AcceleratedChemistry in Microdroplets

Conspectus We suggest that accelerated reactions in confined volumes, specifically in microdroplets that contain water in contact with air, represent a remarkable, indeed a revolutionary chemical phenomenon. This strong claim is justified by the magnitude of the acceleration effect, by evidence for impact in key areas like reaction screening for drug discovery, by its alignment with sustainable chemistry and by the range of natural phenomena, including geological as well as atmospheric processes, where the effect operates. Accelerated processes in microdroplets enable the rapid conversion of quartz microparticles into hydrophilic silica nanoparticles, the late-stage functionalization of complex biomolecules, and the synthesis of heterocyclic compounds through rapid, environmentally benign 'green' processes that contrast strongly with conventional metal-catalyzed routes. The phenomenon is so unexpected, so unusual, that it has raised skepticism ─ as indeed it should. Compelling evidence for its operation is found in automated high-throughput (HT) experiments in which thousands of reactions are carried out at rates of 1 reaction/second and where accelerated processes occur in microdroplets generated from reaction mixtures during their millisecond flight times to give products that are identified by online mass spectrometry (MS) or deposited on surfaces and then bioassayed. Additional evidence comes from early studies of organic ‘name’ reactions while parallel evidence for just how remarkable this ‘water and air’ chemistry is comes from the transformations of N2. This classically unreactive, diatomic molecule can be oxidized to NO2 or reduced to NH3 using nothing but the special interfacial properties of wet microdroplets. The oxidation state of nitrogen ranges from +4 to −3 in these products, and intermediates with oxidation numbers lying within this range are also observed. Just as remarkably, microparticles of minerals, suspended in microdroplets of water, are broken down to generate nanoparticles simply by spraying the mixture and collecting the spray. Evidence that Si–O bonds are cleaved by the superacidic character of the microdroplets stands in contrast with the fact that nanomaterials can be built up by deposition of solvated ions ─ both processes occurring in sprayed microdroplets. Further evidence for the remarkable range of chemistry that occurs under apparently mild conditions lies in the fact that amino acids can be condensed to create peptides in sprayed droplets, while other esters and PFAS ‘forever’ chemicals can be rapidly hydrolyzed in the same medium. Microdroplet chemistry lies at the convergence of three chronologically distinct but methodologically intersecting domains: accelerated molecular reactions, interfacial inorganic chemistry, and materials evolution under nonequilibrium conditions. Each strand emerged independently, yet microdroplets provide a common physical platform in which they merge through shared interfacial and dynamical principles. From these foundations, the field has naturally expanded in diverse chemical and materials directions. One strand emphasizes accelerated chemical reactivity, where bond-forming reactions proceed on millisecond time scales with selectivity and efficiency, enabling rapid synthetic transformations relevant to pharmaceuticals and fine chemicals. A second strand focuses on inorganic and gas–liquid interfacial chemistry, including the formation of small molecules and ions such as NH3, NO2, sulfates, and nitrates, linking microdroplet chemistry to atmospheric, environmental, and geochemical processes. A third strand centers on materials chemistry, where droplets act as transient reactors for the formation of nanoparticles, nanostructures, and solid-phase materials, driven by coupled evaporation, charge and interfacial stresses, and mechanical deformation, connecting microdroplet phenomena to solid-state chemistry, rock weathering, soil formation, and environmental catalysis. These domains and their varied manifestations and interconnections are evident in the literature and will be discussed sequentially.