Table 2 Continuous nonpolar biphasic Sonogashira catalysis of aryl iodides
and phenyl acetylene
reactor is much too short to effect their catalytic transformation.
Consequently, we decided to slow down the transport of
reactants by adding a filling to the reactor. We tested several
different glass pearls with diameters of 1.5–2 mm, 3 mm and 4
mm, saddle rings and glass rings with respect to the permeation
of the reactant/product carrying solvent. The 3 mm glass pearls
turned out to be the best choice. The medium transport times of
the model compound 4-tert-butyltolane were determined by gas
chromatography and for the 3 mm glass pearls found to be 35
min with a feed of 3 ml of solvent per hour and 70 min with a
feed of 1.2 ml h21. The latter time is ideal to effect the catalytic
transformation of the reactants in the Sonogashira coupling.
The composition of the product containing stream was
monitored by GC. It can be seen that for a 4.5 mmol loading
(corresponding to 0.6 mol% of catalyst) of the reactor with
reactants the amount of catalyst present as well as the reaction
time are sufficient to ensure excellent conversions of the various
reactants (Table 1). On increasing the loading of the reactor by
a factor of three to 13.5 mmol (corresponding to 0.2 mol% of
catalyst) several coupling reactions are not complete; obviously
the capacity of the present reactor with the extremely small
catalyst loading is exceeded for some reactions. In order to
boost the capacity of such a reactor one can simply increase the
amount of catalyst and the dimensions of the reactor.
It is very important in this respect to note that there is no
leaching of the catalyst into the product phase, which was
already known from our work on related biphasic catalysis.3–5
Furthermore we need to take a closer look at the partition
coefficients a of the reactants as well as of the products between
the reactant phase (heptane) and the catalyst phase (dmso). Low
coefficients lead to a higher concentration of the reactants in the
catalyst phase and increase the rate of the catalytic transforma-
tion, while on the other hand the efficient elution of product
from the catalyst phase with heptane solvent requires high
values of a. According to our experience partition coefficients
for reactants and products in the range of 0.2 and 20 are useful
and allow the efficient operation of the reactor.13 We have
determined several such partition coefficients a for the
distribution of aryl bromide reactants and of the respective
phenyl acetylene coupled products between n-heptane and
dmso: C6H5Br, product (0.85, 0.21), 4-CH3C6H4Br (1.6, 0.51),
4-tBuC6H4Br (15.1, 0.93), 4-ClC6H4Br (0.41, 0.30),
4-CH3COC6H4Br (0.01, 0.04). Obviously for the more polar
substrates the problem of very small distribution coefficients is
imminent. The obvious solution to this problem is the simple
inversion of the nature of the catalyst phase tag and that of
catalyst and reactant/product phase to result in a nonpolar
biphasic catalysis. In this manner the catalyst has a nonpolar
phase tag (poly-4-methylstyrene, Scheme 1)5 and resides
exclusively in the nonpolar solvent (cyclohexane), while the
polar reactant/product solvent dmso is responsible for the
transport (Scheme 1b).
Substrate 4.5 mmol
R =
conversion (%)a
H
4-CH3
4-Cl
4-OMe
3-CF3
80
60
77
65
84
a Conversion is the averaged amount of product in the product stream.
Catalyst: 0.02 mmol (PhCN)2PdCl2, 0.04 mmol phosphine 2, 0.04 CuI
corresponds to 0.44 mol% catalyst.
Consequently, we have studied the Sonogashira reaction of
several substrates under the conditions of nonpolar biphasic
catalysis, utilizing a cyclohexane catalyst phase and a dmso
reactant/product phase.
The data in Table 2 show that good conversions are obtained,
though not quantitative as the activity of the present catalyst in
cyclohexane is significantly reduced with respect to that in
dmso. An advantage when using dmso as the product phase is
the solubility of the ammonium salts formed in the course of
reaction, which are removed efficiently together with the
products from the reactor.
In conclusion, the immobilisation of polymer tagged cata-
lysts in a stationary solvent and the flow through of reactants
dissolved in another immiscible solvent, allows the conversion
of a continuous feed of reactants into a product stream, as
exemplified by the Sonogashira coupling of aryl halides and
acetylenes. The present approach certainly is not limited to the
Sonogashira reaction and we are currently working towards
expanding the scope of continuous biphasic catalysis to other
reactions such as Heck and Suzuki coupling as well as olefin
metathesis.
This work was supported by the Deutsche Forschungsge-
meinschaft and the Fonds der Chemischen Industrie.
Notes and references
1 J. Hagen, Industrial Catalysis, Wiley-VCH, Weinheim, 1999.
2 D. E. Bergbreiter, Chem. Rev, 2002, 102, 3345.
3 A. Köllhofer and H. Plenio, Chem. Eur. J., 2003, 9, 1416.
4 H. Remmele, A. Köllhofer and H. Plenio, Organometallics, 2003, 22,
4098.
5 A. Datta and H. Plenio, Chem. Commun., 2003, 1504.
6 M. an der Heiden and H. Plenio, Chem. Eur. J., submitted.
7 A. Bösmann, G. Francio, E. Janssen, M. Solinas, W. Leitner and P.
Wasserscheid, Angew. Chem. Int. Ed., 2001, 40, 2697.
8 M. F. Sellin, P. B. Webb and D. J. Cole-Hamilton, Chem. Commun.,
2001, 781.
Table 1 Continuous polar biphasic Sonogashira catalysis of aryl bromides
and phenyl acetylene
9 R. A. Brown, P. Pollett, E. McKoon, C. A. Eckert, C. L. Liotta and P.
G. Jessop, J. Am. Chem. Soc., 2001, 123, 1254.
10 F. Liu, M. B. Abrams, R. T. Baker and W. Tumas, Chem. Commun.,
2001, 433.
11 This is not a directed movement, but a consequence of diffusion and the
respective partition coefficients.
Substrate 4.5 mmol
conversion (%)a
Substrate 13.5 mmol
conversion (%)a
R =
12 In order to avoid loss of the catalyst containing solution at the bottom of
the reactor and to maintain a simple reactor setup (no seals required), the
reactant containing solvent is pumped into the bottom (polar catalysis)
of the reactor via a steel capillary inserted from the top of the reactor. As
the separation of the organic phases at the top of the reactor occurs
rapidly, droplet formation or even emulsions pose no problem and the
two solvents are separated efficiently. In principle, the same applies for
the nonpolar setup of the reactor.
H
> 98
> 98
> 98
88
83
70
53
81
85
4-CH3
4-tBu
4-Cl
3-CF3
> 98
a Conversion is the averaged content of product in the product stream
relative to the solutes.
13 a is defined as the amount of reactant or product in the heptane solution
divided by the amount of reactant or product in the dmso solution.
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