Challenges and Strategies for Synthesizing High Performance Micro and Nanoscale High Entropy Oxide Materials.

High-entropy oxide micro/nano materials (HEO MNMs) have shown broad application prospects and have become hot materials in recent years. This review comprehensively provides an overview of the latest developments and covers key aspects of HEO MNMs, by discussing design principles, computer-aided structural design, synthesis challenges and strategies, as well as application areas. The analysis of the synthesis process includes the role of high-throughput process in large-scale synthesis of HEOs MNMs, along with the effects of temperature elevation and undercooling on the formation of HEO MNMs. Additionally, the article summarizes the application of high-precision and in situ characterization devices in the field of HEO MNMs, offering robust support for related research. Finally, a brief introduction to the main applications of HEO MNMs is provided, emphasizing their key performances. This review offers valuable guidance for future research on HEO MNMs, outlining critical issues and challenges in the current field.

Discovering of Atomically Precise Metal Nanoclusters by High-Throughput Syntheses Platform.

Understanding the complete structure of noble metal nanoclusters is both academically and practically significant. However, progress has been hindered by the low synthetic efficiency of many nanocluster syntheses. In this study, we present the first high-throughput syntheses of homo-gold, homo-copper, and gold-copper alloy nanoclusters in dichloromethane at room temperature. Through high-throughput screening, we successfully obtained three nanoclusters in a single reaction: Au18(SC6H11)14, [Au41Cu66(SC6H11)44](SbF6)3, and an unidentified copper cluster (referred to as Au18, Au41Cu66 , and Cu-NC). The optimized synthesis route was achieved with the assistance of machine learning for experimental data analysis, which also guided the synthesis of other metal nanoclusters such as Au40Cu34(4-S-PhF)40 (Au40Cu34), [Au6Cu6(SPh)12]n ([Au6Cu6]n), and Au18Cu32(3,5-C8H9S)36 (Au18Cu32)). This research demonstrates that high-throughput screening can be a valuable tool in accelerating the development of nanocluster syntheses.

High-Throughput Synthesis of Nanogap-Rich Gold Nanoshells Using Dual-Channel Infusion System.

Gold nanoshells have been actively applied in industries beyond the research stage because of their unique optical properties. Although numerous methods have been reported for gold nanoshell synthesis, the labor-intensive and time-consuming production process is an issue that must be overcome to meet industrial demands. To resolve this, we report a high-throughput synthesis method for nanogap-rich gold nanoshells based on a core silica support (denoted as SiO2@Au NS), affording a 50-fold increase in scale by combining it with a dual-channel infusion pump system. By continuously dropping the reactant solution through the pump, nanoshells with closely packed Au nanoparticles were prepared without interparticle aggregation. The thickness of the gold nanoshells was precisely controlled at 2.3-17.2 nm by regulating the volume of the reactant solution added dropwise. Depending on the shell thickness, the plasmonic characteristics of SiO2@Au NS prepared by the proposed method could be tuned. Moreover, SiO2@Au NS exhibited surface-enhanced Raman scattering activity comparable to that of gold nanoshells prepared by a previously reported low-throughput method at the same reactant ratio. The results indicate that the proposed high-throughput synthesis method involving the use of a dual-channel infusion system will contribute to improving the productivity of SiO2@Au NS with tunable plasmonic characteristics.

Extending Droplet-Based Microfluidic Tools to Single-Atom Heterogeneous Catalysis.

From energy-related transformations to organic syntheses, single-atom heterogeneous catalysts (SACs) are offering new prospects to tackle sustainability challenges. However, scarce design guidelines and poor mechanistic understanding due to a lack of discovery and operando characterization tools impede theirbroader development. This perspective offers a glimpse into how droplet-based microfluidic technologies mayhelp solve both of these issues, and provides technical considerations for platform design to systematically fabricate SACs and study them under operational conditions during liquid-phase organic syntheses.

High-throughput, combinatorial synthesis of multimetallic nanoclusters.

Multimetallic nanoclusters (MMNCs) offer unique and tailorable surface chemistries that hold great potential for numerous catalytic applications. The efficient exploration of this vast chemical space necessitates an accelerated discovery pipeline that supersedes traditional "trial-and-error" experimentation while guaranteeing uniform microstructures despite compositional complexity. Herein, we report the high-throughput synthesis of an extensive series of ultrafine and homogeneous alloy MMNCs, achieved by 1) a flexible compositional design by formulation in the precursor solution phase and 2) the ultrafast synthesis of alloy MMNCs using thermal shock heating (i.e., ∼1,650 K, ∼500 ms). This approach is remarkably facile and easily accessible compared to conventional vapor-phase deposition, and the particle size and structural uniformity enable comparative studies across compositionally different MMNCs. Rapid electrochemical screening is demonstrated by using a scanning droplet cell, enabling us to discover two promising electrocatalysts, which we subsequently validated using a rotating disk setup. This demonstrated high-throughput material discovery pipeline presents a paradigm for facile and accelerated exploration of MMNCs for a broad range of applications.

High-Throughput and Combinatorial Approaches for the Development of Multifunctional Polymers.

High-throughput (HT) development of new multifunctional polymers is accomplished by the combination of different HT tools established in polymer sciences in the last decade. Important advances are robotic/HT synthesis of polymer libraries, the HT characterization of polymers, and the application of spatially resolved polymer library formats, explicitly microarray and gradient libraries. HT polymer synthesis enables the generation of material libraries with combinatorial design motifs. Polymer composition, molecular weight, macromolecular architecture, etc. may be varied in a systematic, fine-graded manner to obtain libraries with high chemical diversity and sufficient compositional resolution as model systems for the screening of these materials for the functions aimed. HT characterization allows a fast assessment of complementary properties, which are employed to decipher quantitative structure-properties relationships. Moreover, these methods facilitate the HT determination of important surface parameters by spatially resolved characterization methods, including time-of-flight secondary ion mass spectrometry and X-ray photoelectron spectroscopy. Here current methods for the high-throughput robotic synthesis of multifunctional polymers as well as their characterization are presented and advantages as well as present limitations are discussed.

High-Throughput Discovery of a Rhombohedral Twelve-Connected Zirconium-Based Metal-Organic Framework with Ordered Terephthalate and Fumarate Linkers.

We report a metal-organic framework where an ordered array of two linkers with differing length and geometry connect [Zr6 (OH)4 O4 ]12+ clusters into a twelve-connected fcu net that is rhombohedrally distorted from cubic symmetry. The ordered binding of equal numbers of terephthalate and fumarate ditopic carboxylate linkers at the trigonal antiprismatic Zr6 core creates close-packed layers of fumarate-connected clusters that are connected along the single remaining threefold axis by terephthalates. This well-defined linker arrangement retains the three-dimensional porosity of the Zr cluster-based UiO family while creating two distinct windows within the channels that define two distinct guest diffusion paths. The ordered material is accessed by a restricted combination of composition and process parameters that were identified by high-throughput synthesis.

High-Throughput Synthesis and Characterization of Aryl Silicones by Using the Piers-Rubinsztajn Reaction.

Arylsilicones are widely exploited for their thermal and optical properties. The creation of phenylsilicone elastomers with specific physical properties is typically done by a "one-off" formulation and test process. Herein, it is demonstrated that high-throughput synthesis methods can be used to rapidly prepare a series of arylsilicone elastomers and then the relative impact of different aryl groups on their physical properties is assessed. Aromatic groups were incorporated into polydimethylsiloxane (PDMS) elastomers by exploiting the relative reactivity of different functional groups in the Piers-Rubinsztajn reaction. To analyze trends in the silicone mechanical properties as a function of increasing aryl concentration-structure/property relationships-libraries of elastomers were both quickly synthesized and characterized by using high-throughput suites starting from low viscosity silicone oils/monomers in 96-well plates. Liquid handling parameters were optimized to effectively work with the silicones. Incorporating aryl instead of alkyl crosslinkers into the PDMS backbone increased the silicone elastomer modulus by approximately 50 % (at a crosslink density of 6 %); elastomers prepared with an aromatic crosslinker with three contact points led to much higher moduli compared with those with one contact point at the same crosslink density. When located at precise rather than random points on the silicone chains, diphenylsilicones had lower moduli than analogous monophenylsilicones.

Machine Learning for Organic Synthesis: Are Robots Replacing Chemists?

Machines learn chemistry: An artificial intelligence algorithm has learned to predict the outcomes of C-N coupling reactions from a few thousand nanomole-scale experiments. This Highlight discusses this work in the context of other state-of-the-art approaches for predicting the yields of organic reactions and explains the significance of the results.

Needleless Electrohydrodynamic Cojetting of Bicompartmental Particles and Fibers from an Extended Fluid Interface.

Electrohydrodynamic cojetting can result in fibers (electrospinning) and particles (electrospraying) with complex, bicompartmental architectures. An important consideration for application of bicompartmental particles and fibers is the limited throughput derived from the use of parallel capillaries, which require laminar flow to form a multifluidic interface. Here, a novel synthesis approach that takes advantage of an extended bicompartmental fluid interface formed at the sharp edge of a 2D plate is reported. Upon application of an electrical potential to the plate, several electrified fluid jets form spontaneously. Depending on the processing conditions, either bicompartmental particles or fibers with well-defined architectures are prepared. Importantly, this needleless process yields production rates that are more than 30 times higher than those of conventional needle-based techniques. Fiber properties, such as morphology or size, are independent of the flow rate, indicating that this process is physically self-regulating by adjusting the number of jets ejecting from the extended fluid interface. The needleless preparation of bicompartmental particles and fibers is an important technological breakthrough that can enable further advances ranging from drug delivery and tissue engineering to industrial applications.

High-Throughput Synthesis of Mixed-Metal Electrocatalysts for CO2 Reduction.

The utilization of CO2 as a feedstock requires fundamental breakthroughs in catalyst design. The efficiencies and activities of pure metal electrodes towards the CO2 reduction reaction are established, but the corresponding data on mixed-metal systems are not as well developed. In this study we show that the near-infrared driven decomposition (NIRDD) of solution-deposited films of metal salts and subsequent electrochemical reduction offers the unique opportunity to form an array of mixed-metal electrocatalyst coatings with excellent control of the metal stoichiometries. This synthetic method enabled us to develop an empirical structure-property correlation to help inform the development of optimized CO2 catalyst compositions.

High-Throughput Synthesis of Diverse Compound Collections for Lead Discovery and Optimization.

Small-molecule intervention of protein function is one central dogma of drug discovery. The generation of small-molecule libraries fuels the discovery pipeline at many stages and thereby resembles a key aspect of this endeavor. High-throughput synthesis is a major source for compound libraries utilized in academia and industry, seeking new chemical modulators of pharmacological targets. Here, we discuss the crucial factors of library design strategies from the perspective of synthetic chemistry, giving a brief historic background and a summary of current approaches. Simple measures of success of a high-throughput synthesis such as quantity or diversity have long been discarded and replaced by more integrated measures. Case studies are presented and put into context to highlight the cross-connectivity of the various stages of the drug discovery process.

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.

PEPR DIADEM: Priority equipment and research program on the development of innovative materials using artificial intelligence.

The quest to develop efficient, sustainable materials from non-critical, non-toxic resources is one of today's most formidable challenges in the current context of energy, transport, digital or healthcare transitions. In response, France launched the pioneering Priority Equipment and Research Program (PEPR) DIADEM in 2022. This innovative initiative, focused on DIscovery Acceleration for the Deployment of Emerging Materials (DIADEM), leverages Artificial Intelligence (AI) to accelerate the innovation chain from conception to realization, revolutionizing Materials Science sustainably. With a strategic emphasis on scientific synergy, PEPR DIADEM aims to expedite the discovery and development of novel materials essential for contemporary and future societal challenges. To achieve this, the program seeks to catalyze breakthroughs in areas ranging from energy efficiency to transportation, digitalization, and healthcare, covering a broad spectrum of materials from metallic alloys to functional nanostructures. Aligned with the Green Deal framework's ambitious targets, PEPR DIADEM addresses the urgent need for accelerated sustainable materials research. By utilizing cutting-edge technologies like rapid synthesis and characterization tools, automation, digital simulations, data management, AI, additive manufacturing, and thin film engineering, the program is set to significantly reshape the materials science landscape. As PEPR DIADEM embarks on its journey of innovation, it not only advances scientific knowledge but also holds the promise of addressing current global challenges and paving the way for a more sustainable and prosperous future.

Accelerated Engineering of Optimized Functional Composite Hydrogels via High-Throughput Experimentation.

The Materials Genome Initiative (MGI) seeks to accelerate the discovery and engineering of advanced materials via high-throughput experimentation (HTE), which is a challenging task, given the common trade-off between design for optimal processability vs performance. Here, we report a HTE method based on automated formulation, synthesis, and multiproperty characterization of bulk soft materials in well plate formats that enables accelerated engineering of functional composite hydrogels with optimized properties for processability and performance. The method facilitates rapid high-throughput screening of hydrogel composition-property relations for multiple properties in well plate formats. The feasibility and utility of the method were demonstrated by application to several functional composite hydrogel systems, including alginate/poly(N-isopropylacrylamide) (PNIPAM) and poly(ethylene glycol) dimethacrylate (PEGDMA)/poly(3,4-ethylenedioxythiophene)-poly(styrenesulfonate) (PEDOT:PSS) hydrogels. The HTE method was leveraged to identify formulations of conductive PEGDMA/PEDOT:PSS composite hydrogels for optimized performance and processability in three-dimensional (3D) printing. This work provides an advance in experimental methods based on automated dispensing, mixing, and sensing for the accelerated engineering of soft functional materials.

Pulsed Light Synthesis of High Entropy Nanocatalysts with Enhanced Catalytic Activity and Prolonged Stability for Oxygen Evolution Reaction.

The ability to synthesize compositionally complex nanostructures rapidly is a key to high-throughput functional materials discovery. In addition to being time-consuming, a majority of conventional materials synthesis processes closely follow thermodynamics equilibria, which limit the discovery of new classes of metastable phases such as high entropy oxides (HEO). Herein, a photonic flash synthesis of HEO nanoparticles at timescales of milliseconds is demonstrated. By leveraging the abrupt heating and cooling cycles induced by a high-power-density xenon pulsed light, mixed transition metal salt precursors undergo rapid chemical transformations. Hence, nanoparticles form within milliseconds with a strong affinity to bind to the carbon substrate. Oxygen evolution reaction (OER) activity measurements of the synthesized nanoparticles demonstrate two orders of magnitude prolonged stability at high current densities, without noticeable decay in performance, compared to commercial IrO2 catalyst. This superior catalytic activity originates from the synergistic effect of different alloying elements mixed at a high entropic state. It is found that Cr addition influences surface activity the most by promoting higher oxidation states, favoring optimal interaction with OER intermediates. The proposed high-throughput method opens new pathways toward developing next-generation functional materials for various electronics, sensing, and environmental applications, in addition to renewable energy conversion.

Automated Peptide Synthesizers and Glycoprotein Synthesis.

The development and application of commercially available automated peptide synthesizers has played an essential role in almost all areas of peptide and protein research. Recent advances in peptide synthesis method and solid-phase chemistry provide new opportunities for optimizing synthetic efficiency of peptide synthesizers. The efforts in this direction have led to the successful preparation of peptides up to more than 150 amino acid residues in length. Such success is particularly useful for addressing the challenges associated with the chemical synthesis of glycoproteins. The purpose of this review is to provide a brief overview of the evolution of peptide synthesizer and glycoprotein synthesis. The discussions in this article include the principles underlying the representative synthesizers, the strengths and weaknesses of different synthesizers in light of their principles, and how to further improve the applicability of peptide synthesizers in glycoprotein synthesis.

Green Enabling Technologies for Competitive Synthesis of Pharmaceutical Lead Compounds.

Combinations of different technologies are at the heart of the development and implementation of new, innovative processes and approaches for Industry 4.0 in the field of medicinal chemistry and drug discovery. Process intensification and advances in high-throughput synthetic techniques can dramatically improve reaction rates in processes for which slow kinetics represents a bottleneck. Easier access to target-based chemical library collections offers wider access to new leads for drug development. Green enabling technologies are a reliable ally for the design of environmentally friendly synthetic processes and more highly competitive pharmaceutical production. Mechanochemistry, microwaves, ultrasound and flow chemistry are mature techniques that can boast drug synthesis when properly integrated into the production chain. In this review, we selected examples from the literature of the last five years related to medicinal chemistry.

High-Throughput Synthesis and Screening of Rapidly Degrading Polyanhydride Nanoparticles.

Combinatorial techniques can accelerate the discovery and development of polymeric nanodelivery devices by pairing high-throughput synthesis with rapid materials characterization. Biodegradable polyanhydrides demonstrate tunable release, high cellular internalization, and dose sparing properties when used as nanodelivery devices. This nanoparticle platform shows promising potential for small molecule drug delivery, but the pace of understanding and rational design of these nanomedicines is limited by the low throughput of conventional characterization. This study reports the use of a high-throughput method to synthesize libraries of a newly synthesized, rapidly eroding polyanhydride copolymer based on 1,8-bis(p-carboxyphenoxy)-3,6-dioxaoctane (CPTEG) and sebacic acid (SA) monomers. The high-throughput method enabled efficient screening of copolymer microstructure, revealing weak block-type and alternating architectures. The high-throughput method was adapted to synthesize nanoparticle libraries encapsulating hydrophobic model drugs. Drug release from these nanoparticles was rapid, with a majority of the payload released within 3 days. Drug release was dramatically slowed at acidic pH, which could be useful for oral drug delivery. Rhodamine B (RhoB) release kinetics generally followed patterns of polymer erosion kinetics, while Coomassie brilliant blue (CBB) released the fastest from the slowest degrading polymer chemistry and vice versa. These differences in trends between copolymer chemistry and release kinetics were hypothesized to arise from differences in mixing thermodynamics. A high-throughput method was developed to synthesize polymer-drug film libraries and characterize mixing thermodynamics by melting point depression. Rhodamine B had a negative χ for all copolymers with <30 mol % CPTEG tested, indicating a tendency toward miscibility. By contrast, CBB χ increased, eventually becoming positive near 15:85 CPTEG:SA, with increasing CPTEG content. This indicates an increasing tendency toward phase separation in CPTEG-rich copolymers. These in vitro results screening polymer-drug interactions showed good agreement with in silico predictions from Hansen solubility parameter estimation and were able to explain the observed differences in model drug release trends.

High Throughput Methods in the Synthesis, Characterization, and Optimization of Porous Materials.

Porous materials are widely employed in a large range of applications, in particular, for storage, separation, and catalysis of fine chemicals. Synthesis, characterization, and pre- and post-synthetic computer simulations are mostly carried out in a piecemeal and ad hoc manner. Whilst high throughput approaches have been used for more than 30 years in the porous material fields, routine integration of experimental and computational processes is only now becoming more established. Herein, important developments are highlighted and emerging challenges for the community identified, including the need to work toward more integrated workflows.