Breaking Solvent Constraints Enables Sustainable Nanoscale Chemical Synthesis by Acoustic Droplet Ejection

Miniaturized chemical synthesis through acoustic droplet ejection (ADE) is transforming reaction discovery by reducing material consumption and enabling highly parallelized, autonomous workflows. However, its application in organic synthesis has remained largely confined to DMSO and aqueous media, restricting solvent exploration and limiting broader process innovation. Often attributed to the intrinsic physics of acoustic transfer, these constraints may instead reflect historical calibration practices. Here, we establish a data-driven framework for expanding ADE-compatible solvent space toward a more applicable nanoscale reaction chemistry. Through systematic gravimetric analysis of 19 high-boiling organic solvents, including water and DMSO as reference fluids, we identify a broad operating window that supports accurate (deviation < 10%) and reproducible (RSD < 8%) dispensing using existing instrumentation. We further validate this framework via automated assembly of a 384-member Suzuki–Miyaura reaction library, where testing of N,N-dimethylformamide and a bio-based alternative solvent dimethyl isosorbide resulted in broad product formation across diverse substrates. This work decouples solvent choice from historical conventions and opens the route to a reaction-agnostic, solvent-flexible, and sustainable approach for high-throughput reaction discovery, enabling ADE workflows to transition from condition-constrained screening tools to general engines for sustainable, data-driven chemical exploration.