High-Throughput Screening of Conditions for Gas–Liquid Reactions Involving Ozone Gas: A Workflow for Rapid Development and Optimization of Scalable Conditions

Abstract Ozone is an attractive, sustainable oxidant for organic synthesis, yet its adoption in pharmaceutical process development is often limited by safety concerns, poor gas–liquid mass transfer, solvent incompatibilities, and challenges in scaling. Herein, a robust, high-throughput workflow for the rapid development and optimization of scalable ozonolysis reactions is reported. Miniaturized screening using a 96-well high-pressure reaction block in which ozone-containing gas flows through the headspace enabled rapid evaluation of solvent systems, cosolvents, and quenching agents under controlled low-temperature conditions, allowing hundreds of experiments to be conducted with minimal material consumption. Key reaction parameters were efficiently translated to larger-scale sparged tube and bubble reactor platforms, demonstrating a consistent performance across scales. Reaction progress monitoring and temperature-dependent studies suggest that the ozonolysis reaction is influenced by gas–liquid mass-transfer control rather than intrinsic kinetic limitation. The use of immiscible solvent mixtures and sodium sulfite as a quenching agent provided clean phase separations and operationally simple workups while mitigating the safety risks associated with peroxide formation. Collectively, this workflow enables the identification, scale-up, and validation of practical ozone-based oxidations within weeks, providing a general and scalable approach for integrating ozone chemistry into sustainable pharmaceutical process development.