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Electrochemical C-H oxidation reactions offer a sustainable route to functionalize hydrocarbons, yet identifying suitable substrates and optimizing synthesis remain challenging. Here, we report an integrated approach combining machine learning and large language models to streamline the exploration of electrochemical C-H oxidation reactions. Utilizing a batch rapid screening electrochemical platform, we evaluated a wide range of reactions, initially classifying substrates by their reactivity, while LLMs text-mined literature data to augment the training set. The resulting ML models for reactivity prediction achieved high accuracy (>90 %) and enabled virtual screening of a large set of commercially available molecules. To optimize reaction conditions for selected substrates, LLMs were prompted to generate code that iteratively improved yields. This human-AI collaboration proved effective, efficiently identifying high-yield conditions for 8 drug-like substances or intermediates. Notably, we benchmarked the accuracy and reliability of 12 different LLMs-including LLaMA series, Claude series, OpenAI o1, and GPT-4-on code generation and function calling related to ML based on natural language prompts given by chemists to showcase potentials for accelerating research across four diverse tasks. In addition, we collected an experimental benchmark dataset comprising 1071 reaction conditions and yields for electrochemical C-H oxidation reactions., (© 2024 The Author(s). Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

The implementation of self-optimizing flow reactors has been mostly limited to model reactions or known synthesis routes. In this work, a self-optimizing flow photochemistry platform is used to develop an original synthesis of the bioactive fragment of Salbutamol and derivatives. The key photochemical steps for the construction of the aryl vicinyl amino alcohol moiety consist of a C-C bond forming reaction followed by an unprecedented, high yielding (>80 %), benzylic oxidative cyclization., (© 2022 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

Automation and microfluidic tools potentially enable efficient, fast, and focused reaction development of complex chemistries, while minimizing resource- and material consumption. The introduction of automation-assisted workflows will contribute to the more sustainable development and scale-up of new and improved catalytic technologies. Herein, the application of automation and microfluidics to the development of a complex asymmetric hydrogenation reaction is described. Screening and optimization experiments were performed using an automated microfluidic platform, which enabled a drastic reduction in the material consumption compared to conventional laboratory practices. A suitable catalytic system was identified from a library of Ru II -diamino precatalysts. In situ precatalyst activation was studied with 1 H/ 31 P nuclear magnetic resonance (NMR), and the reaction was scaled up to multigram quantities in a batch autoclave. These reactions were monitored using an automated liquid-phase sampling system. Ultimately, in less than a week of total experimental time, multigram quantities of the target enantiopure alcohol product were provided by this automation-assisted approach., (© 2022 The Authors. ChemSusChem published by Wiley-VCH GmbH.)

This two-part Review examines how automation has contributed to different aspects of discovery in the chemical sciences. In this second part, we reflect on a selection of exemplary studies. It is increasingly important to articulate what the role of automation and computation has been in the scientific process and how that has or has not accelerated discovery. One can argue that even the best automated systems have yet to "discover" despite being incredibly useful as laboratory assistants. We must carefully consider how they have been and can be applied to future problems of chemical discovery in order to effectively design and interact with future autonomous platforms. The majority of this Review defines a large set of open research directions, including improving our ability to work with complex data, build empirical models, automate both physical and computational experiments for validation, select experiments, and evaluate whether we are making progress towards the ultimate goal of autonomous discovery. Addressing these practical and methodological challenges will greatly advance the extent to which autonomous systems can make meaningful discoveries., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

This two-part Review examines how automation has contributed to different aspects of discovery in the chemical sciences. In this first part, we describe a classification for discoveries of physical matter (molecules, materials, devices), processes, and models and how they are unified as search problems. We then introduce a set of questions and considerations relevant to assessing the extent of autonomy. Finally, we describe many case studies of discoveries accelerated by or resulting from computer assistance and automation from the domains of synthetic chemistry, drug discovery, inorganic chemistry, and materials science. These illustrate how rapid advancements in hardware automation and machine learning continue to transform the nature of experimentation and modeling. Part two reflects on these case studies and identifies a set of open challenges for the field., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

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., (© 2020 Wiley-VCH GmbH.)

We present a fully continuous chip microreactor-based multistage platform for the synthesis of quantum dots with heterostructures. The use of custom-designed chip reactors enables precise control of heating profiles and flow distribution across the microfluidic channels while conducting multistep reactions. The platform can be easily reconfigured by reconnecting the differently designed chip reactors allowing for screening of various reaction parameters during the synthesis of nanocrystals. III-V core/shell quantum dots are chosen as model reaction systems, including InP/ZnS, InP/ZnSe, InP/CdS and InAs/InP, which are prepared in flow using a maximum of six chip reactors in series., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

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., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

As a demonstration of an alternative to the challenges faced with batch pharmaceutical manufacturing including the large production footprint and lengthy time-scale, we previously reported a refrigerator-sized continuous flow system for the on-demand production of essential medicines. Building on this technology, herein we report a second-generation, reconfigurable and 25 % smaller (by volume) continuous flow pharmaceutical manufacturing platform featuring advances in reaction and purification equipment. Consisting of two compact [0.7 (L)×0.5 (D)×1.3 m (H)] stand-alone units for synthesis and purification/formulation processes, the capabilities of this automated system are demonstrated with the synthesis of nicardipine hydrochloride and the production of concentrated liquid doses of ciprofloxacin hydrochloride, neostigmine methylsulfate and rufinamide that meet US Pharmacopeia standards., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Oscillatory flow reactors provide a surface energy-driven approach for automatically screening reaction conditions and studying reaction mechanisms of biphasic nanocrystal ligand-exchange reactions. Sulfide and cysteine ligand-exchange reactions with as-synthesized CdSe quantum dots (QDs) are chosen as two model reactions. Different reaction variables including the new-ligand-to-QD ratio, the size of the particles, and the original ligand type are examined systematically. Based on the in situ-obtained UV/Vis absorption spectra during the reaction, we propose two different exchange pathways for the sulfide exchange reaction., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

We present an automated microfluidic platform for in-flow studies of visible-light photoredox catalysis in liquid or gas-liquid reactions at the 15 μL scale. An oscillatory flow strategy enables a flexible residence time while preserving the mixing and heat transfer advantages of flow systems. The adjustable photon flux made possible with the platform is characterized using actinometry. Case studies of oxidative hydroxylation of phenylboronic acids and dimerization of thiophenol demonstrate the capabilities and advantages of the system. Reaction conditions identified through droplet screening translate directly to continuous synthesis with minor platform modifications., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Within a total residence time of 9 min, the sodium salt of ciprofloxacin was prepared from simple building blocks via a linear sequence of six chemical reactions in five flow reactors. Sequential offline acidifications and filtrations afforded ciprofloxacin and ciprofloxacin hydrochloride. The overall yield of the eight-step sequence was 60 %. No separation of intermediates was required throughout the synthesis when a single acylation reaction was applied to remove the main byproduct, dimethylamine., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Identifying and separating a subpopulation of cells from a heterogeneous mixture are essential elements of biological research. Current approaches require detailed knowledge of unique cell surface properties of the target cell population. A method is described that exploits size differences of cells to facilitate selective intracellular delivery using a high throughput microfluidic device. Cells traversing a constriction within this device undergo a transient disruption of the cell membrane that allows for cytoplasmic delivery of cargo. Unique constriction widths allow for optimization of delivery to cells of different sizes. For example, a 4 μm wide constriction is effective for delivery of cargo to primary human T-cells that have an average diameter of 6.7 μm. In contrast, a 6 or 7 μm wide constriction is best for large pancreatic cancer cell lines BxPc3 (10.8 μm) and PANC-1 (12.3 μm). These small differences in cell diameter are sufficient to allow for selective delivery of cargo to pancreatic cancer cells within a heterogeneous mixture containing T-cells. The application of this approach is demonstrated by selectively delivering dextran-conjugated fluorophores to circulating tumor cells in patient blood allowing for their subsequent isolation and genomic characterization., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

We describe a simple and general method for the preparation and molecular engineering of supported trifunctional catalysts and their application in the representative Cu/TEMPO/NMI-catalyzed aerobic oxidation of benzyl alcohol. The methodology allows in one single step to immobilize, with precise control of surface composition, both pyta, Cu(I) , TEMPO, and NMI sites on azide-functionalized silica particles. To optimize the performance of the heterogeneous trifunctional catalysts, synergistic interactions are finely engineered through modulating the degree of freedom of the imidazole site as well as tuning the relative surface composition, leading to catalysts with an activity significantly superior to the corresponding homogeneous catalytic system., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Control of quantum dot (QD) precursor chemistry has been expected to help improve the size control and uniformity of III-V QDs such as indium phosphide and indium arsenide. Indeed, experimental results for other QD systems are consistent with the theoretical prediction that the rate of precursor conversion is an important factor controlling QD size and size distribution. We synthesized and characterized the reactivity of a variety of group-V precursors in order to determine if precursor chemistry could be used to improve the quality of III-V QDs. Despite slowing down precursor conversion rate by multiple orders of magnitude, the less reactive precursors do not yield the expected increase in size and improvement in size distribution. This result disproves the widely accepted explanation for the shortcoming of current III-V QD syntheses and points to the need for a new generalizable theoretical picture for the mechanism of QD formation and growth., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Currently, kinetic data is either collected under steady-state conditions in flow or by generating time-series data in batch. Batch experiments are generally considered to be more suitable for the generation of kinetic data because of the ability to collect data from many time points in a single experiment. Now, a method that rapidly generates time-series reaction data from flow reactors by continuously manipulating the flow rate and reaction temperature has been developed. This approach makes use of inline IR analysis and an automated microreactor system, which allowed for rapid and tight control of the operating conditions. The conversion/residence time profiles at several temperatures were used to fit parameters to a kinetic model. This method requires significantly less time and a smaller amount of starting material compared to one-at-a-time flow experiments, and thus allows for the rapid generation of kinetic data., (Copyright © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A series of tubes: The continuous manufacture of a finished drug product starting from chemical intermediates is reported. The continuous pilot-scale plant used a novel route that incorporated many advantages of continuous-flow processes to produce active pharmaceutical ingredients and the drug product in one integrated system., (Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The fine chemicals and pharmaceutical industries are transforming how their products are manufactured, where economically favorable, from traditional batchwise processes to continuous flow. This evolution is impacting synthetic chemistry on all scales-from the laboratory to full production. This Review discusses the relative merits of batch and micro flow reactors for performing synthetic chemistry in the laboratory., (Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A preparative scale free-flow IEF device is developed and characterized with the aim of addressing needs of molecular biologists working with protein samples on the milligrams and milliliters scale. A triangular-shape separation channel facilitates the establishment of the pH gradient with a corresponding increase in separation efficiency and decrease in focusing time compared with that in a regular rectangular channel. Functionalized, ion-permeable poly(acrylamide) gel membranes are sandwiched between PDMS and glass layers to both isolate the electrode buffers from the central separation channel and also to selectively adjust the voltage efficiency across the separation channel to achieve high electric field separation. The 50 x 70 mm device is fabricated by soft lithography and has 24 outlets evenly spaced across a pH gradient between pH 4 and 10. This preparative free-flow IEF system is investigated and optimized for both aqueous and denaturing conditions with respect to the electric field and potential efficiency and with consideration of Joule-heating removal. Energy distribution across the functionalized polyacrylamide gel is investigated and controlled to adjust the potential efficiency between 15 and 80% across the triangular separation channel. The device is able to achieve constant electric fields high as 370+/-20 V/cm through the entire triangular channel given the separation voltage of 1800 V, enabling separation of five fluorescent pI markers as a demonstration example.

Rapid free-flow IEF is achieved in a microfluidic device by separating the electrodes from the focusing region with porous buffer regions. Moving the electrodes outside enables the use of large electric fields without the detrimental effects of bubble formation in the active region. The anode and cathode porous buffer regions, which are formed by acrylamide functionalized with immobilized pH groups, allow ion transport while providing buffering capacity. Thermoelectric cooling mitigates the effects of Joule heating on sample focusing at high field strengths (approximately 500 V/cm). This localized cooling was observed to increase device performance. Rapid focusing of low-molecular-weight p/ markers and Protein G-mouse IgG complexes demonstrate the versatility of the technique. Simulations provide insight into and predict device performance based on a well-defined sample composition.

By using chemical vapor deposition (CVD) a range of substrates can be coated with a highly reactive polymer containing pentafluorophenol ester groups. A biotin-modified pattern is generated on the substrate by microcontact printing; such a pattern interacts specifically with fluorescein-conjugated streptavidin and thereby the pattern becomes observable with fluorescence microscopy., (© 2001 WILEY-VCH Verlag GmbH, Weinheim, Fed. Rep. of Germany.)