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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 work, we report the first example of a flow reactor formed by the solid-state metal sheet lamination technique Ultrasonic Additive Manufacturing (UAM) with directly integrated catalytic parts and sensing elements.Not only does UAM technology overcome many of the limitations currently associated with additive manufacturing of chemical reactors, but it also significantly increases the capabilities of such devices.A series of biologically important 1,4-disubstituted 1,2,3-triazole compounds were successfully synthesized and optimized by a Cu-mediated Huisgen 1,3-dipolar cycloaddition reaction using a UAM chemistry set-up.By leveraging the unique properties of UAM and continuous flow processing, the device is able to catalyze ongoing reactions while also providing real-time feedback for reaction monitoring and optimization.
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 simple organic molecule formation1 to pharmaceutical compounds2,3 and natural products4,5,6. More than 50% of reactions in the fine chemical and pharmaceutical industries can benefit from the use of continuous flow processing7.
In recent years, there has been a growing trend of groups looking to replace traditional glassware or flow chemistry equipment with customizable additive manufacturing (AM) chemistry “reaction vessels”8.The iterative design, rapid production, and 3-dimensional (3D) capabilities of these techniques are beneficial for those who wish to customize their devices to a specific 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 printing 7, 15, 16. The lack of robustness and ability of such devices to perform a wide range of chemical reactions/analyses17, 18, 19, 20 is a major limiting factor for broader implementation of AM in this field17, 18, 19, 20 .
Due to the increasing use of flow chemistry and the favorable properties associated with AM, there is a need to explore more advanced techniques that enable users to fabricate flow reaction vessels with enhanced chemical and analytical capabilities.These techniques should enable users to choose from a range of highly robust or functional materials capable of handling a wide range of reaction conditions, while also facilitating various forms of analytical output from the device to allow for reaction monitoring and control.
One additive manufacturing process that has the potential to develop custom chemical reactors is Ultrasonic Additive Manufacturing (UAM).This solid-state sheet lamination technique applies ultrasonic oscillations to thin metal foils in order to join them together layer by layer with minimal bulk heating and a high degree of plastic flow 21 , 22 , 23 .Unlike most other AM technologies, UAM can be directly integrated with subtractive manufacturing, known as a hybrid manufacturing process, in which in-situ periodic computer numerical control (CNC) milling or laser machining defines the net shape of a layer of bonded material 24, 25.This means that the user is not limited by the problems associated with removing residual raw build material from small fluid channels, which is often the case with powder and liquid AM systems26,27,28.This design freedom also extends to the material choices available – UAM can bond thermally similar and dissimilar material combinations in a single process step.The choice of material combinations beyond the melt process means that the mechanical and chemical demands of specific applications can be better met.In addition to solid state bonding, another phenomenon encountered during ultrasonic bonding is the high flow of plastic materials at relatively low temperatures29,30,31,32,33.This unique feature of UAM can facilitate embedding of mechanical/thermal elements between metal layers without damage.UAM embedded sensors can facilitate the delivery of real-time information from the device to the user through integrated analytics.
The authors’ past work32 demonstrated the ability of the UAM process to create metallic 3D microfluidic structures with integrated sensing capabilities.This is a monitoring only device.This paper presents the first example of a microfluidic chemical reactor fabricated by UAM; an active device that not only monitors but also induces chemical synthesis through structurally integrated catalyst materials.The device combines several advantages associated with UAM technology in 3D chemical device manufacturing, such as: the ability to convert full 3D designs directly from computer-aided design (CAD) models into products; multi-material fabrication to combine high thermal conductivity and catalytic materials ; and embedding thermal sensors directly between reagent streams for precise reaction temperature monitoring and control.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 Huisgen 1,3-dipolar cycloaddition.This work highlights how the utilization of materials science and computer-aided design can open up new opportunities and possibilities for chemistry through multidisciplinary research.
All solvents and reagents were purchased from Sigma-Aldrich, Alfa Aesar, TCI or Fischer Scientific and were used without prior purification.1H and 13C NMR spectra recorded at 400 MHz and 100 MHz, respectively, were obtained using a JEOL ECS-400 400 MHz spectrometer or a Bruker Avance II 400 MHz spectrometer and 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 through the following published materials34,35,36,37.The device (Figure 1) was implemented using an ultra-high power, 9kW SonicLayer 4000® UAM system (Fabrisonic, OH, USA).The materials chosen for the fabrication of 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 within a microreactor. Al 6061 O is used as a “bulk” material, also Embedding layer used for analysis; Alloy auxiliary component embedding and annealed condition combined with Cu-110 layer. Al 6061 O is a material that has been shown to be highly compatible with UAM processes38, 39, 40, 41 and has been tested and found Chemically stable with the reagents used in this work. The combination of Al 6061 O with Cu-110 is also considered a compatible material combination for UAM and is therefore a suitable material for this study. 38,42 These devices are listed in Table 1 below.
Reactor fabrication stages (1) Al 6061 substrate (2) Fabrication of bottom channel set to copper foil (3) Embedding of thermocouples between layers (4) Top channel (5) Inlet and outlet (6) Monolithic reactor.
The design philosophy of the fluid path is to use a convoluted path to increase the distance fluid travels within the chip, while keeping the chip at a manageable size.This increase in distance is desirable to increase catalyst/reagent interaction time and provide excellent product yields.The chips use 90° bends at the ends of the straight path to induce turbulent mixing within the device44 and increase the contact time of the fluid with the surface (catalyst).To further increase the mixing that can be achieved, the reactor design features two reagent inlets combined at the Y-junction before entering the serpentine mixing section.The third inlet, which intersects the stream halfway through its residency, is included in the design of future multistep reaction syntheses.
All channels have a square profile (no draft angles), the result of the periodic CNC milling used to create the channel geometry.The channel dimensions are chosen to ensure a high (for a microreactor) volume output, while being small enough to facilitate surface interactions (catalysts) for most of the contained fluids.The appropriate size is based on the authors’ past experience with metal-fluidic devices for the reaction.The internal dimensions of the final channel were 750 µm x 750 µm and the total reactor volume was 1 ml.An integrated connector (1/4″—28 UNF thread) is included in the design to allow simple interfacing of the device with commercial flow chemistry equipment. The channel size is limited by the thickness of the foil material, its mechanical properties, and the bonding parameters used with ultrasonics. At a specific width for a given material, the material will “sag” into the created channel. There is currently no specific model for this calculation, so the maximum channel width for a given material and design is determined experimentally; in this case, a width of 750 μm will not cause sag.
The shape (square) of the channel is determined by using a square cutter.The shape and size of the channels can be altered by CNC machines using different cutting tools to obtain different flow rates and characteristics.An example of creating a curved shape channel using the 125 μm tool can be found in the work of Monaghan45.When the foil layer is deposited in a planar fashion, the overlay of foil material over the channels will have a flat (square) finish.In this work, in order to maintain the symmetry of the channel, a square outline was used.
During a pre-programmed pause in manufacture, thermocouple temperature probes (Type K) are embedded directly within the device between the upper and lower channel groups (Figure 1 – Stage 3).These thermocouples can monitor temperature changes from −200 to 1350 °C.
The metal deposition process is performed by a UAM horn using a 25.4 mm wide, 150 micron thick metal foil.These foil layers are bonded into 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 subtractive process produces the final net 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 equal to the selected tool and CNC process parameters (approximately 1.6 μm Ra in this example).Continuous, continuous ultrasonic material deposition and machining cycles are used throughout the device manufacturing process to ensure dimensional accuracy is maintained and the finished part will meet CNC finish milling accuracy levels.The channel width used for this device is small enough to ensure that the foil material does not “sag” into the fluid channel, so the channel maintains a square cross-section.Possible gaps in foil material and UAM process parameters were determined experimentally by a manufacturing partner (Fabrisonic LLC, USA).
Studies have shown that little elemental diffusion occurs at the UAM bonding interface 46, 47 without additional thermal treatment, so for the devices in this work, the Cu-110 layer remains distinct from the Al 6061 layer and changes abruptly.
Install a pre-calibrated 250 psi (1724 kPa) back pressure regulator (BPR) to the outlet 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 built-in system pressure sensor to verify that the system could maintain a constant steady pressure.Potential temperature gradients across the flow reactor were tested by identifying any differences between the thermocouples embedded within the reactor and those embedded within the FlowSyn chip heating plate.This is achieved by varying the programmable hotplate temperature between 100 and 150 °C in 25 °C increments and noting any differences between the programmed and recorded temperatures.This was achieved using a tc-08 data logger (PicoTech, Cambridge, UK) and accompanying PicoLog software.
The cycloaddition reaction conditions of phenylacetylene and iodoethane were optimized (Scheme 1- Cycloaddition of phenylacetylene and iodoethane Scheme 1- Cycloaddition of phenylacetylene and iodoethane).This optimization was performed by a full factorial design of experiments (DOE) approach, using temperature and residence time as variable parameters, 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 model response was taken as the peak area ratio of triazole product to phenylacetylene starting material and determined by high performance liquid chromatography (HPLC).For consistency of analysis, all reactions were sampled just 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 × 100 mm in size, 5 µm particle size, maintained at 40 °C.The solvent was isocratic 50:50 methanol:water 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.Injection of starting material allows identification of relevant peaks.
Coupling the reactor analysis output to the MODDE DOE software (Umetrics, Malmö, Sweden) allowed a thorough analysis of results trends and determination of optimal reaction conditions for this cycloaddition.Running the built-in optimizer and selecting all important model terms yields a set of reaction conditions designed to maximize product peak area while reducing peak area for acetylene starting material.
The oxidation of surface copper within the catalytic reaction chamber was achieved using a solution of hydrogen peroxide (36%) flowing through the reaction chamber (flow rate = 0.4 mL min-1, residence time = 2.5 min) prior to synthesis of each triazole compound library.
Once an optimal set of conditions was identified, they were applied to a range of acetylene and haloalkane derivatives to allow the compilation of a small library synthesis, thereby establishing the ability to apply these conditions to a wider range of potential reagents (Figure 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).3 mL aliquots of each solution were mixed and pumped through the reactor at 75 µL.min-1 and 150 °C.The total volume was collected into a vial and diluted with 10 mL of ethyl acetate.The sample solution was washed with 3 × 10 mL of water.The aqueous layers were combined and extracted with 10 mL of ethyl acetate; the organic layers were then combined, washed with 3 x 10 mL of brine, dried over MgSO4 and filtered, then the solvent was removed in vacuo.The samples were purified by column chromatography on silica gel 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 acquired using a Thermofischer precision Orbitrap resolution mass spectrometer with ESI as the ionization source.All samples were prepared using acetonitrile as solvent.
TLC analysis was performed on aluminum-backed silica plates.Plates were visualized by UV light (254 nm) or vanillin staining and heating.
All samples were analysed using a VWR Chromaster (VWR International Ltd., Leighton Buzzard, UK) system equipped with an autosampler, column oven binary pump and single wavelength detector.The column used was an ACE Equivalence 5 C18 (150 × 4.6 mm, Advanced Chromatography Technologies Ltd., Aberdeen, Scotland).
Injections (5 µL) were made directly from diluted crude reaction mixture (1:10 dilution) and analyzed with water:methanol (50:50 or 70:30), except for some samples using the 70:30 solvent system (denoted as a star number) at a flow rate of 1.5 mL/min.The column was kept at 40 °C.The detector wavelength is 254 nm.
The % peak area of ​​the sample was calculated from the peak area of ​​the residual alkyne, only the triazole product, and the injection of the starting material allowed the identification of the relevant peaks.
All samples were analyzed using a 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 5% DMF and 2% HNO3 solution, and all samples were diluted 20-fold in sample DMF-HNO3 solution.
UAM utilizes ultrasonic metal welding as a bonding technique for the metal foil material used to build the final assembly.Ultrasonic metal welding utilizes a vibrating metal tool (called a horn or ultrasonic horn) to apply pressure to the foil layer/previously consolidated layer to be bonded while vibrating the material.For continuous operation, the sonotrode is cylindrical and rolls over the surface of the material, bonding the entire area.When pressure and vibration are applied, the oxides on the surface of the material can crack.Continued pressure and vibration can cause asperities of the material to collapse 36 .Intimate contact with locally induced heat and pressure then leads to solid-state bonding at material interfaces; it can also aid adhesion through changes in surface energy48.The nature of the bonding mechanism overcomes many of the problems associated with the variable melt temperature and high temperature after-effects mentioned in other additive manufacturing techniques.This allows for direct bonding (ie, without surface modification, fillers or adhesives) of multiple layers of different materials into a single consolidated structure.
A second favorable factor for UAM 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 oscillation and pressure induces high levels of local grain boundary migration and recrystallization without the large temperature increase traditionally associated with bulk materials.During the construction of the final assembly, this phenomenon can be exploited to embed active and passive components between layers of metal foil, layer by layer.Elements such as optical fibers 49, reinforcements 46, electronics 50, and thermocouples (this work) have all been successfully embedded into UAM structures to create active and passive composite assemblies.
In this work, both the different material bonding and intercalation possibilities of UAM have been used to create the ultimate catalytic temperature monitoring microreactor.
Compared with palladium (Pd) and other commonly used metal catalysts, Cu catalysis has several advantages: (i) Economically, Cu is less expensive than many other metals used in catalysis and is therefore an attractive option for the chemical processing industry (ii) The range of Cu-catalyzed cross-coupling reactions is increasing and appears to be somewhat complementary to Pd-based methodologies51,52,53 (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 bind alkynes in synthesis, For example, bimetallic-catalyzed Sonogashira coupling and cycloaddition with azides (click chemistry) (v)Cu is also able to promote the arylation of several nucleophiles in Ullmann-type reactions.
Examples of heterogenization of all these reactions have recently been demonstrated in the presence of Cu(0).This is largely due to the pharmaceutical industry and the growing focus on metal catalyst recovery and reuse55,56.
Pioneered by Huisgen in the 1960s57, the 1,3-dipolar cycloaddition reaction between acetylene and azide to 1,2,3-triazole is considered a synergistic demonstration reaction.The resulting 1,2,3 triazole moieties are of particular interest as pharmacophore in the field of drug discovery because of their biological applications and use in various therapeutic agents 58 .
This reaction came into focus again when Sharpless and others introduced the concept of “click chemistry”59.The term “click chemistry” is used to describe a robust, reliable and selective set of reactions for the rapid synthesis of new compounds and combinatorial libraries via heteroatom linkage (CXC)60 The synthetic appeal of these reactions stems from their associated high yields , reaction conditions are simple, oxygen and water resistance, and product separation is simple61.
The classical Huisgen 1,3-dipole cycloaddition does not belong to the category of “click chemistry”.However, Medal and Sharpless demonstrated that this azide-alkyne coupling event undergoes 107 to 108 in the presence of Cu(I) compared to the uncatalyzed 1,3-dipolar cycloaddition 62,63 significant rate acceleration.This improved reaction mechanism does not require protecting groups or harsh reaction conditions and yields near complete conversion and selectivity to 1,4-disubstituted 1,2,3-triazoles (anti- 1,2,3-triazole) on a time scale (Figure 3).
Isometric results of conventional and copper-catalyzed Huisgen cycloadditions.Cu(I)-catalyzed Huisgen cycloadditions yield only 1,4-disubstituted 1,2,3-triazoles, whereas thermally induced Huisgen cycloadditions typically yield 1,4- and 1,5-triazoles 1:1 mixture of stereoisomers of azoles.
Most protocols involve reduction of stable Cu(II) sources, such as reduction of CuSO4 or Cu(II)/Cu(0) species co-combination with sodium salts.Compared with other metal-catalyzed reactions, the use of Cu(I) has the major advantages of being inexpensive and easy to handle.
Kinetic and isotopic labelling studies by Worrell et al. 65 showed that, in the case of terminal alkynes, two equivalents of copper are involved in activating the reactivity of each molecule towards 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.Triazolyl copper derivatives are formed by ring shrinkage, followed by proton decomposition to provide 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 in-line, in-situ, process monitoring66,67.UAM proved to be a suitable method for designing and producing highly complex 3D flow reactors made of catalytically active, thermally conductive materials with directly embedded sensing elements (Figure 4).
Aluminum-copper flow reactor fabricated by ultrasonic additive manufacturing (UAM) with complex internal channel structure, embedded thermocouples and catalytic reaction chamber.To visualize internal fluid pathways, a transparent prototype fabricated using stereolithography is also shown.
To ensure the reactors are fabricated for future organic reactions, solvents need to be safely heated above boiling point; they are pressure and temperature tested.The pressure test showed that the system maintains a stable and constant pressure even with an increased system pressure (1.7 MPa).The hydrostatic test was performed at room temperature using H2O as the fluid.
Connecting the embedded (Figure 1) thermocouple to the temperature data logger showed that the thermocouple was 6 °C (± 1 °C) cooler than the programmed temperature on the FlowSyn system.Typically, a 10 °C increase in temperature results in a doubling of the reaction rate, so a temperature difference of just a few degrees can significantly alter the reaction rate.This difference is due to the temperature loss throughout the reactor body due to the high thermal diffusivity of the materials used in the manufacturing process.This thermal drift is consistent and can therefore be accounted for in the equipment setup to ensure accurate temperatures are reached and measured during the reaction.Therefore, this online monitoring tool facilitates tight control of reaction temperature and facilitates more accurate process optimization and development of optimal conditions.These sensors can also be used to identify reaction exotherms and prevent runaway reactions in large-scale systems.
The reactor presented in this work 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 Reported problems related to copper or aluminum alloy processing (ii) improved internal channel resolution compared to powder bed fusion (PBF) techniques such as selective laser melting (SLM)25,69 Poor material flow and rough surface texture26 (iii) Reduced processing temperature, which facilitates direct bonding of sensors, which is not possible in powder bed technology, (v) overcomes poor mechanical properties and sensitivity of polymer-based components components to a variety of common organic solvents17,19.
The functionality of the reactor was demonstrated by a series of copper-catalyzed alkyne azide cycloaddition reactions under continuous flow conditions (Fig. 2).The ultrasonic-printed copper reactor detailed in Figure 4 was integrated with a commercial flow system and used to synthesize library azides of various 1,4-disubstituted 1,2,3-triazoles via the temperature-controlled reaction of acetylene and alkyl groups halides in the presence of sodium chloride (Figure 3).The use of a continuous flow approach mitigates the safety concerns that can arise in batch processes, as 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 Figure 5).
(Top left) Schematic of the setup used to incorporate the 3DP reactor into the flow system (top right) obtained in the optimized (bottom) scheme of the Huisgen cycloaddition 57 scheme between phenylacetylene and iodoethane for optimization and showing the optimized parameters reaction conversion rate.
By controlling the residence time of the reagents in the catalytic part of the reactor and closely monitoring the reaction temperature with a directly integrated thermocouple probe, reaction conditions can be optimized quickly and accurately with minimal time and material consumption.It was quickly determined that the highest conversions were obtained when a residence time of 15 minutes and a reaction temperature of 150 °C were used.From the coefficient plot of the MODDE software, it can be seen that both residence time and reaction temperature are considered important model terms.Running the built-in optimizer using these selected terms generates a set of reaction conditions designed to maximize product peak areas while reducing starting material peak areas.This optimization yielded a 53% conversion of the triazole product, which closely matched the model prediction of 54%.
Based on the literature showing that copper(I) oxide (Cu2O) can act as an effective catalytic species on zero-valent copper surfaces in these reactions, the ability to pre-oxidize the reactor surface prior to carrying out the reaction in flow was investigated70,71.The reaction between phenylacetylene and iodoethane was then performed again under optimal conditions and the yields were compared.It was observed that this preparation resulted in a significant increase in the conversion of the starting material, which was calculated to be >99%.However, monitoring by HPLC showed that this conversion significantly reduced the excessively prolonged reaction time until approximately 90 minutes, whereupon the activity appeared to level off and reach a “steady state”.This observation suggests that the source of catalytic activity is obtained from the surface copper oxide rather than the zero-valent copper substrate.Cu metal is easily oxidized at room temperature to form CuO and Cu2O that are not self-protective layers.This eliminates the need to add an auxiliary copper(II) source for co-composition71.