Synthesis of grignard reagents using mechanochemistry

Abstract

Introduction: The Grignard reaction remains widely used in industry for C–C coupling but carries inherent safety concerns. Delayed initiation and stalled reactions, both caused by the passivating oxide layer on the magnesium, can release the accumulated reaction heat rapidly and destabilize the reaction mixture thermally [1]. Several technologies address these concerns. Flow processes such as packed magnesium bed reactors lower the reactive inventory compared to classical semi-batch operation [2]. Mechanochemistry instead facilitates Grignard formation by mechanical activation of the magnesium [3]. Bead milling, closely related to ball milling, uses microbeads that enhance the reaction properties at high rotational speeds and has recently been applied to a more sustainable amide bond formation [4].

Objective: This work aims to develop a bead mill Grignard process that improves safety through mechanical magnesium activation and continuous processing. Benzyl chloride was chosen as an exemplary substrate, as it is known for its pronounced tendency towards side product formation. The process is transferred from Semi-batch operation to, ultimately, a Single-pass mode, accompanied throughout by a safety assessment. Selectivity serves as the key indicator for comparing the operating modes.