Micro and nanobubble based strategy for gas-liquid-solid multiphase reactions: Palladium-catalysed hydrogenation of carbon-carbon unsaturated bonds

Article abstract of DOI:10.1055/s-0033-1339798

An autoclave-free, gas-liquid-solid multiphase hydrogenation of carbon-carbon unsaturated bonds using hydrogen micro and nanobubbles (MNBs) is developed. The process allows the liquid phase of the reaction mixture to maintain a high concentration of hydrogen gas. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1339798

LETTER
▌2225
lMetteircro and Nanobubble Based Strategy for Gas–Liquid–Solid Multiphase Re-
actions: Palladium-Catalysed Hydrogenation of Carbon–Carbon Unsaturated
Bonds
Micro and Nanobubble Mediated Gas–Liquid–Solid Reactions
Nobuyuki Mase,* Shogo Isomura, Mitsuo Toda, Naoharu Watanabe
Department of Applied Chemistry and Biochemical Engineering, Graduate School of Engineering, and Green Energy Research Division,
Research Institute of Green Science and Technology, Shizuoka University, 3-5-1 Johoku, Hamamatsu, Shizuoka 432-8561, Japan
Fax +81(53)4781196; E-mail: tnmase@ipc.shizuoka.ac.jp
Received: 05.08.2013; Accepted after revision: 22.08.2013
be superior to those obtained via conventional methods in-
Abstract: An autoclave-free, gas–liquid–solid multiphase hydro-
volving vigorous stirring.
genation of carbon–carbon unsaturated bonds using hydrogen micro
and nanobubbles (MNBs) is developed. The process allows the liq-
uid phase of the reaction mixture to maintain a high concentration
of hydrogen gas.
gas–liquid phase (previous work)
CuBr2, 2,2'-bipyridyl
TEMPO, NaOMe
Air-MNB
Key words: gas–liquid–solid multiphase reactions, hydrogenation,
micro and nanobubbles, heterogeneous catalysis, homogeneous ca-
talysis
O
R1
OH
(1)
R1
H
CH3CN/H2O
30 °C, 1–4 h
conv. up to 99%
gas–liquid–solid phase (this work)
Gas–liquid–solid multiphase reactions are a very impor-
tant category of reactions in organic synthesis that are
used for the production of diverse fine chemicals via hy-
drogenation, hydroformylation, carboxylation, and bio-
chemical processes.1 However, it is difficult to perform
such reactions because they often involve the use of high-
pressure gases in pressure-resistant reaction vessels in or-
der to increase the reaction yields. The development of
novel reactor technologies to improve the efficiency in
gas–liquid multiphase reactions is a longstanding chal-
lenge, not only in industrial manufacturing, but also in ac-
ademic research. In the late 1990s, for example,
microreactors emerged as smaller and safer devices for
performing ‘flash chemistry’.2 We have previously re-
ported the use of micro and nanobubbles (MNBs) to de-
velop a new experimental method for a gas–liquid
multiphase reaction in organic synthesis, and improved
significantly the efficiency of the aerobic oxidation of
primary alcohols into aldehydes in the presence of
copper/2,2,6,6-tetramethyl-1-piperidinyloxyl (TEMPO)
catalysts (Scheme 1, equation 1).3 In principle, micro and
nanobubbles could potentially be used for conducting
gas–liquid multiphase reactions other than aerobic oxida-
tion, therefore, we believe that this new methodology is an
important contribution to general gas–liquid multiphase
reactions with simple, safe, and environment-friendly
protocols. In order to further develop this methodology,
the gas–liquid–solid multiphase palladium-catalysed hy-
drogenation of carbon–carbon unsaturated bonds was
evaluated (Scheme 1, equation 2). In this study, the yields
of hydrogenation reactions using H2-MNBs were found to
Pd/Al2O3
(0.01-3 mol%)
H2-MNB
R1
R3
R2
R4
R1
R3
R2
R4
(2)
MeOH
30 °C, 1–6 h
conv. up to 99.9%
Scheme 1 Micro and nanobubble based strategies for aerobic oxida-
tion and hydrogenation
In collaboration with Asupu Company Limited, we have
developed a stainless-steel-free Teflon® generator [MA3-FS,
pumping rate 120–150 mL/min, Figure 1 (a)]. The
H2-MNBs were generated using this device and then
passed into methanol to afford a slightly turbid mixture
[Figure 1 (b)].
Figure 1 (a) The micro and nanobubble generator, (b) the turbid
mixture of methanol and micro and nanobubbles, and plots showing
the degree of hydrogen in distilled water
The measurement of dissolved hydrogen gas levels in dis-
tilled water showed that the Teflon®-MNB generator rap-
idly saturated the solution with hydrogen gas (under a H2
flow rate of 5 mL/min), even without stirring (Figure 1).
On the other hand, bubbling of hydrogen at the same flow
SYNLETT 2013, 24, 2225–2228
Advanced online publication: 30.09.2013
DOI: 10.1055/s-0033-1339798; Art ID: ST-2013-U0754-L
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

2226
N. Mase et al.
LETTER
rate using a conventional gas dispersion tube with a po- The hydrogenations were carried out using three different
rous, fritted glass tip under vigorous stirring (500 rpm) re- methods (Figure 2). Our initial attempts using H2-MNBs
sulted in a lower hydrogen concentration. This finding is [Figure 2 (a), H2 flow rate: 3 mL/min] afforded the desired
similar to that under general hydrogen balloon conditions. product, ethylbenzene (2a), in quantitative yield after five
Although the mole fraction of hydrogen (0.141 × 104) was hours in the presence of palladium on alumina spheres
lower than that of oxygen (0.230 × 104),4 these results in- (0.5 mol%) at 30 °C (Table 1, entry 1). The hydrogenation
dicated that the Teflon®-MNB generator was an effective was complete within one hour when the H2 flow rate was
and well-assembled instrument for dissolving hydrogen increased to 10 mL/min (Table 1, entries 2 and 3). On the
gas in distilled water.
other hand, employing the general hydrogen balloon
method under vigorous stirring [Figure 2 (b)] resulted in a
very low yield of product (Table 1, entry 8). Hydrogen
bubbling (H2 flow rate: 5 mL/min) using a conventional
gas dispersion tube resulted in a poor 38% yield of 2a (Ta-
ble 1, entry 9).
Table 1 A Comparison between Different Hydrogenation Reaction
Conditionsa
Pd/Al2O3
(0.5 mol%)
H2
MeOH (0.25 M)
30 °C
1a (20 mmol)
2a
Entry
Conditions
H2 flow rate Temp
(mL/min) (°C)
Time
(h)
Yield
(%)b
1
2
MNBs
MNBs
MNBs
MNBs
MNBs
MNBs
MNBs
balloon
3
5
30
30
30
50
70
30
30
30
30
30
50
70
30
5
99.9
99.9
99.9
99.9
99.9
99.9
99.9
4.4
2
3
10
5
0.75
2
4
5
5
3
6c
7c
8
5
5
Figure 2 Hydrogenation: the MNB apparatus and the different
methods employed
5
6
d
–
2
Even when the reactions were carried out at a high H2 flow
rate of up to 10 mL/min and/or at high pressure (up to 0.6
MPa), the reaction yields were lower than that obtained
via the MNB-based procedure (Table 1, compare entries
2, 10 and 13). Although reflux condensers and/or a stain-
less-steel autoclave must be used when reactions are per-
formed at high gas flow rates and/or under high pressure
conditions, the MNB-based procedure does not require
such engineering controls. Furthermore, a very interesting
temperature effect was observed. The reaction yields de-
creased significantly on increasing the temperature under
general hydrogen bubbling conditions, whereas high reac-
tivities were still observed under the MNB-based condi-
tions (Table 1, entries 4 and 5 vs 11 and 12). According to
Henry’s law, the solubility of gases usually decreases with
increasing temperature, however, under the MNB-based
conditions, the catalytic activity was not affected on in-
creasing the temperature due to the high hydrogen con-
centration. Furthermore, the catalyst loading could also be
decreased to 0.01 mol% (Table 1, entries 6 and 7).
9
bubbling
bubbling
bubbling
bubbling
autoclave
5
2
38.3
76.0
16.6
4.0
10
11
12
13
10
5
2
3
5
3
e
–
2
35.0
a See reference 5 and the Supporting Information for a description of
the MNB procedure. The reactions were not stirred in entries 1–7; 500
rpm stirring was applied in entries 8–13.
b Determined by GC analyses (column: GL Sciences TC-17).
c Pd/Al2O3 (entry 6: 0.05 mol%, entry 7: 0.01 mol%) was used.
d Atmospheric pressure.
e Pressure was 0.6 MPa.
The hydrogenation of styrene (1a) (20 mmol, 2 g) under
heterogeneous catalysis was selected as a model reaction
to evaluate the reaction efficiency (Table 1). Palladium on
activated carbon (Pd/C) powder is usually employed for
hydrogenation, however, it sometimes requires long oper-
ation times to remove the catalyst by a filtration process.
Moreover, operators have to prevent the filters from clog-
ging during operation in flow reactors. Therefore, palladi-
um on alumina spheres (Pd/Al2O3, 0.5% Pd, 2–4 mm) was
used as the catalyst. These spheres have excellent abra-
sion resistance, but this system is less reactive compared
to palladium on activated carbon powder.
Encouraged by these results, the scope of this MNB-based
hydrogenation was studied with a range of compounds 1
bearing carbon–carbon unsaturated bonds, under the opti-
mised reaction conditions (Table 2).5 Hydrogenated prod-
ucts 2 were obtained in nearly quantitative yields within
12 hours at 30 °C in the presence of 0.5–3 mol% of the
palladium catalyst. Monosubstituted, 1,1-disubstituted
Synlett 2013, 24, 2225–2228
© Georg Thieme Verlag Stuttgart · New York

LETTER
Micro and Nanobubble Mediated Gas–Liquid–Solid Reactions
2227
and 1,2-disubstituted alkenes 1 were hydrogenated gave very poor yields of these alkanes (Table 2, entries
smoothly within three hours, where the yield (MNB)/yield 17–20).
(bubbling) ratio was up to 50 (Table 2, entries 1–8). The
The MNB-based hydrogenation set-up is quite simple.
MNB-based method was found to be effective for less re-
The inlet and outlet tubes were simply connected to the re-
active trisubstituted and tetrasubstituted alkenes 1 in up to
action vessel [Figure 2 (a)]. Therefore, the MNB-based
hydrogenation method may offer significant advantages
30 times higher yield ratios (Table 1, entries 9–16). More-
over, hydrogenation of substrates with triple bonds afford-
to pharmaceutical and industrial processes. To study a
ed the expected saturated compounds in quantitative
multigram-scale synthesis (100 mmol, >10 g), styrene
yields using MNBs, whilst the hydrogen bubbling method
Table 2 Hydrogenation of Unsaturated Compounds 1 into Alkanes 2a
Pd/Al2O3
R1
R2
R1
R3
R2
R4
H2 (5 mL/min)
R3
R4
MeOH, 30°C
1 (20 mmol)
2
Entry
Substrate
Method
Catalyst
(mol%)
Time (h) Yield (%)b Ratioc
Product
1
2
MNB
bubbling
0.5
0.5
2
2
99.9
38.3
2.6
2a
2b
1a
1b
3
4
MNB
bubbling
0.5
0.5
3
3
99.9
12.2
8.2
3.3
5
6
MNB
bubbling
0.5
0.5
3
3
96.0
29.3
1c
2c
OH
OH
7
8
MNB
bubbling
1
1
2
2
99.9
2.0
50
1d
2d
9
10
MNB
bubbling
0.5
0.5
6
6
99.9
24.0
O
O
4.2
4.2
1e
2e
11
12
MNB
bubbling
1
1
12
12
99.9
24.0
HO
HO
1f
2f
13
14
MNB
bubbling
1
1
9
9
93.2
3.1
30
1g
1h
1i
2g
2h
15
16
MNB
bubbling
3
3
6
6
99.9
12.0
8.3
17
18
MNB
bubbling
0.5
0.5
3
3
99.9
2.1
48
2a
OH
OH
HO
19
20
MNB
bubbling
0.5
0.5
4
4
99.9
4.1
24
HO
2j
1j
a See reference 5 for a description of the procedure.
b Determined by GC analyses (column: GL Sciences TC-17).
c Yield (MNB)/yield (bubbling).
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2225–2228

2228
N. Mase et al.
LETTER
(1a, 10.4 g), (E)-3-phenylprop-2-en-1-ol (1d, 13.4 g) or MNB-based reaction system are in progress, the results of
citronellal (1e, 15.4 g) in methanol (1.25 M) was placed in which will be reported in due course.7,8
the reaction vessel containing palladium on alumina
spheres (0.3 mol%). H2-MNBs were introduced via the
MNB generator over 6–20 hours, after which the metha-
Acknowledgment
The JNC corporation is thanked for the generous gift of palladium
catalysts. This study was supported in part by a Grant-in-Aid for
challenging Exploratory Research (No. 21655056) from the Japan
Society for the Promotion of Science (JSPS).
nol was evaporated to give the saturated product 2 (Table
3). Extraction, washing, filtration, or column chromatog-
raphy were not required and the products were obtained in
excellent purities on multigram scales.
Table 3 Multigram-Scale Hydrogenation Using the MNB-Based
Supporting Information for this article is available online at
Methoda
http://www.thieme-connect.com/ejournals/toc/synlett.SupInpfioomgrattr
o
nSupprigI
o
tnnofrmat
Pd/Al2O3 (0.3 mol%)
R1
R2
R4
R1
R3
R2
R4
H2-MNB (10 mL/min)
References
R3
MeOH (1.25 M)
(1) (a) The Handbook of Homogeneous Hydrogenation; de
Vries, J. G.; Elsevier, C. J., Eds.; Wiley-VCH: Weinheim,
2007. (b) Klabunovskii, E.; Smith, G. V.; Zsigmond, A.
Heterogeneous Enantioselective Hydrogenation: Theory
and Practice; Springer: Dordrecht, 2006.
1 (100 mmol)
2
Entry Substrate Quantity Temp
Time
(h)
Product Yield
(%)b
(g)
(°C)
(2) (a) Yoshida, J.-I. Chem. Rec. 2010, 10, 332. (b) Irfan, M.;
Glasnov, T. N.; Kappe, C. O. ChemSusChem 2011, 4, 300.
(c) Jones, R. V.; Godorhazy, L.; Varga, N.; Szalay, D.; Urge,
L.; Darvas, F. J. Comb. Chem. 2006, 8, 110. (d) Kobayashi,
J.; Mori, Y.; Okamoto, K.; Akiyama, R.; Ueno, M.;
Kitamori, T.; Kobayashi, S. Science 2004, 304, 1305.
(3) (a) Mase, N.; Mizumori, T.; Tatemoto, Y. Chem. Commun.
2011, 47, 2086. (b) Mase, N.; Mizumori, T. Piping
Engineering 2011, 53, 48. (c) The preliminary results were
discussed at the summer Symposium of the Japanese Society
for Process Chemistry, Tokyo, Japan, 2010, 1P-32.
(4) Wilhelm, E.; Battino, R.; Wilcock, R. J. Chem. Rev. 1977,
77, 219.
(5) Typical procedure for the hydrogenation of unsaturated
carbon–carbon bonds using the H2-MNB strategy. The
hydrogenation was carried out in a 100 mL vial equipped
with an MNB generator without additional stirring. Alkene
or alkyne 1 (20 mmol) was dissolved in MeOH (80 mL) and
the soln warmed to 30 °C. Using the MNB generator (MA3-
FS), H2-MNBs were introduced into the reactor in the
presence of palladium on alumina spheres (Pd/Al2O3) (0.5%
Pd, 2–4 mm, 0.1 mmol, 0.5 mol%) at a H2 flow rate of 5
mL/min. Aliquots were taken from the mixture periodically
to monitor the reaction progress using GC analysis. After the
completion of the hydrogenation reaction, the MeOH was
evaporated in vacuo to afford the desired alkane 1 in
excellent purity. We further examined the hydrogenation of
styrene (1a) in the presence of the following heterogeneous
catalysts: 5% Pd/C, 5% Pd/C E type, 5% Pd/C NX type, 5%
Pd/C K type and 2.7 wt% Pd/C spheres, however, increasing
back pressure then clogging of the flow system occurred
during operation.
1
2
3
1a
1d
1e
10.4
13.4
15.4
30
50
50
6
10
20
2a
2d
2e
99.9
99.9
97.2
a See reference 5 for a description of the procedure.
b Determined by GC analyses (column: GL Sciences TC-17).
Finally, the application of this MNB-based method under
homogeneous catalysis was studied (Scheme 2). Crab-
tree’s catalyst (iridium complex 3, containing 1,5-cy-
clooctadiene, triscyclohexylphosphine, and pyridine
units), is an air-stable, homogeneous catalytic system uti-
lised in hydrogenation reactions.6 A low catalyst loading
(0.05 mol%) was found to be sufficient for promoting the
hydrogenation of styrene (1a) into ethylbenzene (2a)
(Scheme 2).
PF6
Cy3P
N
Ir
3 (0.05 mol%)
H2
MeOH (0.25 M)
30 °C, 3 h
1a (10 mmol)
2a
H2-method MNB
99.9
Bubbling 0.6 MPa
17.0
10.0
Yield (%)
(6) (a) Crabtree, R. Acc. Chem. Res. 1979, 12, 331. (b) Crabtree,
R. H.; Davis, M. W. J. Org. Chem. 1986, 51, 2655.
(7) The preliminary results were discussed at the 42nd Annual
Meeting of the Union of Chemistry-Related Societies in
Chubu Area, Nagano, Japan, 2011, 1P-08.
(8) Preliminary experimental determinations of the average size
(158 nm) and concentration (0.27 × 108 particles/mL) of H2
nanobubbles using the MA3-FS generator were performed
using a NanoSight LM10-HS. On the other hand, no
formation of H2 nanobubbles was observed under standard
bubbling or balloon conditions.
Scheme 2 Homogeneous hydrogenation
In summary, H2-MNBs have been employed to develop a
novel experimental method for autoclave-free, gas–
liquid–solid multiphase hydrogenations in organic syn-
thesis. A significant improvement in the reaction efficien-
cy was achieved by virtue of this new MNB-based
technique for the reduction of unsaturated carbon–carbon
bonds. Further studies focusing on the scope of this novel
Synlett 2013, 24, 2225–2228
© Georg Thieme Verlag Stuttgart · New York

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