Scale-up of microdroplet reactions by heated ultrasonic nebulization

Dramatically higher rates for a variety of chemical reactions have been reported in microdroplets compared with those in the liquid bulk phase. However, the scale-up of microdroplet chemical synthesis has remained a major challenge to the practical application of microdroplet chemistry. Heated ultrasonic nebulization (HUN) was found as a new way for scaling up chemical synthesis in microdroplets. Four reactions were examined, a base-catalyzed Claisen-Schmidt condensation, an oximation reaction from a ketone, a two-phase oxidation reaction without the use of a phase-transfer-catalyst, and an Eschenmoser coupling reaction. These reactions show acceleration of one to three orders of magnitude (122, 23, 6536, and 62) in HUN microdroplets compared to the same reactions in bulk solution. Then, using the present method, the scale-up of the reactions was achieved at an isolated rate of 19 mg min^-1 for the product of the Claisen-Schmidt condensation, 21 mg min^-1 for the synthesis of benzophenone oxime from benzophenone, 31 mg min^-1 for the synthesis of 4-methoxybenzaldehyde from 4-methoxybenzyl alcohol, and 40 mg min^-1 for the enaminone product of the Eschenmoser coupling reaction.