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. Our focus has been on designing and constructing affordable standard hardware and software modules that serve as a blueprint for chemistry digitization across varied fields. Our platforms can be categorized into four types based on their applications: (i) discovery systems for the exploration of chemical space and novel reactivity, (ii) systems for the synthesis and manufacture of fine chemicals, (iii) platforms for formulation discovery and exploration, and (iv) systems for materials discovery and synthesis. We also highlight the convergent evolution of these platforms through shared hardware, firmware, and software alongside the creation of a unique programming language for chemical and material systems. This programming approach is essential for reliable synthesis, designing experiments, discovery, optimization, and establishing new collaboration standards. Furthermore, it is crucial for verifying literature findings, enhancing experimental outcome reliability, and fostering collaboration and sharing of unsuccessful experiments across different research labs.

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. The system uses a chemical programming language coupled to a digital reactor generator to produce reactors and executable protocols based on text-based literature syntheses. Simultaneously, the platform generates a reaction pressure fingerprint, used to monitor processes within the reactors and remotely perform a protocol quality control. We demonstrate the system by synthesizing five small organic molecules, four oligopeptides and four oligonucleotides, in good yields and purities, with a total of 24,936 base steps executed over 329 h of platform runtime.

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. This approach outlines the process for transforming unit operations into digitized hardware and well-defined instructions that ensure effective synthesis. To demonstrate this, we outline the process for digitizing 3 MIDA boronate building blocks, an ester hydrolysis, a Wittig olefination, a Suzuki-Miyaura coupling reaction, and synthesis of the drug sulfanilamide.

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. We developed these chemical generators for four specific targets; transition metal catalyst precursor tris(dibenzylideneacetone)dipalladium(0) [Pd2(dba)3], oxidising agent Dess-Martin periodinane (DMP), protein photolinking reagent succinimidyl 4,4'-azipentanoate (NHS-diazirine), and the polyoxometalate cluster {P8W48}. The cartridge synthesis of these materials provides high-quality target compounds in good yields which are suitable for subsequent utilization.

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. We validated the concept by directing the automated system to synthesize three pharmaceutical compounds, diphenhydramine hydrochloride, rufinamide, and sildenafil, without any human intervention. Yields and purities of products and intermediates were comparable to or better than those achieved manually. The syntheses are captured as digital code that can be published, versioned, and transferred flexibly between platforms with no modification, thereby greatly enhancing reproducibility and reliable access to complex 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. The synthetic outcomes of the multi-stage reactions can be explored by varying reaction compositions, number of reagents, reaction steps, and reaction times, and these can be tagged to the digital blueprint. To demonstrate the potential of this approach a series of polyoxometalate (POM)-containing metal-organic frameworks (MOFs) unavailable by "one-pot" methods were prepared as well as a set of new MOFs.

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. This in turn guides production of a three-dimensional printed device that encloses the entire synthetic route internally via simple operations. We demonstrate the approach for the γ-aminobutyric acid receptor agonist, (±)-baclofen, establishing a concept that paves the way for the local manufacture of drugs outside of specialist facilities.

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. The steps of the PROCEDURE describe the design and preparation of a 3D digital model of the desired reactionware device and the preparation of this model for use with fused deposition modeling (FDM) type 3D printers. The protocol then further describes the preparation of composite catalyst-silicone materials for incorporation into the 3D-printed device and the steps required to fabricate a reactionware device. This combined approach allows versatility in the design and use of reactionware based on the specific needs of the experimental user. To illustrate this, we present a detailed procedure for the production of one such reactionware device that will result in the production of a sealed reactor capable of effecting a multistep organic synthesis. Depending on the design time of the 3D model, and including time for curing and drying of materials, this procedure can be completed in ∼3 d.

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. The software for controlling the synthesis robot was written in the python programming language and hard-coded for the synthesis of ibuprofen by the method described, opening possibilities for the sharing of validated synthetic 'programs' which can run on similar low cost, user-constructed robotic platforms towards an 'open-source' regime in the area of chemical synthesis.

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. The utility of these devices is shown by the use of 3D printed, high-throughput array reactors to discover two new coordination polymers, optimize the synthesis of one of these, and scale-up its synthesis using larger reactors produced on the same 3D printer. Reactors were also used to produce phase-pure samples of coordination polymers MIL-96 and HKUST-1, in yields comparable to synthesis in traditional apparatus.

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.

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.

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. This enabled reactions to be monitored in situ so that different reactionware architectures could be screened for their efficacy for a given process, with a digital feedback mechanism for device optimization. Furthermore, solely by modifying reactionware architecture, reaction outcomes can be altered. Taken together, this approach constitutes a relatively cheap, automated and reconfigurable chemical discovery platform that makes techniques from chemical engineering accessible to typical synthetic laboratories.

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 modular approach is adopted since different POM precursor crystals can form tubular architectures with a range of large cationic species, producing an ion-exchanged material that combines the large added cations and the large POM-based anions. It is also shown that the process of morphogenesis is electrostatically driven by the aggregation of anionic metal oxides with the dissolved cations. This leads to the formation of a semi-permeable membrane around the crystal. The osmotically driven ingress of water leads to an increase in pressure, and ultimately rupture of the membrane occurs, allowing a saturated solution of the POM to escape and leading to the formation of a "self-growing" microtube in the presence of the cation. It is demonstrated that the growth process is sustained by the osmotic pressure within the membrane surrounding the parent crystal, as tube growth ceases whenever this pressure is relieved. Not only is the potential of the modular approach revealed by the fact that the microtubes retain the properties of their component parts, but it is also possible to control the direction of growth and tube diameter. In addition, the solubility limits of tube growth are explored and translated into a predictive methodology for the fabrication of tubular architectures with predefined physical properties, opening the way for real applications.

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.