材料基因工程技术在分子筛领域中的应用

材料基因工程是近年来材料领域兴起的前沿技术, 其基本理念是融合材料高通量计算、 高通量实验和数据技术加速新材料的设计和研发. 分子筛作为一种重要的化工材料, 因其良好的热稳定性、 较高的比表面积、 独特的孔道结构及可调变的元素组成和酸性, 在气体吸附、 分离、 异相催化和离子交换等工业领域应用广泛. 近年来, 融合高通量计算、 高通量实验和数据库技术的材料基因工程技术正逐步应用于分子筛研发等领域: 高通量计算能够从理论上预测并筛选出具有优异性能的分子筛合成目标、 高通量实验显著提升了分子筛材料合成与表征的效率、 数据库技术则为未来挖掘分子筛材料的合成规律与构效关系奠定了数据基础. 本文主要从这3个方面阐述材料基因工程技术在分子筛材料研发领域的应用及进展, 总结以功能为导向、 定向设计和构筑分子筛材料所面临的机遇与挑战, 并对材料基因工程技术在分子筛领域的前景进行了展望.     

Droplet microfluidics: recent developments and future applications

We report recent advances in the field of droplet-based microfluidics. Specifically, we highlight the unique features of such platforms for high-throughput experimentation; describe functional components that afford complex analytical processing and report on applications in synthesis, high-throughput screening, cell biology and synthetic and systems biology. Issues including the integration of high-information content detection methods, long term droplet stability and opportunities for large scale and intelligent biological experimentation are also discussed.     

The combinatorial approach to asymmetric hydrogenation: phosphoramidite libraries, ruthenacycles, and artificial enzymes

For a more general implementation of asymmetric catalysis in the production of fine chemicals, the screening for new catalysts and ligands must be dramatically accelerated. This is possible with a high-throughput experimentation (HTE) approach. However, implementation of this technology requires the rapid preparation of libraries of ligands/catalysts and consequently dictates the use of simple ligands that can be readily synthesised in a robot. In this concept article, we describe how the development of new ligands based on monodentate phosphoramidites enabled the development of an integral HTE protocol for asymmetric hydrogenation. This "instant ligand library" protocol makes it possible to synthesise 96 ligands in one day and screen them the next day. Further diversity is possible by using mixtures of monodentate ligands. This concept has already led to an industrial application. Other concepts, still under development, are based on chiral ruthenacycles as new transfer hydrogenation catalysts and the use of enzymes as ligands for transition-metal complexes.     

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.     

Gas chromatographic high-throughput screening techniques in catalysis

Discovering highly efficient catalysts is of great scientific and economical interest. Advances in high-throughput assays in combination with sophisticated analytical techniques have increased the rapidity with which catalysts can be identified and optimized. Understanding how kinetics in the mechanism of catalysis is controlled by structural parameters is essential for a directed design of catalysts. To identify such rate-controlling elementary steps and to develop and refine models, comprehensive experimental kinetic data of a broad variety of substrates are necessary. In the present article concepts of high-throughput screening techniques in catalysis using gas chromatography are reviewed in a survey covering the period from 1998 to 2007. To cover also the origins of concepts and groundbreaking experiments in this research area milestones going back to 1950 are also reviewed. The first part of the review will focus on off-line gas chromatographic analysis, the second part on on-line gas chromatographic analysis covering sequential, parallelized and high-throughput multiplexing gas chromatography. The third part presents recent advances in the integration of chemical transformation and analysis in gas chromatography. The present review article describes the state-of-the-art, scope and limitations, and applications of these different high-throughput screening approaches.     

Identifying promising metal–organic frameworks for heterogeneous catalysis via high-throughput periodic density functional theory

Metal–organic frameworks (MOFs) are a class of nanoporous materials with highly tunable structures in terms of both chemical composition and topology. Due to their tunable nature, high-throughput computational screening is a particularly appealing method to reduce the time-to-discovery of MOFs with desirable physical and chemical properties. In this work, a fully automated, high-throughput periodic density functional theory (DFT) workflow for screening promising MOF candidates was developed and benchmarked, with a specific focus on applications in catalysis. As a proof-of-concept, we use the high-throughput workflow to screen MOFs containing open metal sites (OMSs) from the Computation-Ready, Experimental MOF database for the oxidative C—H bond activation of methane. The results from the screening process suggest that, despite the strong C—H bond strength of methane, the main challenge from a screening standpoint is the identification of MOFs with OMSs that can be readily oxidized at moderate reaction conditions. © 2019 Wiley Periodicals, Inc.     

Streamlined Asymmetric Reaction Development: A Case Study with Isatins

Asymmetric reaction development within a day or two has been a dream of synthetic chemists for several decades. We now show that such a task is feasible with a highly efficient streamlined screening strategy using the asymmetric allylation of isatins with a chiral boron complex as a case study. Our high-throughput screening (HTS) method is based on fast optical UV/CD analysis of minute amounts of crude reaction mixtures (≈3 mg scale) and it obviates product isolation and the general need for reference compounds which greatly reduces preliminary work and analysis time. The setup, reaction screening, analysis and data processing for 54 asymmetric allylations of nine different isatins in six different solvents was handled by a single operator in less than 20 work hours. One could easily extend this HTS strategy to hundreds of reactions in roughly the same time frame and further reduce the labor with commercially available automated high-throughput experimentation equipment. The effectiveness of this asymmetric reaction development strategy is confirmed with the upscale synthesis of two representative 3-allyl-3-hydroxyisatins in 98–99 % yield and with 91–94 % ee under optimized conditions.     

Determination of Enantiomeric Excess of Glutamic Acids by Lab-made Capillary Array Electrophoresis

The techniques of combinatorial chemistry have recently been applied to the discovery of new asymmetric catalyst for a variety of organic transformations1-3. Using combina- torial methods, it is straightforward to generate thousands of potential asymmetri…     

New fluorogenic probes for oxygen and carbene transfer: a sensitive assay for single bead-supported catalysts.

A high-throughput screening assay for atom transfer catalysis has been developed. This assay is based on two probes, developed herein, which generate highly fluorescent products upon carbene or oxygen atom transfer. The emission wavelength of probes 1 and 5 shift significantly (up to 90 nm) upon epoxidation, allowing detection of product at 3% conversion. Probe 7 is not fluorescent, while fluorescence emission by carbene insertion/rearrangement product 8 allows detection at less than 1% conversion. Such sensitivity allows for examination of single-bead reactions in a high throughput array format (1536 wells per plate), and provides a broad detection window ranging from single to high turnover numbers. Thousands of metal complexes are evaluated in a single screening experiment. Preliminary screening of a diverse ligand library with probe 7 in the presence of Rh(II) uncovered new catalysts capable of cyclopropanation and C-H insertion.     

A Multifunctional Microfluidic Platform for High-Throughput Experimentation of Electroorganic Chemistry

Electroorganic synthesis is a promising tool to design sustainable transformations and discover new reactivities. However, the added setup complexity caused by electrodes in the system impedes efficient screening of reaction conditions. Herein, we present a microfluidic platform that enables automated high-throughput experimentation (HTE) for electroorganic synthesis at a 15-microliter scale. Two HTE modules are demonstrated: 1) the rapid electrochemical reaction condition screening for a radical–radical cross-coupling reaction on micro-fabricated interdigitated electrodes, and 2) measurements of kinetics for mediated anodic oxidations using the microliter-scale cyclic voltammetry. The presented modular approach could be deployed for a range of other electroorganic chemistry applications beyond the demonstrated functionalities.     

Support vector machines for predictive modeling in heterogeneous catalysis: a comprehensive introduction and overfitting investigation based on two real applications

This works provides an introduction to support vector machines (SVMs) for predictive modeling in heterogeneous catalysis, describing step by step the methodology with a highlighting of the points which make such technique an attractive approach. We first investigate linear SVMs, working in detail through a simple example based on experimental data derived from a study aiming at optimizing olefin epoxidation catalysts applying high-throughput experimentation. This case study has been chosen to underline SVM features in a visual manner because of the few catalytic variables investigated. It is shown how SVMs transform original data into another representation space of higher dimensionality. The concepts of Vapnik-Chervonenkis dimension and structural risk minimization are introduced. The SVM methodology is evaluated with a second catalytic application, that is, light paraffin isomerization. Finally, we discuss why SVMs is a strategic method, as compared to other machine learning techniques, such as neural networks or induction trees, and why emphasis is put on the problem of overfitting.     

Dual Atom Catalysts for Energy and Environmental Applications

The pursuit of high metal utilization in heterogeneous catalysis has triggered the burgeoning interest of various atomically dispersed catalysts. Our aim in this review is to assess key recent findings in the synthesis, characterization, structure-property relationship and computational studies of dual-atom catalysts (DACs), which cover the full spectrum of applications in thermocatalysis, electrocatalysis and photocatalysis. In particular, combination of qualitative and quantitative characterization with cooperation with DFT insights, synergies and superiorities of DACs compare to counterparts, high-throughput catalyst exploration and screening with machine-learning algorithms are highlighted. Undoubtably, it would be wise to expect more fascinating developments in the field of DACs as tunable catalysts.     

超分子双膦配体的构筑及应用研究进展

超分子双膦配体是一类新兴起的基于非共价键作用构筑的双膦配体,近年来引起人们的重视.与传统的共价键连接的双膦配体相比,利用非共价相互作用的可逆性和选择性,超分子双膦配体具有合成简便,组合灵活,易于合成超分子配体库,并利用组合化学的方法对催化体系进行优化和筛选等优点.详细综述了近几年发展的基于氢键、配位键、主客体作用和静电作用等弱相互作用的超分子双膦配体,重点讨论了它们的构建方法以及在不对称催化反应中的应用,并对其发展前景进行了展望.     

A Green and Wide-Scope Approach for Chiroptical Sensing of Organic Molecules through Biomimetic Recognition in Water

Optical chirality sensing has attracted a lot of interest due to its potential in high-throughput screening in chirality analysis. A molecular sensor is required to convert the chirality of analytes into optical signals. Although many molecular sensors have been reported, sensors with wide substrate scope remain to be developed. Herein, we report that the amide naphthotube-based chirality sensors have an unprecedented wide scope for chiroptical sensing of organic molecules. The substrates include, but are not limited to common organic products in asymmetric catalysis, chiral molecules with inert groups or remote functional groups from their chiral centers, natural products and their derivatives, and chiral drugs. The effective chirality sensing is based on biomimetic recognition in water and on effective chirality transfer through guest-induced formation of a chiral conformation of the sensors. Furthermore, the sensors can be used in real-time monitoring on reaction kinetics in water and in determining absolute configurations and ee values of the products in asymmetric catalysis.     

Synthesis, characterization and development of a high-throughput methodology for the discovery of botulinum neurotoxin a inhibitors

Botulinum neurotoxins (BoNTs), etiological agents of the deadly food poisoning disease botulism, are the most toxic proteins currently known. Although only a few hundred cases of botulism are reported in the United States annually, there is growing interest in BoNTs attributable to their potential use as biological warfare agents. Neurotoxicity results from cleavage of the soluble NSF-attachment protein receptor complex proteins of the presynaptic vesicles by the BoNT light chain subunit, a Zn endopeptidase. Few effective inhibitors of BoNT/A LC (light chain) activity are known, and the discovery process is hampered by the lack of an efficient high-throughput assay for screening compound libraries. To alleviate this bottleneck, we have synthesized the peptide SNAPtide and have developed a robust assay for the high-throughput evaluation of BoNT/A LC inhibitors. Key aspects for the development of this optimized assay include the addition of a series of detergents, cosolvents, and salts, including 0.01% w/v Tween 20 to increase BoNT/A LC catalysis, stability, and ease of small molecule screening. To evaluate the effectiveness of the assay, a series of hydroxamate-based small molecules were synthesized and examined with BoNT/A LC. The methodology described is superior to other assays reported to date for the high-throughput identification of BoNT/A inhibitors.     

High-Throughput Diversification of Complex Bioactive Molecules by Accelerated Synthesis in Microdroplets

Late-stage diversification of drug molecules is an important strategy in drug discovery that can be facilitated by reaction screening using high-throughput experimentation. Here we present a rapid method for functionalizing bioactive molecules based on accelerated reactions in microdroplets. Reaction mixtures are nebulized at throughputs better than 1 reaction/second and the accelerated reactions occurring in the microdroplets are followed by desorption electrospray ionization mass spectrometry (DESI-MS). Because the accelerated reactions occur on the millisecond timescale, they allow an overall screening throughput of 1 Hz working at the low nanogram scale. Using this approach, an opioid agonist (PZM21) and an antagonist (naloxone) were diversified using three reactions important in medicinal chemistry: sulfur fluoride exchange (SuFEx) click reactions, imine formation reactions, and ene-type click reactions. Some 269 functionalized analogs of naloxone and PZM21 were generated and characterized by tandem mass spectrometry (MS/MS) after screening over 500 reactions.     

Fluorogenic polypropionate fragments for detecting stereoselective aldolases

A series of fluorogenic polypropionate fragments has been prepared. These undergo retroaldolization to an intermediate aldehyde that liberates the fluorescent product umbelliferone by a secondary beta-elimination reaction. leading to a >20-fold increase in fluorescence (lambda(em) = 460 +/- 20 nm, lambdaex = 360 +/- 20 nm). By applying the principle of microscopic reversibility to the reversible aldol reaction, we can use these substrates to detect stereoselective aldolases. Test substrates are available to probe the classical cases of syn- and anti-selective aldolization (11a-d), Cram/ anti-Cram-selective aldolization (10a-d), and double stereoselective aldolization (3a-h). The selectivity of aldolase antibody 38C2 for these substrates is demonstrated as an example. The assay is suitable for high-throughput screening for catalysis in microtiter plates, and therefore provides a convenient tool for the isolation of new stereoselective aldolases from catalyst libraries.     

High-throughput screening and optimization of photoembossed relief structures

A methodology for the rapid design, screening, and optimization of coating systems with surface relief structures, using a combination of statistical experimental design, high-throughput experimentation, data mining, and graphical and mathematical optimization routines was developed. The methodology was applied to photopolymers used in photoembossing applications. A library of 72 films was prepared by dispensing a given amount of sample onto a chemically patterned substrate consisting of hydrophilic areas separated by fluorinated hydrophobic barriers. Film composition and film processing conditions were determined using statistical experimental design. The surface topology of the films was characterized by automated AFM. Subsequently, models explaining the dependence of surface topologies on sample composition and processing parameters were developed and used for screening a virtual 4000-membered in silico library of photopolymer lacquers. Simple graphical optimization or Pareto algorithms were subsequently used to find an ensemble of formulations, which were optimal with respect to a predefined set of properties, such as aspect ratio and shape of the relief structures.     

Application of parallel synthesis and high-throughput characterization in photocatalyst discovery

The last decade has seen significant progresses in the application of combinatorial approaches and high-throughput screening in photocatalyst discovery. This paper aims at providing a comprehensive review on the parallel synthesis and high-throughput characterization of photocatalysts, including the development of instrumentation, strategy of experiment, preparation of libraries, high-throughput screening technique and data analysis. The review ends with a summary of the remaining challenges and prospects on combinatorial photocatalyst discovery.     

Combinatorial and Evolution-Based Methods in the Creation of Enantioselective Catalysts

Combinatorial methods in the development of enantioselective homogeneous catalysts constitute a new branch of catalysis research. The goal is to prepare libraries of potential asymmetric catalysts, rather than choosing the traditional one-catalyst-at-a-time approach. Several conceptional advancements have been reported in the parallel preparation of chiral ligands. Currently the most meaningful systems constitute modularly constructed ligands on solid supports, which allow high degrees of structural diversity and thus the maximum probability of finding enantioselective catalysts or even new types of ligands for asymmetric catalysis. Search strategies have been developed which amongst other things, lead to catalysts not likely to have been discovered by traditional methods. Genuine application of such strategies involve thousands of catalysts and require high-throughput screening systems capable of assaying enantioselectivity. The first high-throughput ee-screening systems were in fact developed for use in the directed evolution of enantioselective enzymes, a process based on "evolution in the test tube" in which the appropriate methods of random mutagenesis, gene expression, and ee assays are combined. Since no screening system is likely to be universal, different approaches are necessary. Thus far these include assays based on UV/Vis, fluorescence, circular dichroism, mass spectrometry, and even modified gas chromatography as well as special forms of capillary electrophoresis. One of the most efficient systems involves the concept of the mass-spectrometric detection of deuterium-labeled pseudo-enantiomers and pseudo-prochiral compounds with which about 1000 exact ee determinations can be achieved per day, although the assay is restricted to kinetic resolution and/or reactions of prochiral compounds bearing enantiotopic groups. Super-high-throughput screening for enantioselectivity is possible in many cases by making use of chirally modified capillary array electrophoresis in a parallel step. Accordingly, 7000 to 30 000 ee determinations can be carried out per day. These and other analytical developments are expected to stimulate further research in the combinatorial search for asymmetric homogeneous catalysts and in the directed evolution of enantioselective enzymes for use in organic chemistry.