Automated stereocontrolled assembly-line synthesis of organic molecules

Song

et al. 2023

Preprint

Although continuous-flow synthesis using microtubing reactors has provided a wealth of opportunities for photochemical synthesis and has proven particularly beneficial in scaling up processes, handling solids and slow reactions remains major hurdles that have hampered its broad application. Here, we present a solution to these issues by changing the continuous-flow mode to a high-speed circulation-flow mode. The high flow rate set in a circulation microflow reactor overcomes solid sedimentation to prevent clogging and improve mixing efficiency. We successfully conducted 100 g-scale C-N and C-S cross-couplings using a heterogeneous photocatalyst and a nickel catalyst in the microflow reactor that significantly outperformed conventional batch reactors. The photocatalyst was recycled and reused 10 times to achieve kg-scale synthesis without obvious deactivation. Even though the reaction occurred in batch mode, semi-continuous production was achieved via automated feeding and collection, and a photo-promoted gas/liquid/solid three-phase trifluoromethylation reaction was employed to produce the drug trifluridine on a kg scale. Our study suggests that a circulation flow reactor with high flow speed will become a crucial tool in the synthetic chemist’s toolbox, owing to its simple infrastructure, ease of operation and automation, significant efficiency improvement compared to conventional batch reactors, scalability, improved safety and tolerance of solids.

Section: Resultsmentioning

confidence: 99%

High-speed circulation microflow synthesis facilitating practical large-scale heterogeneous photocatalysis

Song

et al. 2023

Preprint

“…Automated reaction screening and optimization has undergone extensive development in the past decade to accelerate the molecule discovery and process optimization. − Especially, the recent emergence of modern artificial intelligence (AI) demands large datasets to train an accurate prediction neural model. Compared to thermal chemistry and photochemistry, complications caused by electrode insertion, wire connection, reactor sealing, and high-cost potentiostats impede the development of automated electrosynthesis platform .…”

Section: Resultsmentioning

confidence: 99%

Wireless Electrochemical Reactor for Accelerated Exploratory Study of Electroorganic Synthesis

Chen,

2023

ACS Cent. Sci.

Electrosynthesis is an emerging tool to construct value-added fine chemicals under mild and sustainable conditions. However, the complex apparatus required impedes the facile development of new electrochemistry in the laboratory. Herein, we proposed and demonstrated the concept of wireless electrochemistry (Wi-eChem) based on wireless power transfer technology. The core of this concept is the dual-function wireless electrochemical magnetic stirrer that provides an electrolysis driving force and mixing simultaneously in a miniaturized form factor. This Wi-eChem system allowed electrochemists to execute electrochemical reactions in a manner similar to traditional organic chemistry without handling wire connections. The controllability, reusability, and versatility were validated with a series of modern electrosynthesis reactions, including electrodecarboxylative etherification, electroreductive olefin−ketone coupling, and electrochemical nickel-catalyzed oxygen atom transfer reaction. Its remarkably simplified operation enabled its facile integration into a fully automated robotic synthesis platform to achieve autonomous parallel electrosynthesis screening.

“…To overcome these, a commercially available robotic platform (Chemspeed Swing Platform) was used, which is capable of performing reactions in an inert environment and at low temperatures. [13] Automated protocols for iterative Matteson homologations and chiral carbenoid homologations were developed, which required adjustments to be made to the standard laboratory procedures. These included vigorous shaking during addition of n-BuLi, and the replacement of volatile diethyl ether for anhydrous t-butyl methyl ether (TBME) as the solvent.…”

Section: Batch Platformsmentioning

confidence: 99%

Recent Developments in Reactor Automation for Multistep Chemical Synthesis

Clayton

2023

Chemistry Methods

Reactor automation is revolutionising the way new chemical processes are discovered and developed. Assigning repetitive aspects of chemical synthesis to machines, such as experimental execution and data collection, provides more time for researchers to focus on critical interpretation and creative problem solving. The ability to autonomously prepare late‐stage intermediates and complex products, rather than just simple starting materials, will play a central role in applications such as the efficient exploration of chemical space and responsive manufacturing. However, translating automated technologies from specific single‐step tasks to more general multistep syntheses remains a significant challenge, owing to high structural diversity and chemical/physical interdependencies between the steps. Robotic batch and continuous flow platforms are gradually becoming more universal, providing access to a wider range of chemistries required to achieve autonomous multistep synthesis. Advances in process analytical technologies have enhanced our ability to monitor interconnected reactions in real‐time, thus accelerating data collection and giving greater process control for ensuring a high standard of safety and product quality. Integration of these tools with control software creates a feedback loop, which can be harnessed for adaptive and flexible multistep screening or holistic self‐optimisation. This review presents recent developments in the application of automated reactor technologies for multistep chemical synthesis, including batch and continuous flow platforms. Specifically, this review highlights how the integration of control software with advanced process analytical technologies and machine learning algorithms are accelerating the synthesis of complex molecules.