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Additive manufacturing is changing the way researchers and industrialists design and manufacture chemical devices to meet their specific needs. In this paper, we report the first example of a flow reactor formed by ultrasonic additive manufacturing (UAM) lamination of a solid metal sheet with directly integrated catalytic parts and sensing elements. UAM technology not only overcomes many of the limitations currently associated with the additive manufacturing of chemical reactors, but also greatly expands the capabilities of such devices. A number of biologically important 1,4-disubstituted 1,2,3-triazole compounds have been successfully synthesized and optimized by a Cu-mediated 1,3-dipolar Huisgen cycloaddition reaction using the UAM chemistry facility. Using the unique properties of UAM and continuous flow processing, the device is able to catalyze ongoing reactions as well as provide real-time feedback to monitor and optimize reactions.
Due to its significant advantages over its bulk counterpart, flow chemistry is an important and growing field in both academic and industrial settings due to its ability to increase the selectivity and efficiency of chemical synthesis. This extends from the formation of simple organic molecules1 to pharmaceutical compounds2,3 and natural products4,5,6. Over 50% of reactions in the fine chemical and pharmaceutical industries can benefit from continuous flow7.
In recent years, there has been a growing trend of groups seeking to replace traditional glassware or flow chemistry equipment with adaptable chemical “reactors”8. The iterative design, rapid manufacturing, and three-dimensional (3D) capabilities of these methods are useful for those who want to customize their devices for a particular set of reactions, devices, or conditions. To date, this work has focused almost exclusively on the use of polymer-based 3D printing techniques such as stereolithography (SL)9,10,11, Fused Deposition Modeling (FDM)8,12,13,14 and inkjet printing7,15. , 16. The lack of reliability and ability of such devices to perform a wide range of chemical reactions/analyses17, 18, 19, 20 is a major limiting factor for the wider application of AM in this field17, 18, 19, 20.
Due to the increasing use of flow chemistry and the favorable properties associated with AM, better techniques need to be explored that will allow users to fabricate flow reaction vessels with improved chemistry and analytical capabilities. These methods should allow users to select from a range of high strength or functional materials capable of operating under a wide range of reaction conditions, as well as facilitate various forms of analytical output from the device to enable monitoring and control of the reaction.
One additive manufacturing process that can be used to develop custom chemical reactors is Ultrasonic Additive Manufacturing (UAM). This solid-state sheet lamination method applies ultrasonic vibrations to thin metal foils to bond them together layer by layer with minimal volumetric heating and a high degree of plastic flow 21, 22, 23. Unlike most other AM technologies, UAM can be directly integrated with subtractive production, known as a hybrid manufacturing process, in which periodic in-situ numerical control (CNC) milling or laser processing determines the net shape of the layer of bonded material 24, 25. This means that the user is not limited to the problems associated with the removal of residual original building material from small liquid channels, which is often the case in powder and liquid systems AM26,27,28. This design freedom also extends to the choice of available materials – UAM can bond combinations of thermally similar and dissimilar materials in a single process step. The choice of material combinations beyond the melting process means that the mechanical and chemical requirements of specific applications can be better met. In addition to solid bonding, another phenomenon that occurs with ultrasonic bonding is the high fluidity of plastic materials at relatively low temperatures29,30,31,32,33. This unique feature of UAM allows mechanical/thermal elements to be placed between metal layers without damage. Embedded UAM sensors can facilitate the delivery of real-time information from the device to the user through integrated analytics.
Previous work by the authors32 demonstrated the ability of the UAM process to create metallic 3D microfluidic structures with embedded sensing capabilities. This device is for monitoring purposes only. This article presents the first example of a microfluidic chemical reactor manufactured by UAM, an active device that not only controls but also induces chemical synthesis with structurally integrated catalytic materials. The device combines several advantages associated with UAM technology in the manufacture of 3D chemical devices, such as: the ability to convert a complete 3D design directly from a computer-aided design (CAD) model into a product; multi-material fabrication for a combination of high thermal conductivity and catalytic materials, as well as thermal sensors embedded directly between the reactant streams for precise control and management of the reaction temperature. To demonstrate the functionality of the reactor, a library of pharmaceutically important 1,4-disubstituted 1,2,3-triazole compounds was synthesized by copper-catalyzed 1,3-dipolar Huisgen cycloaddition. This work highlights how the use of materials science and computer-aided design can open up new possibilities and opportunities for chemistry through interdisciplinary research.
All solvents and reagents were purchased from Sigma-Aldrich, Alfa Aesar, TCI, or Fischer Scientific and used without prior purification. 1H and 13C NMR spectra recorded at 400 and 100 MHz, respectively, were obtained on a JEOL ECS-400 400 MHz spectrometer or a Bruker Avance II 400 MHz spectrometer with CDCl3 or (CD3)2SO as solvent. All reactions were performed using the Uniqsis FlowSyn flow chemistry platform.
UAM was used to fabricate all devices in this study. The technology was invented in 1999 and its technical details, operating parameters and developments since its invention can be studied using the following published materials34,35,36,37. The device (Fig. 1) was implemented using a heavy duty 9 kW SonicLayer 4000® UAM system (Fabrisonic, Ohio, USA). The materials chosen for the flow device were Cu-110 and Al 6061. Cu-110 has a high copper content (minimum 99.9% copper), making it a good candidate for copper catalyzed reactions and is therefore used as an “active layer inside the microreactor. Al 6061 O is used as the “bulk” material. , as well as the intercalation layer used for analysis; intercalation of auxiliary alloy components and annealed state in combination with Cu-110 layer. found to be chemically stable with the reagents used in this work. Al 6061 O in combination with Cu-110 is also considered to be a compatible material combination for UAM and is therefore a suitable material for this study38,42. These devices are listed in Table 1 below.
Reactor fabrication steps (1) 6061 aluminum alloy substrate (2) Fabrication of lower channel from copper foil (3) Insertion of thermocouples between layers (4) Upper channel (5) Inlet and outlet (6) Monolithic reactor.
The fluid channel design philosophy is to use a tortuous path to increase the distance traveled by the fluid inside the chip while maintaining a manageable chip size. This increase in distance is desirable to increase catalyst-reactant contact time and provide excellent product yields. The chips use 90° bends at the ends of a straight path to induce turbulent mixing within the device44 and increase the contact time of the liquid with the surface (catalyst). To further enhance the mixing that can be achieved, the design of the reactor includes two reactant inlets combined in a Y-connection before entering the mixing coil section. The third entrance, which crosses the flow halfway through its residency, is included in the plan for future multi-stage synthesis reactions.
All channels have a square profile (no taper angles), which is the result of the periodic CNC milling used to create the channel geometry. The channel dimensions are chosen to provide a high (for a microreactor) volumetric yield, yet small enough to facilitate interaction with the surface (catalysts) for most of the liquids it contains. The appropriate size is based on the authors’ past experience with metal-liquid reaction devices. The internal dimensions of the final channel were 750 µm x 750 µm and the total reactor volume was 1 ml. A built-in connector (1/4″-28 UNF thread) is included in the design to allow easy interfacing of the device with commercial flow chemistry equipment. Channel size is limited by the thickness of the foil material, its mechanical properties, and the bonding parameters used with ultrasonics. At a certain width for given material, the material will “sag” into the channel created. There is currently no specific model for this calculation, so the maximum channel width for a given material and design is determined experimentally, in which case a width of 750 µm will not cause sag.
The shape (square) of the channel is determined using a square cutter. The shape and size of the channels can be changed on CNC machines using different cutting tools to obtain different flow rates and characteristics. An example of creating a curved channel with a 125 µm tool can be found in Monaghan45. When the foil layer is applied flat, the application of the foil material to the channels will have a flat (square) surface. In this work, a square contour was used to preserve the channel symmetry.
During a programmed pause in production, thermocouple temperature sensors (type K) are built directly into the device between the upper and lower channel groups (Fig. 1 – stage 3). These thermocouples can control temperature changes from -200 to 1350 °C.
The metal deposition process is carried out by the UAM horn using metal foil 25.4 mm wide and 150 microns thick. These layers of foil are connected in a series of adjacent strips to cover the entire build area; the size of the deposited material is larger than the final product as the subtraction process creates the final clean shape. CNC machining is used to machine the external and internal contours of the equipment, resulting in a surface finish of the equipment and channels corresponding to the selected tool and CNC process parameters (in this example, about 1.6 µm Ra). Continuous, continuous ultrasonic material spraying and machining cycles are used throughout the device’s manufacturing process to ensure dimensional accuracy is maintained and the finished part meets CNC fine milling precision levels. The width of the channel used for this device is small enough to ensure that the foil material does not “sag” in the fluid channel, so the channel has a square cross section. Possible gaps in the foil material and the parameters of the UAM process were determined experimentally by the manufacturing partner (Fabrisonic LLC, USA).
Studies have shown that at the interface 46, 47 of the UAM compound there is little diffusion of elements without additional heat treatment, so for the devices in this work the Cu-110 layer remains different from the Al 6061 layer and changes dramatically.
Install a pre-calibrated back pressure regulator (BPR) at 250 psi (1724 kPa) downstream of the reactor and pump water through the reactor at a rate of 0.1 to 1 ml min-1. The reactor pressure was monitored using the FlowSyn pressure transducer built into the system to ensure that the system could maintain a constant steady pressure. Potential temperature gradients in the flow reactor were tested by looking for any differences between the thermocouples built into the reactor and the thermocouples built into the heating plate of the FlowSyn chip. This is achieved by changing the programmed hotplate temperature between 100 and 150 °C in 25 °C increments and monitoring any differences between the programmed and recorded temperatures. This was achieved using the tc-08 data logger (PicoTech, Cambridge, UK) and the accompanying PicoLog software.
The conditions for the cycloaddition reaction of phenylacetylene and iodoethane are optimized (Scheme 1-Cycloaddition of phenylacetylene and iodoethane, Scheme 1-Cycloaddition of phenylacetylene and iodoethane). This optimization was performed using a full factorial design of experiments (DOE) approach, using temperature and residence time as variables while fixing the alkyne:azide ratio at 1:2.
Separate solutions of sodium azide (0.25 M, 4:1 DMF:H2O), iodoethane (0.25 M, DMF), and phenylacetylene (0.125 M, DMF) were prepared. A 1.5 ml aliquot of each solution was mixed and pumped through the reactor at the desired flow rate and temperature. The response of the model was taken as the ratio of the peak area of the triazole product to the starting material of phenylacetylene and was determined using high performance liquid chromatography (HPLC). For analysis consistency, all reactions were taken immediately after the reaction mixture left the reactor. The parameter ranges selected for optimization are shown in Table 2.
All samples were analyzed using a Chromaster HPLC system (VWR, PA, USA) consisting of a quaternary pump, column oven, variable wavelength UV detector and autosampler. The column was an Equivalence 5 C18 (VWR, PA, USA), 4.6 x 100 mm, 5 µm particle size, maintained at 40°C. The solvent was isocratic methanol:water 50:50 at a flow rate of 1.5 ml·min-1. The injection volume was 5 μl and the detector wavelength was 254 nm. The % peak area for the DOE sample was calculated from the peak areas of the residual alkyne and triazole products only. The introduction of the starting material makes it possible to identify the corresponding peaks.
Combining the results of the reactor analysis with the MODDE DOE software (Umetrics, Malmö, Sweden) allowed a thorough trend analysis of the results and determination of the optimal reaction conditions for this cycloaddition. Running the built-in optimizer and selecting all important model terms creates a set of reaction conditions designed to maximize the peak area of the product while decreasing the peak area for the acetylene feedstock.
Oxidation of the copper surface in the catalytic reaction chamber was achieved using a hydrogen peroxide solution (36%) flowing through the reaction chamber (flow rate = 0.4 ml min-1, residence time = 2.5 min) prior to the synthesis of each triazole compound. library.
Once the optimal set of conditions had been determined, they were applied to a range of acetylene and haloalkane derivatives to allow the compilation of a small synthesis library, thereby establishing the possibility of applying these conditions to a wider range of potential reagents (Fig. 1). 2).
Prepare separate solutions of sodium azide (0.25 M, 4:1 DMF:H2O), haloalkanes (0.25 M, DMF), and alkynes (0.125 M, DMF). Aliquots of 3 ml of each solution were mixed and pumped through the reactor at a rate of 75 µl/min and a temperature of 150°C. The entire volume was collected in a vial and diluted with 10 ml of ethyl acetate. The sample solution was washed with 3 x 10 ml of water. The aqueous layers were combined and extracted with 10 ml ethyl acetate, then the organic layers were combined, washed with 3×10 ml brine, dried over MgSO 4 and filtered, then the solvent was removed in vacuo. Samples were purified by silica gel column chromatography using ethyl acetate prior to analysis by a combination of HPLC, 1H NMR, 13C NMR and high resolution mass spectrometry (HR-MS).
All spectra were obtained using a Thermofischer Precision Orbitrap mass spectrometer with ESI as the ionization source. All samples were prepared using acetonitrile as solvent.
TLC analysis was carried out on silica plates with an aluminum substrate. The plates were visualized with UV light (254 nm) or vanillin staining and heating.
All samples were analyzed using a VWR Chromaster system (VWR International Ltd., Leighton Buzzard, UK) equipped with an autosampler, a binary pump with a column oven and a single wavelength detector. An ACE Equivalence 5 C18 column (150 x 4.6 mm, Advanced Chromatography Technologies Ltd., Aberdeen, Scotland) was used.
Injections (5 µl) were made directly from the diluted crude reaction mixture (1:10 dilution) and analyzed with water:methanol (50:50 or 70:30), except for some samples using a 70:30 solvent system (denoted as star number ) at a flow rate of 1.5 ml/min. The column was kept at 40°C. The wavelength of the detector is 254 nm.
The % peak area of the sample was calculated from the peak area of the residual alkyne, the triazole product only, and the introduction of the starting material made it possible to identify the corresponding peaks.
All samples were analyzed using Thermo iCAP 6000 ICP-OES. All calibration standards were prepared using a 1000 ppm Cu standard solution in 2% nitric acid (SPEX Certi Prep). All standards were prepared in a solution of 5% DMF and 2% HNO3, and all samples were diluted 20 times with a sample solution of DMF-HNO3.
UAM uses ultrasonic metal welding as a method of joining the metal foil used to create the final assembly. Ultrasonic metal welding uses a vibrating metal tool (called a horn or ultrasonic horn) to apply pressure to the foil/previously consolidated layer to be bonded/previously consolidated by vibrating the material. For continuous operation, the sonotrode has a cylindrical shape and rolls over the surface of the material, gluing the entire area. When pressure and vibration are applied, the oxides on the surface of the material can crack. Constant pressure and vibration can lead to the destruction of the roughness of the material 36 . Close contact with localized heat and pressure then leads to a solid phase bond at the material interfaces; it can also promote cohesion by changing the surface energy48. The nature of the bonding mechanism overcomes many of the problems associated with the variable melt temperature and high temperature effects mentioned in other additive manufacturing technologies. This allows direct connection (i.e. without surface modification, fillers or adhesives) of several layers of different materials into a single consolidated structure.
The second favorable factor for CAM is the high degree of plastic flow observed in metallic materials even at low temperatures, i.e. well below the melting point of metallic materials. The combination of ultrasonic vibrations and pressure causes a high level of local grain boundary migration and recrystallization without the significant temperature increase traditionally associated with bulk materials. During the creation of the final assembly, this phenomenon can be used to embed active and passive components between layers of metal foil, layer by layer. Elements such as optical fiber 49, reinforcement 46, electronics 50 and thermocouples (this work) have been successfully integrated into UAM structures to create active and passive composite assemblies.
In this work, both different material binding capabilities and UAM intercalation capabilities were used to create an ideal microreactor for catalytic temperature control.
Compared to palladium (Pd) and other commonly used metal catalysts, Cu catalysis has several advantages: (i) Economically, Cu is cheaper than many other metals used in catalysis and is therefore an attractive option for the chemical industry (ii) the range of Cu-catalyzed cross-coupling reactions is expanding and appears to be somewhat complementary to Pd51, 52, 53-based methodologies (iii) Cu-catalyzed reactions work well in the absence of other ligands. These ligands are often structurally simple and inexpensive. if desired, whereas those used in Pd chemistry are often complex, expensive, and air sensitive (iv) Cu, especially known for its ability to bond alkynes in synthesis, such as Sonogashira’s bimetallic catalyzed coupling and cycloaddition with azides (click chemistry) (v) Cu can also promote the arylation of some nucleophiles in Ullmann-type reactions.
Recently, examples of heterogenization of all these reactions in the presence of Cu(0) have been demonstrated. This is largely due to the pharmaceutical industry and the growing focus on recovering and reusing metal catalysts55,56.
The 1,3-dipolar cycloaddition reaction between acetylene and azide to 1,2,3-triazole, first proposed by Huisgen in the 1960s57, is considered to be a synergistic demonstration reaction. The resulting 1,2,3 triazole fragments are of particular interest as a pharmacophore in drug discovery due to their biological applications and use in various therapeutic agents 58 .
This reaction received renewed attention when Sharpless and others introduced the concept of “click chemistry”59. The term “click chemistry” is used to describe a robust and selective set of reactions for the rapid synthesis of new compounds and combinatorial libraries using heteroatomic bonding (CXC)60. The synthetic appeal of these reactions is due to the high yields associated with them. conditions are simple, resistance to oxygen and water, and product separation is simple61.
The classical 1,3-dipole Huisgen cycloaddition does not fall into the “click chemistry” category. However, Medal and Sharpless demonstrated that this azide-alkyne coupling event undergoes 107–108 in the presence of Cu(I) compared to a significant acceleration in the rate of non-catalytic 1,3-dipolar cycloaddition 62,63. This advanced reaction mechanism does not require protecting groups or harsh reaction conditions and provides almost complete conversion and selectivity to 1,4-disubstituted 1,2,3-triazoles (anti-1,2,3-triazoles) over time (Fig. 3 ).
Isometric results of conventional and copper-catalyzed Huisgen cycloadditions. Cu(I)-catalyzed Huisgen cycloadditions give only 1,4-disubstituted 1,2,3-triazoles, while thermally induced Huisgen cycloadditions typically give 1,4- and 1,5-triazoles a 1:1 mixture of azole stereoisomers.
Most protocols involve the reduction of stable sources of Cu(II), such as the reduction of CuSO4 or the Cu(II)/Cu(0) compound in combination with sodium salts. Compared to other metal catalyzed reactions, the use of Cu(I) has the main advantages of being inexpensive and easy to handle.
Kinetic and isotopic studies by Worrell et al. 65 have shown that in the case of terminal alkynes, two equivalents of copper are involved in activating the reactivity of each molecule with respect to azide. The proposed mechanism proceeds through a six-membered copper metal ring formed by the coordination of azide to σ-bonded copper acetylide with π-bonded copper as a stable donor ligand. Copper triazolyl derivatives are formed as a result of ring contraction followed by proton decomposition to form triazole products and close the catalytic cycle.
While the benefits of flow chemistry devices are well documented, there has been a desire to integrate analytical tools into these systems for real-time process monitoring in situ66,67. UAM has proven to be a suitable method for designing and manufacturing very complex 3D flow reactors from catalytically active, thermally conductive materials with directly embedded sensing elements (Fig. 4).
Aluminum-copper flow reactor manufactured by ultrasonic additive manufacturing (UAM) with a complex internal channel structure, built-in thermocouples and a catalytic reaction chamber. To visualize the internal fluid paths, a transparent prototype made using stereolithography is also shown.
To ensure that reactors are made for future organic reactions, solvents must be safely heated above their boiling point; they are pressure and temperature tested. The pressure testing showed that the system maintains a stable and constant pressure even at elevated pressure in the system (1.7 MPa). Hydrostatic tests were carried out at room temperature using H2O as the liquid.
Connecting the built-in (Figure 1) thermocouple to the temperature data logger showed that the thermocouple temperature was 6 °C (± 1 °C) below the programmed temperature in the FlowSyn system. Typically, a 10°C increase in temperature doubles the reaction rate, so a temperature difference of just a few degrees can change the reaction rate significantly. This difference is due to the temperature loss throughout the RPV due to the high thermal diffusivity of the materials used in the manufacturing process. This thermal drift is constant and can therefore be taken into account when setting up the equipment to ensure accurate temperatures are reached and measured during the reaction. Thus, this online monitoring tool facilitates tight control of the reaction temperature and contributes to more precise process optimization and development of optimal conditions. These sensors can also be used to detect exothermic reactions and prevent runaway reactions in large scale systems.
The reactor presented in this paper is the first example of the application of UAM technology to the fabrication of chemical reactors and addresses several major limitations currently associated with AM/3D printing of these devices, such as: (i) Overcoming the noted problems associated with the processing of copper or aluminum alloy (ii) improved internal channel resolution compared to powder bed melting (PBF) methods such as selective laser melting (SLM)25,69 Poor material flow and rough surface texture26 (iii) lower processing temperature, which facilitates direct connecting sensors, which is not possible in powder bed technology, (v) overcoming the poor mechanical properties and sensitivity of polymer-based components to various common organic solvents17,19.
The functionality of the reactor was demonstrated by a series of copper-catalyzed alkinazide cycloaddition reactions under continuous flow conditions (Fig. 2). The ultrasonic printed copper reactor shown in fig. 4 was integrated with a commercial flow system and used to synthesize an azide library of various 1,4-disubstituted 1,2,3-triazoles using a temperature controlled reaction of acetylene and alkyl group halides in the presence of sodium chloride (Fig. 3). The use of the continuous flow approach reduces the safety issues that can arise in batch processes, since this reaction produces highly reactive and hazardous azide intermediates [317], [318]. Initially, the reaction was optimized for the cycloaddition of phenylacetylene and iodoethane (Scheme 1 – Cycloaddition of phenylacetylene and iodoethane) (see Fig. 5).
(Upper left) Schematic of the setup used to incorporate a 3DP reactor into a flow system (upper right) obtained from the optimized (lower) scheme of the Huisgen 57 cycloaddition scheme between phenylacetylene and iodoethane for optimization and showing the optimized conversion rate parameters of the reaction.
By controlling the residence time of the reactants in the catalytic section of the reactor and carefully monitoring the reaction temperature with a directly integrated thermocouple sensor, reaction conditions can be quickly and accurately optimized with a minimum of time and materials. It was quickly found that the highest conversion was achieved using a residence time of 15 minutes and a reaction temperature of 150°C. It can be seen from the coefficient plot of the MODDE software that both the residence time and the reaction temperature are considered important conditions of the model. Running the built-in optimizer using these selected conditions creates a set of reaction conditions designed to maximize product peak areas while decreasing starting material peak areas. This optimization yielded a 53% conversion of the triazole product, which exactly matched the model’s prediction of 54%.