Triphase hydrogenation reactions utilizing palladium-immobilized capillary column reactors and a demonstration of suitability for large scale synthesis

Article abstract of DOI:10.1002/adsc.200505265

We have developed a practical and highly productive system for hydrogenation reactions utilizing capillary column reactors, which occupy less space than ordinary batch systems, are low cost and easy to handle, and show feasibility toward large-scale chemical synthesis. Palladium-containing micelles were immobilized onto the inner surface of the capillaries. Nine palladium-immobilized capillaries were assembled and connected to a T-shaped connector, and hydrogen and a substrate solution were fed to capillaries via the connector. Hydrogenation of 1-phenyl-1-cyclohexene (1) proceeded smoothly to give phenylcyclohexane in quantitative yield. The capillaries themselves occupy only ca. 0.4 mL and a high space-time yield has been achieved (124.3 mg/17 min/0.4 mL). In addition, leaching of palladium was not detected by ICP analysis after reactions.

Full text of DOI:10.1002/adsc.200505265

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DOI: 10.1002/adsc.200505265
Triphase Hydrogenation Reactions Utilizing
Palladium-Immobilized Capillary Column Reactors and a
Demonstration of Suitability for Large Scale Synthesis
Juta Kobayashi, Yuichiro Mori, Shu¯ Kobayashi*
Graduate School of Pharmaceutical Sciences, The University of Tokyo, The HFRE Division, ERATO, Japan Science and
Technology Agency (JST), Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
Fax: (þ81)-3-5684-0634, e-mail: skobayas@mol.f.u-tokyo.ac.jp
Received: July 2, 2005; Accepted: September 9, 2005; Published online: November 11, 2005
Abstract: We have developed a practical and highly
productive system for hydrogenation reactions utiliz-
ing capillary column reactors, which occupy less
space than ordinary batch systems, are low cost and
easy to handle, and show feasibility toward large-
scale chemical synthesis. Palladium-containing mi-
celles were immobilized onto the inner surface of
the capillaries. Nine palladium-immobilized capilla-
ries were assembled and connected to a T-shaped
connector, and hydrogen and a substrate solution
were fed to capillaries via the connector. Hydrogena-
tion of 1-phenyl-1-cyclohexene (1) proceeded
smoothly to give phenylcyclohexane in quantitative
yield. The capillaries themselves occupy only ca.
0.4 mL and a high space-time yield has been ach-
ieved (124.3 mg/17 min/0.4 mL). In addition, leach-
ing of palladium was not detected by ICP analysis af-
ter reactions.
a large interfacial area between the three phases. Inside
the microchannel reactor, the gas phase (hydrogen)
passes through the center of the narrow channel, while
the liquid phase (the solution of substrates) flows along
the surface of the channel where the Pd catalyst exists
(pipe flow). The reactions were complete within 2 mi-
nutes affording the corresponding products quantita-
tively. Although the space-time yield[4] of the system
was found to be much increased compared to those of
the conventional reactors, actual “numbering up” [5] of
the glass chips for a large-scale synthesis may still cause
practical and spatial problems. Herein we report a more
practical and highly productive system utilizing capillary
column reactors,[6] which occupy less space, are low cost,
and are easy to handle, and show feasibility towards
practical large-scale chemical synthesis.
We selected a fused silica capillary (200 mm i.d., 40 cm
length) instead of the previous microchannel system.[7]
Immobilization of the Pd catalyst onto the inner surface
of the capillary was conducted using the microencapsu-
lation method and a related new method called the pol-
ymer-micelle-incarceration method (PMI method)
which was recently developed in our laboratory.[3,8] First,
amine groups were introduced onto the inner surface of
the capillary. Microencapsulated Pd (MC Pd) was used
as the Pd source, and the modified capillary was filled
Keywords: capillary column reactors; heterogeneous
catalysis; hydrogenation; immobilization; palladium;
synthetic methods
Hydrogenation reactions are among the most funda- with the Pd colloidal solution and allowed to stand for
mental and important transformations, and have been 2 days. Finally the capillary was heated at 1508C. This
often used in synthetic organic chemistry.[1] In general, procedure was carried out several times. We found
hydrogenation reactions can be divided into two types that 26.7 mg of the Pd catalyst were immobilized after
based on the phases involved; homogeneous systems this immobilization process (4 times). We then conduct-
and heterogeneous systems. In the latter cases, the solu- ed the hydrogenation using the Pd-immobilized capilla-
bility of hydrogen in the solvents employed is an espe- ry thus obtained. First, one Pd-immobilized capillary
cially important factor affecting the rate of the reaction. was used for optimization of the reaction conditions.
Furthermore, the interfacial area between gas (hydro- The system was assembled as shown in Figure 1. The
gen), liquid (substrate and solvent), and solid (catalyst) Pd-immobilized capillary was connected using a T-shap-
plays a key role, an increased interfacial area can lead to ed connector, to a syringe by a Teflon tube, and also con-
higher reaction rates. We have recently reported hydro- nected to a hydrogen cylinder via a mass-flow controller
genation reactions using a Pd-immobilized microchan- by an SUS tube. The substrate solution was supplied by
nel reactor,[2,3] which showed high efficiency by realizing the syringe under the control of a syringe pump, and the
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Figure 1. The system for the hydrogenation reaction using one Pd-immobilized capillary.
flow of hydrogen was controlled by a mass-flow control-
ler. Hydrogenation reactions were carried out first un-
der the standard condition (the substrate solution;
0.1 mol/L, 0.1 mL/h, hydrogen; 1 mL/min) using 1-phen-
ylcyclohexene (1) as a substrate. Pipe flow (sometimes
liquid ring flow)[9] was observed in this system giving
Figure 2. Assembled Pd-immobilized capillaries for larger
the product in quantitative yield. Encouraged by this re-
sult, we further examined increased concentrations and
flow rates of the substrate solution to realize better pro-
ductivity. We were pleased to find that the reaction also
proceeded quantitatively even when the concentration
was increased up to ca. 0.8 mol/L and the flow rate of
the liquid up to 0.4 mL/h. Under these conditions, ca.
32 times higher productivity has been realized
(0.32 mmol/h). In addition, the TOF was calculated
and found to be ca. 1300/h.
scale synthesis.
Next we examined the feasibility of a larger scale syn-
thesis by using this system. For an initial trial, nine Pd-
immobilized capillaries were assembled and connected
to each other using ordinary 1/16 SUS connectors and
a binding agent (Figure 2). The same system mentioned
above was also used for this bundled capillary reactor,
and the hydrogenation reaction of 1 was examined un-
der the optimized conditions (the substrate solution;
0.1 mol/L, 0.1Â9¼0.9 mL/h, hydrogen; 1Â9¼9 mL/
min) (Figure 3). Unfortunately, the liquid and the gas
were not distributed uniformly to each line, and the yield
was decreased to 89%. We then tried further immobili-
zation of the Pd catalyst twice (totally six times) for each
capillary and retried the reaction under the same condi-
tions. In this case, although the distribution was still
somewhat problematic, the reaction proceeded well to
give the desired product in quantitative yield. We con-
cluded that immobilization of catalyst could compen-
sate for the loss of the uniformity of the flow mode. By
using this system, productivity was increased ca. 280
times over that of the previous system (2.8 mmol/h,
124.3 mg of the product was obtained in 17 min)
(Scheme 1). It should be noted that capillaries them-
selves occupy less space compared with the previous mi-
crochannel reactor (the actual volume of nine capillaries
is around only 0.4 mL, and 0.11 mL if calculated based
Figure 3. The appearance of the system using assembled Pd-
on the volume of the space inside capillaries), and that immobilized capillaries for larger scale synthesis.
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Adv. Synth. Catal. 2005, 347, 1889 – 1892

Triphase Hydrogenation Reactions in Pd-Immobilized Capillary Column Reactors
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tion (4 times), the catalyst loading was determined by ICP anal-
ysis (Pd: 26.7 mg).
Preparation of the Assembled Pd-Immobilized
Capillary
Scheme 1. Hydrogenation reaction using assembled Pd-im-
mobilized capillaries.
Nine Pd-immobilized capillaries were bundled using a com-
pression screw (1/16 in, JASCO) and single ferrule (1/16 in,
JASCO) and connected by a standard binding agent.
quite high space-time yields have been achieved, which
seems to be rather difficult to be realized in normal
batch systems (17 mg/mL/min). In addition, significant
Pd leaching was not detected by ICP analysis
(<0.20 mg) and the reactor was reused several times
without loss of activity.
In summary, we have developed a practical and highly
productive system using a less space-consuming capil-
lary reactor, and shown a promising result towards a
large-scale chemical synthesis. Further improvement
of this system towards a kilogram-scale synthesis as
well as asymmetric catalysis is now in progress.
Hydrogenation using the Assembled Pd-Immobilized
Capillary
The assembled Pd-immobilized capillaries, a syringe for feed-
ing the substrate solution and a hydrogen cylinder were joined
to each other using a three-way connector. The syringe and the
connector were connected by a teflon tube, and an SUS tube
was used for the connection between the hydrogen cylinder
and the connector via a mass-flow controller. 1-Phenylcyclo-
hexene in THF (0.8 mmol of substrate in 1 mLTHF) was added
using a syringe pump at a constant speed (3.6 mL/h), and hy-
drogen gas was fed via a mass-flow controller at a constant
flow rate (9 mL/min). The reaction was conducted at room
temperature and the reaction mixture was collected at the
end of the capillaries. The reaction was stopped after 17 min
and the solvent was removed under vacuum. The conversion
was determined by 1HNMR analysis and cyclohexylbenzene
was obtained quantitatively (yield: 124.3 mg).
Experimental Section
General Methods
1Hand 13C NMR spectra were recorded on a JEOL JNM-
LA300, JNM-LA400 or JNM-LA500 spectrometer in CDCl3.
Tetramethylsilane (TMS) served as an internal standard
(d¼0) for 1HNMR, and CDCl 3 was used as an internal stand-
ard (d¼77.0) for 13C NMR. All solvents and chemicals were
purified based on standard procedures.
Acknowledgements
This work was partially supported a Grant-in-Aid for Scientific
Research from Japan Society of the Promotion of Science.
References and Notes
Immobilization of the Pd Catalyst onto the Inner
Surface of the Capillary
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