Fine-Bubble-Slug-Flow Hydrogenation of Multiple Bonds and Phenols

Article abstract of DOI:10.1055/s-0040-1705948

We describe a promising method for the continuous hydrogenation of alkenes or alkynes by using a newly developed fine-bubble generator. The fine-bubble-containing slug-flow system was up to 1.4 times more efficient than a conventional slug-flow method. When applied in the hydrogenation of phenols to the corresponding cyclohexanones, the fine bubble-slug-flow method suppressed over-reduction. As this method does not require the use of excess gas, it is expected to be widely applicable in improving the efficiency of gas-mediated flow reactions.

Full text of DOI:10.1055/s-0040-1705948

SYNLETT
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2020, 31, A–F
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Integrated Synthesis Using Continuous-
T. Iio et al.
Cluster
Synlett
Fine-Bubble–Slug-Flow Hydrogenation of Multiple Bonds and Phe-
nols
Takuya Iioa
Kohei Nagaia
Tomoki Kozukab
Akhtar Mst Sammia
Kohei Satoa,b,c
Tetsuo Narumia,b,c,d
Nobuyuki Mase*a,b,c,d
a Department of Engineering, Graduate School of Integrated Science and
Technology, Shizuoka University, 3-5-1 Johoku, Hamamatsu, Shizuoka
432-8561, Japan
b Department of Applied Chemistry and Biochemical Engineering, Faculty
of Engineering, Shizuoka University, 3-5-1 Johoku, Hamamatsu, Shizuoka
432-8561, Japan
c Graduate School of Science and Technology, Shizuoka University, 3-5-1 Jo-
hoku, Hamamatsu, Shizuoka 432-8561, Japan
d Research Institute of Green Science and Technology, Shizuoka University,
3-5-1 Johoku, Hamamatsu, Shizuoka 432-8561, Japan
mase.nobuyuki@shizuoka.ac.jp
Published as part of the Cluster Integrated Synthesis Using Continuous-Flow
Technologies
Corresponding Author
Received: 27.08.2020
Accepted after revision: 16.09.2020
Published online: 21.10.2020
m or less, have large gas–liquid surface areas and a self-
pressurizing effect, resulting in an excellent gas dissolu-
tion.6 These characteristics of FBs can enhance the concen-
tration of dissolved reactive gases and improve gas-con-
sumption efficiency, providing increased reaction rates,
even at ambient pressures and temperatures.5 Therefore, an
FB–slug-flow approach has the potential to realize highly
efficient gas-mediated flow reactions without the use of
excess gas (Figure 1B).
DOI: 10.1055/s-0040-1705948; Art ID: st-2020-u0475-c
Abstract We describe a promising method for the continuous hydro-
genation of alkenes or alkynes by using a newly developed fine-bubble
generator. The fine-bubble-containing slug-flow system was up to 1.4
times more efficient than a conventional slug-flow method. When ap-
plied in the hydrogenation of phenols to the corresponding cyclohex-
anones, the fine bubble–slug-flow method suppressed over-reduction.
As this method does not require the use of excess gas, it is expected to
be widely applicable in improving the efficiency of gas-mediated flow
reactions.
Key words flow reaction, gas–liquid reaction, hydrogenation,
alkynes, alkenes, phenols
The flow method is an innovative technology that per-
mits waste minimization and provides enhanced safety,
easy scale-up, better energy efficiency, and lower costs
compared with conventional batch methods.1 In particular,
the flow method is favorable for clean gas–liquid reac-
tions,2–4 as the reaction can be controlled by the introduc-
tion and removal of the gas without using a high-pressure
autoclave.2k,3 However, a drawback of conventional gas–liq-
uid flow methods such as slug flow or pipe flow is that the
gas and liquid are separated in the flow channel and excess
gas must be supplied to improve the reaction efficiency
(Figure 1A).4 To maximize the performance of gas-mediated
reactions, we have developed autoclave-free gas–liquid and
gas–liquid–solid multiphase reactions that use fine bubbles
(FBs) in batch systems.5 FBs, which have diameters of 100
Figure 1 Gas-involved continuous-flow methods
FB generators used in previous studies had high flow
rates of 120–130 mL/min, which limited their use in the
laboratory. Their productivity was also inadequate because
the gas supply rate was 5–10 mL/min and the gas–liquid ra-
tio was only 4–8 vol%.5a We initially developed an FB gener-
ator that can generate FBs at a low flow rate and with a high
gas–liquid ratio by adopting a hybrid system that combines
pressurized dissolution and depressurized generation with
shear force as the FB-generation mechanism (Figure 2A). A
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small pump with a linear drive mechanism was used to de-
liver a liquid-containing gas, permitting low liquid flow
rates (0.01–99.99 mL/min) and high gas–liquid ratios (up to
50 vol%). Nanoparticle tracking analysis (NTA)7 revealed the
presence of nanosized ultrafine bubbles (UFBs)8 with diam-
eters of approximately 140 nm. By using our newly devel-
oped generator, H2 UFBs can be produced at a concentration
of 4.1 × 108 particles/mL by circulation in water for 10 min-
utes. Even in a single operation, H2 UFBs were detected at a
concentration of 6.4 × 107 particles/mL [see Supporting In-
formation (SI), Table S1]. The newly developed FB generator
is now commercially available.9
Table 1 Comparison of Flow-Hydrogenation Reaction Conditionsa
H
H
H2 (FB-slug flow), Pd/C
MeOH, 35 s
1a
2a
(2.0 mL/min)
Entry
Temp (°C) H2 (equiv) Pd/C (mmol) Conv.b (%) Yieldb (%)
1
30
60
60
60
60
60
1
0.47
0.47
0.23
0.47
0.47
0.47
59
86
62
>99
85
3
58
85
62
>99
76
2
2
1
3
1
4
1.5
1
5c
6d
1
a Reaction conditions: styrene (6.2 or 4.1 mmol), MeOH (300 mL), 10 wt%
Pd/C (0.23 or 0.47 mmol), H2 (1.0 mL/min), 35 s.
b Determined by GC analysis (for GC conditions, see the SI).
c H2 supplied by slug flow.
d H2 supplied by the bubbling-flow method. For details of the slug-flow and
bubbling-flow methods, see the SI.
The number concentration of H2 UFBs in water (parti-
cles/mL) was measured by the NTA method. The number of
UFBs in the FB–slug flow was 7.4 times and 57 times larger
than that in the conventional slug- and bubbling-flow
methods, respectively (Table 2). The mean diameters of the
UFBs were 80–130 nm, regardless of the UFB-generation
method. Under the FB–slug-flow conditions, passage
through the Pd/C catalyst halved the number of UFBs and
slightly increased their mean diameter, indicating that H2
UFBs remained after passage through the Pd/C catalyst (Fig-
ure S5). A GC equipped with a dielectric barrier discharge
ionization detector (BID) was used to analyze the total H2
molar concentrations (mM) in the dissolved and dispersed
states. Compared with conventional slug-flow and bub-
bling-flow methods, the FB–slug-flow method produced
the highest H2 molar concentration. Indeed, the dissolution
of a much greater amount of H2 in the FB–slug-flow method
led to differences in the sizes of the gas segments for the
various flow methods (gas: 1–2 mm, liquid: 5–8 mm for
FB–slug flow; gas: 3–6 mm, liquid: 3–4 mm for slug flow;
See SI, Figure S4). These results suggest that the presence of
H2 UFBs can maintain a high H2 concentration in the reac-
tion mixture because the self-pressurization effect of FB5
accelerates the rate of dissolution of H2 in the liquid phase
after H2 is consumed during the reaction. Because of these
effects, the FB–slug-flow method shows a high reaction ef-
ficiency, even at atmospheric pressure.
Figure 2 (A) The new type of FB generator. (B–D) Schematics of vari-
ous reaction systems.
To evaluate the proposed FB–slug-flow method, we in-
vestigated the Pd-catalyzed hydrogenation of styrene as a
model reaction using the newly developed high-perfor-
mance FB generator (Table 1 and Figure 2B). H2 gas and a
solution of styrene (1a) in methanol were continuously
supplied to a temperature-controlled Pd/C-packed reactor
in a column oven. The maximum amount of catalyst (0.47
mmol) that could be loaded into the reactor was used. The
use of a radial-flow column reactor did not increase the
backpressure, even when a powdered Pd catalyst was pres-
ent. The hydrogenation reaction at 30 °C with 1.0 equiva-
lents of H2 and a residence time of 35 seconds gave ethyl-
benzene (2a) in 58% yield (Table 1, entry 1). A higher tem-
perature (60 °C) improved the reactivity, resulting in an 85%
yield (entry 2). Moreover, the hydrogen-consumption effi-
ciency was 85%, which reduced the requirement for excess
gas. A decrease in the catalyst loading led to a decrease in
reactivity (entry 3). However, the hydrogenation reaction
proceeded quantitatively when the concentration of the
substrate was decreased, corresponding to the use of 1.5
equivalents of H2 (entry 4). With the conventional slug-flow
method (Figure 2C) or the bubbling-flow method (Figure
2D), the yields of the hydrogenation reaction were lower
than those from the FB–slug-flow method (entries 2, 5, and
6). The low yield relative to conversion and the absence of
byproducts in the GC analysis suggests that small amounts
of substrates or products were adsorbed onto the catalyst
during the slug-flow reaction.10
Hydrogenation by the FB–slug-flow method was applied
to various alkenes and alkynes. For all substrates, the FB–
slug-flow method resulted in the highest yields of hydroge-
nation products among the tested methods (Table 3). Ter-
minal alkene 1a and disubstituted alkenes 1b and 1c were
hydrogenated smoothly with 2.0 equivalents of H2 to give
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Table 2 Number Concentration of UFBs and Molar Concentration of H2
Entry
Product
Yieldb (%)
FB–slugc
Slug
73
Bubbling
5
Entry Flow condition
Number of UFBsa
H
2 concentration (mM)b
(× 107 particles/mL)
H
H
MeOHc
MeCyd
2
76 (95)
(2b)
1
2
3
FB–slug flow
slug flow
2.00
0.27
0.035
4.1
2.4
2.7
26.5
9.8
bubbling flow
8.3
H
a Determined by NTA analysis; conditions: H2O (2.0 mL/min flow rate), H2
(1.0 mL/min flow rate), r.t.
3
(2c)
73 (97)
85 (95)
63
64
2
H
b Determined by GC-BID analysis.
c Conditions: MeOH (2.0 mL/min flow rate), H2 (1.0 mL/min flow rate), r.t.
d Conditions: methylcyclohexane (MeCy) (0.7 mL/min flow rate), H2 (0.3
mL/min flow rate), r.t.
H
4d
14
(2d)
OH
H
2a–c, respectively, in almost quantitative yields (Table 3,
entries 1–3). When the hydrogen supply was inadequate,
the dehydrogenation of cinnamyl alcohol gave cinnamalde-
hyde, which underwent decarbonylation and subsequent
hydrogenation to give ethylbenzene.11 The bubbling-flow
method gave the desired product 2d in 14% yield (including
byproducts) with 22% conversion, despite mildly reactive
Pd sheets being used instead of reactive powdered Pd/C. In
contrast, the FB–slug-flow method provided an 85% yield of
2d with 92% conversion (entry 4). Acetalization was ob-
served when enones 1e–g were used as substrates. To avoid
this reaction, ethyl acetate was used instead of methanol as
the solvent. The FB–slug-flow method then showed the
highest reactivity at 30 °C, and also prevented competing
formation of phenols through dehydrogenation (entry 5). In
these reactions, carbonyl hydrogenation was suppressed,
permitting olefins to be hydrogenated selectively to give
the desired products 2e–g (entries 5–7). Despite the low re-
activity, the hydrogenation of a tetrasubstituted alkenes 1g
and trisubstituted alkenes 1h and 1i by using 2.0 equiva-
lents of H2 afforded the desired products 2g–i in quantita-
tive or 79% yield (entries 7–9). Terminal or internal alkynes
also reacted quantitatively with 4.0 equivalents of H2 (en-
tries 10 and 11).
O
H
5e,f
(2e)
87 (95)
77
1
H
O
6e
7e
75 (93)
88 (98)
71
84
5
2
(2f)
H
H
O
H
(2g)
H
H
H
8
9
70 (>99)
32 (79)
69 (87)
62
29
51
2
7
1
(2h)
(2i)
H
O
H
H
H
H
H
H
H
10g
(2j)
H
11g
95 (>99)
74
2
(2k)
H
Table 3 Scope of the FB–Slug-Flow Method for Hydrogenation of Mul-
a Reaction conditions: 1 (8.3 mmol), MeOH (400 mL), 10 wt% Pd/C (0.47
mmol), H2 (1.0 mL/min), 60 °C, 35 s.
tiple Bondsa
b Determined by GC analysis (for GC conditions, see the SI).
c Yields obtained by halving the substrate concentration are given in paren-
theses.
R5
R5
R6
H
H
H2 (1.0 mL/min)
Pd/C (0.47 mmol)
R2
R4
R1
R3
R2
R4
R1
R3
H
H
H
H
or
or
d 1.5 wt% Pd/sheet (0.7 mmol) was used at 20 °C.
e EtOAc was used as the solvent.
MeOH
60 °C, 35 s
R6
f The reaction was performed at 30 °C.
1 (2.0 mL/min)
2
g Substrate (4.2 mmol) was used.
Entry
Product
Yieldb (%)
FB–slugc
Slug
76
Bubbling
2
The applicability of the FB–slug-flow method to hydro-
genation was extended to controlling the over-reduction of
phenols to cyclohexanones. Although many efforts have
been made to achieve partial hydrogenation of phenols,
over-reduction to cyclohexanols remains an issue.12,13 How-
ever, the newly developed FB–slug-flow method permitted
a selective hydrogenation reaction to be achieved by strict
H
H
(2a)
1
85 (>99)
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control of the residence time (Table 4). In the first attempt,
Pd/C, methylcyclohexanone, and 4-propylphenol were used
as the catalyst, solvent, and substrate, respectively.14 Al-
though the hydrogenation reaction proceeded when the
FB–slug-flow method was used, the results were unsatisfac-
tory at atmospheric pressure, even at 80 °C (Table 4, entry
1). Therefore, a backpressure regulator was installed after
the catalyst tube to increase the reaction pressure (SI; Fig-
ures S1 and S2). Under the pressurized conditions, the hy-
drogenation efficiency was improved, but the selectivity for
ketone formation decreased owing to over-reduction (Table
4, entries 1–3). Reactions at a lower temperature or with
less H2 to suppress over-reduction resulted in lower conver-
sions but higher selectivities (92:8; entries 4 and 5). Fur-
thermore, the reactivity was not significantly affected by
doubling the catalyst loading to 0.80 mmol (entries 5 and
6). As hydrogen was presumed to flow out of the reaction
system before the adsorption/hydrogenation reaction,
transparent piping was introduced after the catalyst tube to
permit observation of the flow of unreacted hydrogen. As
the residence time was not sufficient for the reaction, it was
increased to 70 s, which provided the 4-propylcyclohexa-
none (4a) in 88% yield with 90:10 selectivity (entry 7). No-
tably, the FB–slug-flow method was superior to both the
slug- and bubbling-flow methods in terms of reactivity and
selectivity (entries 7–9).
The scope of this method for the hydrogenation of phe-
nol derivatives was then evaluated. With unsubstituted
phenol (3b), p-cresol (3c), or m-cresol (3d), the reaction
proceeded in moderate yield and with good selectivity (en-
tries 10–15). In the hydrogenation of 3c, both the FB–slug-
flow method and the conventional slug-flow method gave
the corresponding cyclohexanone in the same yield. How-
ever, the selectivity was superior with the FB–slug-flow
system, indicating that the FB-mediated reaction affects not
only the reactivity but also the selectivity (entries 12 and
13). The reaction of thymol (3e), which has a bulky substit-
uent at the 2-position, gave the desired product in 84% yield
Table 4 Screening of Reaction Conditions and Scope of the FB–Slug-Flow Method for the Hydrogenation of Phenolsa
OH
O
OH
over-reduction
H2, Pd/C (0.40 mmol)
R
R
R
methylcyclohexane (10 mM)
80 °C
back pressure 0.8 MPa
3a–e
4a–e
5a–e
Entry
R
Method
Residence time (s)
H2 (mL/min)
Yield (4 + 5) (%)b
Ratio 4/5
1c
2d
4-Pr (3a)
4-Pr (3a)
4-Pr (3a)
4-Pr (3a)
4-Pr (3a)
4-Pr (3a)
4-Pr (3a)
4-Pr (3a)
4-Pr (3a)
H (3b)
FB–slug
FB–slug
FB–slug
FB–slug
FB–slug
FB–slug
FB–slug
slug
15
15
1.0
1.0
1.0
1.0
0.7
0.7
0.3
0.3
20
22
89
92
22
59
69
88
46
0.1
82
56
66
67
75
63
84
56
78:22
44:56
34:66
92:8
3
15
4e
15
5
30
91:9
6f
30
88:12
90:10
81:19
–
7
70
8
70
9
bubbling
FB–slug
slug
70
10
11
12g
13g
14h
15h
16h
17h
140
140
140
140
100
100
70
0.3
0.3
0.5
0.5
0.3
0.3
0.3
0.3
93:7
H (3b)
89:11
90:10
76:24
98:2
4-Me (3c)
4-Me (3c)
3-Me (3d)
3-Me (3d)
2-i-Pr,5-Me (3e)
2-i-Pr,5-Me (3e)
FB–slug
slug
FB–slug
slug
95:5
FB–slug
slug
>90:10
>90:10
70
a Reaction conditions: phenol 3 (4.0 mmol), methylcyclohexane (400 mL), 10 wt% Pd/C (0.40 mmol), H2 (1.0, 0.7, or 0.3 mL/min), 80 °C, 15–100 s, 0.8 MPa.
b Determined by GC analysis (for GC conditions, see SI).
c Backpressure 0 MPa.
d Backpressure 0.5 MPa.
e At 30 °C.
f Catalyst (0.8 mmol).
g Backpressure 1.0 MPa.
h 5 wt% Pd/C (0.29 mmol).
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–F

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under FB–slug-flow conditions (entry 16). In contrast, the
reaction under conventional slug-flow conditions afforded
the product in 56% yield (entry 17).
Res. 2005, 44, 1742. (c) Jähnisch, K.; Baerns, M.; Hessel, V.;
Ehrfeld, W.; Haverkamp, V.; Löwe, H.; Wille, C.; Guber, A. J. Fluo-
rine Chem. 2000, 105, 117. (d) For flow microreactors with a
cyclone micromixer, see: (e) Hübner, S.; Bentrup, U.; Budde, U.;
Lovis, K.; Dietrich, T.; Freitag, A.; Küpper, L.; Jähnisch, K. Org.
Process Res. Dev. 2009, 13, 952. (f) Dietrich, T. R.; Freitag, A.;
Scholz, R. Chem. Eng. Technol. 2005, 28, 477. For flow microreac-
In methylcyclohexane, the hydrogen concentration un-
der the FB–slug-flow conditions was 2.7–3.2 times higher
than that under the conditions of the conventional flow
methods (Table 2). This higher level of hydrogen in the reac-
tion solution probably contributes to the improved reactivi-
ty. Moreover, the increased hydrogen concentration might
accelerate the desorption rate of partially hydrogenated
products from the catalyst, preventing over-reduction.
In conclusion, a novel FB–slug-flow method was devel-
oped,15 and its wide applicability was confirmed through
the hydrogenation of multiple bonds and by the synthesis
of ketones through partial hydrogenation of phenol deriva-
tives. Towards achieving green sustainable chemistry, the
FB–slug-flow method has potential for replacing conven-
tional gas-involved flow reactions because this environ-
mentally friendly process does not require the use of excess
gas.
tors with
a microfluidic ‘pipe’, see: (g) Chambers, R. D.;
Sandford, G.; Trmcic, J.; Okazoe, T. Org. Process Res. Dev. 2008,
12, 339. (h) Chambers, R. D.; Fox, M. A.; Sandford, G.; Trmcic, J.;
Goeta, A. J. Fluorine Chem. 2007, 128, 29. (i) Chambers, R. D.; Fox,
M. A.; Holling, D.; Nakano, T.; Okazoe, T.; Sandford, G. Lab Chip
2005, 5, 191. For flow microreactors with a microfluidic ‘bol-
lard’, see: (j) Wada, Y.; Schmidt, M. A.; Jensen, K. F. Ind. Eng.
Chem. Res. 2006, 45, 8036. For flow reactors with a tube-in-
tube, see: (k) O’Brien, M. J. CO2 Util. 2017, 21, 580.
(l) Brzozowski, M.; O’Brien, M.; Ley, S. V.; Polyzos, A. Acc. Chem.
Res. 2015, 48, 349. (m) O'Brien, M.; Taylor, N.; Polyzos, A.;
Baxendale, I. R.; Ley, S. V. Chem. Sci. 2011, 2, 1250. (n) O’Brien,
M.; Baxendale, I. R.; Ley, S. V. Org. Lett. 2010, 12, 1596.
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gendum: Top. Curr. Chem. 2019, 377, 7. (b) Mallia, C. J.;
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Funding Information
(5) (a) Mase, N.; Mizumori, T.; Tatemoto, Y. Chem. Commun. 2011,
47, 2086. (b) Mase, N.; Isomura, S.; Toda, M.; Watanabe, N.
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(7) In the NTA method, many particles are individually and simul-
taneously analyzed, and their hydrodynamic diameters are cal-
culated based on the Stokes–Einstein equation, see: (a) Malloy,
A.; Carr, B. Part. Part. Syst. Charact. 2006, 23, 197. (b) Tian, X.;
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This work was supported in part by JSPS KAKENHI Grant Numbers
JP15H03844 and JP18H02012, and MEXT KAKENHI Grant Number
JP18H04397.JapanSocietyforthePro
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Acknowledgment
We thank Kawaken Fine Chemicals Co., Ltd. and Nippon Kodoshi Cor-
poration for their generous gifts of 5 wt% Pd/C and Pd/sheet catalysts,
respectively. We thank Scitem Co., Ltd. for providing us with a radial-
flow column reactor. We acknowledge the members of Ushio Chemix
Corp. for discussion of the partial reduction of phenol. We would like
to thank Editage (www.editage.com) for English language editing.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0040-1705948. Su
p
p
ortingInformatio
n
S
u
p
p
ortingI
n
formatio
n
(8) Ultrafine bubbles (UFBs) are defined as bubbles with diameters
of less than 1000 nm. Although the term nanobubbles (NBs) is
also used to describe bubbles that have diameters of less than
1000 nm, we use the term UFBs in this communication, based
on the appropriate standard: ; ISO 20480-1:2017: Fine Bubble
Technology: General Principles for Usage and Measurement of
Fine Bubbles: Part 1: Terminology; International Standards Orga-
nization: Geneva, 2017;
(9) Model: FBG-OS Type 1: liquid flowrate range: 0.01–99.99
mL/min; maximum gas-feed rate: 50% of liquid volume;
maximum discharge pressure: 5 MPa. Distributor: Process Max-
imize Technologies (PMT) Corporation (2-13-18 Akanedai Aoba-
ku, Yokohama 227-0066, Japan; Phone: +81-90-9104-3595; E-
mail: odajima@dh.catv.ne.jp).
References and Notes
(1) For recent reviews on flow chemistry, see: (a) Rogers, L.; Jensen,
K. F. Green Chem. 2019, 21, 3481. (b) Gérardy, R.; Emmanuel, N.;
Toupy, T.; Kassin, V.-E.; Tshibalonza, N. N.; Schmitz, M.;
Monbaliu, J.-C. M. Eur. J. Org. Chem. 2018, 2301. (c) Plutschack,
M. B.; Pieber, B.; Gilmore, K.; Seeberger, P. H. Chem. Rev. 2017,
117, 11796. (d) Porta, R.; Benaglia, M.; Puglisi, A. Org. Process
Res. Dev. 2016, 20, 2. (e) Rossetti, I.; Compagnoni, M. Chem. Eng.
J. (Amsterdam, Neth.) 2016, 296, 56. (f) Gutmann, B.; Cantillo, D.;
Kappe, C. O. Angew. Chem. Int. Ed. 2015, 54, 6688.
(2) There are various recent approaches for flow gas–liquid reac-
tions: for flow microreactors with
a falling film, see:
(10) Suzuki, S.; Tadano, G.; Sato, K.; Narumi, T.; Mase, N.; Fine-Bubble
Mediated Hydrogenation Reaction of Heterocyclic Compounds,
Presented in part at the 100th Annual Meeting of the Chemical
Society of Japan, Chiba, Japan, March 2020; 2B8-09.
(a) Ziegenbalg, D.; Löb, P.; Al-Rawashdeh, M.; Kralisch, D.;
Hessel, V.; Schönfeld, F. Chem. Eng. Sci. 2010, 65, 3557.
(b) Zanfir, M.; Gavriilidis, A.; Wille, C.; Hessel, V. Ind. Eng. Chem.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–F

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T. Iio et al.
Cluster
Synlett
(11) Keresszegi, C.; Bürgi, T.; Mallat, T.; Baiker, A. J. Catal. 2002, 211,
244.
(12) For selected reviews on the selective hydrogenation of phenol,
see: (a) Kong, X.; Gong, Y.; Mao, S.; Wang, Y. ChemNanoMat
2018, 4, 432. (b) Zhong, J.; Chen, J.; Chen, L. Catal. Sci. Technol.
2014, 4, 3555.
(13) For recent studies on the selective hydrogenation of phenol,
see: (a) Li, X.; Jiang, H.; Hou, M.; Liu, Y.; Xing, W.; Chen, R. Chem.
Eng. J. (Amsterdam, Neth.) 2020, 386, 120744. (b) Zhang, J.;
Zhang, C.; Jiang, H.; Liu, Y.; Chen, R. Ind. Eng. Chem. Res. 2020,
59, 10768. (c) Zhang, J.; Jiang, H.; Liu, Y.; Chen, R. Appl. Surf. Sci.
2019, 488, 555. (d) Valentini, F.; Santillo, N.; Petrucci, C.; Lanari,
D.; Petricci, E.; Taddei, M.; Vaccaro, L. ChemCatChem 2018, 10,
1277. (e) Zhang, H.; Han, A.; Okumura, K.; Zhong, L.; Li, S.;
Jaenicke, S.; Chuah, G.-K. J. Catal. 2018, 364, 354.
(14) The use of Pd/C and cyclohexane was effective for the selective
hydrogenation of phenol to cyclohexanone; see: Higashijima,
M.; Nishimura, S. Bull. Chem. Soc. Jpn. 1992, 65, 2955.
(15) Hydrogenation of Alkenes or Alkynes by the H2-FB-Slug-Flow
Method: Typical Procedure
A 500 mL Duran bottle was charged with a solution of the
appropriate substrate 1 (8.28 mmol) in MeOH (400 mL). The
reactor was charged with 10% Pd/C (1.1 g, 0.47 mmol) and
placed in a column oven (CTO-10AC; Shimadzu, Japan) at 60 °C.
The solution of 1 was delivered at a flow rate of 2.0 mL/min
(residence time in the reactor = 35 s), and H2 gas was delivered
at a flow rate of 1.0 mL/min (1 equiv). The pressure in the front
of the reactor was set to approximately 4 MPa to generate FBs.
After 30 min of operation at 60 °C, the reaction mixture was col-
lected every 10 min and analyzed by GC-FID, without purifica-
tion.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–F