Continuous flow hydrogenation using polysilanesupported palladium/alumina hybrid catalysts

Article abstract of DOI:10.3762/bjoc.7.83

Continuous flow systems for hydrogenation using polysilane-supported palladium/alumina (Pd/(PSi-Al₂O₃)) hybrid catalysts were developed. Our original Pd/(PSi-Al₂O₃) catalysts were used successfully in these systems and the hydrogenation of unsaturated C-C bonds and a nitro group, deprotection of a carbobenzyloxy (Cbz) group, and a dehalogenation reaction proceeded smoothly. The catalyst retained high activity for at least 8 h under neat conditions.

Full text of DOI:10.3762/bjoc.7.83

Continuous flow hydrogenation using polysilane-
supported palladium/alumina hybrid catalysts
Hidekazu Oyamada, Takeshi Naito and Shū Kobayashi*
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2011, 7, 735–739.
Department of Chemistry, School of Science and Graduate School of
Pharmaceutical Sciences, The University of Tokyo, Hongo,
Bunkyo-ku, Tokyo 113-0033, Japan
doi:10.3762/bjoc.7.83
Received: 24 March 2011
Accepted: 04 May 2011
Published: 31 May 2011
Email:
Shū Kobayashi* - shu_kobayashi@chem.s.u-tokyo.ac.jp
This article is part of the Thematic Series "Chemistry in flow systems II".
Guest Editor: A. Kirschning
* Corresponding author
Keywords:
flow chemistry; hydrogenation; polysilane; palladium; reduction
© 2011 Oyamada et al; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
Continuous flow systems for hydrogenation using polysilane-supported palladium/alumina (Pd/(PSi–Al2O3)) hybrid catalysts were
developed. Our original Pd/(PSi–Al2O3) catalysts were used successfully in these systems and the hydrogenation of unsaturated
C–C bonds and a nitro group, deprotection of a carbobenzyloxy (Cbz) group, and a dehalogenation reaction proceeded smoothly.
The catalyst retained high activity for at least 8 h under neat conditions.
Findings
Catalytic hydrogenation is one of the most important methods Heterogeneous catalytic hydrogenation in a batch system has
for the reduction of C–C double and triple bonds, and other recently been applied to continuous flow hydrogenation systems
functional groups. Heterogeneous catalysts including Pd/C, Pt/C for high-throughput synthesis [2-10]. There are several prob-
and Pd/SiO2 are commonly used in reduction reactions both in lems associated with conducting heterogeneous catalytic hydro-
research and industrial environments because of the ease of sep- genation in a batch system. These include the necessity for
aration of the catalysts and products. However, the contamina- filtration of hydrogen-saturated pyrophoric catalysts from flam-
tion of products as a result of leaching of metals from supports mable solvents, the possible requirement to use hydrogen gas
as well as the decreased catalytic activity, are both serious prob- under high pressure, difficulties in the re-use of catalysts (or
lems with the use of conventional heterogeneous catalysts. To inability for their re-use), the need for vigorous stirring to
address these problems, we recently developed novel methods achieve catalytic activity, and the possible necessity for longer
for the immobilization of metal and non-metal catalysts on reaction times, which may lead to undesirable side reactions or
supports. This involved the development of microencapsulated harsh reaction conditions. Continuous flow systems have the
(MC) and polymer-incarcerated (PI) catalysts, which have high potential to overcome these problems and disadvantages. In our
catalytic activity without causing metal leaching [1].
laboratory, PI catalysts were applied to tri-phase hydrogenation
735

Beilstein J. Org. Chem. 2011, 7, 735–739.
reactions in a microreactor system and led to markedly shorter contamination of the starting material. This demonstrated that
reaction times [11]. While the productivity of a single microre- the catalyst retained high activity for at least 8 h, and the
actor is low, increasing the number of reactors (“numbering turnover number (TON) reached 8700.
up”) could readily and substantially increase production.
We also recently reported novel transition metal catalysis
involving the immobilization of Pd or Pt onto polysilane
supports by the microencapsulation method [12]. The Pd cata-
lyst (Pd/PSi) had high activity with no or very little leaching of
Pd, and it could be recovered and re-used in hydrogenation
reactions in batch systems. We then developed polysilane-
Scheme 1: Hydrogenation of ethyl cinnamate.
supported Pd/metal oxide hybrid catalysts [13] using the PI
method (microencapsulation and cross-linking), which were
then applied in these microreactor systems [14]. The hybrid We then investigated the hydrogenation of other substrates. The
catalysts were insoluble, did not swell in any solvent, and were hydrogenation reactions of C–C double and triple bonds in
predicted to be applicable to continuous flow reactors. In this various substrates are shown in Table 1; these proceeded
study, we investigated hydrogenation reactions of C–C double quantitatively at room temperature under neat conditions. The
and triple bonds as well as various other functional groups using products were obtained at approximately 10 g/h through the
continuous flow systems with Pd/(PSi–Al2O3) catalysts.
4 cm3 column.
A schematic diagram of the continuous flow reactor and an The hydrogenation reactions of trans-stilbene and trans-chal-
image of the top of the column are shown in Figure 1. A high cone, as representative solid substrates (Scheme 2), were also
performance liquid chromatography (HPLC) pump was used to examined. The substrates were dissolved in toluene or ethyl
feed the substrate into the central hole in the top of the column, acetate. The reduction of trans-stilbene proceeded quantita-
which was filled with the Pd/(PSi–Al2O3) catalyst. Hydrogen tively, but an overreaction product was obtained (7% yield) in
gas was introduced into the six holes surrounding the central the reduction of trans-chalcone.
hole using a mass flow controller. The column was heated in a
water bath as required. The substrate reacted with the H2 gas We then investigated the hydrogenation of a nitro group
inside the column, and the product was collected downstream of (nitrobenzene) and the deprotection of a carbobenzyloxy (Cbz)
the column.
group (Scheme 3). The hydrogenation reaction of nitrobenzene
proceeded quantitatively under neat conditions, and the depro-
We initially examined the hydrogenation reaction of ethyl tection of Cbz–Ser also proceeded quantitatively in a mixed
cinnamate (Scheme 1) and collected the product for 8 h without solvent system (EtOH/H2O 1:4).
Figure 1: Schematic diagram of the continuous flow reactor (left) and the column top (right).
736

Beilstein J. Org. Chem. 2011, 7, 735–739.
Table 1: Hydrogenation of C–C double and triple bonds.
Entry
1
Substrate
Time (h)
1.5
Product
Yield (TON)
14.9 g (2200)
2
3
4
1.5
1.5
1.5
13.9 g (2400)
18.0 g (2700)
16.3 g (2100)
5
6
1.7
1.5
14.9 g (2300)
19.4 g (1700)
Scheme 2: Hydrogenation of trans-stilbene and trans-chalcone.
Hydrogenation reactions could also be carried out successfully
in water (Scheme 4). The reduction of aqueous maleic acid
proceeded quantitatively. Dehalogenation of p-chlorobenzoic
acid in basic aqueous solution also proceeded smoothly and
benzoic acid was obtained after acid treatment. In the case of
p-chlorophenol, the conversion was complete; however, in this
case some by-product (5%) was also obtained.
In summary, we developed continuous flow systems for hydro-
genation using a Pd/(PSi–Al2O3) catalyst. Our original
Pd/(PSi–Al2O3) catalysts were successfully used in these
systems. In the hydrogenation reactions studied, i.e., the reduc-
tion of unsaturated C–C bonds and a nitro group, deprotection
of a Cbz group, and a dehalogenation reaction, all proceeded
Scheme 3: Hydrogenation of nitrobenzene and deprotection of the
Cbz group.
737

Beilstein J. Org. Chem. 2011, 7, 735–739.
Scheme 4: Hydrogenation in water.
smoothly. The catalysts could be used for a long time, with high Hydrogenation reaction of trans-stilbene (Scheme 2): trans-Stil-
activity being retained for at least 8 h under neat conditions. It bene (Aldrich) in toluene (0.25 M) was fed into the column
is noted that in all cases no Pd leaching was detected (ICP). (maintained at 40 °C in a water bath) using the HPLC pump
Further studies of the application of these systems to large-scale (1.0 mL/min), and H2 gas was introduced into the column using
production are now in progress.
the mass flow controller (11 mL/min). The system was left to
stabilize for 30 min. The product was then sampled over 8 h and
dried in vacuo. The sample was analyzed by 1H NMR, and the
Experimental
The continuous flow reactor system comprised the following full conversion of trans-stilbene to 1,2-diphenylethane was
devices (Figure 1): HPLC pump: Shimadzu LC-6AD or Eyela confirmed. 1H NMR (500 MHz, CDCl3) δ 2.92 (s, 4H),
301. Mass flow controller: Lyntec MC-3000E and RP-300. 7.17–7.21 (m, 6H), 7.26–7.30 (m, 4H).
Column: 10 × 50 mm Eyela glass column filled with 4 g of
Pd/(PSi–Al2O3) and equipped on the top with a glass filter Hydrogenation reaction of nitrobenzene (Scheme 3): Nitroben-
(pore size 10 μm), a 7-hole plate (polychlorotrifluoroethylene; zene was fed into the column (maintained at 70 °C in a water
PCTFE) and a screw cap, and on the bottom with a glass filter bath) using the HPLC pump (0.1 mL/min), and H2 gas was
(pore size 10 μm), a 1-hole plate (PCTFE) and a screw cap. introduced into the column at a pressure of 0.15 MPa. The
Line: A sus tube (outside diameter: 1/16 inch) was used for system was left to stabilize for 30 min and the product then
line A, a PEEK tube (outside diameter: 1/16 inch) was used sampled for 2.5 h. The sample (18.9 g as a mixture of aniline
for line B and a Teflon tube (outside diameter: 3 mm) was and H2O; calculated quantity of aniline = 13.7 g) was analyzed
used for line C.
by GC, and the complete conversion of nitrobenzene to aniline
was confirmed.
Typical procedure for hydrogenation reactions (Table 1, entry
1): Styrene was fed into the column using the HPLC pump, and Hydrogenation reaction of p-chlorobenzoic acid (Scheme 4):
H2 gas was introduced into the column using the mass flow p-Chlorobenzoic acid in H2O (0.33 M, including 2.5 equiv of
controller. The system was left to stabilize for 30 min, and the K2CO3) was fed into the column (maintained at 60 °C in a
product was then sampled over 1.5 h. The sample was analyzed water bath) using the HPLC pump (0.6 mL/min) and H2 gas
by 1H NMR, and the complete conversion of styrene to ethyl was introduced into the column using the mass flow controller
benzene was confirmed. 1H NMR (500 MHz, CDCl3) δ 1.24 (t, (16 mL/min). The system was left to stabilize for 30 min and
J = 7.7 Hz, 3H), 2.65 (q, J = 7.7 Hz, 2H), 7.15–7.23 (m, 3H), the product was then sampled for 8 min. Aqueous HCl (1 N)
7.26–7.30 (m, 2H).
was added to the mixture, which was then extracted twice with
738

Beilstein J. Org. Chem. 2011, 7, 735–739.
AcOEt. The combined organic layers were dried in vacuo. The
sample was analyzed by 1H NMR, and complete dehalogena-
tion of the Cl group was confirmed. 1H NMR (500 MHz,
CDCl3) δ 7.46–7.50 (m, 2H), 7.60–7.63 (m, 1H), 8.12–8.14 (m,
2H).
License and Terms
This is an Open Access article under the terms of the
Creative Commons Attribution License
(http://creativecommons.org/licenses/by/2.0), which
permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
Acknowledgements
This work was partially supported by a Grant-in-Aid for Scien-
tific Research from the Japan Society for the Promotion of
Science (JSPS), Global COE Program, The University of
Tokyo, MEXT, Japan, and NEDO.
The license is subject to the Beilstein Journal of Organic
Chemistry terms and conditions:
(http://www.beilstein-journals.org/bjoc)
References
The definitive version of this article is the electronic one
which can be found at:
1. Akiyama, R.; Kobayashi, S. J. Am. Chem. Soc. 2003, 125, 3412–3413.
doi:10.1021/ja029146j
doi:10.3762/bjoc.7.83
2. Solodenko, W.; Wen, H.; Leue, S.; Stuhlmann, F.;
Sourkouni-Argirusi, G.; Jas, G.; Schönfeld, H.; Kunz, U.; Kirschning, A.
Eur. J. Org. Chem. 2004, 3601–3610. doi:10.1002/ejoc.200400194
3. Yoswathananont, N.; Nitta, K.; Nishiuchi, Y.; Sato, M. Chem. Commun.
2005, 40–42. doi:10.1039/b410014j
4. Jones, R.; Gödörházy, L.; Szalay, D.; Gerencsér, J.; Dormán, G.;
Ürge, L.; Darvas, F. QSAR Comb. Sci. 2005, 24, 722–727.
doi:10.1002/qsar.200540006
5. Jones, R. V.; Godorhazy, L.; Varga, N.; Szalay, D.; Urge, L.; Darvas, F.
J. Comb. Chem. 2006, 8, 110–116. doi:10.1021/cc050107o
6. Desai, B.; Kappe, C. O. J. Comb. Chem. 2005, 7, 641–643.
doi:10.1021/cc050076x
7. Saaby, S.; Knudsen, K. R.; Ladlow, M.; Ley, S. V. Chem. Commun.
2005, 2909–2911. doi:10.1039/b504854k
8. Mennecke, K.; Cecilia, R.; Glasnov, T. N.; Gruhl, S.; Vogt, C.;
Feldhoff, A.; Larrubia Vargas, M. A.; Kappe, C. O.; Kunz, U.;
Kirschning, A. Adv. Synth. Catal. 2008, 350, 717–730.
doi:10.1002/adsc.200700510
9. Irfan, M.; Petricci, E.; Glasnov, T. N.; Taddei, M.; Kappe, C. O.
Eur. J. Org. Chem. 2009, 9, 1327–1334. doi:10.1002/ejoc.200801131
10.Ceylan, S.; Coutable, L.; Wegner, J.; Kirschning, A. Chem.–Eur. J.
2011, 17, 1884–1893. doi:10.1002/chem.201002291
11.Kobayashi, J.; Mori, Y.; Okamoto, K.; Akiyama, R.; Ueno, M.;
Kitamori, T.; Kobayashi, S. Science 2004, 304, 1305–1308.
doi:10.1126/science.1096956
12.Oyamada, H.; Akiyama, R.; Hagio, H.; Naito, T.; Kobayashi, S.
Chem. Commun. 2006, 4297–4299. doi:10.1039/b610241g
13.Oyamada, H.; Naito, T.; Miyamoto, S.; Akiyama, R.; Hagio, H.;
Kobayashi, S. Org. Biomol. Chem. 2008, 6, 61–65.
doi:10.1039/b715220e
14.Ueno, M.; Suzuki, T.; Naito, T.; Oyamada, H.; Kobayashi, S.
Chem. Commun. 2008, 1647–1649. doi:10.1039/b715259k
739