3D-printed devices for continuous-flow organic chemistry

Article abstract of DOI:10.3762/bjoc.9.109

We present a study in which the versatility of 3D-printing is combined with the processing advantages of flow chemistry for the synthesis of organic compounds. Robust and inexpensive 3D-printed reactionware devices are easily connected using standard fittings resulting in complex, custom-made flow systems, including multiple reactors in a series with in-line, real-time analysis using an ATR-IR flow cell. As a proof of concept, we utilized two types of organic reactions, imine syntheses and imine reductions, to show how different reactor configurations and substrates give different products.

Full text of DOI:10.3762/bjoc.9.109

3D-printed devices for
continuous-flow organic chemistry
Vincenza Dragone, Victor Sans, Mali H. Rosnes, Philip J. Kitson
and Leroy Cronin*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2013, 9, 951–959.
School of Chemistry, University of Glasgow, University Avenue,
Glasgow G12 8QQ, UK. Web: http://www.croninlab.com
doi:10.3762/bjoc.9.109
Received: 14 January 2013
Accepted: 25 April 2013
Published: 16 May 2013
Email:
Leroy Cronin* - Lee.Cronin@glasgow.ac.uk
* Corresponding author
This article is part of the Thematic Series "Chemistry in flow systems III".
Guest Editor: A. Kirschning
Keywords:
3D printing; flow chemistry; flow IR; in-line analysis; imine reduction;
imine synthesis; millifluidics; reactionware
© 2013 Dragone et al; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
We present a study in which the versatility of 3D-printing is combined with the processing advantages of flow chemistry for the
synthesis of organic compounds. Robust and inexpensive 3D-printed reactionware devices are easily connected using standard
fittings resulting in complex, custom-made flow systems, including multiple reactors in a series with in-line, real-time analysis
using an ATR-IR flow cell. As a proof of concept, we utilized two types of organic reactions, imine syntheses and imine reductions,
to show how different reactor configurations and substrates give different products.
Introduction
The use of flow chemistry and 3D-printing technology is the virtual design from computer-aided design (CAD) software
expanding in the field of organic synthesis [1-5]. The applica- and reproduces it layer-by-layer until the physical definition of
tion of continuous-flow systems is frequently found in chem- the layers gives the designed object. The significant advantage
istry, and is beginning to have a significant impact on the way of this technique is that the architecture can be concisely
molecules are made [1-3]; on the other hand the application of controlled. 3D printing allows chemists to build devices with
3D-printing technology in synthetic chemistry still has many high precision, including complex geometries and intricate
aspects that can be investigated. The benefits resulting from internal structures such as channels with well-defined size
the utilization of 3D-printing techniques to create bespoke dimensions. Furthermore, understanding the kinetics of the
reactionware for synthetic chemistry have recently been processes can allow the (re-)designing of the reactionware,
reported [4,5].
allowing us to combine additional kinetic knowledge with
reactor designs. Moreover, the additive manufacturing process
3D printing consists of the fabrication of three-dimensional of the devices takes a short time and results in a cheap proce-
physical objects from a digital model [6]. The 3D printer takes dure for the fabrication of fluidic devices [7]. All this is impor-
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Beilstein J. Org. Chem. 2013, 9, 951–959.
tant in chemistry, and in particular for the realization of micro- simplicity of designing and building flow reactors employing
and millifluidic devices.
3D-printing techniques allows for an easy and convenient inte-
gration of devices in a flow setup. Therefore it represents a very
Microfluidic devices compatible with a wide range of organic attractive way to design and build new continuous-flow rigs for
solvents and reagents are usually made of silicon or glass, organic synthesis.
which requires specialized manufacturing techniques and are
Results and Discussion
expensive to fabricate [8]. There is growing interest in the use
of polymers that can be employed to fabricate devices in a rapid Experimental setup
and inexpensive fashion [9]. One of the most commonly The 3D-printed flow reactors used to carry out the organic
employed polymers is poly(dimethylsiloxane) (PMDS), due to syntheses were designed by using a 3D CAD software package
its low cost and the possibility of rapid prototyping. Neverthe- (Autodesk123D®), which is freely distributed and produces
less, it is not suitable for carrying out organic reactions as it can files that can be converted to the correct format read by the
absorb the reactants and will swell in most nonaqueous solvents 3DTouchTM printer. This 3D printer heats a thermopolymer
[8]. 3D-printing technology offers the possibility of employing through the extruder, depositing the material in a layer-by-layer
polypropylene (PP), a thermopolymer that is inert in a range of fashion, converting the design into the desired 3D reactionware.
organic solvents and organic compounds, cheaper than PMDS,
and compatible with the available 3D printers.
The thermoplastic employed to fabricate the devices presented
herein is PP, selected to print robust, inexpensive and chemi-
Herein, we demonstrate the versatility and convenience of using cally inert devices. Comparing PP with other common and
3D-printed reactors for the synthesis of organic compounds, accessible thermoplastics, which have been used in 3D printing
using flow techniques with an in-line ATR-IR flow cell to before, such as polylactic acid (PLA) and polyacrylates, in PP
monitor the reactions in real time. There are several examples of we can find the required characteristics to perform a chemical
different techniques used for real-time analyses in the literature, reaction: thermostability up to 150 °C, high chemical inertia,
such as UV–vis [4,5,10,11], IR [5,10,12-14], and even NMR and low cost. PLA is widely used in medicinal chemistry
spectroscopy [15-17]. The use of in-line spectroscopy allows because of its biocompatibility; however, from a chemical point
for the monitoring of reaction steps that include unstable com- of view its use is limited to a few solvents and organic com-
pounds or hazardous species [18]. Further, the use of such tech- pounds, and to preserve its integrity it can only be used up to
niques may also be used to obtain quantitative information temperatures of 60–66 °C [19]. Polyacrylates consist of a vast
about reaction progress and to rapidly optimize the reaction group of polymers with different physical and chemical prop-
conditions “on the fly”.
erties; however their chemical compatibility is low. In fact they
are not generally recommended for exposure to alcohol, glycols,
First, an in-house designed and 3D-printed reactionware device alkalis, brake fluids, or to chlorinated or aromatic hydrocarbons
was employed for the synthesis of imines from the reaction of a [20]. Therefore, PP was the plastic of choice for the device
range of aldehydes and primary amines. Secondly, two reactors fabrication.
were connected in series to first perform an imine synthesis and
then subsequently an imine reduction, with this second setup The shape of the 3D-printed reactionware devices used herein
showing the potential for using the 3D-printed devices as reli- (Figure 1) was chosen in order to combine a short design and
able tools in multistep synthesis. This showed that the print time with the robustness required for a flow system.
Figure 1: Schematic representation of the 3D-printed reactionware devices employed in this work showing the internal channels. Both have two
inputs (A and B) and one output (C). The main difference consists in the length of the inlets/outlets: the dimension of the inlets/outlets in R1 is 3 mm
and in R2 it is 6 mm where the latter is designed to match the size of standard check-valves.
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Beilstein J. Org. Chem. 2013, 9, 951–959.
Each device has two inlets, followed by a mixing point, a length
of reactor to ensure a controlled residence time (which is given
by dividing the reactor volume by the total flow rate), and one
outlet. The approximate volume of the first reactor (R1, see
Figure 1, left) is ca. 0.4 mL and was employed in the imine
syntheses, while the second reactor (R2, see Figure 1, right) has
a volume of ca. 0.35 mL and was employed connected to
another R2 for the imine reduction processes. All the character-
istics of the devices are summarized in Table 1.
The 3D-printed devices were integrated in the flow systems
using 1.58 mm outer diameter (OD) polytetrafluoroethylene
(PTFE) tubing, with an internal diameter of 0.5 mm and stan-
dard connectors made of polyfluoroelastomer (FPM) and poly-
ether ether ketone (PEEK). PEEK is a harder plastic than PP
and, thus, allowed the screwing of the standard connectors into
the softer PP inlets/outlets of the devices, resulting in a tight
seal to the device. The screw connectors increase the chemical
tolerance of the 3D-printed reactor as well as its chemical
compatibility, compared to our previous devices [5]. The
connectors at the device inlets were equipped with check valves
(made of PEEK with a Chemraz® O-ring, which is compatible
with organic solvents and compounds) to prevent potential
backflow issues. The reactor inlets were connected to the
syringe pumps containing the starting material solutions, whilst
the outlets were connected to the in-line ATR-IR flow cell (see
Figure 2). These improvements are a considerable step forward
compared to our previous report on 3D printing fluidics [5], as
they facilitate the integration of the devices, increase the chem-
ical compatibility, improve the range of pressure that can be
handled by the system, and enable the easy configuration for the
use of ancillary equipment.
Figure 2: Flow system setup, where a R1 is connected to the syringe
pumps and the ATR-IR flow cell with standard connectors.
Device 1: Imine formation
organic reactions under flow conditions [10,21-26]. The flow
Here we show the 3D-printed device as a millifluidic reactor for setup used for these syntheses consists of two syringe pumps,
the synthesis of imines under flow conditions. We monitored each of them connected to one of the inlets of the 3D-printed
the reaction progress with the help of an in-line ATR-IR flow reactionware device R1. The syringe pumps were filled with the
cell, which is a very useful technique for the monitoring of starting materials with a carbonyl compound (1a–c) being
Table 1: 3D-printed reactionware device characteristics.
Entry
Characteristics
R1
R2
1
2
3
4
5
6
printing time (min)
PP mass (g)
248
24.01
367
33.74
dimensions (mm)
internal diameter (mm)
theoretical volumea (mL)
reactor volume
30 × 80.2 × 10
1.5
70 × 30 × 15
1.5
0.54
0.51
0.4
0.35
aThe theoretical internal volumes of the devices are higher than the measured volumes. This is due to the printing process, where the internal channel
diameter is always slightly smaller than the designed one.
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Beilstein J. Org. Chem. 2013, 9, 951–959.
placed in syringe pump no. 1 and with a primary amine (2a–d) sion of 1a to imine 3c (Table 2, entry 3; reaction of 1a
being placed in syringe pump no. 2 (Figure 3).
with 2c), is the same as the formation of 3a, whilst the
formation of 3d (reaction of 1a with 2d) has the highest conver-
sion %.
Table 2: Conversion of benzaldehyde (1a) into imines 3a–d.
Conversion
Figure 3: Carbonyl compounds and primary amines used in the
syntheses reported in this work. Carbonyl compounds: benzaldehyde
(1a); R-(−)-myrtenal (1b); 3-pentanone (1c). Aniline derivatives: aniline
(2a); 3-(trifluoromethyl)aniline (2b); 3-chloroaniline (2c); 3,5-dimethyl-
aniline (2d).
Entry
1
Product
(%)
96
3a
3b
3c
3d
The experiments were conducted using 2 M methanolic solu-
tions of the different substrates. This is convenient from a
processing point of view, since high concentrations favor
increased reaction kinetics [26] whilst minimizing the amount
of waste generated during the downstream work-up [27]. The
reactor output was connected with a length of tubing with a
volume 0.1 mL to the IR flow cell. Hence, the total flow reactor
volume (VR) was 0.5 mL. The syntheses of the imines were
monitored by an in-line ATR-IR flow cell and were conducted
at a total flow rate of 0.25 mL min−1, where two equimolar
methanolic solutions of 1 and 2 were flowed into R1 at the same
flow rate. The residence time was calculated as the time taken
for the solutions to go from the mixing point inside the
3D-printed reactor to the analytical device, thus taking into
account the subsequent pieces of tubing employed, and resulted
to be 2 minutes. The choice of a short residence time is to allow
for a more reliable comparison of the imines synthesized and
also to avoid the formation of the Michael addition adduct [28]
(the thermodynamic compound) in the reaction between com-
pounds 1b and 2a.
2
3
4
85
96
99
Figure 4 shows the effect of the EWG and EDG substituents of
a phenyl ring through the IR spectra of compounds 3b (on the
left) and 3d (on the right). In both graphs the imine spectrum (in
red) is compared with the spectrum of the starting materials
For the first experiment, we studied the reaction of benzalde- (dash line): the aldehyde peak of benzaldehyde (1a) at
hyde (1a) with the aniline derivatives 2a–d (Figure 3), to 1704 cm−1 (in black) disappears when it reacts with compound
synthesize the N-benzylideneanilines 3a–d (see Table 2). The 2d (Figure 4, on the left), while it is still present when
different substituents on the amine compounds have an elec- combined with compound 2b (Figure 4, on the right). 1H NMR
tronic effect on the reactive center, thus influencing the spectroscopy was used to confirm the conversion rate of 1a to
observed conversion, i.e., an electron-donating group (EDG) in the N-benzylideneaniline derivatives 3a–d.
the meta-position of the aniline ring gives a higher percentage
conversion than does an electron-withdrawing group (EWG) To calculate the conversion of the benzaldehyde (1a) into the
[28]. In fact, Table 2 shows that the conversion of benzalde- imines 3a–d when combined with the amines 2a–d, a calibra-
hyde (1a) to imine 3a (Table 2, entry 1; obtained by reacting 1a tion of the IR spectra of benzaldehyde at known concentrations
with 2a), is higher than with the conversion of 1a to imine 3b was obtained. The different concentrations of the substrates
(Table 2, entry 2; obtained by reacting 1a with 2b). The conver- used for the IR analysis do not significantly affect the intensity
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Beilstein J. Org. Chem. 2013, 9, 951–959.
Figure 4: ATR-IR spectra of the synthesis of compounds 3b (on the left) and 3d (on the right). The spectrum on the left shows the reaction that does
not go to completion due to the EWG substituent on the meta-position of the primary amine 2b (see Supporting Information File 1).
of the area of the solvent band at 1022 cm−1 (A1022). Hence, it benzaldehyde (1a) and aniline (2a) were mixed in ratio 1:1 (v/v)
is possible to use the solvent peaks to normalize the different at different flow rates in the range 0.25–1.5 mL min−1. The
spectra, allowing for comparison of the results. From this data a reported spectra are focused in the region of the IR spectra
calibration curve can be obtained dividing the area of the where the conversion of aldehyde 1a to imine 3a can be fol-
benzaldehyde band at 1704 cm−1 (A1704) by A1022, calculated lowed (see Figure 6). Following the red spectra (synthesis of 3a
for five different molar concentrations of the methanolic solu- with the shortest residence time) it can be seen that the imine
tions of benzaldehyde. We used 2 M, 1 M, 0.5 M, 0.25 M and band at 1627 cm−1 is more intense compared to the one in black
0.125 M methanolic solutions of benzaldehyde, and the relative (synthesis of 3a with the highest residence time). The observed
areas were calculated using the corrected solvent-band area conversion range found was between 94% and 97%. Under the
(As*) and adding A1704 to it, in order to minimize the slight studied conditions, very high conversions have been obtained
change of A1022 with the concentration of the benzaldehyde with residence times as low as 20 seconds.
(Figure 5).
Further imine syntheses in-flow were conducted with the
Different flow rates were assayed to elucidate the effect of the 3D-printed millifluidic reactor R1 and monitored with the
reaction time. To synthesize imine 3a, equimolar amounts of in-line ATR-IR (Table 3).
Figure 5: (a) IR spectra of benzaldehyde at different concentrations. The solvent peak at 1022 cm−1 remains constant while the aldehyde peak at
1704 cm−1 increases with the concentration of benzaldehyde. (b) Calibration curve of the different molar concentrations of benzaldehyde is shown.
Equation 1: [benzaldehyde] = −0.432 + 21.56 × A1704 / (A1022 + A1704) and the R2 = 0.993.
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Beilstein J. Org. Chem. 2013, 9, 951–959.
Table 3: Conversion of carbonyl compounds 1b and 1c with aniline
(2a) into imines 3e and 3f.
Entry
Product
Conversion (%)
1
94
Figure 6: Comparison of the IR spectra of imine 3a, derived from
benzaldehyde (1a) and aniline (2a), synthesized at different flow rates.
The conversion of 3a at different flow rates was calculated using the
equation of the calibration curve (see Figure 4), and for a flow rate of
0.25 mL min−1 was 97% and at a flow rate of 1.5 mL min−1, 94%.
3e
3f
2
–
The results of these reactions are summarized in Table 3 where
it can be seen that the reaction between aniline (2a) and R-(−)-
myrtenal (1b) readily takes place to give imine 3e (Table 3,
entry 1), whilst no product can be observed under these condi- subsequently reduced it in the second reactor (R2”). R2’ was
tions for the reaction of 2a with 3-pentanone (1c), due to the connected to the syringe pumps containing the starting ma-
lower reactivity of the latter. For details, see the IR spectrum of terials (compounds 1a and 2a–d) for the imine synthesis as
compound 3f in section 5 of Supporting Information File 1. previously described (but with a longer residence time than
1H NMR spectra were used to calculate the conversion rate of described above, to ensure a complete conversion of the
aldehyde 1b into imine 3e.
substrates), before imines 3a–d were directly introduced to R2”
for the subsequent reduction.
Device 2: Imine reduction
To further prove the reliability of the 3D-printed devices as The reduction of imines is a strategy to synthesize functional-
flow reactors, we decided to connect one reactor to the other ized secondary amines [23,24], although only a few examples
and perform a two steps flow reaction in an automated way. To of reductions in microfluidic devices have been reported in the
this end, we employed two R2 reactionware devices connected literature [5,23-25]. The condensation reactions were conducted
in series (Figure 7), to monitor the formation of the final prod- using a 2 M solution of benzaldehyde (1a) in MeOH as before,
uct using the in-line ATR-IR flow cell. We ran the imine syn- which was pumped through inlet B’ into reactor R2’ at
thesis in the first of the two reactors (R2’), and once formed we 0.0125 mL min−1 and mixed with a 2 M solution of the aniline
Figure 7: Representation of the setup for the two-step flow reaction employed in this work. The first reactor (R2’) is used to synthesize the imines
under previously optimized conditions. The product is then directly introduced into the next reactor (R2”) and mixed with the reducing agent to
produce the secondary amine.
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Beilstein J. Org. Chem. 2013, 9, 951–959.
derivatives 2a–d in MeOH introduced through inlet A’ at the The reactions were followed by monitoring the absence of the
same flow rate, keeping the aldehyde/amine ratio (1:1) (v/v) as imine and aldehyde bands in the in-line ATR-IR flow cell,
described for the imine synthesis in R1. We selected this low focusing the attention on the region of the IR spectrum between
flow rate to obtain a sufficient residence time (tR = 14 min) for 1720 cm−1 and 1550 cm−1, where the disappearance of the
a full conversion of 1a into imines 3a–d. Reactor R2’ was imine band (around 1630 cm−1) can be observed. Figure 8
connected to the inlet A” of a second device (R2”) where the shows the spectra of imine 3b (red) and its corresponding
freshly formed imine was mixed with the reducing agent, reduced product, compound 4b (green) as an example; in the
cyanoborohydride (NaBH3CN) in MeOH (1 M), introduced red spectrum a complete conversion of the aldehyde into imine
through inlet B”, and the two equimolar solutions were pumped 3b can be observed (due to the absence of the aldehyde peak at
through R2” at the same flow rate. The molar and volumetric 1704 cm−1), and in the green spectrum the imine peak at
ratios hydride/imine were kept constant (1:1) to produce the 1632 cm−1 has completely disappeared.
corresponding amines with a residence time of 7 min. The
reducing agent was selected because it is mild but effective, and
it prevents the undesired formation of bubbles or problems
related to over-reduction, which could be expected in this range
of concentrations when using conventional reducing agents,
such as NaBH4. Using this methodology, imines 3a–d were
reduced affording the corresponding secondary amines 4a–d
(Table 4).
Table 4: Table of the compounds used to study the imine reduction.
Figure 8: Example of an ATR-IR graph in which an imine spectrum is
compared with the reduced imine spectrum.
In addition to the IR analysis, compounds 4a–d were collected
and analyzed by mass spectrometry (MS), HPLC and 1H NMR
spectroscopy. In all the studied cases, the analytical data
confirmed full conversion of the substrates into the corres-
ponding amines.
Entry
1
Product 4
Yield (%)
78
4a
Conclusion
We have demonstrated that it is possible to integrate 3D-printed
reactionware devices into a flow system, which highlights the
great versatility and modularity of 3D-printed reaction devices.
The possibility of connecting the reactors using standard fittings
allows for better seals and facilitates the reuse of the devices,
compared to our previously published procedures [5]. Further,
the versatility of the 3D-printed reactionware has been demon-
strated by studying and optimizing the residence time to synthe-
size a range of imines and secondary amines and to monitor the
reactions in real time using in-line IR spectroscopy.
2
3
4
99
96
97
4b
4c
4d
These robust, inexpensive and chemically inert 3D-printed reac-
tors have proven suitable vessels for single-step as well as
multistep reactions in flow. The chemical and thermal stability
of PP makes this generation of custom built flow reactors suit-
able for the investigation of more complex chemistry. There-
1H NMR spectroscopy and MS spectrometry confirmed the presence
of the amines.
1H NMR spectra were used to calculate the conversion rate of the
amines 4a–d.
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Beilstein J. Org. Chem. 2013, 9, 951–959.
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Supporting Information
Supporting Information File 1
3D printing materials and method, experimental and
characterization of compounds.
[http://www.beilstein-journals.org/bjoc/content/
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financial support. Thanks to Saskia Buchwald for the technical
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