Can Accelerated Reactions in Droplets Guide Chemistry at Scale?

Mass spectrometry (MS) is used to monitor chemical reactions in droplets. In almost all cases, such reactions are accelerated relative to the corresponding reactions in bulk, even after correction for concentration effects, and they serve to predict the likely success of scaled‐up reactions performed in microfluidic systems. The particular chemical targets used in these test studies are diazepam, atropine and diphenhydramine. In addition to a yes/no prediction of whether scaled‐up reaction is possible, in some cases valuable information was obtained that helped in optimization of reaction conditions, minimization of by‐products, and choice of catalyst. In a variant on the spray‐based charged droplet experiment, the Leidenfrost effect was used to generate larger, uncharged droplets and the same reactions were studied in this medium. These reactions were also accelerated but to smaller extents than in microdroplets, and they gave results that correspond even more closely to microfluidics data. The fact that MS was also used for online reaction monitoring in the microfluidic systems further enhances the potential role of MS in exploratory organic synthesis.