Robotic Modules for the Programmable Chemputation of Molecules and Materials.

Before leveraging big data methods like machine learning and artificial intelligence (AI) in chemistry, there is an imperative need for an affordable, universal digitization standard. This mirrors the foundational requisites of the digital revolution, which demanded standard architectures with precise specifications. Recently, we have developed automated platforms tailored for chemical AI-driven exploration, including the synthesis of molecules, materials, nanomaterials, and formulations.

An autonomous portable platform for universal chemical synthesis.

Robotic systems for synthetic chemistry are becoming more common, but they are expensive, fixed to a narrow set of reactions, and must be used within a complex laboratory environment. A portable system that could synthesize known molecules anywhere, on demand, and in a fully automated way, could revolutionize access to important molecules. Here we present a portable suitcase-sized chemical synthesis platform containing all the modules required for synthesis and purification.

Digitizing Chemical Synthesis in 3D Printed Reactionware.

Chemistry digitization requires an unambiguous link between experiments and the code used to generate the experimental conditions and outcomes, yet this process is not standardized, limiting the portability of any chemical code. What is needed is a universal approach to aid this process using a well-defined standard that is composed of syntheses that are employed in modular hardware. Herein we present a new approach to the digitization of organic synthesis that combines process chemistry principles with 3D printed reactionware.

Automatic Generation of 3D-Printed Reactionware for Chemical Synthesis Digitization using ChemSCAD.

We describe a system, ChemSCAD, for the creation of digital reactors based on the chemical operations, physical parameters, and synthetic sequence to produce a given target compound, to show that the system can translate the gram-scale batch synthesis of the antiviral compound Ribavirin (yield 43% over three steps), the narcolepsy drug Modafinil (yield 60% over three steps), and both batch and flow instances of the synthesis of the anticancer agent Lomustine (batch yield 65% over two steps) in purities greater than or equal to 96%. The syntheses of compounds developed using the ChemSCAD system, including reactor designs and analytical data, can be stored in a database repository, with the information necessary to critically evaluate and improve upon reactionware syntheses being easily shared and versioned.

3D designed and printed chemical generators for on demand reagent synthesis.

Modern science has developed well-defined and versatile sets of chemicals to perform many specific tasks, yet the diversity of these reagents is so large that it can be impractical for any one lab to stock everything they might need. At the same time, isssues of stability or limited supply mean these chemicals can be very expensive to purchase from specialist retailers. Here, we address this problem by developing a cartridge -oriented approach to reactionware-based chemical generators which can easily and reliably produce specific reagents from low-cost precursors, requiring minimal expertise and time to operate, potentially in low infrastructure environments.

Organic synthesis in a modular robotic system driven by a chemical programming language.

The synthesis of complex organic compounds is largely a manual process that is often incompletely documented. To address these shortcomings, we developed an abstraction that maps commonly reported methodological instructions into discrete steps amenable to automation. These unit operations were implemented in a modular robotic platform by using a chemical programming language that formalizes and controls the assembly of the molecules.

Digital Control of Multistep Hydrothermal Synthesis by Using 3D Printed Reactionware for the Synthesis of Metal-Organic Frameworks.

Hydrothermal-synthesis-based reactions are normally single step owing to the difficulty of manipulating reaction mixtures at high temperatures and pressures. Herein we demonstrate a simple, cheap, and modular approach to the design reactors consisting of partitioned chambers, to achieve multi-step synthesis under hydrothermal conditions, in digitally defined reactionware produced by 3D printing. This approach increases the number of steps that can be performed sequentially and allows an increase in the options available for the control of hydrothermal reactions.

Digitization of multistep organic synthesis in reactionware for on-demand pharmaceuticals.

Chemical manufacturing is often done at large facilities that require a sizable capital investment and then produce key compounds for a finite period. We present an approach to the manufacturing of fine chemicals and pharmaceuticals in a self-contained plastic reactionware device. The device was designed and constructed by using a chemical to computer-automated design (ChemCAD) approach that enables the translation of traditional bench-scale synthesis into a platform-independent digital code.

The digital code driven autonomous synthesis of ibuprofen automated in a 3D-printer-based robot.

An automated synthesis robot was constructed by modifying an open source 3D printing platform. The resulting automated system was used to 3D print reaction vessels (reactionware) of differing internal volumes using polypropylene feedstock via a fused deposition modeling 3D printing approach and subsequently make use of these fabricated vessels to synthesize the nonsteroidal anti-inflammatory drug ibuprofen via a consecutive one-pot three-step approach. The synthesis of ibuprofen could be achieved on different scales simply by adjusting the parameters in the robot control software.

3D printing of versatile reactionware for chemical synthesis.

In recent decades, 3D printing (also known as additive manufacturing) techniques have moved beyond their traditional applications in the fields of industrial manufacturing and prototyping to increasingly find roles in scientific research contexts, such as synthetic chemistry. We present a general approach for the production of bespoke chemical reactors, termed reactionware, using two different approaches to extrusion-based 3D printing. This protocol describes the printing of an inert polypropylene (PP) architecture with the concurrent printing of soft material catalyst composites, using two different 3D printer setups.

3D printed high-throughput hydrothermal reactionware for discovery, optimization, and scale-up.

3D printing techniques allow the laboratory-scale design and production of reactionware tailored to specific experimental requirements. To increase the range and versatility of reactionware devices, sealed, monolithic reactors suitable for use in hydrothermal synthesis have been digitally designed and realized. The fabrication process allows the introduction of reaction mixtures directly into the reactors during the production, and also enables the manufacture of devices of varying scales and geometries unavailable in traditional equipment.

Continuous parallel ESI-MS analysis of reactions carried out in a bespoke 3D printed device.

Herein, we present an approach for the rapid, straightforward and economical preparation of a tailored reactor device using three-dimensional (3D) printing, which can be directly linked to a high-resolution electrospray ionisation mass spectrometer (ESI-MS) for real-time, in-line observations. To highlight the potential of the setup, supramolecular coordination chemistry was carried out in the device, with the product of the reactions being recorded continuously and in parallel by ESI-MS. Utilising in-house-programmed computer control, the reactant flow rates and order were carefully controlled and varied, with the changes in the pump inlets being mirrored by the recorded ESI-MS spectra.

3D-printed devices for continuous-flow organic chemistry.

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.

Configurable 3D-Printed millifluidic and microfluidic 'lab on a chip' reactionware devices.

We utilise 3D design and 3D printing techniques to fabricate a number of miniaturised fluidic 'reactionware' devices for chemical syntheses in just a few hours, using inexpensive materials producing reliable and robust reactors. Both two and three inlet reactors could be assembled, as well as one-inlet devices with reactant 'silos' allowing the introduction of reactants during the fabrication process of the device. To demonstrate the utility and versatility of these devices organic (reductive amination and alkylation reactions), inorganic (large polyoxometalate synthesis) and materials (gold nanoparticle synthesis) processes were efficiently carried out in the printed devices.

Integrated 3D-printed reactionware for chemical synthesis and analysis.

Three-dimensional (3D) printing has the potential to transform science and technology by creating bespoke, low-cost appliances that previously required dedicated facilities to make. An attractive, but unexplored, application is to use a 3D printer to initiate chemical reactions by printing the reagents directly into a 3D reactionware matrix, and so put reactionware design, construction and operation under digital control. Here, using a low-cost 3D printer and open-source design software we produced reactionware for organic and inorganic synthesis, which included printed-in catalysts and other architectures with printed-in components for electrochemical and spectroscopic analysis.

Osmotically driven crystal morphogenesis: a general approach to the fabrication of micrometer-scale tubular architectures based on polyoxometalates.

The process of osmotically driven crystal morphogenesis of polyoxometalate (POM)-based crystals is investigated, whereby the transformation results in the growth of micrometer-scale tubes 10-100 μm in diameter and many thousands of micrometers long. This process initiates when the crystals are immersed in aqueous solutions containing large cations and is governed by the solubility of the parent POM crystal. Evidence is presented that indicates the process is general to all types of POMs, with solubility of the parent crystal being the deciding parameter.

A new C-C bond forming annulation reaction leading to pH switchable heterocycles.

A C-C bond forming reaction resulting from the alpha-addition of carbon based nucleophiles to N-bromoethyl phenanthridinium leads to the formation of 2,3-dihydro-12H-pyrrolo[1,2-f]phenanthridine-based derivatives which undergo reversible ring-opening/closing under pH control.