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Electrochemical synthesis has recently emerged as an environmentally benign method for synthesizing value-added fine chemicals. Its unique reactivity has attracted significant interests of synthetic chemists to develop new redox chemistries. However, compared to conventional chemistry, the increased complexity caused by electrode materials, supporting electrolytes, and setup configurations create obstacles for efficient reaction discovery and optimization. The recent increasing adoption of high-throughput experimentation (HTE) in synthetic chemistry significantly expedites the synthesis development. Considering the potential of implementing HTE in electrosynthesis to tackle the challenges of increased parameter space, this short review aims at providing recent advances in the HTE technology for electrosynthesis, including electrocatalysts screening, device miniaturization, electroanalytical methods, artificial intelligence, and system integration. The discussed contents also cover some topics in HTE electrochemistry for areas other than synthetic chemistry, hoping to spark some inspirations for readers to use interdisciplinary techniques to solve challenges in synthetic electrochemistry.1 Introduction2 Parallelized Reaction Screening3 High-Throughput Screening for Electrocatalysts4 Miniaturization of Screening Devices5 Analytical Methods for Electrosynthesis Screening6 Artificial Intelligence for High-Throughput Screening7 Integrated Screening Systems8 Conclusion and Outlook

Research-scale fully automated flow platform for reaction self-optimization with solids handling facilitates identification of optimal conditions for continuous manufacturing of pharmaceuticals while reducing amounts of raw materials consumed.

The molecular structures synthesizable by organic chemists dictate the molecular functions they can create. The invention and development of chemical reactions are thus critical for chemists to access new and desirable functional molecules in all disciplines of organic chemistry. This work seeks to expedite the exploration of emerging areas of organic chemistry by devising a machine-learning-guided workflow for reaction discovery. Specifically, this study uses machine learning to invent new electrochemical reactions. To this end, we first develop a novel molecular representation that enables the production of general models with limited training data. Next, we employ automated experimentation to test a large number of electrochemical reactions. These reactions are categorized as competent or incompetent mixtures, and a classification model was trained to predict reaction competency. This model is used to screen 38,865 potential reactions in silico and the predictions used to identify a number of new reactions of synthetic or mechanistic interest, 80 % of which are found to be competent. Additionally, we provide the predictions for the 38,865-member set in the hope of accelerating development of this field. We envision that adopting a workflow such as this could enable the rapid development of many fields of chemistry.

The multistep and continuous production of core–shell III–V semiconductor nanocrystals remains a technological challenge. We present a newly designed high-temperature and miniature continuous stirred-tank reactor cascade, for the continuous and scalable synthesis of InP/ZnS core–shell quantum dots with a safer aminophosphine precursor comparing to standard protocols involving (TMS)3P. The resulting InP/ZnS QDs exhibit emissions between 520 and 610 nm, narrow emission linewidths in the range of 46–64 nm and photoluminescence quantum yields up to 42%.

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.

Cutting it close for radical coupling In principle, electrochemistry is an ideal method for radical coupling: One precursor oxidized at the anode pairs up with a counterpart that has been reduced at the cathode. The trouble is that either or both coupling partners might not stay stable long enough to meet in the middle. Mo et al. resolved this issue by closely spacing the electrodes in a microfluidics platform (see the Perspective by Liu et al. ). They showcase coupling of dicyanobenzene as the cathodic radical precursor with a variety of oxidatively generated partners. Science , this issue p. 1352 ; see also p. 1312

The first demonstration of aqueous surfactant-enabled Suzuki–Miyaura couplings run under flow conditions is described. In addition, use of an even more challenging heterogeneous nanoparticle catalyst, containing only 800 ppm of Pd (i.e., 0.08 mol%) in the form of Fe/ppm Pd nanoparticles, is sufficient using a continuous stirred-tank reactor (CSTR).

Visible-light photoredox reactions have been demonstrated to be powerful synthetic tools to access pharmaceutically relevant compounds. However, many photoredox reactions involve insoluble starting...

Computer aided synthesis planning of synthetic pathways with green process conditions has become of increasing importance in organic chemistry, but the large search space inherent in synthesis planning and the difficulty in predicting reaction conditions make it a significant challenge. We introduce a new Monte Carlo Tree Search (MCTS) variant that promotes balance between exploration and exploitation across the synthesis space. Together with a value network trained from reinforcement learning and a solvent-prediction neural network, our algorithm is comparable to the best MCTS variant (PUCT, similar to Google's Alpha Go) in finding valid synthesis pathways within a fixed searching time, and superior in identifying shorter routes with greener solvents under the same search conditions. In addition, with the same root compound visit count, our algorithm outperforms the PUCT MCTS by 16% in terms of determining successful routes. Overall the success rate is improved by 19.7% compared to the upper confidence bound applied to trees (UCT) MCTS method. Moreover, we improve 71.4% of the routes proposed by the PUCT MCTS variant in pathway length and choices of green solvents. The approach generally enables including Green Chemistry considerations in computer aided synthesis planning with potential applications in process development for fine chemicals or pharmaceuticals., A new MCTS variant with a reinforcement learning value network and solvent prediction model proposes shorter synthesis routes with greener solvents.

For many carbon–carbon and carbon–nitrogen bond-forming reactions, the stoichiometric formation of inorganic salt crystals limits continuous flow synthesis by causing precipitation, agglomeration, ...

Electroorganic chemistry has emerged as an environmentally benign tool for synthetic chemists to achieve efficient transformations that are challenging with traditional reagent-based methods. Continuous flow chemistry brings pharmaceutical industry numerous advantages, but implementing electroorganic synthesis in flow is challenging, especially for electroorganic reactions with coupled electrode reactions and slow chemical reactions. We present a continuous electrolysis system engineered for N-hydroxyphthalimide (NHPI) mediated electrochemical aerobic oxidation of benzylic C-H bonds. First, a cation-exchange membrane prevents the crossover of the NHPI anion from anolyte to catholyte avoiding reductive decomposition of NHPI at the cathode, and enables the usage of a cost-effective reticulated vitreous carbon (RVC) cathode instead of a platinum electrode. Second, running the electrochemical flow cell with recycle streams accommodates the inherently slow kinetics of the chemical reaction without phthalimide-N-oxyl (PINO) radical self-decomposition at the anode, and allows the usage of gaseous oxygen as co-oxidant.

Chemical transformations used in fine chemical manufacturing often involve two-phase interaction for which mass transfer limitations can lead to prolonged reaction time and reduced productivity. We present a high-performance miniature continuous stirred-tank reactor (CSTR), with non-contact magnetic coupling providing intensive agitation inside the sealed miniaturized chamber. High-speed imaging of the biphasic hydrodynamics gives an estimated mass transfer coefficient (kLa) on the order of 10 s−1, comparable to commercial passive mixing flow reactors. Case studies with two important biphasic C–C bond-forming reactions: (i) asymmetric alkylation catalyzed by cinchonidine-derived phase-transfer catalyst, and (ii) biphasic Suzuki-Miyaura C–C coupling reactions, demonstrate the versatility of the CSTR unit. Moreover, a detailed kinetic model proposed for phase-transfer reaction systems controlled by the Makosza interfacial mechanism further cross-validates the mass transfer coefficient estimates.

Catalytic gas–liquid reactions have potential as environmentally benign methods for organic synthesis, particularly hydrogenation and oxidation reactions. However, safety and scalability are concerns in the application of gas–liquid reactions. In this work, we develop and demonstrate a scalable, sustainable, and safe thin-layer membrane reactor for heterogeneous Pd-catalyzed hydrogenations and homogenous Cu(I)/TEMPO alcohol oxidations. The implementation of a Teflon amorphous fluoroplastic (AF) membrane and porous carbon cloth in the membrane reactor provides sufficient gas–liquid mass transfer to afford superior performance compared to conventional packed-bed or trickle-bed reactors. The membrane separates the gas from the liquid, which avoids the formation of explosive mixtures for oxygenation reactions and simplifies the two-phase hydrodynamics to facilitate scale-up by stacking modules, while significantly reducing gas consumption. In addition, 3-dimensional simulations deliver insights into the mass transfer and hydrodynamic behavior to inform optimal membrane reactor design and operation.

Enterobactin (Ent)-mediated high-affinity iron acquisition is critical for Gram-negative bacteria to survive in the host. Given the bacteriostatic effect of lipocalin resulting from its potent Ent-binding ability, immune intervention directly targeting Ent is promising for iron-dependent pathogen control. Recently, an Ent conjugate vaccine was reported, but it still has several significant weaknesses. In this study, we sought to develop an innovative Ent conjugate vaccine that can induce a high level of antibodies directed against Ent and to provide solid evidence demonstrating siderophore-binding capacity of Ent-specific antibodies. Using a simple method, we successfully conjugated purified Ent to different carriers, including keyhole limpet hemocyanin (KLH), bovine serum albumin, and CmeC, a vaccine candidate for Campylobacter control. Subcutaneous immunization of rabbits with the KLH-Ent conjugate triggered a strong systemic IgG immune response with an up to 16,384-fold increase in IgG titer directed against whole conjugate and an up to 4,096-fold increase in the level of specific anti-Ent IgG. To evaluate the ability of Ent-specific IgG to bind to the Ent derivatives present in vivo, various Ent derivatives were chemically synthesized and a unique enzyme-linked immunosorbent assay method was developed. The Ent-specific IgG also displayed exceptional reactivity to ferric Ent, a linear trimer of Ent, and different salmochelins. Growth assays further demonstrated that the Ent-specific antibodies significantly inhibited Ent-dependent growth of Campylobacter spp. and Escherichia coli. Collectively, this study reports an efficient method to prepare a new type of Ent conjugate vaccines for inducing a high level of Ent-specific antibodies, which can bind to various Ent derivatives and display lipocalin-like bacteriostatic features. IMPORTANCE Ent-mediated high-affinity iron acquisition is a universal and critical contributor for Gram-negative pathogens to survive and infect hosts. Published information has supported an innovative immune intervention strategy that directly targets Ent to starve pathogens by limiting the availability of iron to be utilized. Compared to a recently published Ent conjugate, there are three advantages of the vaccine described in this study: ease of preparation, induction of high titer of anti-Ent IgG, and the ability of Ent-specific antibodies to bind various Ent derivatives, including the salmochelins that help enteric pathogens evade sequestration of siderophores by host lipocalins. In addition, the Ent-specific antibodies were demonstrated to function similarly to lipocalin to interfere with the Ent-dependent growth of Campylobacter and E. coli under iron-restricted conditions. This study has significant potential for broader applications to prevent and control various Gram-negative infections in humans and animals.

Continuous handling of solids creates challenges for realizing continuous production of pharmaceuticals and fine chemicals. We present a new miniature continuous stirred-tank reactor (CSTR) cascade to handle solid-forming reactions in flow. Single-phase residence time distribution (RTD) measurements of the CSTR cascade reveal nearly ideal CSTR mixing behavior of the individual units. Consistency of experimental and predicted conversions of a Diels–Alder reaction further confirms the CSTR performance. Two solid-forming reactions, (i) glyoxal reacting with cyclohexylamine to form N,N′-dicyclohexylethylenediimine, (ii) sulfonylation of 2-octanol with methanesulfonyl chloride, demonstrate the ability of the reactor cascade to transport solid particles continuously for hours without significant signs of clogging.

Summary Ferric enterobactin (FeEnt) acquisition is a highly efficient and conserved iron scavenging system in Gram-negative bacteria. Recently, we have characterized two FeEnt receptors (CfrA and CfrB) in Campylobacter jejuni and C. coli, the enteric human pathogens that do not produce any siderophores. In this study, whole-genome sequencing and comparative genomic analysis identified a unique Ent trilactone esterase Cee (Cj1376) in C. jejuni. Genomic analysis and biochemical assay strongly suggested that Cee is the sole trilactone esterase in C. jejuni. Thin-layer chromatography and HPLC analyses showed high efficiency of the purified Cee to hydrolyse Ent. Three Cee homologues previously characterized from other bacteria (IroE, IroD and Fes) were also purified and analysed together with Cee, indicating that Cee, Fes and IroD displayed similar hydrolysis dynamics for both apo and ferric forms of Ent while IroE catalysed Ent inefficiently. Unlike cytoplasmic Fes and IroD, Cee is localized in the periplasm as demonstrated by immunoblotting using Cee-specific antibodies. Genetic manipulation of diverse Campylobacter strains demonstrated that Cee is not only essential for CfrB-dependent FeEnt acquisition but also involved in CfrA-dependent pathway. Together, this study identified and characterized a novel periplasmic trilactone esterase and suggested a new model of FeEnt acquisition in Campylobacter.

Membrane proteins present major challenges for structural biology. In particular, the production of suitable crystals for high-resolution structural determination continues to be a significant roadblock for developing an atomic-level understanding of these vital cellular systems. The use of detergents for extracting membrane proteins from the native membrane for either crystallization or reconstitution into model lipid membranes for further study is assumed to leave the protein with the proper fold with a belt of detergent encompassing the membrane-spanning segments of the structure. Small-angle X-ray scattering was used to probe the detergent-associated solution conformations of three membrane proteins, namely bacteriorhodopsin (BR), the Ste2p G-protein coupled receptor from Saccharomyces cerevisiae, and the Escherichia coli porin OmpF. The results demonstrate that, contrary to the traditional model of a detergent-associated membrane protein, the helical proteins BR and Ste2p are not in the expected, compact conformation and associated with detergent micelles, while the ?-barrel OmpF is indeed embedded in a disk-like micelle in a properly folded state. The comparison provided by the BR and Ste2p, both members of the 7TM family of helical membrane proteins, further suggests that the interhelical interactions between the transmembrane helices of the two proteins differ, such that BR, like other rhodopsins,more » can properly refold to crystallize, while Ste2p continues to prove resistant to crystallization from an initially detergent-associated state.« less

Conjugated bile salts take part in micellar formation, a critical step for dietary lipid digestion and absorption. Bile salt hydrolases (BSHs) catalyze the conversion of conjugated bile salts to bi...

1,2-(1′, 1′,2′,2′-tetracyanomethanoxymethano) [60] fullerene has been synthesized. It exhibits stronger ability of accepting electron than pure [60]fullerene. A film of PVK doped with 1.6% by weight of this C60-derivative was prepared and characterized. The measured photoinduced discharge curves and the photoconductivity spectra of the film demonstrate that the photoconductivity of PVK doped with this [60]fullerene derivative is higher than that of PVK doped with pure C60.

Concern about the toxicity of engineered nanoparticles, such as the prototypical nanomaterial C60 fullerene, continues to grow. While, evidence continues to mount that C60 and its derivatives may pose health hazards, the specific molecular interactions of these particles with biological macromolecules require further investigation. In this article, we report combined experimental and theoretical studies on the interaction of one of the most prevalent proteins in the human body, human serum albumin (HSA), with C60 in an aqueous environment. The C60–HSA interaction was probed by circular dichroism (CD) spectroscopy, small-angle neutron scattering (SANS), and atomistic molecular dynamics (MD) simulations to understand C60-driven changes in the structure of HSA in solution. The CD spectroscopy demonstrates that the secondary structure of the protein decreases in α-helical content in response to the presence of C60 (0.68 nm in diameter). Similarly, C60 produces subtle changes in the solution conformation of HSA (an 8.0 nm × 3.8 nm protein), as evidenced by the SANS data and MD simulations, but the data do not indicate that C60 changes the oligomerization state of the protein, such as by inducing aggregation. The results demonstrate that the interaction is not highly disruptive to the protein in a manner that would prevent it from performing its physiological function.

In this article, the room-temperature solution fluorescence quenching of electron-deficient anthracenes such as 9-cyanoanthracene (CNA), 9,10-dicyanoanthracene (DCNA), and 9,10-dichloroanthracene (DCLA) by polysilane copolymers was studied. The fluorescence quenching data was in conformity with the Stern-Volmer equation F 0 /F = 1 + K SV [Q], the F 0 /F-[Q] straight lines were drawn, and the fluorescence quenching constants K SV were obtained. By measuring the fluorescence lifetimes of the anthracenes, the fluorescence quenching rate constants k q were calculated. Based on experiments and references, we tentatively proposed that for the same polysilane copolymer quencher the fluorescence quenching was caused mainly by the polysilane Si-Si chain and affected in a small degree by the side substituents attached to the Si-Si chain. In addition, it was observed that the order of the fluorescence quenching rate constants k q of the above three electron-deficient anthracenes by the same polysilane copolymer was DCNA > CNA > DCLA, which is just in keeping with that of their electron deficiency.

In this paper, a segment-guided depth extraction approach is proposed for monocular image with linear perspective. Firstly, foreground depth is learned from a RGBD database with segment-based calibration to adjust the initial coarse depth, and background depth is estimated from linear perspective by vanishing cues. Then, the foreground depth and background one are linearly combined with a statistically optimal balance factor to obtain a holistic fused depth map. Lastly, bilateral filter is exploited to suppress the depth disturbance with edge-preserving. Experiments demonstrate that the proposed technique can produce accurate and dense depths with distinct object boundaries and correct relation among the object positions for a single image.

This paper proposes an automatic planes extraction approach to recover hypothesis planes of architectural scenes, being easily adopted in interactive-friendly multiview reconstruction systems. There exist many interactive scene reconstruction algorithms designed to model these real worlds, but they are very labor-intensive and difficult to verify whether the resulting 3D models are accurate or not. Motivated by the strongly piecewise planar property of architectural scenes, the hypothesis 3D planes can be generated automatically and flexibly in our work, being faster, more accurate and labor-saving than that of manually processing. Firstly, initial oriented points are reconstructed by using structure-from-motion and patch-based multiview stereo. Secondly, non-parametric density-based clustering technique is exploited to extract plane normal vectors without any presumption on the prior distributions of the normals of the planes, unlike famous Manhattan-world assumption. Then, the offsets of the planes can be estimated to specify the locations of the assumed 3D planes. Each group of the normal vectors and offset distances along the corresponding normals can determine certain candidates of plane structures. The obtained hypothesis planes are very beneficial to interactive-friendly multiview reconstruction with its efficiency and labor-saving, without measuring the sites, locating and digitizing architectural planes or converting existing CAD data.

Ferric enterobactin (FeEnt) acquisition is a highly efficient and conserved iron scavenging system in Gram-negative bacteria. Recently, we have characterized two FeEnt receptors (CfrA and CfrB) in Campylobacter jejuni and C. coli, the enteric human pathogens that do not produce any siderophores. In this study, whole genome sequencing and comparative genomic analysis identified a unique Ent trilactone esterase Cee (Cj1376) in C. jejuni. Genomic analysis and biochemical assay strongly suggested that Cee is the sole trilactone esterase in C. jejuni. Thin layer chromatography and HPLC analyses showed high efficiency of the purified Cee to hydrolyze Ent. Three Cee homologs previously characterized from other bacteria (IroE, IroD, and Fes) were also purified and analyzed together with Cee, indicating that Cee, Fes, and IroD displayed similar hydrolysis dynamics for both apo and ferric forms of Ent while IroE catalyzed Ent inefficiently. Unlike cytoplasmic Fes and IroD, Cee is localized in the periplasm as demonstrated by immunoblotting using Cee-specific antibodies. Genetic manipulation of diverse Campylobacter strains demonstrated that Cee is not only essential for CfrB-dependent FeEnt acquisition but also involved in CfrA-dependent pathway. Together, this study identified and characterized a novel periplasmic trilactone esterase and suggested a new model of FeEnt acquisition in Campylobacter.

Antibiotic growth promoters (AGPs) have been used as feed additives to improve average body weight gain and feed efficiency in food animals for more than 5 decades. However, there is a worldwide trend to limit AGP use to protect food safety and public health, which raises an urgent need to discover effective alternatives to AGPs. The growth-promoting effect of AGPs has been shown to be highly correlated with the decreased activity of intestinal bile salt hydrolase (BSH), an enzyme that is produced by various gut microflora and involved in host lipid metabolism. Thus, BSH inhibitors are likely promising feed additives to AGPs to improve animal growth performance. In this study, the genome of Lactobacillus salivarius NRRL B-30514, a BSH-producing strain isolated from chicken, was sequenced by a 454 GS FLX sequencer. A BSH gene identified by genome analysis was cloned and expressed in an Escherichia coli expression system for enzymatic analyses. The BSH displayed efficient hydrolysis activity for both glycoconjugated and tauroconjugated bile salts, with slightly higher catalytic efficiencies ( k cat / K m ) on glycoconjugated bile salts. The optimal pH and temperature for the BSH activity were 5.5 and 41°C, respectively. Examination of a panel of dietary compounds using the purified BSH identified some potent BSH inhibitors, in which copper and zinc have been recently demonstrated to promote feed digestion and body weight gain in different food animals. In sum, this study identified and characterized a BSH with broad substrate specificity from a chicken L. salivarius strain and established a solid platform for us to discover novel BSH inhibitors, the promising feed additives to replace AGPs for enhancing the productivity and sustainability of food animals.

Sample instability during solid-state NMR experiments frequently arises due to RF heating in aligned samples of hydrated lipid bilayers. A new, simple approach for estimating sample temperature is used to show that, at 9.4 T, sample heating depends mostly on (1)H decoupling power rather than on (15)N irradiation in PISEMA experiments. Such heating for different sample preparations, including lipid composition, salt concentration and hydration level was assessed and the hydration level was found to be the primary parameter correlated with sample heating. The contribution to RF heating from the dielectric loss appears to be dominant under our experimental conditions. The heat generated by a single scan was approximately calculated from the Q values of the probe, to be a 1.7 degrees C elevation per single pulse sequence iteration under typical sample conditions. The steady-state sample temperature during PISEMA experiments can be estimated based on the method presented here, which correlates the loss factor with the temperature rise induced by the RF heating of the sample.