High-throughput Experimentation Techniques Research Articles

Explainable machine learning to enable high-throughput electrical conductivity optimization and discovery of doped conjugated polymers

The combination of high-throughput experimentation techniques and machine learning (ML) has recently ushered in a new era of accelerated material discovery, enabling the identification of materials with cutting-edge properties. However, the measurement of certain physical quantities remains challenging to automate. Specifically, meticulous process control, experimentation and laborious measurements are required to achieve optimal electrical conductivity in doped polymer materials. We propose a ML approach, which relies on readily measured absorbance spectra, to accelerate the workflow associated with measuring electrical conductivity. The classification model accurately classifies samples with a conductivity >∼25 to 100 S/cm, achieving a maximum of 100 % accuracy rate. For the subset of highly conductive samples, we employed a regression model to predict their conductivities, yielding an impressive test R2 value of 0.984. We tested the models with samples of the two highest conductivities (498 and 506 S/cm) and showed that they were able to correctly classify and predict the two extrapolative conductivities at satisfactory levels of errors. The proposed ML-assisted workflow results in an improvement in the efficiency of the conductivity measurements by 89 % of the maximum achievable using our experimental techniques. Furthermore, our approach addressed the common challenge of the lack of explainability in ML models by exploiting bespoke mathematical properties of the descriptors and ML model, allowing us to gain corroborated insights into the spectral influences on conductivity. Through this study, we offer an accelerated pathway for optimizing the properties of doped polymer materials while showcasing the valuable insights that can be derived from purposeful utilization of ML in experimental science.

High-Throughput Optimization of Photochemical Reactions using Segmented-Flow Nanoelectrospray-Ionization Mass Spectrometry.

Within the realm of drug discovery, high-throughput experimentation techniques enable the rapid optimization of reactions and expedited generation of drug compound libraries for biological and pharmacokinetic evaluation. Herein we report the development of a segmented flow mass spectrometry-based platform to enable the rapid exploration of photoredox reactions for early-stage drug discovery. Specifically, microwell plate-based photochemical reaction screens were reformatted to segmented flow format to enable delivery to nanoelectrospray ionization-mass spectrometry analysis. This approach was demonstrated for the late-stage modification of complex drug scaffolds, as well as the subsequent structure-activity relationship evaluation of synthesized analogs. This technology is anticipated to expand the robust capabilities of photoredox catalysis in drug discovery by enabling high-throughput library diversification.

Primary vs. secondary alkylpyridinium salts: a comparison under electrochemical and chemical reduction conditions.

This report details a systematic comparison of the scope of aryl bromides in nickel-catalyzed, reductive cross-electrophile couplings of primary vs. secondary alkylpyridinium salts using both electrochemical and chemical reductants. Facilitated by the use of high-throughput experimentation (HTE) techniques, 37 aryl bromides, including 13 complex, drug-like examples, were investigated. By using primary and secondary substrates differing only by one methylene, we observed that the trends in ArBr scope are similar between the primary and secondary alkylpyridinium salts, although distinctions were observed in isolated cases. In addition, the electrochemical conditions compared favorably to those using chemical reductants, especially among the more complex, drug-like aryl halides.

Buchwald–Hartwig Amination, High-Throughput Experimentation, and Process Chemistry: An Introduction via Undergraduate Laboratory Experimentation

This three-part laboratory experiment investigates key aspects of the Buchwald–Hartwig amination cross-coupling reaction through guided-inquiry learning strategies. The first part of this experiment utilizes high-throughput experimentation techniques to reinforce, explore, and extend fundamental concepts that are represented in the classroom, including the use of air-free Schlenk techniques and heteronuclear NMR analysis. The second component challenges students to evaluate their results to design, set up, and perform a preparative-scale Buchwald–Hartwig amination. Finally, students purify and isolate their products using column chromatography allowing them to fully characterize their target molecules through a variety of analytical techniques. This experiment represents one of the final experiments performed in the fourth-year undergraduate chemistry curriculum and serves as a capstone learning experience for students.

Reaction screening in multiwell plates: high-throughput optimization of a Buchwald-Hartwig amination.

Chemical space is vast, and chemical reactions involve the complex interplay of multiple variables. As a consequence, reactions can fail for subtle reasons, necessitating screening of conditions. High-throughput experimentation (HTE) techniques enable a more comprehensive array of data to be obtained in a relatively short amount of time. Although HTE can be most efficiently achieved with automated robotic dispensing equipment, the benefits of running reaction microarrays can be accessed in any regularly equipped laboratory using inexpensive consumables. Herein, we present a cost-efficient approach to HTE, examining a Buchwald-Hartwig amination as our model reaction. Experiments are carried out in a machined aluminum 96-well plate, taking advantage of solid transfer scoops and pipettes to facilitate rapid reagent transfer. Reaction vials are simultaneously heated and mixed, using a magnetic stirrer, and worked up in parallel, using a plastic filter plate. Analysis by gas chromatography provides the chemist with 96 data points with minimal commitment of time and resources. The best-performing experiment can be selected for scale-up and isolation, or the data can be used for designing future optimization experiments.

High-Throughput Experimentation and Continuous Flow Evaluation of Nucleophilic Aromatic Substitution Reactions.

Nucleophilic aromatic substitution (SNAr) reactions were optimized using high-throughput experimentation techniques for execution under flow conditions. A total of 3072 unique reactions were evaluated with an analysis time of ∼3.5 s per reaction using a system that combines a liquid handling robot for reaction mixture preparation with desorption electrospray ionization (DESI) mass spectrometry (MS) for analysis. The reactions were performed in bulk microtiter arrays with and without incubation. In-house developed software was used to process the data and generate heat maps of the results. This information was then used to select the most promising conditions for continuous synthesis under microfluidic reactor conditions. Our results show that this HTE approach provides robust guidance for narrowing the range of conditions needed for optimization of SNAr reactions.

Subminute micro-isolation of pharmaceuticals with ultra-high pressure liquid chromatography

The drive for faster separations while maintaining quality and yield remains an important consideration for enhanced productivity as well as cost reduction for drug discovery laboratories in the pharmaceutical industry. High-throughput experimentation (HTE) and high-throughput screening (HTS) techniques can benefit from rapid and efficient isolation of product at high purity and recovery from microgram-scale crude reaction mixtures. In this study we describe the isolation of small molecule and biomolecule crude mixtures at the microgram-scale (100–2500 μg) in single or library format with methods as fast as 1.0 min and system pressures averaging 10,000 psi with an ultra-high pressure liquid chromatography (UHPLC) setup. UHPLC technology provides several advantages for rapid (<1.0 min) separations with small-particle (1.8–3.5 μm) size 4.6 × 50 mm C18 columns such as minimal extra column and delay volume, fast detector response time, and higher linear velocities for improved speed and resolution. We typically see a 5–10 fold improvement in purification time and overall sample processing time with low fraction volumes and same-day drying when compared with traditional semi-preparative techniques. There is a significant 50-fold reduction in solvent usage per run, resulting in a much lower cost of solvent and waste handling. Fluidic pathways have been optimized for collection into tared high-density 96 or 384 well 2D barcoded storage tubes in a microtiter plate (MTP) layout. Coupling the system to robotics has enabled us to implement a fully integrated automation platform with additional capabilities for small-scale purification at high speed and reduced cost of materials. The resulting arrays of small-quantity, high-purity compounds enable synthetic route scouting for HTE and HTS for biological target validation.

Capstone Laboratory Experiment Investigating Key Features of Palladium-Catalyzed Suzuki–Miyaura Cross-Coupling Reactions

This two-part laboratory experiment is concerned with investigating key aspects of the Suzuki–Miyaura cross-coupling reaction. The first part of this experiment utilizes high-throughput experimentation techniques to reinforce, explore, and extend fundamental concepts that are presented in the classroom. In contrast, the second part employs guided-inquiry learning strategies to challenge students to design, set up, and perform a preparative-scale Suzuki–Miyaura reaction and suggest workup and isolation protocols. By design, this experiment, which represents one of the final experiments performed in the third-year undergraduate chemistry laboratory program, serves as a capstone learning experience for students.

Reaction: Conventional Polymers—New Tricks Emerging

Vinícius Galhard Grassi is the leader of polymer research at Braskem SA, a leading global chemical and petrochemical company and currently the largest producer of thermoplastic resins in the Americas. He holds a master’s degree in materials science and a doctorate in chemistry from Universidade Federal do Rio Grande do Sul (Brazil) and completed a short assignment at the Max Planck Institute for Polymer Research. Having held different positions at petrochemical companies, he has over 18 years of experience in the research and development of polyolefins and styrene-based polymers, from conception and lab tests to industrial scale-up, processing, advanced characterization, introduction, and market consolidation. Vinícius Galhard Grassi is the leader of polymer research at Braskem SA, a leading global chemical and petrochemical company and currently the largest producer of thermoplastic resins in the Americas. He holds a master’s degree in materials science and a doctorate in chemistry from Universidade Federal do Rio Grande do Sul (Brazil) and completed a short assignment at the Max Planck Institute for Polymer Research. Having held different positions at petrochemical companies, he has over 18 years of experience in the research and development of polyolefins and styrene-based polymers, from conception and lab tests to industrial scale-up, processing, advanced characterization, introduction, and market consolidation. Polymer scientists have been successfully keeping conventional polymers such as polyolefins and styrene-based polymers at the frontier of science by constantly stretching the performance boundaries. For this purpose, scientists have used a combination of tools, including new polymerization methods, new catalysts and co-monomers (from fossil and renewable sources), peroxides and reactor designs, new architectures, polymer modification during processing or by reactive extrusion, and new advanced characterization techniques. In addition to efforts focused on stretching the performance of these conventional polymers, the development of tools such as high-throughput experimentation, multiscale simulation, and machine-learning techniques aims to accelerate the research and development (R&D) of conventional polymers. Although scientists have been playing with the same monomers over the last few decades, the approach is always evolving. The technology has successfully transitioned from lab to market, establishing a clear reference for technology scale-up from grams to thousands of tons while also delivering new grades to fulfill specific customer needs. It is because of this constantly evolving combination of methods and approaches, especially for polyolefins, that these conventional polymers are truly old dogs with new tricks. All these technical efforts have been driven by a consistent commercial demand, wherein intellectual property plays a key role in supporting business strategies. It’s an almost perfect combination of technology push and market pull. Although in-reactor approaches are the preferred route for polymer R&D, post-reactor modification is an exciting alternative for adding special attributes to conventional polymers. This route can overcome some in-reactor restrictions such as catalyst poisoning by chemicals or a lack of economic feasibility due to low production volume. For polyolefins in particular, some nice examples of industrial success are the grafting of polar molecules onto polyethylene and polypropylene with the use of peroxide to increase adhesion or compatibility with polar polymers and high-melt-strength polypropylene for foam applications. Post-reactor modification, like reactive extrusion, is still underutilized as a route for obtaining conventional polymers with improved properties and specific characteristics. This approach has the potential to decrease the translation time from the lab to the market, thus decreasing the R&D expenses. The primary challenge in reactive extrusion technology is controlling the reaction within the very short processing time and complex fluid environment. An additional complication results from the difficulty in accurately characterizing the degree and location of modification when we consider the different mobility of short and long polymer chains. After decades of research on conventional polymers, many combinations of methods and approaches still require exploration, and new variables are constantly evolving. Areas such as artificial intelligence, machine learning, and 3D printing present exciting new technical opportunities; indeed, new tricks are emerging. Catalyst: Advancing Polymer Science by Revisiting Known PlasticsOlsen et al.ChemMay 10, 2018In BriefBradley Olsen earned his PhD in chemical engineering at the University of California, Berkeley, and is an associate professor in the Department of Chemical Engineering at MIT. Since December 2009, he has led a research group in the area of polymer and biopolymer science. Bryan Boudouris earned his PhD in chemical engineering at the University of Minnesota and is the Robert and Sally Weist Associate Professor in the Davidson School of Chemical Engineering and Department of Chemistry at Purdue. His team focuses on the polymer chemistry, polymer physics, and end-use application of macromolecules for energy and clean-water applications. Full-Text PDF Open Archive

The Evolution of Chemical High-Throughput Experimentation To Address Challenging Problems in Pharmaceutical Synthesis.

The structural complexity of pharmaceuticals presents a significant challenge to modern catalysis. Many published methods that work well on simple substrates often fail when attempts are made to apply them to complex drug intermediates. The use of high-throughput experimentation (HTE) techniques offers a means to overcome this fundamental challenge by facilitating the rational exploration of large arrays of catalysts and reaction conditions in a time- and material-efficient manner. Initial forays into the use of HTE in our laboratories for solving chemistry problems centered around screening of chiral precious-metal catalysts for homogeneous asymmetric hydrogenation. The success of these early efforts in developing efficient catalytic steps for late-stage development programs motivated the desire to increase the scope of this approach to encompass other high-value catalytic chemistries. Doing so, however, required significant advances in reactor and workflow design and automation to enable the effective assembly and agitation of arrays of heterogeneous reaction mixtures and retention of volatile solvents under a wide range of temperatures. Associated innovations in high-throughput analytical chemistry techniques greatly increased the efficiency and reliability of these methods. These evolved HTE techniques have been utilized extensively to develop highly innovative catalysis solutions to the most challenging problems in large-scale pharmaceutical synthesis. Starting with Pd- and Cu-catalyzed cross-coupling chemistry, subsequent efforts expanded to other valuable modern synthetic transformations such as chiral phase-transfer catalysis, photoredox catalysis, and C-H functionalization. As our experience and confidence in HTE techniques matured, we envisioned their application beyond problems in process chemistry to address the needs of medicinal chemists. Here the problem of reaction generality is felt most acutely, and HTE approaches should prove broadly enabling. However, the quantities of both time and starting materials available for chemistry troubleshooting in this space generally are severely limited. Adapting to these needs led us to invest in smaller predefined arrays of transformation-specific screening "kits" and push the boundaries of miniaturization in chemistry screening, culminating in the development of "nanoscale" reaction screening carried out in 1536-well plates. Grappling with the problem of generality also inspired the exploration of cheminformatics-driven HTE approaches such as the Chemistry Informer Libraries. These next-generation HTE methods promise to empower chemists to run orders of magnitude more experiments and enable "big data" informatics approaches to reaction design and troubleshooting. With these advances, HTE is poised to revolutionize how chemists across both industry and academia discover new synthetic methods, develop them into tools of broad utility, and apply them to problems of practical significance.

Cis‐4‐Alkoxydialkyl‐ andcis‐4‐Alkoxydiarylprolinol Organocatalysts: High Throughput Experimentation (HTE)‐Based and Design of Experiments (DoE)‐Guided Development of a Highly Enantioselectiveaza‐Michael Addition of Cyclic Imides to α,β‐Unsaturated Aldehydes

AbstractA diverse family (37 compounds) of cis‐4‐alkoxydiorganylprolinol derivatives has been prepared and evaluated in organocatalysis for the first time. The combined use of high throughput experimentation (HTE) techniques with efficient analytical methods has led to the identification of two superior catalysts for the enantioselective addition of succinimide to α,β‐unsaturated aldehydes. Further optimization of the reaction conditions with design of experiments (DoE) techniques established the catalyst of choice for the considered aza‐Michael reaction, the corresponding adducts (12 examples) being obtained in good yields and excellent enantioselectivities (succinimide and maleimide donors). The synthetic versatility of these Michael adducts is illustrated by a two‐step sequence leading to enantiopure 1,3‐amino alcohols.magnified image

High Throughput Experimentation (HTE) Directed to the Discovery, Characterization and Evaluation of Materials

We attempt to take a strategic view of the development and application of HTE techniques across a broad spectrum of chemical, material and earth sciences, looking for unifying assumptions and approaches. We consider why much of the development of HTE technologies and techniques, as well as the majority of their application, have taken place in industry or in institutes or centers working closely with industry. And we look for commonalities and synergies across diverse HTE application areas, taking examples from the energy, catalysis, formulations and biotechnology fields.

ChemInform Abstract: Palladium‐Catalyzed α‐Arylation of Benzylic Phosphine Oxides.

A novel approach to prepare diarylmethyl phosphine oxides from benzyl phosphine oxides via deprotonative cross-coupling processes (DCCP) is reported. The optimization of the reaction was guided by High-Throughput Experimentation (HTE) techniques. The Pd(OAc)2/Xantphos-based catalyst enabled the reaction between benzyl diphenyl or dicyclohexyl phosphine oxide derivatives and aryl bromides in good to excellent yields (51–91%).

Palladium-Catalyzed α-Arylation of Benzylic Phosphine Oxides

A novel approach to prepare diarylmethyl phosphine oxides from benzyl phosphine oxides via deprotonative cross-coupling processes (DCCP) is reported. The optimization of the reaction was guided by High-Throughput Experimentation (HTE) techniques. The Pd(OAc)2/Xantphos-based catalyst enabled the reaction between benzyl diphenyl or dicyclohexyl phosphine oxide derivatives and aryl bromides in good to excellent yields (51-91%).

Diaryl Sulfoxides from Aryl Benzyl Sulfoxides: A Single Palladium‐Catalyzed Triple Relay Process

A novel approach to produce diaryl sulfoxides from aryl benzyl sulfoxides is reported. Optimization of the reaction conditions was performed using high-throughput experimentation techniques. The [Pd(dba)2 ]/NiXantPhos catalyst system successfully promotes a triple relay process involving sulfoxide α-arylation, CS bond cleavage, and CS bond formation. The byproduct benzophenone is formed by an additional palladium-catalyzed process. It is noteworthy that palladium-catalyzed benzylative CS bond cleavage of sulfoxides is unprecedented. A wide range of aryl benzyl sulfoxides, as well as alkyl benzyl sulfoxides with various (hetero)aryl bromides were employed in the triple relay process in good to excellent yields (85-99 %). Moreover, aryl methyl sulfoxides, dibenzyl sulfoxides, and dimethylsulfoxide could be utilized to generate diaryl sulfoxides involving multiple catalytic cycles by a single catalyst.

Transition-Metal-Free Catalysts for the Sustainable Epoxidation of Alkenes: From Discovery to Optimisation by Means of High Throughput Experimentation

Transition-metal-free oxides were studied as heterogeneous catalysts for the sustainable epoxidation of alkenes with aqueous H₂O₂ by means of high throughput experimentation (HTE) techniques. A full-factorial HTE approach was applied in the various stages of the development of the catalysts: the synthesis of the materials, their screening as heterogeneous catalysts in liquid-phase epoxidation and the optimisation of the reaction conditions. Initially, the chemical composition of transition-metal-free oxides was screened, leading to the discovery of gallium oxide as a novel, active and selective epoxidation catalyst. On the basis of these results, the research line was continued with the study of structured porous aluminosilicates, gallosilicates and silica-gallia composites. In general, the gallium-based materials showed the best catalytic performances. This family of materials represents a promising class of heterogeneous catalysts for the sustainable epoxidation of alkenes and offers a valid alternative to the transition-metal heterogeneous catalysts commonly used in epoxidation. High throughput experimentation played an important role in promoting the development of these catalytic systems.

Implementation of High Throughput Experimentation Techniques for Kinetic Reaction Testing

Successful implementation of High throughput Experimentation (EE) tools has resulted in their increased acceptance as essential tools in chemical, petrochemical and polymer R&D laboratories. This article provides a number of concrete examples of EE systems, which have been designed and successfully implemented in studies, which focus on deriving reaction kinetic data. The implementation of high throughput EE tools for performing kinetic studies of both catalytic and non-catalytic systems results in a significantly faster acquisition of high-quality kinetic modeling data, required to quantitatively predict the behavior of complex, multistep reactions.

Reversed-Polarity Synthesis of Diaryl Ketones via Palladium-Catalyzed Cross-Coupling of Acylsilanes

Acylsilanes serve as acyl anion equivalents in a palladium-catalyzed cross-coupling reaction with aryl bromides to give unsymmetrical diaryl ketones. Water plays a unique and crucial activating role in these reactions. High-throughput experimentation techniques provided successful reaction conditions initially involving phosphites as ligands. Ultimately, 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane was identified as giving a longer-lived catalyst with higher turnover numbers. Its use, in conjunction with a palladacycle precatalyst, led to optimal reaction rates and yields. Scope and limitations of this novel method are presented along with initial mechanistic insight.

Enantioselective Synthesis of (1R,2S)-1-Amino-2-vinylcyclopropanecarboxylic Acid Ethyl Ester (Vinyl-ACCA-OEt) by Asymmetric Phase-Transfer Catalyzed Cyclopropanation of (E)-N-Phenylmethyleneglycine Ethyl Ester

A concise asymmetric synthesis of (1R,2S)-1-amino-2-vinylcyclopropanecarboxylic acid ethyl ester, a key intermediate in the preparation of many hepatitis C virus inhibitors, is described. Stereoselective cyclopropanation of (E)-N-phenylmethyleneglycine ethyl ester was effected by treatment with trans-1,4-dibromo-2-butene in the presence of a catalytic amount of a chiral phase-transfer catalyst. Microscale high-throughput experimentation techniques were successfully used to identify a cinchonidine-derived catalyst that provided (1R,2S)-1-(E)-N-phenylmethyleneamino-2-vinylcyclopropanecarboxylic acid ethyl ester in up to 84% ee. This was translated to a lab scale process to attain 78% yield and 77.4% ee. Chiral purity upgrade and isolation of the ester was accomplished via preparatory supercritical fluid chromatography followed by crystallization of the ester as its tosylate salt. The improved synthesis described herein represents a potentially more economical preparation of this valuable intermediate.

Optimization of manganese content by high-throughput experimentation of Pt/WO –ZrO2–Mn catalysts

Abstract A library of Pt/WO x –ZrO 2 –Mn catalysts was developed in order to optimize the manganese content in this catalytic system for the isomerization of n -hexane. The catalysts were synthesized, characterized and screened using high-throughput experimentation (HTE) techniques. The catalysts were prepared by surfactant-assisted coprecipitation whereas the characterization was done by X-ray diffraction (XRD), Raman and UV–vis spectroscopy. For this second screening, several catalysts with different manganese contents were prepared; it was found that the incorporation of Mn modifies the anchorage of tungsten on the zirconia surface, thus improving its catalytic properties, in terms of the n -hexane conversion and selectivity, depending on the catalyst composition. These results suggest that this methodology allows the optimization of manganese and tungsten contents on these solid catalysts.