Continuous-flow homogeneous catalysis using the temperature-controlled solvent properties of supercritical carbon dioxide

Article abstract of DOI:10.1039/c0cc02251a

A fully integrated continuous process for homogeneous catalysed reactions in scCO₂ has been developed exploiting the tunable solvent properties of scCO₂. A heated condenser situated above the reaction zone leads to a phase split under isobaric conditions resulting in efficient catalyst retention and recirculation. Continuous isomerisation of allylic alcohols was carried out for over 200 hours time-on-stream demonstrating the viability of this approach.

Full text of DOI:10.1039/c0cc02251a

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Continuous-flow homogeneous catalysis using the temperature-controlled
solvent properties of supercritical carbon dioxidew
a
*a and Walter Leitner*ab
Thomas Harwardt, Giancarlo Francio
`
Received 30th June 2010, Accepted 22nd July 2010
DOI: 10.1039/c0cc02251a
A fully integrated continuous process for homogeneous catalysed
reaction and separation step under different sets of parameters
is a major restriction for the design of continuous-flow
reactions in scCO
2
has been developed exploiting the tunable
. A heated condenser situated above
1
2
solvent properties of scCO
2
processes.
the reaction zone leads to a phase split under isobaric conditions
resulting in efficient catalyst retention and recirculation.
Continuous isomerisation of allylic alcohols was carried out
for over 200 hours time-on-stream demonstrating the viability
of this approach.
In the present contribution, we describe a novel approach
for continuous flow catalysis which integrates reaction and
separation into one unit operation by exploiting the tuneable
solvent properties of scCO . While the catalytic transformation
2
occurs under homogeneous single phase conditions in the
bottom part of the apparatus (reaction zone), efficient catalyst
separation and recirculation is achieved by a phase split in the
upper part (separation zone). The phase split is induced by a
temperature increase under isobaric conditions resulting in a
reduced density. This is achieved using a special reactor design
incorporating a built-in heat-exchanger (Fig. 1) similar to the
‘‘hot finger’’ described by Zosel in his seminal investigation on
Homogeneous catalysis is an attractive technology for advanced
synthesis and offers highly selective access to fine chemicals
1
and pharmaceuticals. However, separation and reuse of the
high-value catalysts is one major challenge for industrial scale
applications. Moreover, the stringent regulations for (noble)
metal residues in chemical and especially pharmaceutical
products must be taken into account for the proper design
1
3
separation processes with supercritical fluids.
2
of processes and the choice of the separation sequence.
The isomerisation of allylic alcohols yielding carbonyl
compounds catalysed by metal–phosphine complexes (Scheme 1)
was chosen as a test reaction for validating the process
Multiphase catalysis has proven to be a viable approach to
catalyst immobilisation with high stability and low levels of
leaching, and some of these techniques have been established
3
on an industrial scale. The concept relies on the presence of
two immiscible phases with distinct solvent properties for the
catalyst and the products, creating an effective physico-
chemical barrier that leads to separation and retention of the
2
catalyst. In recent years, supercritical carbon dioxide (scCO )
has received increasing interest as a mobile phase in continuous
4
flow multiphase catalysis. A range of highly polar and/or
low volatile solvents form two phase systems with scCO
2
,
which can be exploited to immobilize catalysts under
5
6
scCO
2
-flow in liquid or supported liquid phases. This
concept has been demonstrated using for example ionic
7
liquids, polyethyleneglycol, or high boiling products as the
8
9
1
0
liquid phase containing the catalyst.
Fig.
integrated reaction and catalyst separation using temperature-
controlled CO -solubility.
1 Principle of continuous-flow homogeneous catalysis by
However, catalyst separation can be also achieved in scCO2
alone without the need of a permanent separate phase. In a
two-step process, the reaction is carried out under single phase
2
conditions and then a switch to a biphasic product/CO
system is induced upon density reduction during the extraction
2
1
1
2
of the products with fresh CO (CESS procedure). Excellent
levels of separation between products and catalysts have been
obtained with this technique, but the need to operate the
a
Institut fu¨r Technische und Makromolekulare Chemie,
RWTH Aachen University, Worringerweg 1, 52074 Aachen,
Germany. E-mail: francio@itmc.rwth-aachen.de,
leitner@itmc.rwth-aachen.de; Fax: (+)49-(0)241-80-22177
Max-Planck-Institut fu¨r Kohlenforschung, Mu¨lheim an der Ruhr,
Germany
b
w Electronic supplementary information (ESI) available: Experimental
procedure for the continuous isomerisation of 1-octene-3-ol. See DOI:
1
0.1039/c0cc02251a
Scheme 1 Catalytic isomerisation of allylic alcohols.
Chem. Commun., 2010, 46, 6669–6671 6669
This journal is c The Royal Society of Chemistry 2010

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À1
concept. This atom-economical transformation finds application
in a variety of natural product synthesis as well as in bulk-
with a calculated density of ca. 0.71 g mL in the reaction
À1
zone, which is strongly lowered to ca. 0.17 g mL in the
1
4
chemical production. As model substrates 3-butene-2-ol (1a)
and 1-octene-3-ol (1b) were selected, which have analogous
substitution pattern at the terminal double bond, but very
distinct volatilities (bp 96–97 1C for 1a and 180 1C for 1b).
The integrated reactor/separator unit for continuous
synthesis under high-pressure conditions was established with
the necessary periphery for precise dosing of fluids and
separation zone by the temperature gradient. The sample
collected from the exit stream after 24 h showed almost full
conversion, whereas after 48 h only 50% of the substrate was
transformed. After 72 h almost no conversion was observed
anymore (Fig. 4). Product samples were largely colourless
indicating that the temperature-induced density gradient
served as an efficient barrier to prevent the catalyst from
escaping the reactor. Indeed, close inspection of the dismounted
unit after the reaction revealed that the catalyst was deposited
as a yellow film in the hot separation zone, while the reaction
zone was virtually catalyst-free. This proves that the catalyst
was efficiently precipitated upon density reduction, but it was
not transported back into the reaction zone leading to a
gradual decrease and ultimately stop of conversion (Fig. 2).
In order to establish a ‘‘vehicle’’ for recirculating the
catalyst, the formation of liquid phase droplets in the separation
zone falling down to the reaction zone was envisaged. Zosel
described in his work on ‘‘destraction’’ with supercritical fluids
already the possibility to generate a reflux by means of a
1
5
pressure control. The central part of this set-up provides
the possibility to define a temperature gradient between the
bottom (reaction zone) and the upper part (separation zone) of
the reactor (Fig. 2). The reaction zone consists of a 20 mL
window autoclave. On the top of it, a heat exchanger with a
volume of ca. 150 mL is connected constituting the separation
zone. Its layout consists of an inverted pipe-in-pipe system and
allows for visual monitoring of the state of operation through
high-pressure windows in the outer wall. The inner tube is
heated by a circulating heating fluid, whereas the outer wall
can be heated electrically or cooled by ventilation. After the
back-pressure regulator, the exit stream passes through a cold
trap, where the products are collected.
1
3
heated condenser (‘‘hot finger’’). In contrast to conventional
reflux conditions, where a liquid phase is formed by cooling a
vapour phase, the liquid phase is generated by temperature
increase from the supercritical fluid in this case.
In preliminary experiments, the isomerisation of 3-butene-2-ol
2
in scCO was studied in batch mode to identify a suitable
catalyst. The combination of [Rh(cod) ]BArF as the metal
2
2
precursor and the CO -philic fluorinated ligand 3-H F -TPP
6
11
For 3-butene-2-ol 1a no reflux could be achieved under
various conditions since the low boiling point of this substrate
prohibited the formation of a liquid phase. In contrast, the
2
yielded a soluble and active catalyst to conduct the target
reaction under single phase conditions (Scheme 1). A ligand-
À1
to-metal ratio of 3.5 led to the highest TOF (145 h ) at 50 1C
2
phase behaviour of 1-octene-3-ol 1b/CO mixtures showed
and was therefore applied in the continuous flow experiments.
In a representative continuous flow experiment a catalyst
loading of 15 mg (0.013 mmol) Rh precursor and 58 mg
that the formation of a liquid phase upon temperature increase
under isobaric conditions is possible for this substrate. Fig. 3
2
shows the dew point curve for defined mixtures of CO and 1b
(
0.045 mmol) phosphine ligand was applied. Feed rates were
À1
monitored visually in a window-equipped autoclave at
125 bar. Phase separation was observed already at 85 1C at
3 weight% content and at 65 1C at 5 weight% content.
The temperature for the phase separation did not change
significantly upon increasing the content of 1b up to
À1
À1
adjusted to 3.9 g h (89 mmol h ) for CO
À1
2
and 0.11 g h
(
1.5 mmol h ) for 1a, corresponding to a substrate content of
2
.7 weight% and a residence time of 6 h. The system pressure
in the integrated reactor/separator unit was held constant at
00 bar throughout the experiment. The temperature of the
1
6
2
20 weight%.
reaction zone was kept at T = 35 1C, whereas the temperature
of the separation zone was set to Tsep = 120 1C. Under these
conditions, a single phase was observed throughout the unit
Consequently, the process parameters for the continuous
flow isomerisation of 1b were adjusted to maintain a single
phase in the reaction zone (Fig. 3, one phase region) and to
induce a phase split in the separation zone through a suitable
temperature gradient (Fig. 3, two phase region). A typical
continuous isomerisation of 1b was performed at 132 bar,
r
r
setting a reaction temperature of T = 80 1C, a separation
temperature of Tsep = 100 1C and a substrate content in the
feed stream of 4.2 weight%. A catalyst system, generated
1
7
Fig. 2 Flow sheet of the continuous-flow set-up (left) and photo-
graph of the integrated reactor/separator unit with the built-in heat
exchanger (right).
2
Fig. 3 Phase behaviour of CO /1-octen-3-ol mixtures at 150 bar.
6
670 Chem. Commun., 2010, 46, 6669–6671
This journal is c The Royal Society of Chemistry 2010

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density gradient of the supercritical phase between the reaction
and the separation zone of an integrated unit under isobaric
conditions. The dramatically reduced solubility of the catalyst
in the separation zone accounts for efficient catalyst retention.
The formation of a liquid phase at the heat exchanger allows
to recirculate the catalyst. This situation could be maintained
stable for over 200 hours time-on-stream demonstrating the
viability for long term operation. This approach avoids the use
of any additional solvent to constitute the catalyst phase and
operates under fully homogeneous conditions in the reaction
zone, defining a unique scenario in the area of multiphase
catalysis.
Fig. 4 Time/conversion profiles of the continuous isomerisation of
-butene-2-ol 1a (m) and 1-octene-3-ol 1b (K) under reflux conditions
in scCO
The authors thank Dr Lasse Greiner and Dr-Ing. Clemens
Minnich for fruitful discussion. We gratefully acknowledge
generous support by the Deutsche Forschungsgemeinschaft
3
2
.
(project: LE 930/10-1, C-CESS) and the Fonds der Chemischen
Industrie.
Notes and references
1
2
3
Applied Homogeneous Catalysis with Organometallic Compounds,
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Cole-Hamilton and R. P. Tooze, Springer, Dordrecht, 2006.
Multiphase
W. A. Herrmann, I. T. Horva
H. Olivier-Bourbigou, and D. Vogt, Wiley-VCH, Weinheim,
st edn, 2005.
Homogeneous
Catalysis,
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Cornils,
´
th, W. Leitner, S. Mecking,
1
Fig. 5 Refluxing liquid at the heat exchanger during the continuous
isomerisation of 1b.
4 Chemical Synthesis using Supercritical Fluids, ed. P. G. Jessop and
W. Leitner, Wiley-VCH, Weinheim, 2010.
5
6
J. Langanke and W. Leitner, Top. Organomet. Chem., 2008, 23, 91.
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2
8
3 6
in situ from [RuCp(MeCN) ]PF and 4-H F -TPP, was used
for these experiments (Scheme 1). Already by applying this
relatively low temperature gradient of 20 1C, condensation of
a liquid phase occurred on the hot condenser surface and a
reflux was observed (Fig. 5). As seen in Fig. 5, the yellow
colour of the refluxing liquid indicates that it effectively
dissolves the catalyst and recycles it back into the reaction
zone, where the droplets merge instantaneously with the
homogeneous high density supercritical phase. Stationary
reflux operation was maintained over a considerable time
U. Hintermair, T. Ho
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¨
fener, T. Pullmann, G. Francio and
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¨
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À1
À1
period at feed rates of 18.3 g h (0.42 mol h ) for CO
À1
2
À1
and 0.8 g h (2.8 mmol h ) for 1b, corresponding to a
residence time of 5 hours.
5
531–5538.
10 Note that ‘‘inverted’’ biphasic systems with the catalyst in the
scCO phase have also been described: M. McCarthy, H. Stemmer
and W. Leitner, Green Chem., 2002, 4, 501; K. Burgemeister,
V. H. Gego, G. Francio, L. Greiner, H. Hugl and W. Leitner,
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performance over a long time could be achieved. The time/
conversion profile of an experiment with more than 200 hours
time-on-stream shows that after a short start-up period of a
few residence times a stationary level of nearly full conversion
was maintained over 72 hours (circles in Fig. 4). Conversion
decreased only after 96 hours and was still in the range of 50%
after 200 h. ICP-OES measurements revealed an upper limit
for the contamination of the colourless product stream of
2
`
Chem.–Eur. J., 2007, 13, 2798.
11 D. Koch and W. Leitner, J. Am. Chem. Soc., 1998, 120, 13398;
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`
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2 C. M. Gordon, W. Leitner, in ref. 2, p. 215.
1
13 K. Zosel, Angew. Chem., 1978, 90, 748–755.
1
4 R. C. van der Drift, E. Bouwman and E. Drent, J. Organomet.
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1
0 to 25 ppm for Ru and 5 to 7 ppm for the residual phosphor
content.
In conclusion, the integration of reaction and catalyst
separation for continuous homogeneous catalysis using scCO
1
2
16 A slightly higher solubility in scCO
less polar products 2a and 2b.
2
is expected for the corresponding
as the only reaction medium and separation fluid has been
demonstrated for the Rh- and Ru-catalysed isomerisation of
allylic alcohols. The concept relies on a temperature induced
17 C. Slugovc, E. Ruba, R. Schmid and K. Kirchner, Organometallics,
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This journal is c The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 6669–6671 6671