Ionic liquid droplet as e-microreactor

Article abstract of DOI:10.1021/ac060481q

A powerful approach combining a droplet-based, open digital microfluidic lab-on-a-chip using task-specific ionic liquids as soluble supports to perform solution-phase synthesis is reported as a new tool for chemical applications. The negligible volatility of ionic liquids enables their use as stable droplet reactors on a chip surface under air. The concept was validated with different ionic liquids and with a multicomponent reaction. Indeed, we showed that different ionic liquids can be moved by electrowetting on dielectric (EWOD), and their displacement was compared with aqueous solutions. Furthermore, we showed that mixing ionic liquids droplets, each containing a different reagent, in "open" systems is an efficient way of carrying supported organic synthesis. This was applied to Grieco's tetrahydroquinolines synthesis with different reagents. Analysis of the final product was performed off-line and on-line, and the results were compared with those obtained in a conventional reaction flask. This technology opens the way to easy synthesis of minute amounts of compounds ad libitum without the use of complex, expensive, and bulky robots and allows complete automation of the process for embedded chemistry in a portable device. It offers several advantages, including simplicity of use, flexibility, and scalability, and appears to be complementary to conventional microfluidic lab-on-a-chip devices usually based on continuous-flow in microchannels.

Full text of DOI:10.1021/ac060481q

Anal. Chem. 2006, 78, 4909-4917
Ionic Liquid Droplet as e-Microreactor
Philippe Dubois,†,§ Gilles Marchand,*,† Yves Fouillet,† Jean Berthier,† Thierry Douki,‡ Fatima Hassine,§
Said Gmouh,§ and Michel Vaultier*,§
Department of Technology for Biology and Health, CEA/LETI, 17 rue des Martyrs, 38054 Grenoble, France, Department of
Basic Research into Condensed Mater, CEA/DSM, 17 rue des Martyrs, 38054 Grenoble, France, and Institute of Chemistry,
University of Rennes1, UMR CNRS 6510, 263 avenue Ge´ne´ral Leclerc, 35042 Rennes, France
reactions and producing the desired products faster and in greater
yield and purity. However, these microsystems, usually consisting
of a network of micrometer-sized channels embedded into a solid
substrate, suffer from several drawbacks, such as large dead
volumes or frequent obstruction of the channels. Moreover, in
continuous flow microfluidic systems, constant hydrodynamic
pressure can be difficult to maintain (especially for viscous liquids),
or surface charges are hard to control (when an electroosmotic
pumping is used). In an attempt to avoid these problems, Zheng
and Ismagilov7 have described a continuous flow microfluidic
system in which droplets are separated by liquid spacers, but
complex protocols are relatively difficult to perform with this
system. To overcome all these difficulties, it has been proposed8,9
that droplet microreactors containing reagents, samples, etc.,
could be displaced on two-dimensional chips (as opposed to
microfluidic channels) by various fluidic actuators, such as
acoustic waves or, more often, electrowetting on dielectric
(EWOD). Those droplet microfluidic systems have several ad-
vantages, such as complex fluidic connections and associated
problems (as previously described) can be avoided. Furthermore,
this so-called digital10 approach gives great flexibility in the
creation and handling of droplet microreactors. We, thus, decided
to use this technology in our attempt to create a chemical
microprocessor.
Most of the applications reported so far, however, are biological
reactions, such as PCR (polymerase chain reaction),11,12 and are
performed in aqueous solvents, which are often not suitable for
chemical synthesis. Only recent works have described the use of
organic solvents in such systems.13 Furthermore, volatile organic
solvent (VOS) droplets evaporate very rapidly in open microsys-
tems due to their high volatility. On the other hand, manipulating
VOS droplets in closed microsystems or under oil would introduce
other problems, such as complications in the fluidic connections
(comparable to microchannel systems), cross-contaminations, and
oil/solvent miscibility. Using digital microfluidic “open” systems
A powerful approach combining a droplet-based, open
digital microfluidic lab-on-a-chip using task-specific ionic
liquids as soluble supports to perform solution-phase
synthesis is reported as a new tool for chemical applica-
tions. The negligible volatility of ionic liquids enables their
use as stable droplet reactors on a chip surface under air.
The concept was validated with different ionic liquids and
with a multicomponent reaction. Indeed, we showed that
different ionic liquids can be moved by electrowetting on
dielectric (EWOD), and their displacement was compared
with aqueous solutions. Furthermore, we showed that
mixing ionic liquids droplets, each containing a different
reagent, in “open” systems is an efficient way of carrying
supported organic synthesis. This was applied to Grieco’s
tetrahydroquinolines synthesis with different reagents.
Analysis of the final product was performed off-line and
on-line, and the results were compared with those ob-
tained in a conventional reaction flask. This technology
opens the way to easy synthesis of minute amounts of
compounds ad libitum without the use of complex,
expensive, and bulky robots and allows complete automa-
tion of the process for embedded chemistry in a portable
device. It offers several advantages, including simplicity
of use, flexibility, and scalability, and appears to be
complementary to conventional microfluidic lab-on-a-chip
devices usually based on continuous-flow in microchan-
nels.
In recent years, lab-on-a-chip systems dedicated to biotechno-
logical and chemical applications have attracted growing interest.1-6
Compared to traditional batch reaction, miniaturized systems allow
the use of very small quantities of reagents while optimizing the
* Address correspondence to either author. (Marchand) Fax: 33-43878-
5787. E-mail: gilles.marchand@cea.fr. (Vaultier) Fax: 33-223236955. E-mail:
michel.vaultier@univ-rennes1.fr.
† CEA/LETI.
‡ CEA/DSM.
§ University of Rennes1.
(7) Zheng, B.; Ismagilov, R. F. Angew. Chem., Int. Ed. 2005, 44, 2520-2523.
(8) Taniguchi, T.; Torii, T.; Higuchi, T. Lab Chip 2002, 2, 19-23.
(9) Pollack, M. G.; Shenderov, A. D.; Fair, R. B. Lab Chip 2002, 2, 96-101.
(10) Gong, J.; Fan, S.-K.; Kim, C.-J. Tech. Dig. IEEE Int. Conf. Micro Electro Mech.
Syst.′, 17th, Maastricht, The Netherlands, January 25-29, 2004, p 355.
(11) Srinivasan, V.; Pamula, V. K.; Fair, R. B. Lab Chip 2004, 4, 310-315.
(12) Fouillet, Y.; Jary, D.; Brachet, A. G.; Chabrol, C.; Boutet, J.; Clementz, P.;
Lauro, D.; Charles, R.; Peponnet, C. Micro Total Anal. Syst. 2005, Boston,
MA, 2005, pp 59-69.
(1) Fletcher, P. D. I.; Haswell, S. J.; Pombo-Villar, E.; Warrington, B. H.; Watts,
P.; Wong, S. Y. F.; Zhang, X. Tetrahedron 2002, 58, 4735-4757.
(2) Pennemann, H.; Watts, P.; Haswell, S.; Hessel, V.; Lo¨we, H. Org. Proc. Res.
Dev. 2004, 8, 422-439.
(3) Watts, P.; Haswell, S. Chem. Eng. Technol. 2005, 28, 290-302.
(4) Watts, P.; Haswell, S. Chem. Soc. Rev. 2005, 34, 235-246.
(5) Marchand, G.; Delattre, C.; Campagnolo, R.; Pouteau, P.; Ginot, F. Anal.
Chem. 2005, 77, 5189-5195.
(6) Mallard, F.; Marchand, G.; Ginot, F.; Campagnolo, R. Biosens. Bioelectron.
(13) Chatterjje, D.; Hetayothin, B.; Wheeler, A. R.; King, D. J.; Garrell, R. L. Lab
Chip 2006, 6, 199-206
2005, 20, 1813-1820.
10.1021/ac060481q CCC: $33.50 © 2006 American Chemical Society
Published on Web 05/26/2006
Analytical Chemistry, Vol. 78, No. 14, July 15, 2006 4909

Figure 1. (A) Picture of the chip (10 mm × 7 mm). (B) Schematic representation of the chip. Each electrode (1) ((800 µm)2), of the matrix is
electrically connected to a conducting layer (2). The electrodes (1) were covered with an insulating (3) and hydrophobic (4) layer. The chip has
a first catenary (25-µm diameter) (5), essential for the electrowetting, and a second (6), allowing two electrodes for electrochemical measurements.
A generator (7) is connected to the electrodes.
(with no coverage) has several advantages from a technological
point of view, as we recently suggested.14 We therefore decided
to use ionic liquids (ILs) in our chemical microprocessor,
assuming that these particular solvents could be used in open
microsystems without evaporating.
Recent works have explored the behavior of some RTILs in
electrowetting,s13,30 but the authors did not describe associated
applications. In our study, we have explored the possibility of using
droplets of RTILs and TSILs as stable microreactors on an open
digital microfluidic chip11 using electrowetting on dielectric as the
fluidic actuator. This rapidly appeared to be a very promising
approach for low-volume organic synthesis in solution. The very
low evaporation rate of ionic liquids allows handling of very small
volume droplets without cover or oil, thus simplifying the experi-
ments, facilitating direct access to the droplets, and avoiding
possible cross-contaminations within the oil layer between drop-
lets. Furthermore, complex protocols can be achieved on such a
system due to the easy displacement of droplets by EWOD. In
this paper, we describe our results, showing the specific behavior
of ionic liquids when subjected to EWOD actuation, and the use
of this powerful technology for the easy handling of reagents and
efficient completion and monitoring of a multicomponent reaction.
Ionic liquids have recently attracted considerable attention.
Some of them, the so-called room temperature ionic liquids
(RTILs), are free-flowing liquids at room temperature. Due to their
negligible vapor pressure, they are considered “greener” alterna-
tives to VOSs. Numerous applications of RTILs as nonaqueous
polar alternatives in biphasic systems, as extraction solvents,15 or
as electrolytes16,17 have been reported. They are also used in
organic synthesis18-21 and organometallic or enzymatic22 catalysis.
Moreover, a unique subclass of ionic liquids, task-specific ionic
liquids (TSILs) have greatly widened the utilization scope of ionic
liquids.23-27 Their functional groups, covalently linked to the cation,
the anion, or both, confer additional properties to these salts,
thereby expanding their potential applications far beyond those
of conventional ionic liquids. Moreover, TSILs and RTILs can be
combined in solutions. Hence, supported synthesis in a homoge-
neous solution can be achieved, which is a major advantage.28,29
EXPERIMENTAL SECTION
Description of the Chip. In our system, as shown in Figure
1, the chip consists of a network of gold electrodes structured on
silicon; a dielectric layer to avoid electrochemical reactions during
the actuation of electrodes; a hydrophobic layer, necessary to
obtain a contact angle compatible with electrowetting; and a gold
microcatenary, which enables the polarization of the droplet and
its guidance during displacement. These experiments were
performed under air in an “open” microsystem. A second catenary
that allows electrochemical measurements between the first and
the second catenaries can be added. To generate droplets from a
reservoir (“closed” microsystem), the first catenary can be
replaced by a plate recovered with a metallic transparent layer
(indium tin oxide) and a Teflon layer.
Fabrication of the Device. In this technology, one wafer of
silicon and one microstructured metal layer are needed. After
performing wet oxidation (2 µm) on the wafer, the gold electrodes
((800 µm)2) were formed by deposition of a 5-nm layer of Cr and
then 300 nm of Au on the wafer, followed by patterning using
standard microfabrication techniques. Next, the wafer was coated
with a 300-nm layer of silicon nitride (ꢀR ) 7.8) deposited by
PECVD followed by an etching of this layer for electrical contact.
(14) Fouillet, Y.; Jeanson, H.; Jary, D.; Constantin, O.; Vauchier, C. Proc. 7th Int.
Conf. Miniaturized Chem. Biochem. Anal. Syst. October 5-9, 2003, 61.
(15) Visser, A.; Swatloski, R. P.; Reichert, W. M.; Mayton, R.; Sheff, S.; Wierzbicki,
A.; Davis, J. H., Jr.; Rogers, R. D. Chem. Commun. 2001, 135-136.
(16) Yoshizawa, M.; Narita, A.; Ohno, H. Aust. J. Chem. 2004, 57, 139-144.
(17) Lagrost, C.; Carrie´, D.; Vaultier, M.; Hapiot, P. J. Phys. Chem. A 2003, 107,
745-752.
(18) Wasserscheid, P.; Welton, T. Ionic Liquids in Synthesis; Wiley-VCH: Wein-
heim, Germany, 2003.
(19) Rogers, R. D.; Seddon, K. R. Science 2003, 302, 792-793.
(20) Welton, T. Chem. Rev. 1999, 99, 2071-2083.
(21) Fraile, J. M.; Garcia, J. I.; Herrerias, C. I.; Mayoral, J. A.; Carrie´, D.; Vaultier,
M. Tetrahedron: Asymmetry 2001, 12, 1891-1894.
(22) Lozano, P.; De Diego, T.; Carrie´, D.; Vaultier, M.; Iborra, J. L. Chem.
Commun. 2002, 692-693.
(23) Fraga-Dubreuil, J.; Bazureau, J. P. Tetrahedron Lett. 2001, 42, 6097-6100.
(24) Hakkou, H.; Vanden Eynde, J. J.; Hamelin, J.; Bazureau, J. P. Tetrahedron
2004, 60, 3745-3753.
(25) Handy, S. T.; Okello, M. J. Org. Chem. 2005, 70, 2874-2877.
(26) Visser, A. E.; Swatloski, R. P.; Reichert, W. M.; Mayton, R.; Sheff, S.;
Wierzbicki, A.; Davis, J. H., Jr.; Rogers, R. D. Environ. Sci. Technol. 2002,
36, 2523-2529.
(27) Davies, J. H., Jr. Chem. Lett. 2004, 33, 1072-1077.
(28) Vaultier, M.; Gmouh, S. French patent nï. FR 2845084 application nï. 2002-
11910, WO 2004 029004.
(29) Vaultier, M.; Gmouh, S.; Hassine, F. French patent nï. FR 2857360,
application nï. 2003-8413, WO 2005 005345.
(30) Millefiorini, S.; Traczyck, A. H.; Sedev, R.; Efthimiadis, J.; Ralston, J. J. Am.
Chem. Soc. 2006, 128, 3098-3101.
4910 Analytical Chemistry, Vol. 78, No. 14, July 15, 2006

After sawing off the wafer, an ∼1-µm spin-coated layer of
amorphous Teflon-AF-1601 of DuPont (ꢀR ) 1.9) was deposited
on the chips.
Packaging of Chips. The chips (10 mm × 7 mm) were glued
on a PCB support and connected by wire bonding (gold wires,
25 µm). The wire bonding machine was also used to create a
network of thin metallic catenaries (25 µm) over the chip, required
for EWOD actuation.
Electrowetting Curves. The contact angle of a 1-µL droplet
on the surface was measured with a commercial apparatus
(Digidrop from GBX) with an image software using the drop
profile method. The software calculates the contact angle from
the fit of the drop shape. The voltage was supplied by an AC
voltage generator. The frequency was fixed at 3 kHz. The
generator delivers an efficient variable output of 0 to 90 V (rms).
Instrumentation. The packaged chip was connected to
electrical switches driven by a computer that can activate the
different electrodes and control the displacement of droplets.
Voltammetric measurements for detection were performed on
a chip connected to an EGG-PAR model 283 potentiostat equipped
with Echem software.
Reagents. Indene, 4-nitroaniline, 4-bromoaniline, aniline, 4-bro-
mobenzaldehyde, 4-nitrobenzaldehyde, and trifluoroacetic acid
were purchased through Aldrich-Sigma and used without further
purification.
Ionic Liquids Preparation. 1-Butyl-3-methylimidazolium tet-
rafluoroborate [bmim][BF4] (B) and 1-butyl-3-methylimidazolium
hexafluorophosphate [bmim][PF6] (C) are commercially available
(Merck KGaA) and were used without further purification. The
other ionic liquids were synthesized according to protocols
established in the laboratory and described in the Supporting
Information.
Grieco’s Reaction. Synthesis of [3-(4-formylbenzoyloxy)-propyl]-
trimethylammonium tetrafluoroborate 1. In a sealed flask, to one
equiv of 1-chloropropan-3-ol was added 2 equiv of trimethylamine
(45 wt % aqueous solution) and the minimum volume of acetoni-
trile to obtain a monophasic reaction medium. The flask was
heated to 70 °C overnight. After elimination of volatiles and
solvents under vacuum, the residue was washed with diethyl ether
and recrystallized from acetone, leading to a white solid. To 1
equiv of 3-hydroxypropyltrimethylammonium chloride dissolved
in acetonitrile were added 1.5 equiv of N,N′-dicyclohexylcarbodi-
imide, 1.5 equiv of 4-carboxybenzaldehyde, and 0.02 equiv of
4-(dimethylamino)pyridine. The reaction was carried out in a flask
at room temperature for 4 h. Solvents were removed by vacuum
distillation, and the ester created was removed by washing with
water. A 1.5-equiv portion of HBF4 (50% water solution) was added
to the previous ester and mixed for 2 h at room temperature. After
filtration and evaporation of water, product 1 was obtained as a
white solid. Yield: 90%. 1H NMR (200 MHz, CD3CN) δ: 2.10-2.33
(m, 2H), 3.05 (s, 9H), 3.36-3.55 (m, 2H), 4.45 (t, 2H, J ) 5.8 Hz),
8.00 (dd, 2H, J1 ) 1.6 Hz, J2 ) 6.6 Hz), 8.13 (dd, 2H, J1 ) 1.4 Hz,
J2 ) 8.3 Hz), 10.10 (s, 1H). 13C NMR (50 MHz, CD3CN) δ: 22.08,
52.66 (t, J ) 3.8 Hz), 61.53, 63.52 (t, J ) 3.0 Hz), 129.10, 129.80,
134.39, 139.27, 164.89, 192.04. ESI-MS for C+: calcd, 250.3; found,
250.2.
pyltrimethylammonium chloride (see synthesis above) dissolved
in acetonitrile were added 1.5 equiv of N,N′-dicyclohexylcarbodi-
imide, 1.5 equiv of 4-nitrobenzo¨ıc acid, and 0.02 equiv of 4-(di-
methylamino)pyridine. The reaction was carried out in a flask at
room temperature for 4 h. Solvents were removed by vacuum
distillation, and the ester created was removed by washing with
water. Afterward, the reduction of the nitro group was performed
by the addition of 0.01 equiv of Pd/C and stirring at room
temperature under 5 bar pressure of hydrogen for 48 h. The
metathesis was performed by adding 1.1 equiv of bis(trifluorom-
ethylsulfonyl)imide lithium dissolved in the minimum of water.
After 2 h of stirring at room temperature, water was eliminated,
and the solution was washed with diethyl ether. After filtration
and evaporation of water, product 5 was obtained as a white solid.
Yield: 93%. 1H NMR (200 MHz, acetone-d6): 2.35-2.54 (m, 2H),
3.41 (s, 9H), 3.78-3.92 (m, 2H), 4.5 (t, 2H), 5.51 (s, 2H), 6.58 (d,
2H), 7.84 (d, 2H). 13C NMR (50.32 MHz, acetone d6) δ: 24.17,
54.12 (t, JC-N ) 4.1 Hz), 61.72, 65.60, 114.25, 118.33, 121.17 (q,
JC-F ) 320.9 Hz), 132.72, 154.74, 167.08. HRMS (FAB) for (2C+,
NTf2-)+: calcd, 754.2379; found 754.2379.
Synthesis of the Internal Reference M. In a seal flask, to 1 equiv
of 3-hydroxypropyltrimethylammonium chloride (see synthesis
above) dissolved in acetonitrile was added 1.2 equiv of bis-
(trifluoromethylsulfonyl)imide lithium dissolved in the minimum
of water. After 2 h of stirring at room temperature, water was
eliminated, and the solution was washed with diethyl ether. To 1
equiv of this alcohol dissolved in acetonitrile 1.1 equiv of dansyl
chloride dissolved in CH2Cl2 and 1.2 equiv of K2CO3 was added,
and the mixture was mixed 36 h at room temperature. After
evaporation of organic solvents, the mixture was washed with
diethyl ether and then with water. The internal reference (yellow
solid) was obtained after vacuum evaporation of residual solvents.
Yield ) 10%. 1H NMR (200 MHz, acetone-d6) δ:2.35 (m, 2H), 2.93
(s, 6H), 3.37 (s, 9H), 3.64 (m, 2H), 4.21 (t, 2H), 7.35 (d, 1H), 7.65-
7.8 (q, 2H), 8.2-8.35 (q, 2H), 8,72 (d, 1H). 13C NMR (200 MHz,
acetone-d6) δ: 23.03, 45.00, 53.10 (JC-N ) 4.1 Hz), 63.5, 67.8, 116.1,
117.1, 119.2, 123.8, 129.2, 129.8, 131.0, 131.2, 132.0. ESI-MS for
C+: calcd, 351.17; found, 351.27.
Reaction in Droplets. Three solutions were prepared: solu-
tion A, a 0.20 M solution of 1 or 5 dissolved by heating in [tmba]-
[NTf2] (1 equiv); solution B, a 0.5 M solution of the respective
aniline (2a, 2b, or 2c) or benzaldehyde (6a or 6b); and solution
C, a 2 M solution of indene 3 (10 equiv) in the same solvent as
1. The TFA (10 equiv) was added in solution A with 1 or in
solution B with 5. To determine the conversion rate, the internal
reference, M, was added at a concentration of 0.02 M in solution
A. Drops of 0.3 µL of solutions A, B, and C were deposited on the
chip using an Eppendorf micropipet. The drops were merged
successively. All displacement and merging were performed with
a tension of 55 V rms. The actuation of electrodes was switched,
and the reaction was carried out at room temperature for 1 h.
After incubation, either the droplet was analyzed by electrochemi-
cal detection or it was taken off with a micropipet and the reaction
was quenched by washing with a large excess of diethyl ether.
Residual ether was removed under vacuum. Samples were diluted
in 50 µL of a 1:1 mixture of acetonitrile/water, and 10 µL of each
was injected into the HPLC. Samples were analyzed using a
column Supelcosil C18 LC-318 on a Waters Alliance 2695 HPLC
Synthesis of 3-[(4-aminobenzoyloxy)-propyl]-trimethylammonium
Bis(trifluoromethylsulfonyl)imide 5. To 1 equiv of 3-hydroxypro-
Analytical Chemistry, Vol. 78, No. 14, July 15, 2006 4911

Figure 2. (A) Principle of electrowetting on dielectric (EWOD). The contact angle (θ) of the droplet is modified when a voltage is applied
between the surface and the catenary. (B) Chemical synthesis mechanism on an e-microreactor (see Experimental Section) followed by the
off-line or on-line analysis of the final product. An ionic liquid droplet containing a given reagent is moved on the chip by EWOD and merged
with the other ionic liquid droplets containing the other reagents. (C) Left: design of a multiplexed chip8 that would allow performing synthesis
in parallel. Right: example of a complex fluidic processor12 (26 mm × 21 mm) designed for parallel syntheses. (a) Electrode bus for fluidic
communication (1 mm2 for each electrode), (b) reservoir entry, (c) reagent storage and dispensing (volume, 1-3 µL), and (d) reservoir for TSIL
dispensing (volume, 100 nL).
and Waters UV detector 2487 at 254 nm. The rest of the samples
were diluted in 1 mL of a 1:1 mixture of acetonitrile/water and
analyzed by ESI-MS in a Thermo LTQ with glass picotip.
Electrospray ionization was carried out in the positive mode at
an ionization potential of 1300 V. Scans were recorded at 20 scans/
min.
HPLC (off-line analysis), or directly on the chip, that is, by
electrochemical measurement, as discussed in this article (on-
line analysis). The latter opens the way to complete automation
of the synthesis process for completely integrated (embedded)
chemistry on a portable device.
Finally, the simplicity and flexibility of EWOD actuation
combined with the possibility of multiplexing8,10,31 reactions on
two-dimensional chips offer the opportunity to design powerful
tools for high-throughput combinatorial synthesis of organic
compounds, protocol optimization, or multistep synthesis, as
shown in Figure 2C.
Constitutive Law of Ionic Liquids under EWOD Actuation.
The EWOD technology is based on the observation that an
electrical field modifies the contact angle of a conducting droplet
on a hydrophobic substrate11 (Figure 2A). This principle is
described by the Lippmann-Young equation (eq 1) and was first
reported by Berge,32
RESULTS AND DISCUSSION
Principle of the System. The electronic microreactor (e-
microreactor, Figure 2) described in this paper is an “open” digital
microfluidic chip on which electrowetting on dielectric (EWOD)
actuation is used to displace ionic liquid droplets.
Electrowetting on dielectric is an actuation mechanism used
for conducting liquids; it is based on the principle of controlling
the surface’s wetability by applying a voltage. EWOD actuation
thus allows moving and merging ionic liquid droplets (microre-
actors) containing different reagents in a very flexible way.
Moreover, the negligible vapor pressure of ionic liquids allows
handling very small liquid volumes (<1 µL) on open microsys-
tems. Chemical syntheses with minute amounts of reagents
(especially useful for potentially explosive or expensive reactions)
are, therefore, made possible. The reactions can be achieved in
solution using ionic liquid matrixes, such as RTILs. Moreover,
supported chemistry could be achieved on soluble supports, such
as TSILs. In this case, the excess of reagents and byproducts could
be eliminated at the end of the reaction by simply washing or
heating the droplets. The final product can be analyzed either by
an external detection system, such as mass spectrometry or by
1 C
2 γLG
cos θ ) cos θ0 +
V 2
(1)
where θ0 is the natural contact angle, θ is the contact angle when
the electric field is actuated, C is the capacitance per surface unit
of the layer between the electrodes and the liquid, V is the applied
(31) Fan, S. K.; Hashi, C.; Kim, C. J. IEEE Conf. MEMS, Kyoto, Japan, Jan. 2003,
694.
(32) Berge, B. Acade´mie des Sciences, C. R. t.317, se´rie II, 1993, 157-163.
4912 Analytical Chemistry, Vol. 78, No. 14, July 15, 2006

Figure 3. Langevin’s function for the NH4HCO3 25mM + 0.05% Tween 20 buffer, deionized water, and various ionic liquids. Contact angles
were measured on 1-µL droplets.
In Figure 3, the calculated curve (Langevin’s function) and our
experimental data for biological buffers with surfactants, DI water,
and ionic liquids have been superimposed. We thus observed that
the Langevin’s function could be used to fit empirically the
electrowetting curves. Thus, it appears that, similar to biological
buffers and water, ionic liquids follow the same extended Lipp-
mann-Young law. Therefore, ILs, biological buffers, and water
are ruled by the same constitutive law; however, we should note
that for water and for the biological buffer, the experimental points
do not fit perfectly with the Langevin function. This fact is certainly
due to the evaporation of those solutions, whereas for ionic liquids,
which are not sensitive to evaporation, data points fit well with
Langevin function, except for the first two or three points (this
fact is not fully understood yet).
Finally, an estimation of the hysteresis for different RTILs on
Teflon under air was performed from the advancing and receding
angles on electrowetting curves. Thus, values around 2-3° for
[tmba][NTf2], [bmim][NTf2], and [C10H20NO3][NTf2]; around 7°
for [bmim][BF4]; and 8° for [bmim][PF6] were determined.
Moreover, the hysteresis seems to depend on the nature of the
anion.
Motion of Ionic Liquids. As shown in Table 1, ionic liquids
demonstrated particular behaviors on a hydrophobic surface under
air, as compared to water. These particular behaviors are smaller
contact angles (θ0 ) 70-94° for ILs versus 110° for water) and
low surface tensions (34-46 mN/m for RTILs versus 72 mN/m
for water). An addition of 1% Tween 20 to water was necessary to
obtain contact angles and surface tensions close to ionic liquids
values. Furthermore, their contact angle at saturation (θs) is
smaller than water. It is also important to notice that the studied
ILs exhibit very high viscosity values (η), between 80 and 300
cP, as compared to 0.89 cP for water, at 25 °C.35
voltage, and γLG is the surface tension between the drop and the
surrounding fluid (air or insulating liquid).
In Figure 3, a plot of the values of γ (cos θ - cos θ0) versus
V2 on a Teflon-coated chip under air for different ionic liquids, a
biological buffer containing 0.05% Tween 20, and deionized water
(DI water) is reported. As recently reported by Millefiorni et al.,30
we confirmed that the electrowetting of ionic liquids is less
efficient than aqueous salt solutions. On the other hand, the
comparison of electrowetting curves of DI water and ionic liquids
showed that, in function of ionic liquids, the efficiency of the
electrowetting is higher or lower than or similar to water.
Note that the same cation bmim+ with three different anions
leads to three different behaviors. Indeed, the maximum saturation
is reached for [bmim][PF6], whereas the minimum is obtained
-
with [bmim][NTf2]. On the other hand, for the same anion NTf2
with four different cations, only two distinct behaviors were
observed. This could be explained by, on one hand, the relatively
closed structures of the cations bmim+ and tmba+ and, on the
other hand, the strong similarity of structure between the cations
C10H20NO3+ and C9H17NO2+ (see Supporting Information). Thus,
we suggest that both the anion and the cation have an influence
on the electrowetting curves. However, as well-established, we
showed that the Lippmann-Young relation is only valid at low
voltage. Indeed, the experimental curves are linear at low voltages
(with a coefficient equal to C/2γ ), whereas a saturation threshold,
of which the origin is completely unclear at high voltage, was
observed.33
It has recently been observed that the Langevin equation (eq
2) models well the experimental values of biological buffer with
surfactants.34
1
3X
L(X) ) coth(3X) -
(2)
(3)
As a result of these differences, different dynamic behaviors
of aqueous solutions, as compared to ionic liquids, were expected,
Thus, we obtained the following equation (eq 3).
(33) Mugele, F.; Baret, J.-C. J. Phys.: Condens. Matter 2005, 17, R705.
(34) Berthier, J.; Raccurt, O.; Clementz, P.; Jary, D.; Peponnet, C.; Fouillet, Y.
Nanotechnolology Conference and Trade Show, Anaheim, CA, May 8-12, 2005.
(35) Bagno, A.; Butts, C.; Chiappe, C.; D’Amico, F.; Lord, J. C. D.; Pieraccini, D.;
Rastrelli, F. Org. Biomol. Chem. 2005, 3, 1624-1630.
CV2
cos θ - cos θ0
cos θS - cos θ0
) L
(
)
2γ(cos θS - cos θ0)
Analytical Chemistry, Vol. 78, No. 14, July 15, 2006 4913

smaller hysteresis level of ionic liquids on Teflon. On the other
hand, Vmin for ionic liquids and a biological buffer containing 1%
of Tween 20 are similar.
Table 1. Physical Characteristics of Ionic Liquids in
Comparison with Watera
c
d
ionic liquids
γb
θ0
θS
V mine V maxf Fg
νh
In addition, the elongation along the main axis of motion when
the movement of the droplet starts is more important for ILs than
for water. With our camera (25 pictures/s), we can see that the
whole droplet of water is displaced when the next electrode is
switched on, whereas for ionic liquids, the front of the droplet
moves first and the back of the droplet follows. This is a
consequence of the high viscosity of RTILs, their relatively high
wettability (smaller contact angles), and their weak surface
tension. Finally, these physical characteristics of ILs have two
consequences: an important stretching of ionic liquids was
possible, and the displacement speed of droplets is smaller in
comparison with water. Motion speeds were measured by record-
ing the droplet’s motion on an open EWOD system under air,
consisting of a row of (800 µm)2 electrodes. Typical values of RTIL
motion speeds are between 1 and 10 mm/s, and we noted that
the speed increases with the potential, whereas the maximum
displacement speed of deionized water on the same chip has been
evaluated at 120 mm/s.
[tmba][NTf2] A
34.5 77 30-45 18 ( 1 48 ( 2 1.43 57
46.3 94.2 40-45 22 ( 3 58 ( 2 1.17 103.7
43.6 94.8 30-40 26 ( 1 58 ( 2 1.37 223.7
33.9 76.5 30-35 18 ( 2 53 ( 3 1.43
76.5 30-32 18 ( 2 48 ( 3
[bmim][BF4] B
[bmim][PF6] C
[bmim][NTf2] D
[teba] [NTf2] E
[emim][NTf2] F
[C8H19BrN][NTf2] G
[C7H16NO2][NTf2] H
[C25H54N][OTf] I
[C6H16NO][NTf2] J
[C9H17NO2][NTf2] K 37.4 85.1 28-30 21 ( 2 63 ( 3 1.44
[C10H20NO3][NTf2] L 39.4 86.6 33-40 22 ( 1 58 ( 3 1.44
deionized water
NH4HCO3 25 mM
+ 0.05% Tween20
NH4HCO3 25 mM
+ 1% Tween20
81.1 35-40 23 ( 2 58 ( 2
85.7 30-35 27 ( 2 48 ( 3
89.5 31-36 30 ( 2 58 ( 3
79.5 30-35 22 ( 2 53 ( 2
89.1 30-35 28 ( 2 58 ( 2
-
72.5 110 85-90 40 ( 3 63 ( 3
65.7 98 50-55 23 ( 2 65 ( 5
1
1
0.89
38
81
20 ( 3
i
1
a All measurements were made at room temperature. b Surface
tensions (mN‚m) were measured with the pendant drop method on a
drop shape analysis system G10/DSA10. c Nonactuated contact angles
(°). d Contact angle at saturation (°) (all contact angles were measured
using a commercial Digidrop GBX system, with droplets of 1 µL).
e Minimum actuation voltage (V rms) to displace a droplet of 0.4 µL
on a row of(800 µm)2 electrodes. f Saturation voltage (V rms). g Density
in g‚mL-1 h Kinematic viscosity (mm2/s) measured with Ubbelohde
.
(Schott) micro-viscosimeter. i For buffer + 1% Tween 20, the elec-
trowetting curve is impossible to record because of the evaporation
and the very long equilibration time.
Application to a Multicomponent Reaction. Since we
showed that ionic liquids droplets can be moved by EWOD on a
Teflon surface, the next step was to exploit this possibility to
perform multicomponent chemical reactions. We chose a tetrahy-
droquinoline synthesis via a three-component reaction, as de-
scribed by Grieco et al.36,37 to validate this concept.38
which is confirmed by our observation of the motions of these
different liquids.
This reaction was chosen for several reasons: (i) tetrahydro-
quinolines are an important class of biologically active com-
pounds;39 (ii) we wanted to demonstrate the feasibility of a
relatively complex reaction; (iii) this reaction occurs rapidly at
room temperature with a quantitative yield and has been demon-
strated on solid supports.37 In this reaction, an aniline reacts with
an aldehyde in the presence of an electron-rich olefin and an acidic
catalyst (trifluoroacetic acid (TFA)) to produce tetrahydroquino-
lines (Figure 4). To establish a reference, the reaction was first
performed in a flask (macrovolume). The task-specific onium salt
We first determined the two limits of the working potentials
Vmin and Vmax (Table 1). The first limit is the minimum potential
necessary to displace a droplet, and the second limit is the
maximum potential above which the contact angle is stabilized
(due to the saturation phenomenon (Figure 3)). Under air, ILs
showed a wider working interval than water. Indeed, the minimum
potential to move ionic liquid droplets (18-30 V) is lower than
that of water (40 V), whereas the saturation threshold is similar
for both. We assume that these smaller minimum potentials are
due to a smaller surface tension, γLG, according to eq 1 and a
Figure 4. Schematic representation of the reaction described by Grieco in a droplet microreactor.
4914 Analytical Chemistry, Vol. 78, No. 14, July 15, 2006

Figure 5. Structure of internal reference, M, and comparison of the chromatograms of the macro- and microscale reactions after the reaction
of 1 with 2a and 3. The observed byproduct in this chromatogram corresponds to a residual protonated p-nitroaniline, as confirmed by the mass
spectrum in Figure 6.
1 or 5 (0.2 M) was dissolved in a few milliters of an ionic liquid
matrix, such as ([tmba][NTf2]), then 2.5 equiv of benzaldehydic
derivates 2 or anilinic derivates 6, an excess of indene 3, and an
excess of trifluoroacetic acid were successively added to this
solution. After incubation for 1 h, the condensation products 4 or
7 were characterized by NMR and ESI-MS. The times of retention
of these products in HPLC were determined, as well.
analyses of the molecular ion (see Supporting Information). The
reaction with all the compounds described in Figure 4 gave correct
results, too.
To quantify the reaction in droplets, we set up an HPLC
method using an internal reference. Indeed, whereas the direct
determination of the conversion rate is easy in macrovolume, this
determination is blemished with errors when microvolumes are
used. Thus, we introduced into the reactional mix a reference
molecule M, inert versus the initial products, the final product,
and the eventual byproducts, and this response in UV/HPLC is
stable and reproducible. Then the ratio between the initial TSIL
and the internal reference was determined at the start and at the
end of the reaction. The conversion rate was estimated using the
following equation,
These reactions were then transposed to the droplet microre-
actors. Hence, a 0.2-µL droplet of [tmba][NTf2] containing 1 or
5 and 10 equiv of TFA as described above was deposited on the
chip and displaced by EWOD at 55 V. This droplet converged
toward a second droplet of ionic liquid containing 2.5 equiv of
the derivate 2 or 6. After coalescence, the resulting droplet was
merged with a third droplet containing an excess of indene. The
reaction was incubated within 1 h at room temperature, then the
final droplet was taken off the chip and washed with ether to
eliminate the excess of 2 or 6 and 3. The mixture was then
injected into the HPLC, and the chromatogram was compared
with that obtained in macrovolume. As shown in Figure 5, the
retention time for the compound 4a obtained in the droplet is
similar to the retention time of the final product obtained in
macrovolume. This result was confirmed by the ESI-MS analysis.
Indeed, as shown in Figure 6, the obtained molecular ion for the
compound 4a at 486.5 amu is in agreement with the expected
structure of the final product and identical to the product obtained
in macrovolume. This result was confirmed by MS2 and MS3
T ) 1 - X′/X
(4)
where X is the ratio between the HPLC traces of the initial TSIL
and the internal reference of the starting solution and X′ is the
ratio between the HPLC traces of the final TSIL and the internal
reference after 1 h of incubation.
(36) Grieco, P.; Bahas, A. Tetrahedron Lett. 1988, 29, 5855-5858.
(37) Kiselyov, A.; Armstrong, R. W. Tetrahedron Lett. 1997, 38, 6163-6166.
(38) Dubois, Ph.; Marchand, G.; Fouillet, Y.; Peponnet, C.; Chabrol, C.; Berthier,
J.; Vaultier, M. Proc. Micro Total Anal. Syst., Boston, Oct. 2005, Vol. 1, pp
412-414.
(39) Katritzky, A. R.; Rachwal, S.; Rachwal, B. Tetrahedron 1996, 52, 15031-
15070.
Analytical Chemistry, Vol. 78, No. 14, July 15, 2006 4915

Figure 6. Mass spectrum of the droplet of ionic liquid after a 1-h incubation period at room temperature of 1, 2a, and 3 and then washing with
ether. I, tmba+ (m/z theor ) 116.14); II, protonated p-nitroaniline (m/z theor ) 139.05); III, trace of the starting TSIL 1 (m/z theor ) 250.14); IV,
cation of the internal reference M (m/z theor ) 351.17); V, molecular ion of 4a (m/z theor ) 486.24); VI, adduct [2tmba+, NTf2
]
- + (m/z theor )
512.20; found ) 512.27); VII, adduct [protonated p-nitroaniline, NTf2-, tmba+
]
(m/z theor ) 535.11).
+
Then, with this method, we estimated a conversion rate
between 98 and 100% according to the compounds. Moreover,
good agreement between the reactions performed in the droplet
and in the macrovolume was shown.
The on-line chip analysis was performed as the following. The
droplet containing the final product 7a was moved by EWOD
toward an analytical area. The analysis was achieved by electro-
chemical detection between two gold catenaries on a chip (the
chip is described in the Experimental Section). The first catenary
permits the electrowetting and acts as a working electrode during
the detection. The second one is both the counter electrode and
the reference electrode. Thus, as shown in Figure 7, a cathodic
peak, identical to that obtained in macrovolume, was observed at
-1.46 V versus the gold reference electrode. This signal corre-
sponds to the reduction of the final product, and its magnitude
reflects indirectly the concentration of the final product (Randles-
Sevcik’s relation).
Applying a similar approach as above, one can easily imagine
a complex microsystem with an architecture inspired from Figure
2C.12 This microsystem would enable the on-demand synthesis
of organic compounds in very small quantities by parallel
synthesis, combinatorial chemistry, or convergent synthesis. The
TSIL droplet would be dispensed from a reservoir and react on
the electrode row (reaction bus) with different reagents generated
from secondary reservoirs. This could be performed in an open
or closed system. Different reactions can be conducted in parallel
on different reaction buses, and the final droplets can be mixed
Figure 7. Cyclic voltammogram of 7a in [tmba][NTf2] at a gold
electrode (φ ) 25 µm); v ) 50 mV s-1; V versus gold electrode.
for convergent synthesis. This concept should bring important
benefits, as compared to classical synthesis on microtiter plates,
principally in terms of volumes of reagents and size of the
equipment. Indeed, our approach should enable the researcher
to achieve several reactions on a few square centimeters and avoid
the use of bulky liquid-handling robots. Furthermore, future
integration of analytical tools on the chip, such as real-time
4916 Analytical Chemistry, Vol. 78, No. 14, July 15, 2006

monitoring of the reaction and final product analysis, should
improve these systems, paving the way to fully integrated systems.
mization of protocols, synthesis of dangerous products, and
embedded chemistry on a portable device.
ACKNOWLEDGMENT
CONCLUSIONS
This work was supported in part by the Ministe`re de la
In summary, we have described in this paper a powerful and
Recherche. We thank the members of BIOSOC project (CEA/
LETI) and A. Fonverne for their technical assistance. We also
thank R. Campagnolo, P. Le Ber, and F. Vinet (CEA/LETI) for
helpful discussions.
flexible tool to synthesize minute amounts of organic compounds
by using droplets of ionic liquids as microreactors and electrowet-
ting as the fluidic motor. First, we checked that ionic liquids are
compatible with EWOD actuation, even if their behavior is
different from that of water. We were able to show that these
droplets can be moved and combined on our system. This has
been demonstrated with task-specific ionic liquids, TSILs, which
when properly functionalized can be used as efficient soluble
supports for supported organic synthesis. The multicomponent
Grieco’s reaction was used to validate the above hypothesis. It
can be concluded that this original concept should impact many
areas, notably combinatorial chemistry, parallel synthesis, opti-
SUPPORTING INFORMATION AVAILABLE
Procedures for synthesis of ionic liquids and mass spectra after
synthesis in droplets. This material is available free of charge via
the Internet at http://pubs.acs.org.
Received for review March 16, 2006. Accepted April 20,
2006.
AC060481Q
Analytical Chemistry, Vol. 78, No. 14, July 15, 2006 4917