The synthesis of Grignard reagents, which are formed by the reaction of magnesium and organic halides (RX), is hazardous because of the highly exothermic nature of this reaction. In this work, calorimetry and infrared (IR) spectroscopy were used to identify the exothermic mechanism and process hazards for the synthesis of n-butylmagnesium bromide Grignard reagent (n-BuMgBr) in diethyl ether (DE), tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), cyclopentylmethyl ether (CPME), and diethylene glycol butyl ether (DGBE). The latter three solvents were chosen by the substitution principle of the “inherent safety” design concept, which aims to reduce the risk of the target reaction in a fundamental manner. An EasyMax102 calorimeter was used to characterize the exothermic behavior of the reactions using isothermal and isoperibolic experiments carried out in a semi-batch glass reactor coupled with an IR probe to monitor changes in the species and concentrations during the reaction process. An adiabatic TAC-500A calorimeter was also used to understand the adiabatic decomposition behavior of the products obtained in the isothermal experiments under the worst-case (cooling failure and thermal runaway) scenario. Meanwhile, density functional theory calculations were performed to understand the reaction pathway and associated energies based on the experimental data. Further, the risk assessment of thermal runaway was analyzed using a risk matrix and a Stoessel criticality diagram. The results indicate that the risk of the reactions when using 2-MeTHF, CPME, and DGBE are all class 1, making reactions in these solvents inherently safer than those using DE or THF, which were both class-3 risks. These findings provide further evidence that 2-MeTHF, CPME, and DGBE are safer than the typical solvents used for the industrial production of Grignard reagents.

由于镁与有机卤化物（RX）反应形成的格利雅试剂的合成非常危险，因为该反应具有很高的放热性。在这项工作中，量热法和红外（IR）光谱被用来确定用于合成的放热机制和过程危害Ñ -butylmagnesium溴化物的格利雅试剂（Ñ -BuMgBr）在二乙醚（DE），四氢呋喃（THF），2-甲基四氢呋喃（2-MeTHF），环戊基甲基醚（CPME）和二甘醇丁基醚（DGBE）。后三种溶剂是根据“固有安全性”的替代原则选择的设计概念，旨在从根本上降低目标反应的风险。使用EasyMax102量热计来表征反应的放热行为，该反应使用等温和等代谢实验在半间歇玻璃反应器中进行，该反应器与IR探针配合使用，以监测反应过程中物质和浓度的变化。绝热的TAC-500A量热仪还用于了解在最坏情况（冷却失效和热失控）情况下通过等温实验获得的产品的绝热分解行为。同时，根据实验数据进行了密度泛函理论计算，以了解反应路径和相关能量。进一步，使用风险矩阵和Stoessel临界图分析了热失控的风险评估。结果表明，使用2-MeTHF，CPME和DGBE时的反应风险均为1级，因此与使用DE或THF的溶剂（均属于3级风险）相比，在这些溶剂中的反应固有地更安全。这些发现提供了进一步的证据，证明2-MeTHF，CPME和DGBE比工业生产格氏试剂的典型溶剂更安全。