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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.