Is Reaction Acceleration of Microdroplet Chemistry Favorable to Controlling the Enantioselectivity?

Microdroplet chemistry has been proven to amazingly accelerate many chemical and biological reactions in the past 2 decades. Current microdroplet accelerated reactions are predominantly symmetric synthetic but minorly asymmetric synthetic reactions, where stereoselectivity is scarcely concerned. This study selected unimolecular and bimolecular reactions, multicomponent Passerini reactions, and enzymatic ketone reduction as the model reactions to illustrate whether reaction acceleration of microdroplet chemistry is favorable to retaining a chiral center and controlling the enantioselectivity or not. The results illustrated that microdroplet chemistry did not disrupt pre-existing stereogenic centers in chiral starting materials during reactions but did harm to stereospecificity in asymmetric catalysis by chiral catalysts and chiral organic ligands with the exclusion of enzymatic reactions. Our preliminary study reminds us of more cautions to the product enantioselectivity when conducting asymmetric catalysis in microdroplets. We also hope this study may promote more valuable further research on the stereoselectivity of microdroplet chemistry.

Suzuki C-C Coupling in Paper Spray Ionization: Microsynthesis of Biaryls and High-Sensitivity MS Detection of Aryl Bromides.

Suzuki-Miyaura cross-coupling is one of the most powerful strategies for constructing biaryl compounds. However, classic Suzuki-Miyaura coupling suffers from hour-scale reaction time and competitive protodeboronation. To address these problems, a mild nonaqueous potassium trimethylsilanolate (TMSOK)-assisted Suzuki-Miyaura coupling strategy was designed for the microsynthesis of biaryls in paper spray ionization (PSI). Due to the acceleration power facilitated by microdroplet chemistry in reactive PSI, the microsynthesis of biaryls by reactive PSI was accomplished within minutes with comparable yields to the bulk, showing good substrate applicability from 32 Suzuki-Miyaura reactions of aryl bromides and aryl boronic acid/borates bearing different substituents. Based on the above TMSOK-assisted Suzuki-Miyaura coupling strategy, we further developed a high-sensitivity and selective PSI mass spectrometry (MS) method for quantitative analysis of aryl bromides, a class of environmentally persistent organic pollutants that cannot be directly detected by ambient mass spectrometry due to their low ionization efficiency. In situ derivatization of aryl bromides was achieved with aryl borates bearing quaternary ammonium groups in PSI. The proposed PSI-MS method shows good linearity over the 0.01-10 µmol L-1 range with low detection limits of 1.8-4.8 nmol L-1 as well as good applicability to the rapid determination of six aryl bromides in three environmental water samples. The proposed PSI-MS method also shows good applicability to brominated flame retardants (polybrominated diphenyls/diphenyl esters). Overall, this study provides a simple, rapid, low-cost, high-sensitivity, and high-selectivity strategy for trace aryl bromides and other brominated pollutants in real samples with minimal/no sample pretreatment.

Direct Phosphonylation of N-Phenyltetrahydroisoquinolines in Microdroplets.

Because of their unique properties and high biological activities, organophosphorus compounds have been used worldwide in agricultural, industrial, medicinal, and veterinary applications. Conventional strategies for direct phosphonylation suffer from the usage of stoichiometric or excessive metallic or nonmetallic catalysts and long reaction times under harsh conditions, leading to a strong desire for environment-friendly protocols for phosphonylation. A protocol for the accelerated phosphonylation of N-phenyltetrahydroisoquinolines in minutes was developed without the use of any catalyst in microdroplets. The phosphonylation process was completed (>85% yields) in 10 min at 40 °C using 0.8 equiv 2,3-dicyano-5,6-dichlorobenzoquinone as the oxidant and acetonitrile as the solvent. The microdroplet phosphonylation strategy showed good suitability to alkyl phosphites and N-phenyltetrahydroisoquinolines bearing electron-withdrawing and electron-donating substitutes, and the yields of the microdroplet reaction were much greater than those of the bulk (accelerated by two orders of magnitude from the ratio of the rate constants using the microdroplet and the bulk method). Furthermore, microdroplet phosphonylation can be scaled up to a 1-phenyl-2-dimethylphosphonite-1,2,3,4-tetrahydroisoquinoline amount of 510 mg h-1 by spraying 0.1 mol L-1 N-phenyltetrahydroisoquinoline at 300 µL min-1. These figures of merit make it a promising alternative to classic organic methodologies for the synthesis of organophosphorus compounds.