Integrated 3D-printed reactionware for chemical synthesis and analysis. / Symes, Mark D.; Kitson, Philip J.; Yan, Jun; Richmond, Craig J.; Cooper, Geoffrey J. T.;. ARTICLES PUBLISHED ONLINE: 15 APRIL | DOI: /NCHEM Integrated 3D-printed reactionware for chemical synthesis and analysis Mark D. Integrated 3D-printed reactionware for chemical synthesis and analysis. Mark D. Symes, Philip J. Kitson, Jun Yan, Craig J. Richmond, Geoffrey J. T. Cooper.
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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.
The use of flow chemistry and 3D-printing technology is expanding in the field of organic synthesis . The application of continuous-flow systems is frequently found in chemistry, and is beginning to have a significant impact on the way molecules are made  ; on the other hand the application of 3D-printing technology in synthetic chemistry still has many aspects that can be investigated. The benefits resulting from the utilization of 3D-printing techniques to create bespoke reactionware for synthetic chemistry have recently been reported [4,5].
The 3D printer takes the virtual design from computer-aided design CAD software and reproduces it layer-by-layer until the physical definition of the layers gives the designed object. The significant advantage of this technique is that the architecture can be concisely controlled. Furthermore, understanding the kinetics of the processes can allow the re- designing of the reactionware, allowing us to combine ofr kinetic knowledge with reactor designs. Moreover, the additive manufacturing process of the devices takes a short time and results in a cheap procedure for the fabrication of fluidic eeactionware .
All this is important in chemistry, and in particular for the realization of micro- and millifluidic devices. Microfluidic devices compatible with a wide range of organic solvents and reagents are usually made of silicon or glass, which requires specialized manufacturing techniques and are expensive to fabricate . There is growing interest in the use of polymers that can be employed to fabricate devices in a rapid and inexpensive fashion . One of the most commonly employed polymers is poly dimethylsiloxane PMDSdue to its low cost and the possibility of rapid prototyping.
Nevertheless, it is not suitable for carrying out organic reactions as it can absorb the reactants and will swell in most nonaqueous solvents . Herein, we demonstrate the versatility and convenience of using 3D-printed reactors for the synthesis of organic compounds, using qnd techniques with an in-line ATR-IR flow cell to monitor the reactions in real time.
There are several examples of different techniques used for real-time analyses in the literature, such as UV—vis [4,5,10,11]IR [5,10,]and even NMR spectroscopy . The use of in-line spectroscopy allows for the monitoring of reaction steps that include unstable compounds or hazardous species . First, an in-house designed and 3D-printed reactionware device was employed for the synthesis of imines from the reaction of a range of aldehydes and primary amines.
Secondly, two reactors were connected in series to first perform an imine synthesis and then subsequently an imine reduction, with this second setup showing the potential for using the 3D-printed devices as reliable tools in multistep synthesis.
This showed that the simplicity of designing and building flow reactors employing 3D-printing techniques allows for an easy and convenient integration of devices in a flow setup. Therefore it represents a very attractive way integrater design and build new continuous-flow rigs for organic synthesis.
This reactionwage printer heats a thermopolymer through the extruder, depositing the material in a layer-by-layer fashion, converting the design into the desired 3D reactionware. The thermoplastic employed to fabricate the devices presented herein is PP, selected to print robust, inexpensive and chemically inert devices.
Comparing PP with other common and accessible thermoplastics, which have been used in 3D printing before, such as polylactic acid PLA and polyacrylates, in PP we can find the required characteristics to perform a chemical reaction: Polyacrylates consist of a vast group of polymers with different physical and chemical properties; however their chemical compatibility is low.
In fact they are not generally recommended for exposure to alcohol, glycols, alkalis, brake fluids, or to chlorinated or aromatic hydrocarbons .
Integrated 3D-printed reactionware for chemical synthesis and analysis
Therefore, PP was the plastic of choice for the device fabrication. 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. Schematic representation of the 3D-printed reactionware devices employed in this work showing the i 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 rateand one analysus.
This is due to the printing process, where the internal channel diameter is always slightly smaller than the integratex one. The 3D-printed devices were integrated in the flow systems using 1. The screw connectors increase the chemical tolerance of the 3D-printed reactor as well as its chemical compatibility, compared to our previous devices .
These improvements are a considerable step forward compared to our previous report on 3D printing fluidics as they facilitate the integration of the devices, increase the chemical compatibility, improve the range of pressure that can be handled by the system, and enable the easy configuration for the use of ancillary equipment.
Here we show the 3D-printed device as a millifluidic reactor for the synthesis of imines under flow conditions.
We monitored the reaction progress ane the help of an in-line ATR-IR flow cell, which is a very useful technique for the monitoring of organic reactions under flow conditions [10,]. The flow setup used for these dhemical consists of two syringe pumps, each of them connected to one of the inlets of the 3D-printed reactionware device R1. The syringe pumps were filled with the starting materials with a carbonyl compound 1a — c being placed in syringe pump no.
Carbonyl compounds and primary amines used in the syntheses reported in this work. The experiments were conducted using 2 M methanolic chsmical of the different substrates. This is convenient from a processing point of view, since high concentrations favor increased reaction kinetics  whilst minimizing the amount of waste generated during the downstream work-up .
The reactor output was connected with a length of tubing with a volume 0. Hence, the total flow reactor volume V R was 0. 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. 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  the thermodynamic compound in the reaction between compounds 1b and 2a. The different substituents on the amine compounds have an electronic effect on the reactive center, thus influencing the observed conversion, i. Conversion of benzaldehyde 1a into imines 3a — d.
In both graphs the imine spectrum in red is compared with the spectrum of the starting materials dash line: ATR-IR spectra of the synthesis of compounds 3b on the left and 3d on the right. To calculate the conversion of the benzaldehyde 1a into the imines 3a — d when combined with the amines 2a — da calibration of the IR spectra of benzaldehyde at known concentrations was obtained.
Hence, it is possible to use the solvent peaks to normalize the different spectra, allowing for comparison of the results. Different flow rates were assayed to elucidate the effect of the reaction time.
To synthesize imine 3aequimolar amounts of benzaldehyde 1a and aniline 2a were mixed in ratio 1: Under the studied conditions, very high conversions have been obtained with residence times as low as 20 seconds. Comparison of the IR spectra of imine 3aderived from benzaldehyde 1a and aniline 2asynthesized at different flow rates. Comparison of the IR spectra of imine 3aderived from benzaldehyde 1a and aniline 2asynthesi Conversion of carbonyl compounds 1b and 1c with aniline 2a into imines 3e and 3f.
To further prove the reliability of the 3D-printed devices as flow reactors, we decided to connect one reactor to the other and perform a two steps flow reaction in an automated way.
Representation of the setup for the two-step flow reaction employed in this work. The reduction of imines is a strategy to synthesize functionalized secondary amines [23,24]although only a few examples of reductions in microfluidic devices have been reported in the literature [5,]. 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 NaBH 4.
Table of the compounds used to study the imine reduction. In all the studied cases, the analytical data confirmed full conversion of the substrates into the corresponding amines. 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 . Further, the versatility of the 3D-printed reactionware has been demonstrated by studying and optimizing the residence time to synthesize a range of imines and secondary amines and to monitor the reactions in real time using in-line IR spectroscopy.
These robust, inexpensive and chemically inert 3D-printed reactors 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 suitable for the investigation of more complex chemistry. We strongly believe that the ease of combining robust and cheap devices with other instruments in the laboratory can lead us to build new reactionware for the faster optimization of chemical processes as well as opening the potential for the discovery and implementation of array chemistry.
We are currently investigating the effect of the device architecture on the reaction performed by using 3D-printed reactors made of PP, testing their robustness and chemical inertia in different environments, and designing new geometries to further develop the 3D printing technology and the 3D-printed reactionware, as well as the development of a range of universal chemical modules.
Thanks to Saskia Buchwald for the technical support and Dr. Mathieson for helpful discussion.
3D-printed devices for continuous-flow organic chemistry
RosnesPhilip J. Kitson and Leroy Cronin. Jump to Figure 1. Jump to Figure 2.
Jump to Figure 3. Jump to Figure 4. Jump to Figure 5. Jump to Figure 6. Jump to Figure 7. Jump to Figure 8. Supporting Information File 1: Selection and Application; Marcel Dekker, Inc.: Acta, 39— Organometallics22, — CO;2-V Return to citation in text: