Use of Catalytic Static Mixers for Continuous Flow Gas-Liquid and Transfer Hydrogenations in Organic Synthesis

Article abstract of DOI:10.1021/acs.oprd.7b00180

Catalytic static mixers were used for the continuous flow hydrogenation of alkenes, alkynes, carbonyls, nitro- and diazo-compounds, nitriles, imines, and halides. This technique relies on tubular reactors fitted with 3D printed static mixers which are coated with a catalytic metal layer, either Pd or Ni. Additive manufacturing of the metal mixer scaffold results in maximum design flexibility and is compatible with deposition methods such as metal cold spraying which allow for mass production and linear process scale up. High to full conversion was achieved for the majority of substrates, demonstrating the flexibility and versatility of the catalytic static mixer technology. In the example of an alkyne reduction, the selectivity of the flow reactor could be directed to either yield an alkene or alkane product by simply changing the reactor pressure.

Full text of DOI:10.1021/acs.oprd.7b00180

Full Paper
The use of catalytic static mixers for continuous flow gas-
liquid and transfer hydrogenations in organic synthesis
Christian Harald Hornung, Xuan Nguyen, Antony Carafa, James Gardiner, Andrew J
Urban, Darren Fraser, Mike Horne, Dayalan Gunasegaram, and John Tsanaktsidis
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.7b00180 • Publication Date (Web): 28 Jun 2017
Downloaded from http://pubs.acs.org on June 29, 2017
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Submitted to: Organic Process Research & Development
The use of catalytic static mixers for continuous flow gas-liquid and
transfer hydrogenations in organic synthesis
a
a
a
a
a
Christian H. Hornung* , Xuan Nguyen , Antony Carafa , James Gardiner , Andrew Urban , Darren
a
b
a
a
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Fraser , Mike D. Horne , Dayalan R. Gunasegaram , John Tsanaktsidis
*
christian.hornung@csiro.au
[
[
a] CSIRO Manufacturing, Bag 10, Clayton South, Victoria 3169, Australia.
b] CSIRO Minerals Resources, Bag 10, Clayton South, Victoria 3169, Australia.
ABSTRACT
Catalytic static mixers were used for the continuous flow hydrogenation of alkenes, alkynes,
carbonyls, nitro- and diazo-compounds, nitriles, imines, and halides. This technique relies on tubular
reactors fitted with 3D printed static mixers which are coated with a catalytic metal layer, either Pd
or Ni. Additive manufacturing of the metal mixer scaffold results in maximum design flexibility and is
compatible with deposition methods such as metal cold spraying which allow for mass production
and linear process scale up. High to full conversion was achieved for the majority of substrates,
demonstrating the flexibility and versatility of the catalytic static mixer technology. In the example of
an alkyne reduction, the selectivity of the flow reactor could be directed to either yield an alkene or
alkane product by simply changing reactor pressure.
Keywords: flow chemistry, hydrogenation, heterogeneous catalysis, supported catalyst, additive
manufacture, static mixer
Introduction
New solutions combining heterogeneous catalysis with flow chemistry have attracted much interest
in the area of organic chemistry over the past years, in large part because they encompass several
1
–4
principles of green chemistry and process intensification. The advantages of flow chemistry over
5
–10
classical batch procedures have been demonstrated in numerous publications.
Compared to their
homogeneous liquid phase counterparts, reactors for heterogeneous catalytic reactions are
significantly more complex and specialised, hence their implementation in organic synthesis in the
laboratory and in industrial production has not been as widespread and straight forward. The
majority of flow chemistry devices for heterogeneous catalysis developed to date can be viewed as
variations of one of the following three concepts: fixed beds containing porous catalytic particles or
beads; porous monoliths with embedded catalyst; porous catalytic layers deposited onto chip- or
11–19
plate-type structures.
Compared to these more conventional approaches, our tubular Catalytic
Static Mixer (CSM) concept presented herein, has a series of advantages, which we outlined in detail
2
0
in our previous work. We used additive manufacture to build the mixer scaffold of the CSM,
followed by deposition of the catalytic layer via electroplating or cold spraying. Static mixers are
classically used to ensure continuous mixing or mixing at the entry of a reactor. Mixer design can
vary depending on flow conditions and fluid properties, and the choice of design can have a major
impact on the performance of the chemical reaction process. By using additive manufacturing
techniques, such as 3D metal printing, limitations of conventional subtractive metal forming
methods can be overcome, resulting in an almost complete freedom of design. In 2010 a polymeric
2
1
flow chemistry concept for heterogeneous catalysis was published which inspired the development
our CSM technology. These early polymeric capillary reactor devices were made by polymer melt
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extrusion followed by immobilisation of a palladium(0) catalyst on and inside the polymer wall. Due
to limited temperature stability of the polymer matrix, these devices could only be used for
reactions at temperatures up to 60 °C, while our metal system can be operated at up to 250 °C.
Herein we present a series of hydrogenation reactions, reducing alkenes, alkynes, carbonyls, nitro-
and diazo-compounds, nitriles, imines, and halides on CSMs containing nickel(0) or palladium(0). The
results from these reactions were quantified in terms of turn-over frequency (TOF) and space time
yield (STY), to make them easily comparable to other reactor devices. Due to the hierarchical
structure (scaffold guiding the fluid flow + porous layer containing the active catalyst), CSM reactors
are inherently more adaptable and versatile than many other hydrogenation reactors.
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Experimental
Catalytic Static Mixers
CSMs are static mixers, coated with a catalytic active layer, which can be fitted inside a tubular
reactor geometry, as shown in Figure 1. All CSMs were prepared at CSIRO using a combination of
additive manufacturing and metal deposition techniques. Two prototype flow reactors were
constructed containing either four or twelve catalytic tube sections, hence one CSM set consists of
either four or twelve identical mixers.
Figure 1. CSM fitted inside a stainless steel tube.
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Table 1. Physical properties of CSM sets; catalyst coatings: Ni(0) and Pd(0); deposition methods:
electroplating (EP) and cold spraying (CS); scaffold materials: 316L stainless steel; uncoated (non-
catalytic) control set: X-X-4
.
catalyst
Pd-EP-1
Pd-EP-2
Ni-CS-3
X-X-4
no. CSMs
m
CSM [g]
27.0
73.8
96.5
64.7
m
cat [g]
0.4
1.3
6.0
-
V
CSM [ml]
V
R
[ml]
13.4
40.6
38.1
43.6
ɸ
[%]
78.8
81.2
76.3
87.5
4
3.6
9.2
11.7
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A total of four catalyst sets were prepared for this work (see Table 1). Two different metal catalysts
were deposited, namely Pd(0) using electroplating and Ni(0) using cold spraying. The scaffold
material chosen for all samples was 316L stainless steel and the design chosen is shown in Figure 1.
This mixer design was developed by CSIRO and optimised for mixing, heat transfer and maximum
surface area for catalyst deposition. Initial computational fluid dynamics simulations have shown
that our design performs well for liquid and liquid-liquid phase flow at low Reynolds numbers of
typically below 2300. For baseline comparison, a set of uncoated mixers was prepared, X-X-4, which
did not contain a catalytic layer. The CSM sets were weighed before and after coating (mass after
coating: mCSM) in order to determine the amount of catalyst deposited, mcat. Their combined
R
displacement volume, VCSM, was determined in order to calculate the remaining reactor volume, V ,
and porosity of the CSM, ɸ (see supporting information).The physical data of the CSM sets is collated
in Table 1 and SEM images of some of these mixers coated with Pd (0) or Ni(0) are shown in Figure 2.
Several SEM images were taken along the length of the CSMs, conforming the relative uniformity of
the catalyst coating.
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Figure 2. (a+b) SEM images of an electroplated Pd coating on a 3D printed stainless steel scaffold,
(c+d) SEM images of a cold sprayed Ni coating on a 3D printed stainless steel scaffold.
Additive Manufacture of CSM scaffolds
All 3D printed CSMs were manufactured on the Arcam A1 electron beam melting 3D printer using
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16L stainless steel powder. The machine process parameters were set by trial for this powder.
Arcam Electron Beam Melting (EBM) uses an electron beam to melt and fuse metal powders, layer-
by-layer, into three-dimensional parts. The process takes place under vacuum in a powder bed
where a rake feeds a layer of powder over a starting plate on a vertically movable table. A typical
starting bed temperature for 316L stainless steel is 850 °C. Supports underneath the CSM scaffolds
were built ;these are 0.5 mm diameter and 3 mm long support pillars that aid in the melting process
to avoid swelling of the part above the plane of the powder layer. A ‘net’ theme is used for the
melting of the mixers due to their fine cross-sections. At the end of the build the unfused powder is
removed from the mixer by grit-blasting with the same powder material. Further details of the
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0
general 3D printing process of CSMs have been described in previous work.
Catalyst Deposition using Electroplating
Thin adherent layers of metallic palladium were electroplated onto the static mixers using an axial
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flow cell and standard galvanostatic (constant current) procedures
. The electrodes in this flow
cell were arranged concentrically with the mixer as the central electrode to ensure an even current
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distribution. Prior to electrodeposition, the mixers were thoroughly cleaned and activated using
published methods to ensure the deposits were uniform and adherent. The cleaning and activation
procedure used for the 316L stainless steel mixers was a simultaneous activation – electroplating
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process in Watt’s Bath (acidic nickel chloride), as described in ASTM B254-92(2014).
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Catalyst Deposition using Metal Cold Spraying
A Plasma Giken PCS-1000 cold spray system, fitted with a water-cooled, one-piece, tungsten carbide
nozzle with a 3 mm throat, was used to spray nickel powder (particle size range: 10 to 20 µm; d50
5 µm). The conditions described herein produced Ni coatings with high porosity and high
=
1
metallurgical bonding, which was confirmed by SEM images of the cross-section of the Ni layer. For
this work a new custom system was designed and constructed to allow catalysts to be sprayed more
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0
efficiently than the method we had previously reported. This system utilized two stepper motors
mounted in opposing directions on a common rail. Scaffolds were then held in tension between the
shafts of the motors by means of spring couplers and end holding split rods. These types of couplers
can be used even with a small amount of misalignment between the motors and/or mixer
attachment points. Multiple scaffolds were held between the shafts by concatenating them together
with custom-made couplers. To allow this system to grip the scaffolds effectively, the mixers were
designed and made with flat tabs on each end. These tabs were made sufficiently strong to not
break during spraying but weak enough to be removed after spraying. To prevent any breakage of
the scaffolds from the high speed impact of particles and gas from cold spray process, an aluminium
backing plate with a semi-circular cross section was mounted and positioned just behind the
mounted scaffolds. This backing plate was removed and replaced, as necessary, to prevent fouling of
the mixer rotation by excessive overspray coating. A computer program was written in LabVIEW™ to
simultaneously rotate the shafts of the motors in opposing directions, i.e., clockwise and anti-
clockwise as viewed from the shaft. Rotating speeds of up to 300 rpm were used whilst cold spraying
the scaffolds. The new method resulted in an increase of productivity and higher surface coverage of
catalyst on accessible surfaces of the scaffold. Detailed information on the general cold spraying
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process and on the specific conditions used in our previous work can be found in Avril et al.
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Figure 3. Schematic diagram of the cold spray set-up for coating nickel onto a 3D printed metal
scaffold; highlighted in light blue is the location of the CSM scaffolds.
Reactor Design
The continuous flow reactor set-up was designed and built by CSIRO. The set-up could either be run
with a rectangular reactor module, housing four CSMs (Mk 1, built by Cambridge Reactor Design to
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CSIRO’s specifications, see also previous work ) or a cylindrical reactor module housing twelve CSMs
(Mk 2, built by CSIRO). Figure 4 shows a process flow diagram of the reactor set-up and Figure 5
shows photographs of the Mk 1 and Mk 2 reactor modules. The Mk 2 module was used herein for
reactions using gaseous hydrogen and the Mk 1 module was used for transfer hydrogenations using
ammonium formate. The Mk 2 module with its cylindrical body and two endplates presents an
improvement over our previous Mk 1 design, as it holds three times as many CSMs, equating to
three times the reaction volume on a similar reactor foot print. Changeover time between catalyst
sets was also shortened by using the Mk 2 design. The Mk 2 module is heated electrically using a
heating mantle and is shielded and insulated by a stainless steel box. A detailed description of the
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Mk 1 reactor was previously reported in our earlier work. Further details on the Mk 2 reactor
configuration and a comparison between the Mk1 and Mk2 reactors for the hydrogenation of vinyl
acetate can be found in the supporting information.
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Figure 4. Process flow diagram of the tubular flow reactor set-up for continuous flow
hydrogenations with gaseous H (Mk 2) or for continuous flow transfer hydrogenations (Mk 1); the
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gas line, highlighted in red, was only used for reactions with gaseous H (Mk 2 configuration).
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Mk 1 reactor
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CSMs
Mk 2 reactor
2 CSMs
1
Figure 5. Photographs of the two continuous flow hydrogenation reactors; Mk 1 reactor
configuration housing four CSMs was used for transfer hydrogenations using a liquid line only; Mk 2
reactor configuration housing 12 CSMs was used for hydrogenations with a gaseous H
2
line and a
liquid substrate line.
Continuous flow hydrogenation reactions using gaseous H (Mk 2 configuration)
2
A series of continuous flow experiments with hydrogen gas were conducted on the Mk 2
configuration, investigating the hydrogenation of several substrates, containing C-C double and
triple bonds, carbonyl-, nitro-, nitrile-, imine-, and halide-groups. A typical hydrogenation of vinyl
acetate (VAc) using the Mk 2 reactor configuration was conducted as follows:
First the CSMs inside the reactor (Pd-EP-2) were activated by flowing hydrogen over them at 16 bar,
1
N
20 °C and a gas flow rate of 67.9 mL /min. The activation was conducted for 60 min. After
activation the reactor was flushed with solvent, ethanol (EtOH), using the liquid reagent pump. The
substrate, VAc, was dissolved in EtOH to a concentration of 2 mol/L. Upon start-up of the reactor
system, hydrogen gas was introduced, together with the washing solvent to prime the reactor, and
the parameters for the reaction were adjusted to the following: reactor pressure, p
R
= 16 bar, liquid
ꢀ
ꢀ
flow rate, V = 1 mL/min, gas flow rate inside the reactor at reaction pressure, V = 5 mL/min,
normal gas flow rate measured by the hydrogen mass flow controller, V = 67.9 mL
ꢁ
ꢂ,ꢃ
ꢀ
/min, gas to
ꢂ,ꢄ
N
liquid ratio, G/L = 5, reactor temperature, T
R
= 120 °C. Once pressure and temperature had
stabilised, the liquid feed was changed from solvent to stock solution, thus starting the reaction. The
clear product, ethyl acetate in the solvent, was collected at the outlet of the reactor in several
1
fractions, which were then analysed by H-NMR and GC. Further details on analysis methods and
reagents can be found in the supporting information.
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Continuous flow transfer hydrogenation reactions (Mk 1 configuration)
A series of continuous flow transfer hydrogenation experiments were conducted on the Mk 1
reactor configuration, investigating the reduction of several substrates, containing nitro- and halide-
groups. A typical hydrogenation of p-nitroanisole using this set-up was conducted as follows:
Ammonium formate in methanol (MeOH) in the presence of a palladium coated static mixer was
used to effect the transfer hydrogenation. This procedure was based on previous work by Ram and
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Ehrenkaufer and Barret and Spilling. A solution of p-nitroanisole (153 mg, 1 mmol), and
ammonium formate (315 mg, 4.6 mmol) in MeOH (3 mL) was passed through the Mk 1 reactor,
fitted with the CSM set Pd-EP-1, and heated at 130 °C at 12 bar, at a flow rate of 1 mL/min. The
eluent was collected and the solvent was evaporated to give p-methoxyaniline which was then
1
analysed by H-NMR (see Table 3 vide infra). This continuous flow transfer hydrogenation procedure
was adopted from earlier work using a palladium(0) catalyst immobilised on a polymeric continuous
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flow capillary reactor and triethylsilane as the hydrogen source.
Results and discussion
Hydrogenation of alkenes, alkynes, halides, carbonyls and organic nitrogen compounds
The two rector configurations described above were used for a series of continuous flow
hydrogenations using the Pd or Ni CSM sets described in Table 1. A series of model substrates
containing alkene, alkyne, nitrile, imine, nitro, diazo, halide and carbonyl groups were reduced.
2
Table 2 shows all examples reacted on the Mk 2 set-up using gaseous H ; table 3 shows all examples
reacted on the Mk 1 set-up using the transfer hydrogenation approach. This presents the first
demonstration of a transfer hydrogenation reaction inside a CSM reactor. A series of other flow
chemistry reactor procedures for transfer hydrogenations have previously been described in the
2
1,27–29
literature,
but none of them use a combination of additive manufacture and supported
catalyst. For most of our examples in the tables below only one hydrogenation product was
detected; where there were more than one, details are given in the table or in the text below. The
reactive groups reduced during operation are highlighted in red for each example.
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Table 2. Substrates (reactive groups reduced during process are highlighted in red), reaction
conditions (substrate concentration in the liquid feed, reactor pressure, liquid flow rate and gas flow
rate at reactor pressure) and results (conversion, TOF, and STY) from hydrogenation experiments
using Ni and Pd catalysts in the Mk 2 reactor. All reactions were conducted at 120 °C. For entries 2.1,
2
.2, 2.4, 2.5, 2.7, 2.8, 2.9 and 2.10, EtOH was used as solvent, for all others EtOAc was used.
Entry
Substrate
Conc.
M]
Catalyst
p
[bar]
ꢅꢆ
ꢅꢇ,ꢈ
Conv.
[%]
TOF
[h ]
STY
[g L h ]
-1
-1
-1
-1 -1
0
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0
1
2
3
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0
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0
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0
1
2
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8
9
0
[
[mL min ] [mL min ]
2
2
2
2
.1
.2
.3
.4
2
Pd-EP-2
20
1
1
1
1
5
5
4
5
100
7.26
254
2
Ni-CS-3
Pd-EP-2
Pd-EP-2
20
20
24
97
1.15
1.36
1.96
264
65
0.5
1
75
O
O
54
96
2
.5
2
Ni-CS-3
24
1
5
6
0.07
22
a
a
2
.6
0.5
2
Pd-EP-2
Ni-CS-3
20
16
1
1
4
5
100
1.80
1.18
75
a
.7
a
2
100
322
b
b
b
c
b
2
2
.8
1
1
Pd-EP-2
Pd-EP-2
Ni-CS-3
Pd-EP-2
20
24
24
24
2
1
8
8
5
8
68
4.96
3.13
0.07
3.27
237
149
22
b
.9
86
b
2
.10
0.5
1
0.5
2
48
c
2
.11
100
176
d
d
2
.12
0.5
1
Pd-EP-2
Pd-EP-2
20
24
1
2
4
8
65
1.07
7.11
66
2
.13
.14
.15
98
99
78
87
397
2
2
0.5
1
Pd-EP-2
Pd-EP-2
Pd-EP-2
20
20
20
1
2
2
4
8
8
1.80
5.66
6.31
112
353
393
2.16
1
2
.17
1
Pd-EP-2
20
2
8
30
2.18
136
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.18
.19
NO2
Cl
0.5
0.5
Pd-EP-2
Pd-EP-2
20
20
1
1
4
4
86
94
1.56
1.71
100
109
2
.20
0.5
0.5
Pd-EP-2
Pd-EP-2
20
20
1
1
4
4
70
80
1.27
1.45
81
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60
2.21
119
2
2
.22
.23
0.5
Pd-EP-2
20
1
4
61
1.11
84
0.5
1
Pd-EP-2
Pd-EP-2
20
20
1
2
4
8
62
61
1.12
4.43
63
2.24
328
2
.25
0.5
2
Pd-EP-2
X-X-4
20
20
1
1
4
5
92
0
1.67
-
110
-
e
2
.26
a) multiple products identified, see Scheme 1 and Figure 6, conversion is based on total consumption of substrate; b)
multiple products identified, see Scheme S1 and Figure S1 in supporting information, conversion is based on total
consumption of substrate; c) multiple products identified, see Scheme 2 and Figure 7, conversion is based on total
consumption of substrate; d) multiple products identified: 59% β-methylstyrene, 2% propylbenzene, 4% allylbenzene,
conversion is based on total consumption of substrate; e) control experiment with an uncoated mixer set.
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2
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2
2
2
2
2
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Table 3. Substrates (reactive groups reduced during process are highlighted in red), reactor pressure,
conversion, TOF and STY, from transfer hydrogenation experiments using ammonium formate and
the Pd catalyst Pd-EP-1 in the Mk 1 reactor. All reactions were conducted at 130 °C with a liquid flow
rate of 1 ml/min. All substrates were used at concentration of 0.33 M in MeOH.
Entry
3.1
Substrate
p
[bar]
Conv.
[%]
TOF
[h ]
STY
[g L h ]
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-
1
-1 -1
0
1
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7
8
9
0
1
2
3
4
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
12
31 1.48
36 1.72
87 4.17
17 0.81
3
3
3
.2
.3
.4
20
20
20
65
176
35
3.5
12
12
10 0.48
20 0.96
23
45
3
.6
3
3
.7
.8
12
12
100 4.76
65 3.11
225
191
High catalytic activity was observed throughout both experimental sets presented in tables 2 and 3.
The hydrogenation reactions using a gaseous H feed reached high conversions of >75 % for the
2
majority of examples and full or close to full conversion in several cases; for the transfer
hydrogenations conversions were generally lower, but for some entries conversions >75% were
achieved. Turn-over frequencies and space time yields of the H gas experiments were higher than
2
-
1
-1 -1
for the transfer hydrogenations (max TOF: 7.3 vs 4.8 h ; max STY: ~400 vs ~200 g L h ) ,
demonstrating that the H gas operation is the more efficient process. While the H gas
2
2
hydrogenations were more efficient and used a much cheaper hydrogen source, the transfer
hydrogenations are more convenient, especially on small laboratory scale, as no gas handling
upstream of the reactor is required. The control experiment using an uncoated mixer set, X-X-4,
listed as entry 2.26, resulted in no conversion of the VAc starting material.
Selectivity of the CSM hydrogenation reactor
In the process of evaluating the CSM reactor for the above mentioned examples, a series of
interesting selectivity effects were observed. In some cases these selective hydrogenations could be
influenced by changing the operation parameters of the reactor, meaning that for the same catalyst
and substrate combination a different product could be formed depending on the reactor pressure
and flow rates used. In most heterogeneous catalytic applications, selectivity is influenced by a
number of factors, and most commonly selectivity towards a desired product is adjusted by the
3
0
choice of catalyst, rather than the operation parameters. This means that a CSM reactor can be
operated in a much more flexible setting than systems that require a catalyst change over to control
selectivity. In the following, a few of the entries from Table 2, for which we observed an interesting
selectivity effect, are singled out and discussed in further detail.
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The hydrogenation of phenyl acetylene (entries 2.6 and 2.7) can progress through the unsaturated
styrene intermediate to the fully hydrogenated ethyl benzene, as shown in Scheme 1. Using a Ni
CSM set, we could influence selectivity either towards styrene or ethylbenzene, by simply changing
the process conditions, reactor pressure and G/L (see Fig. 5). Using mild conditions (16 bar, G/L = 5,
c = 2 mol/L), we achieved full conversion of starting material with a ratio of 9:1 of styrene to
ethylbenzene in the product. When using forcing conditions (24 bar, G/L = 10, c = 1 mol/L), we
achieved full conversion of starting material to ethylbenzene; no presence of styrene was detected
in the product. This demonstrates how selectivity of the CSM reactor was changed from partial
reduction to full reduction of the alkyne by simply changing process parameters. This makes this
reactor system tuneable to yield different products without the need to change catalyst. In
comparison, most examples in the literature are concerned with the influence of the catalyst on the
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58
59
60
3
1
32
selectivity of the catalytic process; e.g. Bianchini et al. and Duca et al. describe the selective
hydrogenation of phenyl acetylene on supported Pd catalysts or ruthenium complexes and Jia et al.
3
3
3
4
and Kang et al. describe the selective hydrogenation of acetylene over Au/Al
2
O
3
or TiO
2
-added Pd
catalysts.
Scheme 1. Consecutive hydrogenation of phenyl acetylene to styrene and ethyl benzene.
100
1
00
9
8
0
0
9
8
7
6
5
0
0
0
0
0
70
60
50
40
30
20
10
0
40
30
2
0
0
0
1
2M
2bar 16bar 20bar 24bar 24bar
G/L=5 G/L=5 G/L=5 G/L=5 G/L=10
2M
2M
2M
1M
1
8
bar 12 bar 16 bar 20 bar 24 bar
phenyl acetylene styrene ethyl benzene
CAL
HCAL
COH
HCOH
Figure 6. Hydrogenation of phenyl acetate
using Ni CS-3 and the Mk-2 configuration.
Figure 7. Hydrogenation of cinnamaldehyde
(CAL) to hydrocinnamaldehyde (HCAL),
cinnamyl alcohol (COH) and hydrocinnamyl
alcohol (HCOH) using PD-EP-2 and the Mk-2
configuration.
The hydrogenation of benzyl cyanide (entries 2.8 to 2.10) resulted in high selectivity towards the
primary amine, and only showed minor amounts of the undesired dimeric side product between 3
and 9% (see Scheme S1 and Figure S1 in the supporting information). The conversions were medium
to good with values as high as 86%. The reduction of nitriles is a frequently occurring industrial
operation in the pharmaceuticals and food supplements area, and unwanted formation of secondary
3
5
amine dimers are a known problem .
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Scheme 2. Hydrogenation pathway of cinnamaldehyde (CAL), yielding cinnamyl alcohol (COH),
hydrocinnamaldehyde (HCAL) and hydrocinnamyl alcohol (HCOH).
The hydrogenation of cinnamaldehyde (entry 2.11 and Scheme 2), a substrate containing a carbonyl
group and a C-C double bond, was performed on Pd. At 24 bar full conversion of the starting
material was achieved, whereby the majority, 60%, was hydrogenated to the corresponding
saturated aldehyde hydrocinnamaldehyde (HCAL); 37% of the fully hydrogenated hydrocinnamyl
alcohol (HCOH) and 3% of the unsaturated alcohol, cinnamyl alcohol (COH) made up the remaining
product. This trend was also observed at lower reactor pressures which yielded lower conversions
(see Figure 7). These results show that the Pd catalyst was more selective towards the reduction of
the double bond than the aldehyde. This is in contrast to our previous work where a Pt CSM was
2
0
used, favouring the reduction of the aldehyde. Similar to the case of phenyl acetylene, the product
composition and hence selectivity of the hydrogenation process could be influenced by the chosen
reactor pressure. In contrast, most literature is concerned with the influence of the catalyst on the
selectivity of the hydrogenation of cinnamaldehyde, rather than the influence of the process
3
6
37
38
parameters (see for example work by Tessonnier et al., Vu et al. and Zhang et al. ).
Analogously, the reduction of cinnamyl chloride (entry 2.12) was expected to result in two
intermediates and a fully hydrogenated product. Here the following products were observed: 59% β-
methylstyrene, 2% propylbenzene, 4% allylbenzene.
methoxyaniline
chloroaniline
1
00
90
80
94
86
87
7
8
7
0
7
6
5
0
0
0
40
30
3
0
2
0
0
0
1
ortho
meta
para
Figure 8. Hydrogenation of ortho-, meta- and para-substituted nitro benzenes to the corresponding
anilines using Pd-EP-2 and the Mk-2 configuration.
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Furthermore the influence of different substituents on the benzene ring for the hydrogenation of
nitro benzenes was investigated. The entries 2.15 to 2.20 and the graph in Figure 8 show reactions
conducted under comparable conditions on the Mk 2 reactor using Pd-EP-2. Here, ortho-, meta- and
para-substituted methoxy nitro benzenes and chloro nitro benzenes were hydrogenated to the
corresponding anilines. It can be seen from Figure 8 that the meta-substituted nitro benzenes
showed the highest reactivity, closely followed by the ortho-substituted isomers. The para-
substituted isomers showed significantly lower reactivity than the other two.
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Catalyst leaching
In order to investigate catalyst leaching, a series of dedicated steady state operations were
performed on the Mk 2 reactor over several days, using the catalyst sets Pd-EP-2 and Ni-CS-3 for the
hydrogenation of VAc. A total of 1 L of product solution was processed during these reactions on
each CSM set. The reactor performance was checked frequently by NMR showing that no significant
drop in conversion was observed over the entire period of operation. The combined product
solutions were then concentrated and a total of four samples were submitted for ICP-OES. The
product stream from these steady state experiments contained on average 140 ppb Ni, 553 ppb Fe
and 30 ppb Cr for Ni-CS-3 and >1 ppb Pd, 266 ppb Ni, 568 ppb Fe and 218 ppb Cr for Pd-EP-2. These
results show that both the Pd and the Ni catalysts are very well bound to the substrate, and that the
majority of the soluble metal was Fe, which is a contamination that can be attributed to the stainless
20
steel reactor tubing and/or the CSM substrate. This data is consistent with previous findings.
Conclusion
In this work we present a series of hydrogenation reactions performed on a novel continuous flow
reactor system, using 3D printed catalytic static mixers. The CSMs were designed and printed in
house, and the catalyst was deposited using either cold spraying or electroplating. The cost of
manufacture of our 3D printed mixers are estimated to be lower by a factor of 10 to 100 compared
to commercial metallic static mixers of similar dimensions, as labour intensive welding or other
joining steps can be avoided when building the mixers in one print. This new approach has a series of
interesting improvements over current state of the art chemical reactor systems for heterogeneous
catalysis: a) tubular reactor technology is simple, well understood and it offers excellent control over
the chemical reaction when using IDs between 3 and 10 mm; b) 3D printing allows for rapid design
and manufacture of tailored mixer solutions for many different liquid and gas flow applications;
c) the potential to mass manufacture CSMs using techniques such as cold spraying is a major benefit
over existing complex multicomponent catalyst systems; d) changeover of catalyst is straight
forward, leading to a versatile and easy to maintain continuous flow reactor system which creates
the potential to greatly reduce downtime of industrial operations during maintenance and
changeover cycles; e) scale-up from laboratory to production can be achieved in fewer and less time
and labour intensive steps than classical batch scale-up. The reaction examples presented herein,
which include the reduction of alkenes, alkynes, carbonyls, nitro- and diazo-compounds, nitriles,
imines, and halides represent many different classes of industrial hydrogenations used in the
manufacture of pharmaceuticals, fine chemicals, food products, polymers, agrochemicals and
others. In one example, the reduction of an alkyne, it was possible to change selectivity simply by
adjusting process parameters such as reactor pressure in order to either yield an alkene or an alkane
product. This work showcases the versatility, efficiency and robustness of the CSM technology for
different heterogeneous catalytic reductions and its great potential for use in R&D laboratories and
as a scale-up tool for fine chemical and pharmaceutical production.
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Acknowledgements
The authors thank Winston Liew for ICP-OES measurements, Teresa Kittel-Sherri for SEM
characterisation and Jean-Pierre Veder, Theo Rodopoulos and Oliver Hutt for many helpful
discussions.
0
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Supporting Information
The supplementary material contains information on used reagents, analysis procedures, reactor
design and operation, calculation of CSM porosity, mean residence times and gas flow rates inside
the reactor, a comparison between the Mk1 and Mk2 reactors for the hydrogenation of vinyl acetate
and experiments on the hydrogenation of benzyl cyanide and cinnamaldehyde in ethanol.
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Graphic abstract for ToC:
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4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
ACS Paragon Plus Environment