Designing and Engineering Atomically Dispersed Metal Catalysts for CO2 to CO Conversion: From Single to Dual Metal Sites.

The electrochemical CO2 reduction reaction (CO2 RR) is a promising approach to achieving sustainable electrical-to-chemical energy conversion and storage while decarbonizing the emission-heavy industry. The carbon-supported, nitrogen-coordinated, and atomically dispersed metal sites are effective catalysts for CO generation due to their high activity, selectivity, and earth abundance. Here, we discuss progress, challenges, and opportunities for designing and engineering atomic metal catalysts from single to dual metal sites. Engineering single metal sites using a nitrogen-doped carbon model was highlighted to exclusively study the effect of carbon particle sizes, metal contents, and M-N bond structures in the form of MN4 moieties on catalytic activity and selectivity. The structure-property correlation was analyzed by combining experimental results with theoretical calculations to uncover the CO2 to CO conversion mechanisms. Furthermore, dual-metal site catalysts, inheriting the merits of single-metal sites, have emerged as a new frontier due to their potentially enhanced catalytic properties. Designing optimal dual metal site catalysts could offer additional sites to alter the surface adsorption to CO2 and various intermediates, thus breaking the scaling relationship limitation and activity-stability trade-off. The CO2 RR electrolysis in flow reactors was discussed to provide insights into the electrolyzer design with improved CO2 utilization, reaction kinetics, and mass transport.

High Throughput Multidimensional Kinetic Screening in Continuous Flow Reactors.

An automated high throughput multidimensional reaction screening platform based on an inline Fourier-transform infrared spectroscopy is presented. By combining flow chemistry, machine automation and inline analysis, the platform is able to screen reactions in multidimensions (residence time, monomer concentration, degree of polymerization, reaction temperature and monomer conversion) rapidly and efficiently way. Kinetic data libraries associated with high data precision (absolute error <4 %), high reproducibility and high data density are built with ease from the platform. To test the method, we screened the reversible addition-fragmentation chain transfer polymerization of methyl acrylate in unmatched detail, and the ring opening metathesis polymerization of methyl-5-norbornene-2-carboxylate. The method we introduce is a key step in providing "big data" for data driven research in the future, and already at present allows for precise prediction of reaction outcomes within the high-dimensional chemical parameter space that is screened.

Recent Advances in the Electrochemical Synthesis of Organosulfur Compounds.

Organosulfur compounds are being widely used in medicinal chemistry, as well as in organic transformations and in synthetic applications. Because of their interest in many areas, the development of sustainable and green synthetic methods to access various organosulfur compounds has a high influence on the chemistry community. Electroorganic synthesis has become a very valuable methodology for the synthesis of organosulfur compounds during the last decade. The use of electrochemical technology offers a green, sustainable and safe alternative to prepare and modify such compounds. This review summarises recent developments in the preparation of organosulfur compounds such as sulfoxides, sulfones, sulfinic esters, sulfonamides, thiosulfonates, sulfonyl fluorides and sulfoximines under electrochemical reaction conditions.

The Longer Route can be Better: Electrosynthesis in Extended Path Flow Cells.

This personal account provides an overview of work conducted in my research group, and through collaborations with other chemists and engineers, to develop flow electrolysis cells and apply these cells in organic electrosynthesis. First, a brief summary of my training and background in organic synthesis is provided, leading in to the start of flow electrosynthesis in my lab in collaboration with Derek Pletcher. Our work on the development of extended path electrolysis flow reactors is described from a synthetic organic chemist's perspective, including laboratory scale-up to give several moles of an anodic methoxylation product in one day. The importance of cell design is emphasised with regards to achieving good performance in laboratory electrosynthesis with productivities from hundreds of mg h-1 to many g h-1 , at high conversion in a selective fashion. A simple design of recycle flow cell that can be readily constructed in a small University workshop is also discussed, including simple modifications to improve cell performance. Some examples of flow electrosyntheses are provided, including Shono-type oxidation, anodic cleavage of protecting groups, Hofer-Moest reaction of cubane carboxylic acids, oxidative esterification and amidation of aldehydes, and reduction of aryl halides.

Aqueous Flow Reactor and Vapour-Assisted Synthesis of Aluminium Dicarboxylate Metal-Organic Frameworks with Tuneable Water Sorption Properties.

Energy-efficient indoors temperature and humidity control can be realised by using the reversible adsorption and desorption of water in porous materials. Stable microporous aluminium-based metal-organic frameworks (MOFs) present promising water sorption properties for this goal. The development of synthesis routes that make use of available and affordable building blocks and avoid the use of organic solvents is crucial to advance this field. In this work, two scalable synthesis routes under mild reaction conditions were developed for aluminium-based MOFs: (1) in aqueous solutions using a continuous-flow reactor and (2) through the vapour-assisted conversion of solid precursors. Fumaric acid, its methylated analogue mesaconic acid, as well as mixtures of the two were used as linkers to obtain polymorph materials with tuneable water sorption properties. The synthesis conditions determine the crystal structure and either the MIL-53 or MIL-68 type structure with square-grid or kagome-grid topology, respectively, is formed. Fine-tuning resulted in new MOF materials thus far inaccessible through conventional synthesis routes. Furthermore, by varying the linker ratio, the water sorption properties can be continuously adjusted while retaining the sigmoidal isotherm shape advantageous for heat transformation and room climatisation applications.

Flow Chemistry in Contemporary Chemical Sciences: A Real Variety of Its Applications.

Flow chemistry is an area of contemporary chemistry exploiting the hydrodynamic conditions of flowing liquids to provide particular environments for chemical reactions. These particular conditions of enhanced and strictly regulated transport of reagents, improved interface contacts, intensification of heat transfer, and safe operation with hazardous chemicals can be utilized in chemical synthesis, both for mechanization and automation of analytical procedures, and for the investigation of the kinetics of ultrafast reactions. Such methods are developed for more than half a century. In the field of chemical synthesis, they are used mostly in pharmaceutical chemistry for efficient syntheses of small amounts of active substances. In analytical chemistry, flow measuring systems are designed for environmental applications and industrial monitoring, as well as medical and pharmaceutical analysis, providing essential enhancement of the yield of analyses and precision of analytical determinations. The main concept of this review is to show the overlapping of development trends in the design of instrumentation and various ways of the utilization of specificity of chemical operations under flow conditions, especially for synthetic and analytical purposes, with a simultaneous presentation of the still rather limited correspondence between these two main areas of flow chemistry.

Platinum- and CuOx -Decorated TiO2 Photocatalyst for Oxidative Coupling of Methane to C2 Hydrocarbons in a Flow Reactor.

Oxidative coupling of methane (OCM) is considered one of the most promising catalytic technologies to upgrade methane. However, C2 products (C2 H6 /C2 H4 ) from conventional methane conversion have not been produced commercially owing to competition from overoxidation and carbon accumulation at high temperatures. Herein, we report the codeposition of Pt nanoparticles and CuOx clusters on TiO2 (PC-50) and use of the resulting photocatalyst for OCM in a flow reactor operated at room temperature under atmospheric pressure for the first time. The optimized Cu0.1 Pt0.5 /PC-50 sample showed a highest yield of C2 product of 6.8 µmol h-1 at a space velocity of 2400 h-1 , more than twice the sum of the activity of Pt/PC-50 (1.07 µmol h-1 ) and Cu/PC-50 (1.9 µmol h-1 ), it might also be the highest among photocatalytic methane conversions reported so far under atmospheric pressure. A high C2 selectivity of 60 % is also comparable to that attainable by conventional high-temperature (>943 K) thermal catalysis. It is proposed that Pt functions as an electron acceptor to facilitate charge separation, while holes could transfer to CuOx to avoid deep dehydrogenation and the overoxidation of C2 products.

Transaminase-Catalyzed Continuous Synthesis of Biogenic Aldehydes.

The physiological role of biogenic aldehydes, such as 3,4-dihydroxyphenylacetaldehyde (DOPAL), has been associated with cardiovascular and neurodegenerative disorders. The availability of these substrates is limited and robust synthetic methodologies would greatly facilitate further biological studies. Herein, a transaminase-mediated single-step process in continuous mode, which leads to excellent product yields (90-95 %), is reported. Coimmobilization of the pyridoxal phosphate (PLP) cofactor eliminated the need for exogenous addition of this reagent without affecting the longevity of the system, delivering a truly self-sufficient process.

Precise Polymer Synthesis by Autonomous Self-Optimizing Flow Reactors.

A novel continuous flow system for automated high-throughput screening, autonomous optimization, and enhanced process control of polymerizations was developed. The computer-controlled platform comprises a flow reactor coupled to size exclusion chromatography (SEC). Molecular weight distributions are measured online and used by a machine-learning algorithm to self-optimize reactions towards a programmed molecular weight by dynamically varying reaction parameters (i.e. residence time, monomer concentration, and control agent/initiator concentration). The autonomous platform allows targeting of molecular weights in a reproducible manner with unprecedented accuracy (<2.5 % deviation from pre-selected goal) for both thermal and light-induced reactions. For the first time, polymers with predefined molecular weights can be custom made under optimal reaction conditions in an automated, high-throughput flow synthesis approach with outstanding reproducibility.

Sustainable and Continuous Synthesis of Enantiopure l-Amino Acids by Using a Versatile Immobilised Multienzyme System.

The enzymatic synthesis of α-amino acids is a sustainable and efficient alternative to chemical processes, through which achieving enantiopure products is difficult. To more address this synthesis efficiently, a hierarchical architecture that irreversibly co-immobilises an amino acid dehydrogenase with polyethyleneimine on porous agarose beads has been designed and fabricated. The cationic polymer acts as an irreversible anchoring layer for the formate dehydrogenase. In this architecture, the two enzymes and polymer colocalise across the whole microstructure of the porous carrier. This multifunctional heterogeneous biocatalyst was kinetically characterised and applied to the enantioselective synthesis of a variety of canonical and noncanonical α-amino acids in both discontinuous (batch) and continuous modes. The co-immobilised bienzymatic system conserves more than 50 % of its initial effectiveness after five batch cycles and 8 days of continuous operation. Additionally, the environmental impact of this process has been semiquantitatively calculated and compared with the state of the art.

Highly Productive Oxidative Biocatalysis in Continuous Flow by Enhancing the Aqueous Equilibrium Solubility of Oxygen.

We report a simple, mild, and synthetically clean approach to accelerate the rate of enzymatic oxidation reactions by a factor of up to 100 when compared to conventional batch gas/liquid systems. Biocatalytic decomposition of H2 O2 is used to produce a soluble source of O2 directly in reaction media, thereby enabling the concentration of aqueous O2 to be increased beyond equilibrium solubility under safe and practical conditions. To best exploit this method, a novel flow reactor was developed to maximize productivity (g product L-1 h-1 ). This scalable benchtop method provides a distinct advantage over conventional bio-oxidation in that no pressurized gas or specialist equipment is employed. The method is general across different oxidase enzymes and compatible with a variety of functional groups. These results culminate in record space-time yields for bio-oxidation.

A stereoselective, catalytic strategy for the in-flow synthesis of advanced precursors of rasagiline and tamsulosin.

The diastereoselective, trichlorosilane-mediate reduction of imines, bearing different and removable chiral auxiliaries, in combination either with achiral bases or catalytic amounts of chiral Lewis bases, was investigated to afford immediate precursors of chiral APIs (Active Pharmaceutical Ingredients). The carbon-nitrogen double bond reduction was successfully performed in batch and in flow mode, in high yields and almost complete stereocontrol. By this metal-free approach, the formal synthesis of rasagiline and tamsulosin was successfully accomplished in micro(meso) flow reactors, under continuous flow conditions. The results of these explorative studies represent a new, important step towards the development of automated processes for the preparation of enantiopure biologically active compounds.

Organocatalyzed Photo-Atom Transfer Radical Polymerization of Methacrylic Acid in Continuous Flow and Surface Grafting.

The organocatalyzed photo-atom transfer radical polymerization (photoATRP) using 10-phenylphenothiazine as catalyst is studied toward its use in methacrylic acid (MAA) polymerization and surface grafting. The organocatalyzed photoATRP of methyl methacrylate (MMA) is first optimized for continuous flow synthesis in order to assess the livingness of the polymerization. MMA can be polymerized in batch and in flow; however, conversions are limited by the loss of bromine functionality and hence high conversions have to be traded in with increasing dispersities. Also, MAA is polymerized successfully in continuous flow with similar limitations. Flow conditions are transferred to surface grafting from silanized silicon wafers. The presence of ATRP initiators after silanization is confirmed by secondary ion mass spectrometry and X-ray photoelectron spectroscopy. Dense polymethacrylic acid brush films are successfully produced, which is not directly accessible via classical copper-mediated ATRP techniques.

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.

Stereoselective Catalytic Synthesis of Active Pharmaceutical Ingredients in Homemade 3D-Printed Mesoreactors.

3D-printed flow reactors were designed, fabricated from different materials (PLA, HIPS, nylon), and used for a catalytic stereoselective Henry reaction. The use of readily prepared and tunable 3D-printed reactors enabled the rapid screening of devices with different sizes, shapes, and channel dimensions, aimed at the identification of the best-performing reactor setup. The optimized process afforded the products in high yields, moderate diastereoselectivity, and up to 90 % ee. The method was applied to the continuous-flow synthesis of biologically active chiral 1,2-amino alcohols (norephedrine, metaraminol, and methoxamine) through a two-step sequence combining the nitroaldol reaction with a hydrogenation. To highlight potential industrial applications of this method, a multistep continuous synthesis of norephedrine has been realized. The product was isolated without any intermediate purifications or solvent switches.

A systems approach towards an intelligent and self-controlling platform for integrated continuous reaction sequences.

Performing reactions in flow can offer major advantages over batch methods. However, laboratory flow chemistry processes are currently often limited to single steps or short sequences due to the complexity involved with operating a multi-step process. Using new modular components for downstream processing, coupled with control technologies, more advanced multi-step flow sequences can be realized. These tools are applied to the synthesis of 2-aminoadamantane-2-carboxylic acid. A system comprising three chemistry steps and three workup steps was developed, having sufficient autonomy and self-regulation to be managed by a single operator.

Synthetic Chemistry in Flow: From Photolysis & Homogeneous Photocatalysis to Heterogeneous Photocatalysis.

Photocatalytic synthesis of value-added chemicals has gained increasing attention in recent years owing to its versatility in driving many important reactions under ambient conditions. Selective hydrogenation, oxidation, coupling, and halogenation with a high conversion of the reactants have been realized using designed photocatalysts in batch reactors with small volumes at a laboratory scale; however, scaling-up remains a critical challenge due to inefficient utilization of incident light and active sites of the photocatalysts, resulting in poor catalytic performance that hinders its practical applications. Flow systems are considered one of the solutions for practical applications of light-driven reactions and have experienced great success in photolytic and homogeneous photocatalysis, yet their applications in heterogeneous photocatalysis are still under development. In this perspective, we have summarized recent progress in photolytic and photocatalytic synthetic chemistry performed in flow systems from the view of reactor design with a special focus on heterogeneous photocatalysis. The advantages and limitations of different flow systems, as well as some practical considerations of design strategies are discussed.

Solar-Driven Continuous CO2 Reduction to CO and CH4 using Heterogeneous Photothermal Catalysts: Recent Progress and Remaining Challenges.

The urgent need to reduce the carbon dioxide level in the atmosphere and keep the effects of climate change manageable has brought the concept of carbon capture and utilization to the forefront of scientific research. Amongst the promising pathways for this conversion, sunlight-powered photothermal processes, synergistically using both thermal and non-thermal effects of light, have gained significant attention. Research in this field focuses both on the development of catalysts and continuous-flow photoreactors, which offer significant advantages over batch reactors, particularly for scale-up. Here, we focus on sunlight-driven photothermal conversion of CO2 to chemical feedstock CO and CH4 as synthetic fuel. This review provides an overview of the recent progress in the development of photothermal catalysts and continuous-flow photoreactors and outlines the remaining challenges in these areas. Furthermore, it provides insight in additional components required to complete photothermal reaction systems for continuous production (e. g., solar concentrators, sensors and artificial light sources). In addition, our review emphasizes the necessity of integrated collaboration between different research areas, like chemistry, material science, chemical engineering, and optics, to establish optimized systems and reach the full potential of this technology.

A combined continuous microflow photochemistry and asymmetric organocatalysis approach for the enantioselective synthesis of tetrahydroquinolines.

A continuous-flow asymmetric organocatalytic photocyclization-transfer hydrogenation cascade reaction has been developed. The new protocol allows the synthesis of tetrahydroquinolines from readily available 2-aminochalcones using a combination of photochemistry and asymmetric Brønsted acid catalysis. The photocylization and subsequent reduction was performed with catalytic amount of chiral BINOL derived phosphoric acid diester and Hantzsch dihydropyridine as hydrogen source providing the desired products in good yields and with excellent enantioselectivities.

[3 + 2]-Cycloadditions of nitrile ylides after photoactivion of vinyl azides under flow conditions.

The photodenitrogenation of vinyl azides to 2H-azirines by using a photoflow reactor is reported and compared with thermal formation of 2H-azirines. Photochemically, the ring of the 2H-azirines was opened to yield the nitrile ylides, which underwent a [3 + 2]-cycloaddition with 1,3-dipolarophiles. When diisopropyl azodicarboxylate serves as the dipolarophile, 1,3,4-triazoles become directly accessible starting from the corresponding vinyl azide.