A Versatile Compact Parahydrogen Membrane Reactor.

We introduce a Spin Transfer Automated Reactor (STAR) that produces continuous parahydrogen induced polarization (PHIP), which is stable for hours to days. We use the PHIP variant called signal amplification by reversible exchange (SABRE), which is particularly well suited to produce continuous hyperpolarization. The STAR is operated in conjunction with benchtop (1.1 T) and high field (9.4 T) NMR magnets, highlighting the versatility of this system to operate with any NMR or MRI system. The STAR uses semipermeable membranes to efficiently deliver parahydrogen into solutions at nano to milli Tesla fields, which enables 1 H, 13 C, and 15 N hyperpolarization on a large range of substrates including drugs and metabolites. The unique features of the STAR are leveraged for important applications, including continuous hyperpolarization of metabolites, desirable for examining steady-state metabolism in vivo, as well as for continuous RASER signals suitable for the investigation of new physics.

Shear-Induced Alignment of Anisotropic Nanoparticles in a Single-Droplet Oscillatory Microfluidic Platform.

Flow-induced alignment of shape-anisotropic colloidal particles is of great importance in fundamental research and in the fabrication of structurally anisotropic materials; however, rheo-optical studies of shear-induced particle orientation are time- and labor-intensive and require complicated experimental setups. We report a single-droplet oscillatory microfluidic strategy integrated with in-line polarized light imaging as a strategy for studies of shear-induced alignment of rod-shape nanoparticles. Using an oscillating droplet of an aqueous isotropic suspension of cellulose nanocrystals (CNCs), we explore the effect of the shear rate and suspension viscosity on the flow-induced CNC alignment and subsequent relaxation to the isotropic state. The proposed microfluidic strategy enables high-throughput studies of shear-induced orientations in structured liquid under precisely controlled experimental conditions. The results of such studies can be used in the development of structure-anisotropic materials.

Material-Efficient Microfluidic Platform for Exploratory Studies of Visible-Light Photoredox Catalysis.

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.

In-Situ Microfluidic Study of Biphasic Nanocrystal Ligand-Exchange Reactions Using an Oscillatory Flow Reactor.

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.

Multiphase Oscillatory Flow Strategy for in Situ Measurement and Screening of Partition Coefficients.

Taking advantage of the difference between the surface energies of aqueous and organic solvents on a Teflon substrate, a fully automated small-scale strategy is developed on the basis of gas-driven oscillatory motion of a biphasic slug for high-throughput in situ measurement and screening of partition coefficients of organic substances between aqueous and organic phases. The developed oscillatory flow strategy enables single partition coefficient data point measurement within 8 min (including the sample preparation time) which is 360 times faster than the conventional "shake-flask" method, while using less than a 30 µL volume of the two phases and 9 nmol of the target organic substance. The developed multiphase strategy is validated using a conventional shake-flask technique. Finally, the developed strategy is extended to include automated screening of partition coefficients at physiological temperature.

Switchable water: microfluidic investigation of liquid-liquid phase separation mediated by carbon dioxide.

Increase in the ionic strength of water that is mediated by the reaction of carbon dioxide (CO2) with nitrogenous bases is a promising approach toward phase separation in mixtures of water with organic solvents and potentially water purification. Conventional macroscale studies of this complicated process are challenging, due to its occurrence via several consecutive and concurrent steps, mass transfer limitation, and lack of control over gas-liquid interfaces. We report a new microfluidic strategy for fundamental studies of liquid-liquid phase separation mediated by CO2 as well as screening of the efficiency of nitrogenous agents. A single set of microfluidic experiments provided qualitative and quantitative information on the kinetics and completeness of water-tetrahydrofuran phase separation, the minimum amount of CO2 required to complete phase separation, the total CO2 uptake, and the rate of CO2 consumption by the liquid mixture. The efficiency of tertiary diamines with different lengths of alkyl chain was examined in a time- and labor-efficient manner and characterized with the proposed efficiency parameter. A wealth of information obtained using the MF methodology can facilitate the development of new additives for switchable solvents in green chemistry applications.

Microfluidic studies of CO2 sequestration by frustrated Lewis pairs.

Frustrated Lewis pairs (FLPs) comprising sterically hindered Lewis acids and bases offer the capability to reversibly capture CO2 under mild reaction conditions. The determination of equilibrium constants and thermodynamic properties of these reactions should enable assessment of the efficiency of a particular FLP system for CO2 sequestration and provide insights for design of new, efficient formulations of FLP catalysts for CO2 capture. We have developed a microfluidic approach to studies of FLP-CO2 reactions, which provides their thermodynamic characterization that is not accessible otherwise. The approach enables the determination of the equilibrium reaction constants at different temperatures, the enthalpy, the entropy, and the Gibbs energy of these reactions, as well as the enhancement factor. The microfluidic methodology has been validated by applying it to the well-characterized reaction of CO2 with a secondary amine. The microfluidic approach can be applied for fundamental thermodynamic studies of other gas-liquid reactions.

Microfluidic generation of composite biopolymer microgels with tunable compositions and mechanical properties.

To develop an understanding of the nature of complex, spatiotemporal interactions between cells and the extracellular matrix (ECM), artificial ECMs formed from hydrogels with a particular spectrum of properties are being developed at a rapid pace. We report the microfluidic generation of small, monodisperse composite agarose-gelatin hydrogel modules (microgel particles) that can be used for cell encapsulation and can serve as instructive cellular microenvironments. The agarose component of the microgels gelled under reduced temperature, while gelatin modified with phenolic hydroxyl groups underwent peroxidase-catalyzed gelation. Microgel composition, structure, morphology, and rigidity were tuned in a high-throughput manner. The results of this work are important for the generation of libraries of cell-laden polymer microgels for single-cell analysis, tissue engineering, and fundamental studies of the role of local microenvironments in cell fate.

Microfluidic studies of carbon dioxide.

Carbon dioxide (CO2) sequestration, storage and recycling will greatly benefit from comprehensive studies of physical and chemical gas-liquid processes involving CO2. Over the past five years, microfluidics emerged as a valuable tool in CO2-related research, due to superior mass and heat transfer, reduced axial dispersion, well-defined gas-liquid interfacial areas and the ability to vary reagent concentrations in a high-throughput manner. This Minireview highlights recent progress in microfluidic studies of CO2-related processes, including dissolution of CO2 in physical solvents, CO2 reactions, the utilization of CO2 in materials science, and the use of supercritical CO2 as a "green" solvent.

Performance metrics to unleash the power of self-driving labs in chemistry and materials science.

With the rise of self-driving labs (SDLs) and automated experimentation across chemical and materials sciences, there is a considerable challenge in designing the best autonomous lab for a given problem based on published studies alone. Determining what digital and physical features are germane to a specific study is a critical aspect of SDL design that needs to be approached quantitatively. Even when controlling for features such as dimensionality, every experimental space has unique requirements and challenges that influence the design of the optimal physical platform and algorithm. Metrics such as optimization rate are therefore not necessarily indicative of the capabilities of an SDL across different studies. In this perspective, we highlight some of the critical metrics for quantifying performance in SDLs to better guide researchers in implementing the most suitable strategies. We then provide a brief review of the existing literature under the lens of quantified performance as well as heuristic recommendations for platform and experimental space pairings.

Facile Synthesis of Cu-Doped TiO2 Particles for Accelerated Visible Light-Driven Antiviral and Antibacterial Inactivation.

In this work, we present a facile and scalable hydrolysis-based route for the synthesis of copper-doped TiO2 particles for highly effective light-activated antiviral and antibacterial applications. The performance of the synthesized Cu-doped TiO2 particles is then evaluated using solution-phase antimicrobial photodynamic inactivation assays. We demonstrate that the Cu-doped TiO2 particles can successfully inactivate a wide range of pathogens with exposure to light for 90 min, including bacteria ranging from methicillin-resistant Staphylococcus aureus (99.9999%, ∼6 log units) to Klebsiella pneumoniae (99.93%, ∼3.3 log units), and viruses including feline calicivirus (99.94%, ∼3.4 log units) and HCoV-229E (99.996%, ∼4.6 log units), with the particles demonstrating excellent robustness toward photobleaching. Furthermore, a spray-coated polymer film, loaded with the synthesized Cu-doped TiO2 particles achieves inactivation of methicillin-resistant S. aureus up to 99.998% (∼4.8 log units). The presented results provide a clear advance forward in the use of metal-doped TiO2 for aPDI applications, including the scalable synthesis (kg/day) of well-characterized and robust particles, their facile incorporation into a nontoxic, photostable coating that may be easily and cheaply applied to a multitude of surfaces, and a broad efficacy against drug-resistant Gram-positive and Gram-negative bacteria, as well as against enveloped and nonenveloped viruses.

Autonomous nanomanufacturing of lead-free metal halide perovskite nanocrystals using a self-driving fluidic lab.

Lead-based metal halide perovskite (MHP) nanocrystals (NCs) have emerged as a promising class of semiconducting nanomaterials for a wide range of optoelectronic and photoelectronic applications. However, the intrinsic lead toxicity of MHP NCs has significantly hampered their large-scale device applications. Copper-base MHP NCs with composition-tunable optical properties have emerged as a prominent lead-free MHP NC candidate. However, comprehensive synthesis space exploration, development, and synthesis science studies of copper-based MHP NCs have been limited by the manual nature of flask-based synthesis and characterization methods. In this study, we present an autonomous approach for the development of lead-free MHP NCs via seamless integration of a modular microfluidic platform with machine learning-assisted NC synthesis modeling and experiment selection to establish a self-driving fluidic lab for accelerated NC synthesis science studies. For the first time, a successful and reproducible in-flow synthesis of Cs3Cu2I5 NCs is presented. Autonomous experimentation is then employed for rapid in-flow synthesis science studies of Cs3Cu2I5 NCs. The autonomously generated experimental NC synthesis dataset is then utilized for fast-tracked synthetic route optimization of high-performing Cs3Cu2I5 NCs.

Continuous Ligand-Free Catalysis Using a Hybrid Polymer Network Support.

Although the pharmaceutical and fine chemical industries primarily utilize batch homogeneous reactions to carry out chemical transformations, emerging platforms seek to improve existing shortcomings by designing effective heterogeneous catalysis systems in continuous flow reactors. In this work, we present a versatile network-supported palladium (Pd) catalyst using a hybrid polymer of poly(methylvinylether-alt-maleic anhydride) and branched polyethyleneimine for intensified continuous flow synthesis of complex organic compounds via heterogeneous Suzuki-Miyaura cross-coupling and nitroarene hydrogenation reactions. The hydrophilicity of the hybrid polymer network facilitates the reagent mass transfer throughout the bulk of the catalyst particles. Through rapid automated exploration of the continuous and discrete parameters, as well as substrate scope screening, we identified optimal hybrid network-supported Pd catalyst composition and process parameters for Suzuki-Miyaura cross-coupling reactions of aryl bromides with steady-state yields up to 92% with a nominal residence time of 20 min. The developed heterogeneous catalytic system exhibits high activity and mechanical stability with no detectable Pd leaching at reaction temperatures up to 95 °C. Additionally, the versatility of the hybrid network-supported Pd catalyst is demonstrated by successfully performing continuous nitroarene hydrogenation with short residence times (<5 min) at room temperature. Room temperature hydrogenation yields of >99% were achieved in under 2 min nominal residence times with no leaching and catalyst deactivation for more than 20 h continuous time on stream. This catalytic system shows its industrial utility with significantly improved reaction yields of challenging substrates and its utility of environmentally-friendly solvent mixtures, high reusability, scalable and cost-effective synthesis, and multi-reaction successes.

AlphaFlow: autonomous discovery and optimization of multi-step chemistry using a self-driven fluidic lab guided by reinforcement learning.

Closed-loop, autonomous experimentation enables accelerated and material-efficient exploration of large reaction spaces without the need for user intervention. However, autonomous exploration of advanced materials with complex, multi-step processes and data sparse environments remains a challenge. In this work, we present AlphaFlow, a self-driven fluidic lab capable of autonomous discovery of complex multi-step chemistries. AlphaFlow uses reinforcement learning integrated with a modular microdroplet reactor capable of performing reaction steps with variable sequence, phase separation, washing, and continuous in-situ spectral monitoring. To demonstrate the power of reinforcement learning toward high dimensionality multi-step chemistries, we use AlphaFlow to discover and optimize synthetic routes for shell-growth of core-shell semiconductor nanoparticles, inspired by colloidal atomic layer deposition (cALD). Without prior knowledge of conventional cALD parameters, AlphaFlow successfully identified and optimized a novel multi-step reaction route, with up to 40 parameters, that outperformed conventional sequences. Through this work, we demonstrate the capabilities of closed-loop, reinforcement learning-guided systems in exploring and solving challenges in multi-step nanoparticle syntheses, while relying solely on in-house generated data from a miniaturized microfluidic platform. Further application of AlphaFlow in multi-step chemistries beyond cALD can lead to accelerated fundamental knowledge generation as well as synthetic route discoveries and optimization.

Development and applications of a microfluidic reactor with multiple analytical probes.

We report the development of a versatile microfluidic (MF) reactor with multiple analytical probes, which can be used for (i) quantitative characterisation of molecular vibrational signatures of reactants or products, (ii) the localised real-time monitoring of temperature and (iii) site-specific measurements of pH of the reaction system. The analytical probes utilised for in situ reaction analysis include an ATR-FTIR probe, a temperature probe, and a pH probe. We demonstrate the applications of the MF reactor with integrated probes for the parallel monitoring of multiple variables in acid/base neutralisation reaction, of changes in buffer pH, temperature, and vibrational absorption bands, and for monitoring the kinetics of the reaction between CO(2) and a buffer system with therapeutic applications.

Continuous Room-Temperature Hydrogen Release from Liquid Organic Carriers in a Photocatalytic Packed-Bed Flow Reactor.

Despite the potential of hydrogen (H2 ) storage in liquid organic carriers to achieve carbon neutrality, the energy required for H2 release and the cost of catalyst recycling have hindered its large-scale adoption. In response, a photo flow reactor packed with rhodium (Rh)/titania (TiO2 ) photocatalyst was reported for the continuous and selective acceptorless dehydrogenation of 1,2,3,4-tetrahydroquinoline to H2 gas and quinoline under visible light irradiation at room temperature. The tradeoff between the reactor pressure drop and its photocatalytic surface area was resolved by selective in-situ photodeposition of Rh in the photo flow reactor post-packing on the outer surface of the TiO2 microparticles available to photon flux, thereby reducing the optimal Rh loading by 10 times compared to a batch reactor, while facilitating catalyst reuse and regeneration. An example of using quinoline as a hydrogen acceptor to lower the energy of the hydrogen production step was demonstrated via the water-gas shift reaction.

Recyclable cooperative catalyst for accelerated hydroaminomethylation of hindered amines in a continuous segmented flow reactor.

Synthesis of hindered amines using the atom-efficient hydroaminomethylation (HAM) route remains a challenge. Here, we report a general and accelerated HAM in segmented flow, achieved via a cooperative effect between rhodium (Rh)/N-Xantphos and a co-catalyst (2-Fluoro-4-methylbenzoic acid) to increase the reactivity by 70 fold when compared to Rh/Xantphos in batch reactors. The cooperation between Rh and the co-catalyst facilitates the cleavage of the H-H bond and drives the equilibrium-limited condensation step forward. Online reaction optimization expands the scope to include alkyl, aryl, and primary amines. In-flow solvent tuning enables selectivity switching from amine to enamine without the need for changing the ligand. Furthermore, leveraging the ionic nature of the catalyst, we present a robust Rh recovery strategy up to 4 recycles without loss of activity.

Continuous Room-Temperature Hydrogen Release from Liquid Organic Carriers in a Photocatalytic Packed-Bed Flow Reactor.

Invited for this month's cover is the group of Prof. Dr. Milad Abolhasani at North Carolina State University. The image shows an energy-efficient strategy for on-site and room-temperature hydrogen release from liquid organic hydrogen carriers. The Research Article itself is available at 10.1002/cssc.202200733.

Flow Chemistry: A Sustainable Voyage Through the Chemical Universe en Route to Smart Manufacturing.

Microfluidic devices and systems have entered many areas of chemical engineering, and the rate of their adoption is only increasing. As we approach and adapt to the critical global challenges we face in the near future, it is important to consider the capabilities of flow chemistry and its applications in next-generation technologies for sustainability, energy production, and tailor-made specialty chemicals. We present the introduction of microfluidics into the fundamental unit operations of chemical engineering. We discuss the traits and advantages of microfluidic approaches to different reactive systems, both well-established and emerging, with a focus on the integration of modular microfluidic devices into high-efficiency experimental platforms for accelerated process optimization and intensified continuous manufacturing. Finally, we discuss the current state and new horizons in self-driven experimentation in flow chemistry for both intelligent exploration through the chemical universe and distributed manufacturing.

Intensified recovery of switchable hydrophilicity solvents in flow.

We present an integrated flow chemistry strategy using two membrane-based flow reactors to enhance the extraction and recovery rates of switchable hydrophilicity solvents (SHSs) by five times compared to batch reactors. The developed green flow chemistry strategy achieves an overall single-pass recovery efficiency of 60.1% for 2-(dibutyl amino)ethanol.