf
55
72
3
65
75
4
1-ClC4 LiN(Tf)2
65
62
5
1-ClC8
1-ClC8
1-ClC8
KPF6
KBF4
KOTf
65
83
6
pyr
60
68
7
pyr
55
60
8
pyr
1-ClC8 LiN(Tf)2
65
traces
85
9
1-mpyr
1-mpyr
1-mpyr
1-ClC8
1-ClC8
1-ClC8
KPF6
KBF4
KOTf
95
10
11
113
81
104
79
*Carried out with two temperature steps, 120° and 180°C.
**1-mim: 1-methylimidazole; pyr: pyridine; 1-mpyr: methylpyrrolidine.
Conclusions
In summary, we have developed a simple, efficient and rapid one-pot procedure to synthesize
second generation Ils, which made it possible to use poorly reactive but inexpensive alkyl chlorides.
MW/US combined irradiation and closed-vessel MW have proven to be advantageous activation
techniques that dramatically increase yields and purity levels of products, cutting down reaction times.
Low-boiling chloroalkanes and heterocycles required the closed-vessel MW procedure. Under
conventional heating in pressure-resistant Pyrex tubes, the reaction occurred in longer reaction times,
often with acceptable yields.

Molecules 2008, 13
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Synthesized ILs were purified during the workup (extraction from water with organic solvents or
washes with water or diethyl ether). Isolated yields of ILs were calculated as mean values from three
experiments. Through 1H-NMR [19], we could establish a >95% purity degree (for organic impurities)
and through ion-exchange chromatography we evaluated inorganic impurities, such as free halide
content in second generation ILs (falling in the range 200-2500 ppm).
Experimental
General
Commercially available reagents were used without further purification. Reactions were carried
out in a closed vessel in a professional multimode oven (Microsynth - Milestone, BG - Italy). For
simultaneous MW/US irradiation the oven was equipped with a US probe featuring a pyrex® horn
(frequency 21.4 kHz, tip diameter 17 mm) developed in the author’s laboratory at the University of
Turin in collaboration with Danacamerini sas (TO - Italy) [7]. The reactor was efficiently cooled by
circulation of a MW-inert liquid (Galden H270, Solvay-Solexis, MI - Italy) refrigerated at 2°C by a
chiller. The US probe (20 kHz, max power 250 W) with a titanium horn is commercially available
1
from Danacamerini sas. IR spectra were recorded on a Shimadzu FT-IR8001 spectrophotometer; H-
13
and C-NMR spectra on a Bruker Avance 300 spectrometer, respectively at 300 and 75MHz (25°C).
Chemical shifts were calibrated to the CDCl3 residual peak (7.27 for 1H- and 77.16 for 13C NMR).
General procedure
1-Methylimidazole, pyridine or 1-methylpyrrolidine (40 mmol), the appropriate salt for anion
exchange (40 mmol) and the chloroalkane (40 mmol) were placed either in a 100 mL two-necked
round-bottomed flask (for simultaneous MW/US irradiation) or in a pressure-resistant reactor
(Milestone) for MW irradiation in a closed vessel. Reactions under conventional heating in a
thermostatted oil bath were carried out in a pressure-resistant Pyrex tube while for US irradiation a
titanium horn was inserted in the flask containing the reaction mixture. Reaction times, operating
power and temperatures are reported in the tables. The reaction mixtures were poured into acetone
(100 mL) and filtered on a Celite® pad, then the solvent was removed under vacuum. Hydrophobic ILs
were washed with water (4x20 mL) and diethyl ether (4x20 mL), to be finally dried under vacuum at
90°C (3 h). Hydrophilic ILs were dissolved in water (50 mL) and extracted with dichloromethane
(4x25 mL); solvents were removed under vacuum and products washed with diethyl ether (4x20 mL)
1
13
to be finally dried at 90°C under vacuum (3 h). All products were analyzed by H- and C-NMR, IR
spectroscopy as well as ion-exchange chromatography thereby confirming their structures and a
satisfying degree of purity. Yield values are averages from the results of two/three experiments.
Acknowledgements
This work has been carried out under the auspices of the European Union COST Action D32
(Working Group D32/006). MIUR (FIRB 2003) and Regione Piemonte (CIPE 2004), are grateful
acknowledged for financial support.

Molecules 2008, 13
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Sample Availability: Samples of all the compounds described herein are available from the authors.
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