Accelerated investigation of complex reaction cascades via digital aerosol chemistry coupled to online mass spectrometry

The study of self-assembly is complicated by the fleeting nature of many intermediates, as well as poor observability due to insoluble products and reaction conditions that preclude real-time monitoring. This obscures mechanisms and prevents reaction optimisation. We present a novel programmable platform combining aerosol chemistry with online mass spectrometry that radically expands the scope and efficiency of observing the formation of self-assembled structures via reaction cascades via a rapid feedback loop that facilitates exploration of diverse stoichiometries and reaction conditions. We demonstrate the versatility of our workflow via three distinct case studies: anion-initiated polymerization of cyanoacrylate, macrocyclic Schiff base synthesis, and the self-assembly of a covalent organic framework. Real-time online mass spectrometry revealed short-lived intermediates across all systems, helping to elucidate reaction pathways and mechanisms. Product distribution was shown to be responsive to the timing and activation of reagent aerosol sources, opening up the possibility of programmatic control over reaction outcomes and algorithmic optimisation for specific products. The wide applicability of this automated workflow — amenable to the study of small molecules, as well as linear and networked macromolecules — is amplified by its exceptionally short feedback loop thanks to near-instant reagent release and rapid mass-spectrometric readout. A powerful and efficient tool for mechanism elucidation as well as the synthesis and discovery of complex functional architectures, it has potential applications in catalysis, materials science, and sustainable industrial processes.