High-yield gram-scale organic synthesis using accelerated microdroplet/thin film reactions with solvent recycling

Abstract

A closed system has been designed to perform microdroplet/thin film reactions with solvent recycling capabilities for gram-scale chemical synthesis. Claisen-Schmidt, Schiff base, Katritzky and Suzuki coupling reactions show acceleration factors relative to bulk of 15 to 7700 times in this droplet spray system. These values are much larger than those reported previously for the same reactions in microdroplet/thin film reaction systems. The solvent recycling mode of the new system significantly improves the reaction yield, especially for reactions with smaller reaction acceleration factors. The microdroplet/thin film reaction yield improved on recycling from 33% to 86% and from 32% to 72% for the Katritzky and Suzuki coupling reactions, respectively. The Claisen-Schmidt reaction was chosen to test the capability of this system in gram scale syntheses and rates of 3.18 g per h and an isolated yield of 87% were achieved.

A critical analysis of electrospray techniques for the determination of accelerated rates and mechanisms of chemical reactions in droplets

“…There have been some exciting recent developments in this eld with the formation of large product quantities from preparative synthesis with electrosprayed or sonic sprayed reaction mixtures, up to 3 g per hour. 22,111,112 The distinct goal of understanding the mechanism of reaction rate enhancement in droplets, and how the various possible factors shown in Fig. 2 contribute to such enhancement, requires mastery of the multi-phase kinetics present in the ESI/ESSI-MS experiments.…”

Automated High-Throughput System Combining Small-Scale Synthesis with Bioassays and Reaction Screening

“…Nonetheless, it is important to highlight that despite this uncertainty in reaction location, DESI-based screening of organic reactions is valid and useful, as the conditions found optimal using DESI-MS can be readily translated to more conventional scaled-up synthesis methods such as flow chemistry (besides already existing droplet-based scale-up systems). 89 We have demonstrated this compatibility extensively for the synthesis of products of pharmaceutical interest, such as lomustine, a first-line agent for the treatment of brain tumors and second-line agent for Hodgkin’s lymphoma, 9 and HSN608, a potent pan-active FLT3 inhibitor lead compound for the treatment of acute myeloid leukemia. 12 Furthermore, we have shown in multiple cases that the results obtained by high-throughput DESI-MS are directly comparable to traditional LC-MS screening, although the DESI-based analysis is orders of magnitude faster.…”

“…65,67,86–88 Furthermore, it has been demonstrated that simply collecting the droplets sprayed from a reaction mixture allows the collection of milligram amounts of reaction product. 89 This capability confers a clear advantage for reaction screening: considerable product yields (obtained through a microdroplet-accelerated reaction) can be obtained with little to no incubation time prior to analysis. This is exemplified in the results of the 188 combinatorial reactions on a single plate screened using microdroplet-accelerated reactions with no bulk incubation time ( Fig.…”

Chemical Reaction Monitoring by Ambient Mass Spectrometry

“…Cooks also introduced a scaled-up method with a production rate of 98 mg/h in a thin film (Wei et al, 2017). Recently, the production rate by microdroplet synthesis has been scaled up to approximately 50 mg/min (Nie et al, 2020), which holds great potential for large-scale synthesis by microdroplets.…”