An integrated self-optimizing programmable chemical synthesis and reaction engine

Abstract

Robotic platforms for chemistry are developing rapidly but most systems are not currently able to adapt to changing circumstances in real-time. We present a dynamically programmable system capable of making, optimizing, and discovering new molecules which utilizes seven sensors that continuously monitor the reaction. By developing a dynamic programming language, we demonstrate the 10-fold scale-up of a highly exothermic oxidation reaction, end point detection, as well as detecting critical hardware failures. We also show how the use of in-line spectroscopy such as HPLC, Raman, and NMR can be used for closed-loop optimization of reactions, exemplified using Van Leusen oxazole synthesis, a four-component Ugi condensation and manganese-catalysed epoxidation reactions, as well as two previously unreported reactions, discovered from a selected chemical space, providing up to 50% yield improvement over 25–50 iterations. Finally, we demonstrate an experimental pipeline to explore a trifluoromethylations reaction space, that discovers new molecules.

A limitation of robotic platforms in chemistry is the lack of feedback loops to adjust the conditions in-operando. Here the authors present a dynamically programmable robotic system that uses sensors for real-time adaptation, achieving yield improvements in syntheses and discovering new molecules.