Low pressure Pd-catalyzed carbonylation in an ionic liquid using a multiphase microflow system

Article abstract of DOI:10.1039/b600970k

A low pressure microflow system was developed for palladium-catalyzed multiphase carbonylation reactions in an ionic liquid. The microflow system resulted in superior selectivity and higher yields in carbonylative Sonogashira coupling and amidation reactions of aryl iodides compared to the conventional batch system. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b600970k

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Low pressure Pd-catalyzed carbonylation in an ionic liquid using a
multiphase microflow system{
Md. Taifur Rahman, Takahide Fukuyama,* Naoya Kamata, Masaaki Sato and Ilhyong Ryu*
Received (in Cambridge, UK) 23rd January 2006, Accepted 11th April 2006
First published as an Advance Article on the web 28th April 2006
DOI: 10.1039/b600970k
multiphase (ionic liquid–substrate–CO) through a heated capillary
tube reactor acting as a residence time unit to give the desired
products.
A low pressure microflow system was developed for palladium-
catalyzed multiphase carbonylation reactions in an ionic liquid.
The microflow system resulted in superior selectivity and higher
yields in carbonylative Sonogashira coupling and amidation
reactions of aryl iodides compared to the conventional batch
system.
We carried out a Pd-catalyzed carbonylative Sonogashira
coupling of aryl iodides
1 and phenylacetylene (2) in
[BMIm]PF6, as the first model reaction (eqn (1)).4 For example,
The benefits of having an exceedingly high surface-to-volume ratio
and efficient heterogeneous mass-transfer in microchannels have
led many researchers to study continuous flow systems using
microreactors for heterogeneous catalytic reactions.1,2 We pre-
viously reported that a continuous microflow system can be quite
useful for the catalytic reactions, which employ ionic liquids (IL) as
the reaction medium and catalyst-support.3 Thus, Pd-catalyzed
cross-coupling reactions, such as the Sonogashira reaction3a and
the Mizoroki–Heck reaction3b can be carried out with efficient
catalyst recycling in a continuous microflow system. In this
communication, we report on the successful application of
catalytic microflow reactions to Pd-catalyzed carbonylation
reactions using CO gas under pressurized conditions. We found
that Pd-catalyzed carbonylation reactions in ionic liquids,
when conducted in conjunction with a microreactor, proceeded
efficiently, even at low CO pressures.
Table 1 Pd-catalyzed carbonylative three-component coupling of 1
and 2a
CO
pressure System/Product/Yieldb
Entry
1
1
2
Microflow 3a (83%) 4a (—)
Batch 3a (25%) 4a (60%)
5 atm
3
4
5
6
Microflow 3a (80%) 4a (—)
Batch 3a (14%) 4a (65%)
Microflow 3b (77%) 4b (—)
Batch 3b (67%) 4b (21%)
1a
3 atm
5 atm
Using the microflow system outlined in Fig. 1, we examined the
Pd-catalyzed carbonylation of iodoarenes in an ionic liquid. The
microflow system used in this study consists of two T-shaped
micromixers (T-1 and T-2) and a stainless tube reactor as well as
equipment designed to ensure the pressurized microflow of CO.
This continuous microflow approach involves the mixing of an
ionic liquid containing the Pd-catalyst with CO and the substrates,
successively, in different micromixers and then passing the
7
8
Microflow 3b (77%) 4b (—)
Batch 3b (44%) 4b (39%)
Microflow 3c (92%) 4c (—)
Batch 3c (36%) 4c (37%)
1b
3 atm
5 atm
9
10
11
12
Microflow 3d (72%) 4d (—)
Batch 3d (65%) 4d (16%)
5 atm
a
Fig. 1 Schematic diagram of the microflow system.
Reaction conditions. Microflow:
1 (7 mmol), 2 (8.4 mmol,
1.2 equiv.), Et3N (25.2 mmol, 3.6 equiv.), CO (5 or 3 atm), Pd-cat.
(1 mol%), [BMIm]PF6 (17 mL); flow rates: mixture of 1, 2 and Et3N
(0.04 mL min21), Pd/[BMIm]PF6 (0.14 mL min21), CO (1.0 mL
min21); 120 uC; residence time: 12 min. Batch: 1 (1.0 mmol), 2
(1.2 equiv), Et3N (3.6 equiv.), Pd-cat. (1 mol%), [BMIm]PF6
Department of Chemistry, Graduate School of Science, Osaka
Prefecture University, Sakai, Osaka, 599-8531, Japan.
E-mail: ryu@c.s.osakafu-u.ac.jp; Fax: 81-72-254-9695;
Tel: 81-72-254-9695
{ Electronic supplementary information (ESI) available: Experimental
details. See DOI: 10.1039/b600970k
b
(3.0 mL), CO (5 or 3 atm); 120 uC, reaction time: 1 h. Yields were
determined from 1H NMR.
2236 | Chem. Commun., 2006, 2236–2238
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Table 2 Pd-catalyzed single/double carbonylation of aryl iodidesa
Entry
1
Substrate
CO
System/Products/Yieldsb
Microflow
5a (6%)
6a (80%)
1a (—)
1a
20 atm
2
3
Batch
5a (11%)
5e (5%)
6a (63%)
6e (85%)
1a (22%)
1a (—)
Microflow
20 atm
15 atm
4
Batch
5e (4%)
6e (70%)
1e (17%)
5
Microflow
Batch
5e (10%)
5e (11%)
6e (68%)
6e (52%)
1a (—)
1e
6
1e (17%)
a
Reaction conditions. Microflow: 1 (14.0 mmol), Et2NH (70 mmol, 5.0 equiv.), CO (20 or 15 atm), Pd-cat. (0.5 mol%) in [BMIm]PF6 (17 mL);
flow rates: mixture of 1 and Et2NH (0.04 mL min21), Pd/[BMIm]PF6 (0.14 mL min21), CO (0.25 mL min21); 80 uC; residence time: 34 min.
b
Batch: 1 (2.66 mmol), Et2NH (5.0 equiv.), Pd-cat. (0.5 mol%), [BMIm]PF6 (2.0 mL), CO (20 or 15 atm), 80 uC, reaction time: 5 h. Yields
were determined from 1H NMR.
at a CO pressure of 20 atm, a batch reaction gave a,b-acetylenic
ketone 3a as the sole product in 83% yield, whereas when the
reaction was conducted at 5 atm of CO, the Sonogashira coupling
product 4a was produced in 60% yield as the dominant product
over the desired product 3a (25%) (Table 1, entry 2). In sharp
contrast, the use of the microflow system gave 3a (83%)
exclusively, even at 5 atm of CO pressure, and the formation of
non-carbonylation product 4a was not observed (entry 1). By
further lowering the CO pressure to 3 atm, the microflow system
still yielded 3a (80%) exclusively (entry 3), whereas in the batch
reaction, carbonylation selectivity further diminished giving 3a in
only 14% (entry 4). This tendency generally holds for other
substrates, 1b, 1c and 1d, as well (entries 5–12).5 Thus the
microflow system showed excellent performance in producing
solely the acetylenic ketones 3, even under reduced CO pressures,
without the formation of the Sonogashira byproduct 4.
This hypothesis was tested by carrying out carbonylative-
coupling reactions of 1d with 2 under 5 atm of CO pressure with
variable volumes of [BMIm]PF6 with a constant IL/CO surface
area using an autoclave (Fig. 2a). The results showed that the
selectivity for carbonylation increased with increasing value of the
IL/CO surface area-to-IL volume ratio (Fig. 2b).
Given the remarkably high efficiency of a microflow system for
carbonylative-Sonogashira coupling reactions, we examined the
applicability of our system for the Pd-catalyzed carbonylation of
aromatic iodides in the presence of a secondary amine, which is
being extensively investigated with regard to single/double
carbonylation selectivity (eqn (2)).6,7 Thus, when we carried out
the carbonylation of iodobenzene (1a) in the presence of Et2NH at
a CO pressure of 20 atm, the microflow system produced the
a-keto amide 6a in 80% yield along with 6% of amide 5a in 34 min
(Table 2, entry 1), while a batch reaction suffered from a low
conversion of 1a, consequently resulting in an inferior yield of 6a
(63%) even after 5 h (entry 2). Similarly, taking another substrate,
4-iodotoluene (1e), and carrying out the reactions at various CO
pressures (20 and 15 atm), the yields of the a-keto amide 6e were
higher in the case of the microflow system than that in a batch
system for all cases examined (entries 3–6).
Since CO exhibits low solubility in highly viscous ionic liquids,8
carbonylation selectivity is presumed to be controlled by the
diffusion efficiency of CO. The extent of CO diffusion into the
bulk of IL in a batch reactor can be altered by varying (i) the CO
pressure and/or (ii) the surface-to-area ratio by taking different
amounts of IL.
Fig. 2 Controlled carbonylation experiment taking different volumes of
IL in a 50 mL autoclave reactor and using the same molar concentrations
of 1d (0.33 M), 2 (0.40 M), Et3N (1.19 M) and Pd-catalyst A (1.0 mol%) in
each run.
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Additional studies suggest that at low pressure, the diffusivity of
CO into the ionic liquid bulk is a limiting factor for determining
the carbonylation/non-carbonylation selectivity ratio in a batch
system.
The authors wish to thank the Research Association of
Microchemical Process Technology (MCPT), Japan and the
New Energy and Industrial Technology Development
Organization (NEDO) for financial assistance.
Notes and references
1 For recent reviews on microchemical technology in synthesis, see: (a)
W. Ehrfeld, V. Hessel and H. Lehr, Top. Curr. Chem., 1998, 194, 233; (b)
W. Ehrfeld, V. Hessel and H. Lo¨we, in Microreactor: New Technology for
Modern Chemistry, WILEY-VCH, Weinheim, 2000; (c) P. D. I. Fletcher,
S. J. Haswell, E. Pombo-Villar, B. H. Warrington, P. Watts, S. Y. F.
Wong and X. Zhang, Tetrahedron, 2002, 58, 4735; (d) K. Ja¨hnisch,
V. Hessel, H. Lo¨we and M. Baerns, Angew. Chem., Int. Ed., 2004, 43,
406; (e) P. Watts and S. J. Haswell, Chem. Soc. Rev., 2005, 34, 235.
2 For recent reviews on microreactors in heterogeneous catalysis, see: (a)
A. Kirschning and G. Jas, Top. Curr. Chem., 2004, 242, 209; (b)
G. N. Doku, W. Verboom, D. N. Reinhoudt and A. V. D. Berg,
Tetrahedron, 2005, 61, 2733; (c) L. Kiwi-Minsker and A. Renken, Catal.
Today, 2005, 110, 2; For recent studies also see: (d ) J. Kobayashi,
Y. Mori, K. Okamoto, R. Akiyama, M. Ueno, T. Kitamori and
S. Kobayashi, Science, 2004, 304, 28; (e) R. Abdallah, V. Meille, J. Shaw,
D. Wenn and C. de Bellefon, Chem. Commun., 2004, 372; (f)
N. Yoswathananont, K. Nitta, Y. Nishiuchi and M. Sato, Chem.
Commun., 2004, 40; (g) D. I. Enache, G. H. Hutchings, S. T. Taylor,
R. Natividad, S. Raymahasay, J. K. Winterbottom and E. H. Stitt, Inds.
Eng. Chem. Res., 2005, 44, 6295; (h) Y. Oenal, M. Lucas and P. Claus,
Chem.-Ing.-Tech., 2005, 77, 101.
3 (a) T. Fukuyama, M. Shinmen, S. Nishitani, M. Sato and I. Ryu, Org.
Lett., 2002, 4, 1691; (b) S. Liu, T. Fukuyama, M. Sato and I. Ryu, Org.
Process Res. Dev., 2004, 8, 477.
4 We recently reported on the autoclave version of this reaction in IL:
T. Fukuyama, R. Yamaura and I. Ryu, Can. J. Chem., 2005, 83, 711.
5 When DMF was used as the reaction medium instead of an ionic liquid,
no such difference between the microflow system and the batch system
was observed.
6 (a) F. Ozawa, H. Soyama, H. Yanagihara, I. Aoyama, H. Takino,
K. Izawa, T. Yamamoto and A. Yamamoto, J. Am. Chem. Soc., 1985,
107, 3235; (b) E. Mizushima, T. Hayashi and M. Tanaka, Green Chem.,
2001, 3, 76.
Fig. 3 Photographic images of the flow regime inside the capillary tube
(id = 1000 mm).
To obtain a better understanding of the higher efficiency of our
microflow system over the batch reactor, we decided to visualize
the real time microflow patterns using transparent capillary tubes.
The photographic images revealed the occurrence of a segmented
plug-flow inside the microscale channels (Fig. 3). When the IL and
CO were mixed in the first T-shaped m-mixer (T-1), a segmented
IL–CO plug flow resulted (Photo A) which, after mixing with the
substrates (1b, 2 and Et3N) at the second T-mixer (T-2), again gave
an alternate IL–substrate–CO plug flow (Photo B). When this IL–
substrate–CO flow was fed into the residence time unit
(temperature 120 uC), the substrate-phase dissolved in the IL-
phase giving a liquid–gas segmented flow regime (Photo C). Thus,
the superior efficiency of the microflow system over the batch
reactor can be attributed to the occurrence of plug flow, because,
this type of flow regime might have provided a large specific
interfacial area between the CO and liquid phase9 and facilitated
the diffusion of CO into the thin IL (approximately 2.0 mm) plugs.
On the contrary, for batch reactions, such a large interfacial area-
to-volume ratio or efficient CO diffusion through IL cannot be
obtained because mechanical stirring is the only means for
multiphase mixing.
In summary, palladium-catalyzed carbonylation reactions in a
microflow system were carried out in an ionic liquid, which can
function as a recyclable reaction media and catalyst support. The
results clearly demonstrate that liquid–gas segmented microflow
offered excellent selectivity and high yields for carbonylation
reactions even when conducted at relatively lower CO pressures.
7 cf. P. W. Miller, N. J. Long, A. J. de Mello, R. Vilar, J. Passchier and
A. Gee, Chem. Commun., 2006, 546.
8 At 295 K and 1.0 bar CO solubility in [BMIm]PF6 is 1.47 mM, whereas
for toluene it is 7.3 mM. For details see: C. A. Ohlin, P. J. Dyson and
G. Laurenczy, Chem. Commun., 2004, 1070.
9 B. K. H. Yen, A. Gu¨nther, M. A. Schmidt, K. F. Jensen and
M. G. Bawendi, Angew. Chem., Int. Ed., 2005, 44, 5447.
2238 | Chem. Commun., 2006, 2236–2238
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