3D-Printed Polypropylene Continuous-Flow Column Reactors: Exploration of Reactor Utility in SNAr Reactions and the Synthesis of Bicyclic and Tetracyclic Heterocycles

Article abstract of DOI:10.1002/ejoc.201701111

3D printing has the potential to transform the way in which chemical reactions are carried out due to its low-cost, ease-of-use as a technology and its capacity to expedite the development of iteratively enhanced prototypes. In this present study, we developed a novel, low-cost polypropylene (PP) column reactor that was incorporated into an existing continuous-flow reactor for the synthesis of heterocycles. The utility and solvent resistance of the printed devices were explored in S_NAr reactions to produce substituted aniline derivatives and in the synthesis of bicyclic and tetracyclic heterocycles. Using this approach, a range of heterocyclic compounds was synthesised including the core structure of the natural product (±)-γ-lycorane and structurally complex compounds based on the tetracyclic core of the erythrina alkaloids.

Full text of DOI:10.1002/ejoc.201701111

A Journal of
Accepted Article
Title: 3D Printed Polypropylene Continuous-Flow Column Reactors:
Exploration of Reactor Utility in SNAr Addition Reactions and the
Synthesis of Bicyclic and Tetracyclic Heterocycles
Authors: Zenobia Xerxes Rao, Bhaven Patel, Alessandra Monaco, Zi
Jing Cao, Marta Barniol-Xicota, Enora Pichon, Mark Ladlow,
and Stephen Hilton
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201701111
Link to VoR: http://dx.doi.org/10.1002/ejoc.201701111
Supported by

10.1002/ejoc.201701111
European Journal of Organic Chemistry
COMMUNICATION
3D Printed Polypropylene Continuous-Flow Column Reactors:
Exploration of Reactor Utility in SNAr Addition Reactions and the
Synthesis of Bicyclic and Tetracyclic Heterocycles
Zenobia X. Rao[a], Bhaven Patel[a], Alessandra Monaco[a], Zi Jing Cao[a], Marta Barniol-Xicota[b], Enora
Pichon[a], Mark Ladlow[c], Stephen T. Hilton*[a]
such as reductions or the formation of metal organic frameworks
amongst others.4 Whilst previously reported 3D printed reactors
have been used for both batch and flow chemistry, their potential
in flow-based reactions is clear, due to its widespread applicability
in both research and industrial chemical processes as a result of
the increased reproducibility, facile automation, improved safety
and ease of transfer to large-scale production available in flow.5-7
Despite its potential, flow-chemistry remains a challenge to
research groups due to the costs of the machines themselves and
the associated reactors. Current manufacturing technologies are
highly expensive and allow for the production of microlitre-scale
reactors in inert polymer or glass with a two-dimensional pattern
of flow channels of millilitre-scale reactors in polymer and metal
tubing, or glass chips with channels which cost in excess of $2000
each.5-7 As such, the integration of 3D printing with flow-
chemistry’s low-costs of raw material (PP -$15/Kg) and ease of
use as a technology in the development of iterative flow-reactor
prototypes is an attractive prospect for synthetic chemistry.
As a result of the obvious potential advantages of linking
flow-chemistry to 3D printing, we were interested in combining
these two technologies via the 3D printing of low-cost column flow
reactors that could be used with existing continuous flow devices,
which would then be applicable to a range of chemical reactions.
Herein, we now report on the results of our approach, which was
realised using a Uniqis FlowSyn continuous flow reactor system
with a 3D printed column designed to fit within the space of the
existing column reactor segment as shown below (Figure 1).
Abstract: 3D printing has the potential to transform the way in which
chemical reactions are carried out due to its low-cost, ease-of-use as
a technology and its capacity to expedite the development of
iteratively enhanced prototypes. In this present study, we developed
a novel, low-cost polypropylene (PP) column reactor that was
incorporated into an existing continuous-flow reactor for the synthesis
of heterocycles. The utility and solvent resistance of the printed
devices were explored in SNAr reactions to produce substituted aniline
derivatives and in the synthesis of bicyclic and tetracyclic heterocycles.
Using this approach, a range of heterocyclic compounds were
synthesised including the core structure of the natural product ()--
lycorane and the synthesis of structurally complex compounds based
on the tetracyclic core of the Erythrina alkaloids.
3D-printing has undergone rapid development over the last
decade, moving from the field of engineering through to a wide-
range of scientific disciplines, due to its ease of use as a
technology and the diminishing cost of 3D printers, with a wider
range of materials that are now available.1 It has become a novel
manufacturing method used to fabricate low-cost bespoke objects
with facile control of size and geometry with intricate internal
structures with well-defined lengths and volumes.2 There are a
range of 3D printing technologies in use, but perhaps the one with
the most widespread applicability is that based on Fused
Deposition Modelling (FDM), which focuses on layer by layer
printing of well-defined structural objects with accuracies as low
as 50 microns.2 Whilst most FDM printers use acrylonitrile
butadiene styrene (ABS) or polylactic acid (PLA) as filament,
these are not widely applicable to chemical synthesis. As such,
recent reports have focussed on the printing of chemical reactors
using polyamide or polypropylene, which is resistant to higher
temperatures and compatible with a large range of solvents and
chemicals but is often challenging to 3D print.3 Reactions using
such inert polymers have focussed on simple chemical reactions,
[a]
Miss, Z, Rao, Dr, A, Monaco, Dr B. Patel, Mr Z. Jing Cao, Miss E,
Pichon, Dr, S.T., Hilton
Department of Pharmaceutical and Biological Chemistry, UCL
School of Pharmacy, 29-39 Brunswick Square, London, WC1N 1AX
United Kingdom. E-mail: s.hilton@ucl.ac.uk
Figure 1. A) Uniqsis FlowSyn continuous flow reactor system showing the
column heater block; B) Column reactor designed using Tinkercad software
designed to fit the heating unit of the flow system.
http://www.stephen-hilton.com
[b]
[c]
Dr M. Barniol-Xicota, Laboratori de Quimica Farmaceutica, Facultat
́ ̀
de Farmacia, and Institute of Biomedicine (IBUB), Universitat de
̀
Cognizant of the fact that any printed flow reactor device
should be compatible with a wide range of synthetic chemistry and
conditions, we elected to explore their utility in SNAr reactions in
the first instance, due to the harsh conditions associated with
these reactions.8 This key reaction has been utilized in the
synthesis of commercial drugs such as zyprexa 1,9 zyvox 2,10
Barcelona, Av. Joan XXIII, s/n, Barcelona E-08028, Spain.
Dr Mark Ladlow, Uniqsis Ltd, 29 Station Road, Shepreth, Cambs,
SG8 6GB, United Kingdom.
Supporting information for this article is given via a link at the end of
the document
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10.1002/ejoc.201701111
European Journal of Organic Chemistry
COMMUNICATION
moxifloxacin 3 and erlotinib 4.11,12 In addition, we were also
interested in investigating their potential in the synthesis of
bicyclic heterocycles and more complex structures based on the
natural products erythratin 5-7 and lycorane 8, 9 as they would
provide ready proof of principle of the utility of the reactors to a
wider scope of synthetic chemistry (Figure 2).13-15
Figure 3. Illustration of the 3D printing of the column reactor directly onto an
LDPE board to avoid shrinkage and adhesion to the build plate and the ease of
production of up to six in one print.
Reactors were printed in groups of up to 6 in ~10 hours and
each reactor had an average mass of 21 g with an internal coil
diameter of 2 mm and a theoretical internal volume of 1.6 mL and
a cost of less than $0.50 per reactor. Columns were printed using
100% infill and a material flow rate of 110% in order to provide a
contiguous sealed surface. Use of a lower material flow rate
resulted in gaps in the print due to the tendency of polypropylene
to contract once it had exited the nozzle. We next explored the
reactors in the FlowSyn flow reactor system and their ability to be
used for chemical reactions. Reactors were tapped out to provide
a screw thread suitable for PEEK fittings as shown below (Figure
4).
Figure 2. Selected synthetic targets for exploration of the scope of 3D printed
polypropylene reactors.
In order to develop a reactor for use with the FlowSyn flow
reactor system, the column reactor space was measured using
Vernier callipers and an initial design realised using Tinkercad
free online software (Autodesk) (Supplementary Information).16
The reactor contained a central column, which would be in direct
contact with the centre of the column reactor space and heated
by the system, and as such, would not need expensive adaptation
or further engineering (Figure 1). The solvent flow path for the
reactor was designed as an internal spiral, which would facilitate
prolonged contact with the outside hot surface of the column block
to carry out chemical reactions as shown above (Figure 1). Once
complete, the STL (surface tessalation language) file was
exported into Cura software and the reactor printed on an
Ultimaker2 3D printer in polypropylene (Supplementary
Information).17 The 3D printing of polypropylene proved
challenging as there are scant reports of its use in the literature,
nor the exact printing conditions.2,3 Initial attempts failed due to
poor adherence with the 3D printer build plate. Following
experimentation, we found that printing directly onto an LDPE
board, where the first layer could be directly melted into the solid
surface enabled us to successfully print out the desired reactor
(Figure 3 and Supplementary Information).2
Figure 4. Integration of the 3D Printed PP reactor into the column heating
compartment of the FlowSyn flow reactor system using PEEK fittings.
We elected to explore SNAr reactions with the 3D printed
flow reactor in the first instance due to the relatively harsh
synthetic conditions employed in the reaction to explore the limits
of the 3D printed PP reactors using polar solvents and high
temperatures to access compounds such as 1-4.8-12 We initially
screened the reaction between 2-fluoronitrobenzene 10 and
phenylethylamine 11 using DMF as solvent in order to develop
optimised conditions (Scheme 1 and Table 1). Reactions were
carried out using the FlowSyn flow reactor system and the
percentage conversion of the reactions was determined from the
1H NMR spectrum of the crude reaction mixture.18
Scheme 1. Reaction conditions selected for exploration of reactor utility.
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10.1002/ejoc.201701111
European Journal of Organic Chemistry
COMMUNICATION
Table 1. Screening of conditions for the SNAr reaction between
phenylethylamine 11 and 2-fluoronitrobenzene 10.
As outlined above, the reactors proved suitable for a range
of reactions involving both 2-fluoronitrobenzene 10 and methyl 4-
fluoro-3-nitrobenzoate 13 with good conversions to the SNAr
addition products 15a-15j in all cases except that for the less
reactive aniline (15h, Table 2, Entry 8). Pleasingly, the same
column could be used up to five times for different reactions
without loss of integrity. However, further continued use beyond
this led to leakage of solvent around the PEEK fittings.
As a result of the successful demonstration of the
applicability of the 3D printed polypropylene column reactors to
withstand high temperatures and polar solvents such as DMF, we
next elected to explore their utility in the synthesis of heterocycles
related to the core of the Erythrina 5-7 and lycorane 8 and 9 family
of natural products.13-15 We have previously described an efficient
approach to the core structures of these compounds and others
using microwave accelerated synthesis of the bicyclic 17 and
tetracyclic cores 18 from the acylal precursors 16 using 1,2-
dichloroethane as the solvent and BF3 as the Lewis acid in an
intramolecular acylal (IAC) cyclisation approach (Scheme 3).19-21
Entry
Pump
Flow Rate
[ml/min]
A
Pump
Flow Rate
[ml/min]
B
Column
Temperature
[C]
Conv./
Isol.
[%][a]
21
1
2
3
4
1.00
0.50
0.16
0.13
0.65
0.32
0.16
0.08
100
100
150
150
36
66 (63)
55
[a] Determined by 1H NMR analysis of the crude reaction mixture.
Following reaction screening, it was clear that the printed
reactors were able to withstand relatively harsh conditions (150
C, Table 1, Entry 3) with good conversion to the addition product
(66% conversion, 63% isolated) and a residence time of 5 minutes
in the printed reactor. As a result of the fact that the reactor is held
in the column unit of the flow reactor, it can to be heated to a high
temperature although it is worth noting that it required cooling
prior to removal to avoid warping. With the optimised conditions
in hand, we next carried out additional reactions with a range of
amines and 2-fluoronitrobenzene 10 and methyl 4-fluoro-3-
nitrobenzoate 13 (Scheme 2 and Table 2). Reactions were carried
out at 150 C using a flow rate of 0.16 mL/ min for both the
electrophile and DIPEA and 0.16 mL/ min for the amine (Table 2).
Scheme 3. Previous reported IAC approach to the bicyclic core of lycorane 17
and the tetracyclic core of the erythrina alkaloids 18.
As such, we envisaged that the column reactors would
prove suitable for the synthesis of complex heterocycles related
to polycyclic natural products as our previously used microwave
conditions could readily be translated into continuous flow via
replication of the reaction conditions in the 3D printed flow
reactor.21 In the first instance, we decided to explore the synthesis
of bicyclic heterocycles. Using the previously optimised conditions,
where the IAC precursors were reacted with boron trifluoride at
65 C in the microwave for 15 minutes,19-21 IAC precursors were
mixed with BF3 in 1,2-DCE and passed through the 3D printed
flow reactor at a slightly elevated temperature of 80 C at a flow
rate of 0.1 ml/min giving a residence time of 16 minutes (1.6 mL
internal volume), thus replicating the microwave conditions
(Scheme 4).
Scheme 2. SNAr reaction between 10 and 13 and a range of amines.
Table 2. Reaction of a range of amines and fluoronitrobenzenes under SNAr
reaction conditions with 3D printed polypropylene reactors.
Entry
Electrophile
Amine[a]
Product
Conv.
[%][b]
1
2
3
4
5
6
7
8
9
10
10
10
10
13
13
13
13
13
13
13
benzylamine
15a
15b
15c
15d
15e
15f
47
4-chlorobenzylamine
4-methoxybenzylamine
phenylethylamine
benzylamine
65
57
100
100
100
97
4-chlorobenzylamine
4-methoxybenzylamine
aniline
15g
15h
15i
24
butylamine
95
allylamine
15j
100
Scheme 4. IAC reaction using the 3D printed flow reactor.
[a] Reactions were carried out at 150 C and a flow rate of 0.16 mL/min for
pumps A/ B. [b] Determined by 1H NMR analysis of the crude reaction mixture.
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10.1002/ejoc.201701111
European Journal of Organic Chemistry
COMMUNICATION
Cyclisation precursors were dissolved in anhydrous DCE
and BF3.OEt2 (5 equiv) was added, whereupon the solutions were
subsequently passed through a pre-warmed (80 °C) PP reactor
with a flow rate of 0.1 mL/min using a single pump. Compounds
synthesised in this manner are shown below (Table 3).
7
40
Table 3. IAC cyclisation to synthesise bicyclic heterocycles using the 3D printed
polypropylene reactor.
8
77
Entry
Cyclisation Precursor
Product
Isolated
Yield
[%]
1
34
9
39
2
3
4
51
70
43
10
75
As can be seen above, all IAC cyclisation precursors gave
good yields of the cyclised products (34-77%) using the 3D
printed polypropylene reactors. Yields were comparable to the
previously reported microwave conditions and were also
comparable in terms of reaction time albeit at a slightly elevated
temperature.21 Compound 40 was obtained in excellent yield and
represents an important intermediate in the synthesis of the
lycorane family of compounds.21 With the synthesis of bicyclic
heterocycles in hand, we next elected to explore the synthesis of
compounds related to the tetracyclic core of the Erythrina alkaloid
family. As per the conditions used previously in the synthesis of
bicyclic heterocycles, the IAC tetracyclic precursor 41 was
dissolved in anhydrous DCE and BF3.OEt2 (5 equiv) added and
the reaction mixture passed through the 3D printed reactor at a
flow rate of 0.1 mL/min using a single pump (Scheme 5, Table
4).19
5
61
6
47
Scheme 5. IAC reaction to access tetracyclic heterocycles related to the
erythratin core.
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10.1002/ejoc.201701111
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COMMUNICATION
Table 4. IAC cyclisation to synthesise tetracyclic heterocycles using the 3D
printed polypropylene reactor.
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We have previously demonstrated that this Lewis acid
mediated domino cyclisation process, which facilitates the
simultaneous formation of the B and C ring of the erythrina core
43 leads to the formation of a single diasteroisomer of the product
44.19 Pleasingly, upon cyclisation, the tetracyclic products 44 and
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yields which were comparable to reactions carried out in the
microwave.19 As such they represent a facile approach to the
scalable synthesis of complex heterocycles using the 3D printed
polypropylene reactors.
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fitted in an existing FlowSyn continuous flow reactor system. We
demonstrated that it is resistant to solvents such as DMF and
dichloroethane and that it is capable of being used in SNAr
reactions as well as to access substituted bicyclic heterocycles
and complex tetracycles related to natural products. As such, it
represents an excellent demonstration of the potential of
developing and using bespoke low-cost 3D printed reactors in
synthetic chemistry. Further studies on additional reactors are
currently under way in our laboratory and will be reported in due
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Acknowledgements
This work was gratefully supported by an FNS visiting
postdoctoral fellowship grant to A.M. [P2GEP2_151840] and an
EPSRC first grant to S.T.H [EP/J01544X/1]. We thank the EPSRC
UK National Mass Spectrometry facility and Swansea University
for spectroscopic services.
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Keywords:
3D-printing,
continuous-flow,
reactionware,
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10.1002/ejoc.201701111
European Journal of Organic Chemistry
COMMUNICATION
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[21]
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10.1002/ejoc.201701111
European Journal of Organic Chemistry
COMMUNICATION
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COMMUNICATION
Zenobia Rao[a], Bhaven Patel[a],
Alessandra Monaco[a], Zi Jing Cao[a],
Marta Barniol-Xicota[b], Enora Pichon[a],
Mark Ladlow[c], Stephen T.
Hilton*[a]Author(s), Corresponding
Author(s)*
Page No. – Page No.
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3D Printed Polypropylene Continuous-
Flow Column Reactors: Exploration of
Reactor Utility in SNAr Addition
Reactions and the Synthesis of
Bicyclic and Tetracyclic Heterocycles
Low-cost inert polypropylene (PP) continuous flow reactors were designed and 3D printed for use in a FlowSyn continuous
flow reactor. Reactor utility was explored in reactions ranging from SNAr addition reactions through to formation of complex
heterocycles. It was shown that they are an inexpensive source of reactors for continuous flow, facilitating the synthesis of a
range of heterocycles.
This article is protected by copyright. All rights reserved.