Suzuki-Miyaura coupling reactions in aqueous microdroplets with catalytically active fluorous interfaces

Article abstract of DOI:10.1039/b911594c

Using microfluidic techniques and a novel fluorous-tagged palladium catalyst, we generated droplet reactors with catalytically active walls and used these compartments for small molecule synthesis.

Full text of DOI:10.1039/b911594c

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Suzuki–Miyaura coupling reactions in aqueous microdroplets
with catalytically active fluorous interfacesw
Ashleigh B. Theberge,*a Graeme Whyte,a Max Frenzel,a Luis M. Fidalgo,a
Robert C. R. Woottonb and Wilhelm T. S. Huck*a
Received (in Cambridge, UK) 12th June 2009, Accepted 12th August 2009
First published as an Advance Article on the web 28th August 2009
DOI: 10.1039/b911594c
Using microfluidic techniques and a novel fluorous-tagged
palladium catalyst, we generated droplet reactors with catalytically
active walls and used these compartments for small molecule
synthesis.
end we sought a continuous phase immiscible with both
organic and aqueous phases.
Fluorous solvents are immiscible with organic and aqueous
phases and have been used extensively in droplet-based
microfluidics.1 Such a system with a fluorous continuous phase
and aqueous or organic dispersed phase draws parallels with
existing techniques in the field of fluorous biphasic catalysis
(FBC) conducted in bulk reaction vessels.13 While most of the
described applications of FBC involve elevated temperatures
to create a monophasic reaction mixture, FBC can also be
used at room temperature when the reaction is designed to
proceed at the fluorous–organic interface.13 Droplet-based
microfluidics provides an opportunity for controlling such
interfaces.
In the drive towards miniaturizing and automating chemical
and biological experiments, droplet-based microfluidics has
emerged as a powerful research platform.1 Generating discrete
droplets in an immiscible continuous (carrier) phase allows
reactions to be compartmentalized into femtolitre to nanolitre
volumes. In essence, each droplet reactor is analogous to the
traditional chemist’s flask, with the added advantages of
reduced reagent consumption, rapid mixing, automated
handling, and continuous processing.1 Building on advances
in continuous flow chemistry,2 droplet-based microfluidics has
been used to conduct a variety of organic reactions.3–7 This
platform provides opportunities for handling precious
reagents that are not possible with conventional synthetic
techniques and has been used to screen reaction conditions
using microgram amounts of starting material.3 Moreover,
the encapsulation provided by microdroplets enables their
application to precipitate-forming reactions that cannot be
conducted in conventional continuous flow microreactors due
to channel clogging.4
Here, we present a method for biphasic catalysis that
incorporates the efficiency and control of droplet-based
microfluidics with emerging fluorous phase chemistry. We
generated droplet reactors with catalytically active walls by
using a fluorous ligand which both solubilized a transition
metal catalyst in fluorous solvents while also acting as a
surfactant and hence accumulating at the fluorous–water
interface (Fig. 1). Moreover, our fluorous ligand allowed
for reactivity under ambient, aqueous conditions inside the
droplet reactors.
It is well known that the high surface-to-volume ratio
inherent to the dimensions of the droplets and the internal
flow circulations in droplets in microfluidic channels can
significantly enhance mass transfer between the dispersed
and continuous phases.8–12 Onal et al. reported a triphasic
¨
hydrogenation using organic reagent droplets and hydrogen
gas bubbles dispersed in an aqueous catalytic stream.9
Phase-transfer mediated nitration,10 Claisen–Schmidt,11 and
hydrolysis12 reactions have also been carried out using
droplet-based microfluidics. In this work we aimed to use
the multiphase nature of microdroplets to facilitate biphasic
catalytic reactions. We envisioned anchoring a catalyst in the
carrier phase such that it could assemble at the droplet ‘wall,’
catalyzing reactions inside each droplet microreactor. To this
a Melville Laboratory for Polymer Synthesis, Department of
Chemistry, University of Cambridge, Lensfield Road, Cambridge,
UK CB2 1EW. E-mail: abt30@cam.ac.uk, wtsh2@cam.ac.uk;
Fax: +44 (0)1223-334-866; Tel: +44 (0)1223-331-797
b School of Pharmacy and Biomolecular Sciences, Liverpool John
Moores University, Byrom Street, Liverpool, UK L3 3AF
w Electronic supplementary information (ESI) available: Reaction
conditions for fluidic experiments and the synthesis of the fluorinated
ligand (1). See DOI: 10.1039/b911594c
Fig. 1 Cartoon representation of microdroplets with catalytically
active interfaces. Fluorous-tagged palladium catalyst (a) and aqueous
reagents (b) were pumped into the T-junction, forming monodisperse
aqueous droplets surrounded by the fluorous continuous phase.
Product is formed as the droplets flow through the channel (c and d).
Reaction time is linearly proportional to distance along the tubing and
the controllable flow rates.
ꢀc
This journal is The Royal Society of Chemistry 2009
Chem. Commun., 2009, 6225–6227 | 6225

View Article Online
To demonstrate the feasibility of this catalytic approach,
we carried out the palladium-catalyzed Suzuki–Miyaura
reaction14 as a model. In order to allow the catalyst to take
part in the reaction but prevent its transport to the aqueous
dispersed phase, we designed and synthesized a novel fluorous
ligand (1, see ESIw) based on a recently described hydrophilic
guanidine motif,15 as represented in Fig. 1a. Complexation of
this ligand with palladium acetate formed a catalyst that was
soluble in fluorous solvents, enabled the Suzuki–Miyaura
coupling inside the droplet reactors, and ensured that the
palladium catalyst remained in the continuous fluorous phase.
While a limited number of fluorinated ligands have been
designed for Suzuki–Miyaura reactions,16 to the best of our
knowledge this is the first example showing these reactions
under fully aqueous, room temperature, and ambient reaction
conditions.
Table 1 Fluorous biphasic Suzuki–Miyaura couplings in droplets
Residence
timea/h
Yieldb
(%)
Entry
R–Br
(OH)2B–R0
1
2
3
3
90
77
99
3
0.75
4
1
8
91
63
Several groups have shown that tubing can be used as an
efficient microreactor as well as a vessel for the production of
monodisperse emulsions.3,4,6,12 Compared to other micro-
fluidic platforms that require microchip fabrication, using
tubing reduces costs and is more accessible to synthetic
chemistry laboratories. We used a T-junction17 to generate
monodisperse droplets in fluorinated (PTFE) tubing, injecting
the fluorous catalyst (Fig. 1a) and the aqueous reagents
(Fig. 1b) perpendicular to each other. The reaction progressed
as the droplets flowed through the tubing forming the Suzuki
coupling products (Fig. 1c and d). The reaction time could be
controlled either by varying the total flow rate of the solutions
or by changing the length of the reaction tube.
5
a
Tubing length was adjusted to achieve the desired residence time
while maintaining fluorous/aqueous flow rates of 690/414 ml hꢁ1
b
except where noted in the ESIw. Determined by HPLC as described
in the ESIw.
closed-loop catalyst recycler to achieve a fully automated
system capable of performing a wide array of reactions with
minimal amounts of catalyst.
To demonstrate continuous catalyst recycling, we reused the
carrier phase multiple times in combination with substrates
that showed intermediate reactivity (Table 1, entry 1, 1 h
residence time). By recirculating the fluorous phase approxi-
mately four times, while continuously forming new droplets
from fresh reagent solution, we were able to improve the
overall amount of product produced three-fold. At this stage,
the fluorous phase was still catalytically active, indicating
that it could be used in additional reactions and the overall
turnover could be improved further. Additionally, ICP-MS of
the aqueous phase after a reaction using fresh catalyst solution
With the fluidic system and fluorous ligand chemistry in
place, we applied this catalytic technique to a series of aryl
bromides and boronic acids (Table 1). Our droplet-based
biphasic reaction conditions afforded good yields of the
desired biaryl coupling products, with reaction times on the
same order as observed for the monophasic reaction.15
Typically only 5% of the boronic acid homocoupling product
was observed by HPLC. For some sets of substrates droplet
fusion occurred at longer residence times, but high yields were
still obtained. Gratifyingly, even deactivated aryl bromides
reacted with this room temperature flow chemistry
(entries 1 and 2). para- and meta-bromo benzoic acid reacted
rapidly (r1 h) with unsubstituted and substituted phenyl-
boronic acids to give the cross-coupling product in high yield
(entries 3 and 4). The method was also extended to hetero-
cyclic halides, with modification of the total flow rates and
fluorous : aqueous flow rate ratio to force this less reactive
system (Entry 5).
We further exploited the continuous nature of this system
by showing that the catalytically active fluorous phase could
be recycled in an uninterrupted fashion. This contrasts with
biphasic reactions in bulk reactors, where it is necessary to
stop the reaction in order to facilitate phase separation. To
realize continuous fluorous phase recycling, droplets were
pooled at the end of the reaction channel, the aqueous and
fluorous phases were separated by density, and the fluorous
phase was pumped back into the droplet formation module to
catalyze further reactions in the reaction channel (Fig. 2). In
the future, automatic reagent dispensing technologies, such as
robot sippers or autosamplers, could be incorporated with this
Fig. 2 Schematic representation of the microfluidic setup used to
recycle the catalytically active fluorous continuous phase (green).
Insets a and b show the T-junction for droplet formation and the
separating column used for online emulsion separation, respectively.
For visual contrast, red dye (rather than reagent solution) was used as
the dispersed phase.
ꢀc
This journal is The Royal Society of Chemistry 2009
6226 | Chem. Commun., 2009, 6225–6227

View Article Online
without the addition of an organic co-solvent. Furthermore
the reaction proceeds under mild, room temperature conditions
making it particularly attractive for late-stage coupling appli-
cations that could benefit from microfluidic efficiency and
minimal reagent consumption. Fluorous oils are widely used
for droplet-based microfluidics. While they are typically
favored for their physical properties and are often used merely
to compartmentalize droplets within a channel, we hope that
this work will stimulate interest in using the fluorous phase
itself to facilitate chemical reactions.
Fig. 3 (a) Optical micrograph of droplet reactors with catalytically
active walls. The product of the reaction precipitates allowing for
visualization of the reaction progress. The reaction pictured is shown
in Table 1, entry 1. (b) Reaction kinetics plots based on HPLC analysis
of the reaction mixtures after different residence times. Lines are
included to guide the eye.
This work was supported by the RCUK Basic Technology
Programme on Microfluidic Microdroplet Reactors and EC
Framework 6 Research Project MiFem. The authors gratefully
acknowledge Dr Abdeslam El-Harrak, Lucas Frenz, and
Dr Felix Kleinschmidt for helpful discussions.
showed less than 0.5 ppm of palladium. Considering the
original concentration of palladium in the fluorous phase, this
represents less than 2% of the total palladium, indicating that
the degree of palladium leaching into the aqueous phase was
minimal.
Notes and references
1 H. Song, J. D. Tice and R. F. Ismagilov, Angew. Chem., Int. Ed.,
2003, 42, 768; J. Atencia and D. J. Beebe, Nature, 2005, 437, 648;
H. Song, D. L. Chen and R. F. Ismagilov, Angew. Chem., Int. Ed.,
2006, 45, 7336; S.-Y. Teh, R. Lin, L.-H. Hung and A. P. Lee, Lab
Chip, 2008, 8, 198; F. Courtois, L. F. Olguin, G. Whyte, F. Bratton,
W. T. S. Huck, C. Abell and F. Hollfelder, ChemBioChem, 2008, 9,
439.
2 B. P. Mason, K. E. Price, J. L. Steinbacher, A. R. Bogdan and
D. T. McQuade, Chem. Rev., 2007, 107, 2300; I. R. Baxendale,
J. Deeley, C. M. Griffiths-Jones, S. V. Ley, S. Saaby and
G. K. Tranmer, Chem. Commun., 2006, 2566.
3 T. Hatakeyama, D. L. Chen and R. F. Ismagilov, J. Am. Chem. Soc.,
2006, 128, 2518.
4 S. L. Poe, M. A. Cummings, M. P. Haaf and D. T. McQuade,
Angew. Chem., Int. Ed., 2006, 45, 1544.
5 Z. T. Cygan, J. T. Cabral, K. L. Beers and E. J. Amis, Langmuir,
2005, 21, 3629.
6 O. Benali, M. Deal, E. Farrant, D. Tapolczay and R. Wheeler,
Org. Process Res. Dev., 2008, 12, 1007.
As mentioned, using this setup it is possible to dial in a
variety of different parameters, providing a means for online
reaction optimization. In many cases, the product precipitates
(Fig. 3a), providing an immediate visual signal for the reaction
progress which can be used to adjust reaction conditions in
real time to improve yield. For further optimization, samples
can be quenched and analyzed by HPLC offline to quantify
product formation. In the future, integration of emerging
techniques for chemical characterization in microdroplets18
could be used to facilitate online optimization and characteri-
zation. The residence time of the droplets within the tubing
translates into the reaction time, so the kinetics of the reaction
can be monitored by either changing the total flow rate of the
fluids or the length of the reaction channel. Fig. 3b shows that
the reaction progress for two different substrate combinations
can easily be followed by changing tubing length. The
tunability of the synthesis platform allows for facile modifi-
cation and optimization. Studies toward optimizing reaction
yield and efficiency by varying droplet size and velocity, for
example, are ongoing within our laboratories.
7 B. Ahmed-Omer, D. A. Barrow and T. Wirth, Tetrahedron Lett.,
2009, 50, 3352.
8 J. R. Burns and C. Ramshaw, Lab Chip, 2001, 1, 10; P. Mary,
V. Studer and P. Tabeling, Anal. Chem., 2008, 80, 2680; M. Rhee
and M. A. Burns, Langmuir, 2008, 24, 590.
¨
9 Y. Onal, M. Lucas and P. Claus, Chem. Eng. Technol., 2005, 28,
972.
¨ ¨
10 G. Dummann, U. Quittmann, L. Groschel, D. W. Agar, O. Worz
and K. Morgenschweis, Catal. Today, 2003, 79–80, 433.
11 J.-X. Mu, X.-F. Yin and Y.-G. Wang, Synlett, 2005, 3163.
12 B. Ahmed, D. Barrow and T. Wirth, Adv. Synth. Catal., 2006, 348,
1043.
13 I. T. Horva
Acc. Chem. Res., 1998, 31, 641.
14 N. Miyaura, K. Yamada and A. Suzuki, Tetrahedron Lett., 1979,
20, 3437; N. Miyaura and A. Suzuki, Chem. Rev., 1995, 95, 2457.
15 S. Li, Y. Lin, J. Cao and S. Zhang, J. Org. Chem., 2007, 72, 4067.
16 S. Schneider and W. Bannwarth, Helv. Chim. Acta, 2001, 84, 735;
C. Rocaboy and J. A. Gladysz, Tetrahedron, 2002, 58, 4007;
In summary, we have combined two enabling technologies,
droplet-based microfluidics and fluorous biphasic catalysis,
to create controlled catalytic interfaces for organic synthesis
in flow. Using commercially available tubing and tees, we
produced aqueous reagent droplets in a continuous stream of
fluorous catalyst. The Suzuki–Miyaura reaction progressed
while the droplets with catalytically active ‘walls’ flowed
through the reaction channel, affording an array of products
in good yield. The encapsulation provided by the droplets
allowed us to conduct precipitate-forming reactions and
use the precipitation as a visual cue to facilitate rapid
optimization. We have also developed green conditions for
the widely used Suzuki–Miyaura reaction by designing and
synthesizing a novel fluorous guanidine ligand that facilitates
Suzuki couplings under fluorous–aqueous biphasic conditions
th and J. Rabai, Science, 1994, 266, 72; I. T. Horvath,
´ ´ ´
A. Garcia-Bernabe, C. Tzschucke, W. Bannwarth and R. Haag,
´
Adv. Synth. Catal., 2005, 347, 1389; M.-G. Shen, C. Cai and
W.-B. Yi, J. Fluorine Chem., 2007, 128, 1421.
17 T. Thorsen, R. W. Roberts, F. H. Arnold and S. R. Quake, Phys.
Rev. Lett., 2001, 86, 4163.
18 L. M. Fidalgo, G. Whyte, B. T. Ruotolo, J. L. P. Benesch,
F. Stengel, C. Abell, C. V. Robinson and W. T. S. Huck, Angew.
Chem., Int. Ed., 2009, 48, 3665; L. M. Fidalgo, G. Whyte,
D. Bratton, C. F. Kaminski, C. Abell and W. T. S. Huck, Angew.
Chem., Int. Ed., 2008, 47, 2042; J. Pei, Q. Li, M. S. Lee,
G. A. Valaskovic and R. T. Kennedy, Anal. Chem., 2009, 81, 6558.
ꢀc
This journal is The Royal Society of Chemistry 2009
Chem. Commun., 2009, 6225–6227 | 6227