Encapsulated droplet array for intensified micromole-scale high-throughput reaction screening

The automated high-throughput experimentation (HTE) technology facilitates exploring enormous parametric space of chemical reactions with minimal time and material consumptions. However, the widely used microwell plate-based and flow-based screening approaches are limited by their ability to handle harsh reaction conditions and highly parallel combinatorial screening, respectively. Herein, we report an encapsulated droplet array (EDA) technology to overcome these challenges. By confining microliter-scale reaction droplets within a chemically inert polypropylene pocket reinforced by an aluminum chassis, it enables reactions to be executed under elevated temperatures (up to 105 °C) and pressures (up to 7 atm) in a massively parallel manner (48 reactions per EDA plate). Its versatility and applicability for combinatorial screening under harsh conditions are demonstrated across various bond-forming chemistries, including aminolysis reaction, amide condensation, nucleophilic aromatic substitution (S_NAr) reaction, Buchwald-Hartwig C-N amination, solid-supported palladium catalyzed Suzuki-Miyaura coupling, and metallophotoredox catalyzed C(sp²)-C(sp³) coupling. In addition, a fully automated platform is developed to achieve end-to-end droplet preparation, encapsulation, reaction, and analysis, illustrating the seamless integration with standard automated liquid-handling systems.