Scalable Continuous Synthesis of Grignard Reagents from in Situ-Activated Magnesium Metal

Abstract

The continuous synthesis of Grignard reagents has been investigated under continuous processing conditions using Mg turnings at variable liquid throughputs and concentrations. A novel process window easily accessible through continuous processing was employed, namely, using a large molar access of Mg turnings within the reactor and achieving Mg activation by mechanical means. A laboratory and a 10-fold-increased pilot-scale reactor setup were built and evaluated, including integrated inline analytics via ATR-IR measurements. The main goal of this work was to explore the full potential of classic Grignard reagent formation through the use of scalable flow chemistry and to allow for fast and safe process optimization. It was found that on both the laboratory and pilot scales, full conversion of the employed halides could be achieved with a single passage through the reactor. Furthermore, Grignard reagent yields of 89−100% were reached on the laboratory scale.

Mechanochemical Grignard Reactions with Gaseous CO2 and Sodium Methyl Carbonate**

“…Probably, this extra step enlarged surface areas and removed passivated metal surfaces, as previously suggested for flowchemistry setups of magnesium insertions into aryl halide bonds and for the industrial scale production of Grignard reagents. [3,15,16] Although many mechanochemical reactions are solventfree, [17] trace amounts of solvents often significantly affect the reaction rates. Such liquid-assisted grinding (LAG) conditions can be quantified by the parameter η [η = V (solvent in μL)/m (reagents in mg)].…”

Scalable Continuous Synthesis of Organozinc Reagents and Their Immediate Subsequent Coupling Reactions

“…For the synthesis of RZnX reagents, a laboratory-scale reactor as designed and manufactured via 3D laser melting by Fraunhofer IMM for Grignard reagent formation was used. For the case of filling with Mg turnings, a behavior close to plug-flow was found (Bodenstein numbers of up to 93 at flow rates between 1 and 4 mL/min), and a similar behavior is expected here; however, it has not been investigated in detail for Zn granules.…”

“…Laboratory-scale reactor for the synthesis of organometallic reactive intermediates via solids processing. Used with permission from ref . Copyright 2020 American Chemical Society.…”

Recent Advances in Nonprecious Metal Catalysis

“…While examples of sp 2 –sp 3 C–C coupling of unactivated boronic ester nucleophiles with alkyl halides mediated by well-defined Fe complexes are starting to emerge, , albeit with strong bases, Kumada coupling is more frequently encountered, and examples of such couplings on a large scale in the synthesis of pharmaceuticals have been reported. − Although Grignard reagents are quite reactive, functional group tolerance can be obtained due to the mild operating conditions of Fe-catalyzed Kumada coupling, which promote the desired coupling over impurity formation. , As a large number of boronic acids or esters are prepared through the intermediacy of a Grignard reagent (or the more reactive aryl lithium), interception of these intermediates could improve throughput as well as reduce PMI (process mass intensity). Furthermore, the possibility of forming Grignard reagents in a continuous, on-demand manner would improve the overall safety of such a process …”

“…Furthermore, the possibility of forming Grignard reagents in a continuous, on-demand manner would improve the overall safety of such a process. 46 Although a large number of ligands (phosphine, Nheterocyclic carbenes, amine, amides and ureas, etc.) have been shown to effectively modulate the activity of Fe-based catalysts, 47−52 the current scope of the electrophilic partner does not include neutral or electron-rich aryl chlorides.…”