Enabling Technologies in Carbohydrate Chemistry: Automated Glycan Assembly, Flow Chemistry and Data Science.

The synthesis of defined oligosaccharides is a complex task. Several enabling technologies have been introduced in the last two decades to facilitate synthetic access to these valuable biomolecules. In this concept, we describe the technological solutions that have advanced glycochemistry using automated glycan assembly, flow chemistry and data science as examples. We highlight how the synergies between these different technologies can further advance the field, with progress toward the realization of a self-driving lab for glycan synthesis.

Intraligand Charge Transfer Enables Visible-Light-Mediated Nickel-Catalyzed Cross-Coupling Reactions.

We demonstrate that several visible-light-mediated carbon-heteroatom cross-coupling reactions can be carried out using a photoactive NiII precatalyst that forms in situ from a nickel salt and a bipyridine ligand decorated with two carbazole groups (Ni(Czbpy)Cl2 ). The activation of this precatalyst towards cross-coupling reactions follows a hitherto undisclosed mechanism that is different from previously reported light-responsive nickel complexes that undergo metal-to-ligand charge transfer. Theoretical and spectroscopic investigations revealed that irradiation of Ni(Czbpy)Cl2 with visible light causes an initial intraligand charge transfer event that triggers productive catalysis. Ligand polymerization affords a porous, recyclable organic polymer for heterogeneous nickel catalysis of cross-coupling reactions. The heterogeneous catalyst shows stable performance in a packed-bed flow reactor during a week of continuous operation.

Heterogeneous metallaphotoredox catalysis in a continuous-flow packed-bed reactor.

Metallaphotoredox catalysis is a powerful and versatile synthetic platform that enables cross-couplings under mild conditions without the need for noble metals. Its growing adoption in drug discovery has translated into an increased interest in sustainable and scalable reaction conditions. Here, we report a continuous-flow approach to metallaphotoredox catalysis using a heterogeneous catalyst that combines the function of a photo- and a nickel catalyst in a single material. The catalyst is embedded in a packed-bed reactor to combine reaction and (catalyst) separation in one step. The use of a packed bed simplifies the translation of optimized batch reaction conditions to continuous flow, as the only components present in the reaction mixture are the substrate and a base. The metallaphotoredox cross-coupling of sulfinates with aryl halides was used as a model system. The catalyst was shown to be stable, with a very low decrease of the yield (≈1% per day) during a continuous experiment over seven days, and to be effective for C-O arylations when carboxylic acids are used as nucleophile instead of sulfinates.

Energy-Efficient Solar Photochemistry with Luminescent Solar Concentrator Based Photomicroreactors.

The sun is the most sustainable light source available on our planet, therefore the direct use of sunlight for photochemistry is extremely appealing. Demonstrated here, for the first time, is that a diverse set of photon-driven transformations can be efficiently powered by solar irradiation with the use of solvent-resistant and cheap luminescent solar concentrator based photomicroreactors. Blue, green, and red reactors can accommodate both homogeneous and multiphase reaction conditions, including photochemical oxidations, photocatalytic trifluoromethylation chemistry, and metallaphotoredox transformations, thus spanning applications over the entire visible-light spectrum. To further illustrate the efficacy of these novel solar reactors, medicinally relevant molecules, such as ascaridole and an intermediate of artemisinin, were prepared as well.

Applications of Continuous-Flow Photochemistry in Organic Synthesis, Material Science, and Water Treatment.

Continuous-flow photochemistry in microreactors receives a lot of attention from researchers in academia and industry as this technology provides reduced reaction times, higher selectivities, straightforward scalability, and the possibility to safely use hazardous intermediates and gaseous reactants. In this review, an up-to-date overview is given of photochemical transformations in continuous-flow reactors, including applications in organic synthesis, material science, and water treatment. In addition, the advantages of continuous-flow photochemistry are pointed out and a thorough comparison with batch processing is presented.

A Fully Automated Continuous-Flow Platform for Fluorescence Quenching Studies and Stern-Volmer Analysis.

Herein, we report the first fully automated continuous-flow platform for fluorescence quenching studies and Stern-Volmer analysis. All the components of the platform were automated and controlled by a self-written Python script. A user-friendly software allows even inexperienced operators to perform automated screening of novel quenchers or Stern-Volmer analysis, thus accelerating and facilitating both reaction discovery and mechanistic studies. The operational simplicity of our system affords a time and labor reduction over batch methods while increasing the accuracy and reproducibility of the data produced. Finally, the applicability of our platform is elucidated through relevant case studies.

A Leaf-Inspired Luminescent Solar Concentrator for Energy-Efficient Continuous-Flow Photochemistry.

The use of solar light to promote chemical reactions holds significant potential with regard to sustainable energy solutions. While the number of visible light-induced transformations has increased significantly, the use of abundant solar light has been extremely limited. We report a leaf-inspired photomicroreactor that constitutes a merger between luminescent solar concentrators (LSCs) and flow photochemistry to enable green and efficient reactions powered by solar irradiation. This device based on fluorescent dye-doped polydimethylsiloxane collects sunlight, focuses the energy to a narrow wavelength region, and then transports that energy to embedded microchannels where the flowing reactants are converted.

Development of an Off-Grid Solar-Powered Autonomous Chemical Mini-Plant for Producing Fine Chemicals.

Photochemistry using inexhaustible solar energy is an eco-friendly way to produce fine chemicals outside the typical laboratory or chemical plant environment. However, variations in solar irradiation conditions and the need for an external energy source to power electronic components limits the accessibility of this approach. In this work, a chemical solar-driven "mini-plant" centred around a scaled-up luminescent solar concentrator photomicroreactor (LSC-PM) was built. To account for the variations in solar irradiance at ground level and passing clouds, a responsive control system was designed that rapidly adapts the flow rate of the reagents to the light received by the reaction channels. Supplying the plant with solar panels, integrated into the module by placing it behind the LSC to utilize the transmitted fraction of the solar irradiation, allowed this setup to be self-sufficient and fully operational off-grid. Such a system can shine in isolated environments and in a distributed manufacturing world, allowing to decentralize the production of fine chemicals.

Discovering New Chemistry with an Autonomous Robotic Platform Driven by a Reactivity-Seeking Neural Network.

We present a robotic chemical discovery system capable of navigating a chemical space based on a learned general association between molecular structures and reactivity, while incorporating a neural network model that can process data from online analytics and assess reactivity without knowing the identity of the reagents. Working in conjunction with this learned knowledge, our robotic platform is able to autonomously explore a large number of potential reactions and assess the reactivity of mixtures, including unknown chemical spaces, regardless of the identity of the starting materials. Through the system, we identified a range of chemical reactions and products, some of which were well-known, some new but predictable from known pathways, and some unpredictable reactions that yielded new molecules. The validation of the system was done within a budget of 15 inputs combined in 1018 reactions, further analysis of which allowed us to discover not only a new photochemical reaction but also a new reactivity mode for a well-known reagent (p-toluenesulfonylmethyl isocyanide, TosMIC). This involved the reaction of 6 equiv of TosMIC in a "multistep, single-substrate" cascade reaction yielding a trimeric product in high yield (47% unoptimized) with the formation of five new C-C bonds involving sp-sp2 and sp-sp3 carbon centers. An analysis reveals that this transformation is intrinsically unpredictable, demonstrating the possibility of a reactivity-first robotic discovery of unknown reaction methodologies without requiring human input.

Solar Photochemistry in Flow.

In recent years, photochemistry has been a highly active research field. This renaissance is linked to the upsurge of photoredox catalysis, a versatile platform for synthetic methodologies using visible light photons as a traceless reagent. In contrast with UV, visible light constitutes almost half of the ground solar irradiance, making the use of solar light in chemistry a sustainable and viable possibility. However, the direct use of sunlight to power chemical reactions is still little explored. This can be explained by both the hurdles associated with solar radiation (e.g., its variability, irreproducibility, high IR content, etc.) and the need for a specialized photoreactor. Most of these issues can be tackled with technological solutions, and especially with the recourse to flow chemistry. Flow chemistry goes hand in hand with photochemistry thanks to the uniform irradiation it provides to the reaction. Furthermore, a continuous-flow reactor can be easily integrated with different solar collectors (including compound parabolic concentrators and luminescent solar concentrators) and constitutes the most efficient approach to solar photochemistry. After a description of the characteristics of the solar radiation relevant to chemistry, this chapter critically describes the different type of solar photoreactors and their applications in synthetic organic chemistry. Finally, an outlook on the future of solar photochemistry in flow is included.

Scale-up of a Luminescent Solar Concentrator-Based Photomicroreactor via Numbering-up.

The use of solar energy to power chemical reactions is a long-standing dream of the chemical community. Recently, visible-light-mediated photoredox catalysis has been recognized as the ideal catalytic transformation to convert solar energy into chemical bonds. However, scaling photochemical transformations has been extremely challenging due to Bouguer-Lambert-Beer law. Recently, we have pioneered the development of luminescent solar concentrator photomicroreactors (LSC-PMs), which display an excellent energy efficiency. These devices harvest solar energy, convert the broad solar energy spectrum to a narrow-wavelength region, and subsequently waveguide the re-emitted photons to the reaction channels. Herein, we report on the scalability of such LSC-PMs via a numbering-up strategy. Paramount in our work was the use of molds that were fabricated via 3D printing. This allowed us to rapidly produce many different prototypes and to optimize experimentally key design aspects in a time-efficient fashion. Reactors up to 32 parallel channels have been fabricated that display an excellent flow distribution using a bifurcated flow distributor (standard deviations below 10%). This excellent flow distribution was crucial to scale up a model reaction efficiently, displaying yields comparable to those obtained in a single-channel device. We also found that interchannel spacing is an important and unique design parameter for numbered-up LSC-PMs, which influences greatly the photon flux experienced within the reaction channels.