A publication in Angewandte Chemie International Edition

A new paradigm for reaction optimization in organic chemistry



Accelerating the optimization of new processes while minimizing waste generation by combining Quantum Chemistry, Artificial Intelligence, and cutting-edge micro/mesofluidic technologies. Credit : Pauline Bianchi/CiTOS

A study conducted at the CiTOS Lab potentially reshapes the preparation of high-value compounds in organic chemistry. This innovative approach combines Quantum Chemistry and Artificial Intelligence, enabling the generation of optimized process conditions within minutes, completely waste-free. In silico conditions are then instructed to an automated lab-scale flow synthesis system, which executes them within record time. The project establishes a robust foundation for a radical shift in the approach to preparing high-value organic compounds. The results of this study are now published in Angewandte Chemie International Edition.

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et up just over ten years ago by Jean-Christophe Monbaliu, the Center for Integrated Technology and Organic Synthesis (CiTOS) is based on an interdisciplinary strategy combining synthetic organic chemistry, physical and computational organic chemistry and micro/mesofluidic process technology. "Over the past decade, we have gained a renowned expertise in developing innovative, versatile, and efficient fluidic processes for the production of high-value compounds. Our work aims to provide practical solutions to redefine chemical production in the current environmental and safety context," continues the Director of CiTOS. While the adoption of new micro/mesofluidic reactor technologies has often been presented as a de facto solution for agile and safe processes, their implementation remains limited, in part due to the difficulty of anticipating the feasibility of a reaction in these reactors. "It is not easy to change decades worth of expertise with current production tools, and a too radical paradigm shift often faces a form of conservatism despite technological promises," adds the CiTOS director and investigator at the WEL Research Institute.

Fundamental research in organic chemistry primarily relies on the development of new methods and reagents that exploit specific reactivities, allowing to access to molecular diversity and the properties of a wide range of high-value products. This research involves iterative processes of optimization and selection to maximize yields. These iterative processes are both time-consuming, resource-intensive, and waste-generating, even with new micro/mesofluidic technologies. This is particularly concerning in cases where resources are limited or when toxic, highly active, or unstable compounds are involved.

To further accelerate the adoption of micro/mesofluidic technologies, a predictive model combining quantum chemistry and artificial intelligence (ML-DFT) has been developed at CiTOS. "This model predicts experimental data with high precision, such as optimal conditions for temperature, pressure, and reaction time to achieve a desired yield," explains Pauline Bianchi, first author of the study and F.R.S.-FNRS doctoral candidate at CiTOS. The optimized conditions are obtained in silico, solely through computational methods, and do not generate any chemical waste. "These calculated optimal conditions are then executed by an automated flow system. Artificial Intelligence-reinforced Quantum Chemistry protocols swiftly provide non-generic conditions for the synthesis of a wide range of organic derivatives. This is a distinctive advantage for creating molecular diversity when no pre-existing experimental data exist" Pauline Bianchi further elaborates. This ML-DFT requires computational power that is readily available in many chemistry laboratories, facilitating its widespread adoption.

This tool has been successfully applied to electrophilic aminations, a class of reactions particularly relevant to pharmaceutical compound manufacturing. This research holds both fundamental and applied significance, as evidenced by its use in physical organic chemistry to understand reactivity and its application in an industrial collaboration with Mithra Pharmaceuticals.    

Scientific reference

Bianchi, J.-C. M. Monbaliu, Revisiting the Paradigm of Reaction Optimization in Flow with a Priori Computational Reaction Intelligence, Angew. Chem. Int. Ed. 2023, e202311526. https://doi.org/10.1002/anie.202311526   

Full article is available in Open Access

Your contacts at ULiège

Pauline Bianchi

Jean-Christophe Monbaliu


Funding

  • F.R.S.-FNRS (Incentive grant for scientific research MIS F453020F, Jean-Christophe Monbaliu; PhD Fellowship ASP 1.A.054.21F, Pauline Bianchi)
  • WEL Research Institute (WEL-T Advanced WEL-T-CR-2023 A – 05, "Smart Flow Systems", Jean-Christophe Monbaliu).
  • University of Liège, (“Crédit d’opportunité stratégique du Conseil universitaire de la Recherche et de la Valorisation” under Grant No. OPP_CURV_22-44)
  • Computational resources were provided by the “Consortium des Équipements de Calcul Intensif” (CÉCI), funded by the “Fonds de la Recherche Scientifique de Belgique” (F.R.S.-FNRS) under Grant No. 2.5020.11a and by the Walloon Region.

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