Preparation of Grignard Reagents:  FTIR and Calorimetric Investigation for Safe Scale-Up

Preparation of Grignard reagents from organic halides and magnesium pose potential safety hazards on scale-up due to their high exothermic potential which can lead to overpressurization, discharge of contents, or explosion. One of the main challenges arises in ensuring the reaction has initiated before excessive accumulation of organic halide occurs or that the reaction does not stall and then reinitiate. Specifically, in production-scale equipment, it is sometimes difficult to ascertain whether initiation has occurred at all and whether it is safe to proceed. By using in situ infrared technology (FTIR), we have developed a method for safer scale-up of Grignard chemistry that can definitively identify that initiation has occurred. The process would involve adding approximately 5% of the organic halide charge and waiting for the initiation to occur using an in situ FTIR probe. FTIR spectroscopy can be used to monitor the accumulation of the halide and reveal when initiation occurs by the resulting decrease in the infrared absorbance. Once it has been determined that the organic halide has reacted as a result of the initiation, it is safe to proceed with the remaining halide charge. The organic halide concentration can then be continuously monitored after initiation to ensure the reaction does not stall or to halt the feed if it does stall. Further, it was shown that IR can be used to quantify the amount of water that is present in THF which is needed to confirm that the THF is dry. The IR results along with reaction calorimetry and vent-sizing data are discussed.