Communications
DOI: 10.1002/anie.201005263
Catalyst Recycling
Suzuki Coupling Reactions in Three-Phase Microemulsions**
Henriette Nowothnick, Jochanan Blum, and Reinhard Schomꢀcker*
The Suzuki cross-coupling reaction is one of the most widely
used reactions for the synthesis of polymers, liquid crystals,
agrochemicals, and pharmaceuticals. Because of growing
environmental awareness, industry is developing “green”
approaches, for example, the prevention of waste rather than
its treatment. In this context the use of water instead of
organic solvents, which are often toxic and difficult to remove
because of their high boiling points, is desirable as well as the
use of nontoxic reagents.[1] Based on the development of
water-soluble ligands,[2,3] first described in the early 1970s, the
easy separation of catalyst dissolved in an aqueous phase and
product dissolved in the organic phase has become possible.
The Rhꢀne–Poulenc process, the hydroformylation of pro-
pene to n-butylaldehyde, is so far the only industrial process
that employs two-phase catalysis with a water-soluble cata-
lyst.
Today the concept of biphasic catalysis is particulary
advanced by the use of fluorous solvents,[4] ionic liquids, and
supercritical fluids—all regarded as green solvents. However,
these media have not been used for coupling reactions
because of unsatisfactory yields and the insolubility of Pd
species[5,6] relative to the reactions in conventional solvents.
Additionally, the salts generated may retard the reaction and
make product isolation and catalyst recovery, for example,
from ionic liquids, difficult and expensive.
In our present study, we extended the concept of biphasic
catalysis to three-phase systems that allow for easy phase
separation and catalyst recycling in one step. The beneficial
effect of three-phase systems is well known in phase-transfer
catalysis,[7,8] where the third phase is often obtained by
accident, because of the solubility of the phase-transfer
catalyst in the applied solvents. In our study we used self-
assembling surfactant systems[9] with adjustable phase behav-
ior and employ them as the reaction medium for a Suzuki
coupling reaction: the synthesis of 4’-methyl-2-biphenylcar-
bonitrile (Scheme 1), an important intermediate for the
production of sartans. We investigated three-phase systems
based on nonionic surfactants of the type C12Ex (E = degree of
ethoxylation, x = 5–8), because the degree of ethoxylation can
Scheme 1. Suzuki coupling reaction of 2-bromobenzonitrile and 4-
tolueneboronic acid.
be used to tune the phase behavior such that the three-phase
region occurs at the reaction temperature (see the Supporting
Information).[10] Such systems have been described as versa-
tile media for a Heck reaction catalyzed by a supported
palladium catalyst.[11]
Because catalyst recycling is still a challenge in homoge-
neous catalysis and remains a serious drawback, we set out to
find a solution for product separation/isolation, catalyst
recycling, and the simultaneous removal of the salts; this
has never been reported for Suzuki coupling reactions before.
In benchmark experiments we used conventional polar
solvents like acetonitrile/water for the coupling reaction.
Then the alternative approach was studied by replacement of
the polar solvent by an alkane/water/surfactant mixture.
Polar aprotic solvents are often used for coupling
reactions because they solubilize high concentrations of
both reactants and the required bases. No mass-transfer
limitations occur if the catalyst is also dissolved in the same
phase as the reactants. It should be noted that the addition of
water is necessary and increases the reaction rate, also when a
non-water-soluble catalyst is used, because of the activation of
boronic acid by the inorganic base.[12] It can be seen from
Table 1, entries 1 and 2, that the coupling reaction is very fast
in acetonitrile, also when the initial concentrations of
reactants are doubled. However, the separation of the
product and the catalyst is difficult, and the catalyst cannot
Table 1: Conversion of the Suzuki coupling in different reaction media.[a]
Entry
Media
a[b]
g[b]
Cat.
Conv. [%][c]
[mol%]
1
2
CH3CN/H2O
0.5
0.5
–
–
0.5
0.25
98
83
[*] H. Nowothnick, Prof. Dr. R. Schomꢀcker
Institut fꢁr Chemie, Technische Universitꢀt Berlin
Strasse des 17. Juni 124–126, 10623 Berlin (Germany)
Fax: (+49)30-3147-9552
3
4
5
6
heptane/H2O/
surfactant
0.9
0.5
0.5
0.5
–
–
0.03
0.03
0.5
0.5
0.5
15
77
96
62
E-mail: schomaecker@tu-berlin.de
0.25
J. Blum
Institute of Chemistry, The Hebrew University
Jerusalem 91904 (Israel)
Fax: (+972)2651-3832
[a] CH3CN/water=(44.5:38.8) g or heptane/water=(38.8:38.8) g (a=
0.5) as solvent for 5.5 mmol 2-bromobenzonitrile, 6.05 mmol
(1.1 equiv) 4-tolueneboronic acid, 6.88 mmol (1.25 equiv) K2CO3; or
twice the concentration of the reactants at constant catalyst concen-
tration: 6 mg Pd(OAc)2 and 78 mg TPPTS as the water-soluble catalyst at
bei 608C. [b] a=oil fraction of mixture, g=surfactant fraction of
mixture. [c] Conversion after 1 h.
[**] The financial support of the DFG (grant SCHO 687/8-1 is kindly
acknowledged.
Supporting information for this article is available on the WWW
1918
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 1918 –1921