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

Abstract

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 ventsizing data are discussed.

Pro und kontra Strömungsreaktoren in der Synthese

“…B. zersetzen. Zur Vermeidung können spektroskopische78 oder kalorimetrische79 In‐situ‐Methoden angewendet werden, allerdings können Konzentrations‐ und Temperaturgradienten sowie niedrige Messgeschwindigkeiten auch bei solchen Methoden die kinetischen Ergebnisse verschleiern. Bei speziellen Mikroreaktoren mit separater Zuführung von Quenchreagentien und spektrokopischer Online‐Überwachung, z.…”

Grignard reagent formation via C–F bond activation: a centenary perspective

“…because of impurities in the reaction mixture) and the addition of an organic halide is continued, the reaction will have the potential for a run-away situation once the initiation starts. However, this problem can be addressed by proper reaction monitoring (by spectroscopic 89 or mass balance-based 90 methods) and adjustment of the organohalide addition rate. In this section, another problem that arises due to the presence of trifluoromethyl groups and has not been entirely understood so far, is discussed.…”

Process Development and Control with Recent New FBRM, PVM, and IR

“…Figure 4 shows the 3D reaction spectra in the selected spectral region and profiles of maleic anhydride, Different residence times of reaction (6,12,24, and 48 min) are achieved as the total flow rate is varied from 1600 to 800, 400, and 200 μL/min, respectively. As the residence time varies, the reaction reaches several steady states at different degrees of completion (Figure 4b).…”

“…2 IR spectrometers are widely used for either online, at-line, or offline measurements because they can be used to elucidate reaction mechanisms and obtain kinetic information for the design of robust processes, achieving safer process scale-up. 6 Recent advances in IR instrumentation have added more flexibility to the existing IR analyzers in the lab and at scale-up facilities. With a miniaturized interferometer, process IR can utilize reduced-size optics that bring forth high light throughput, allowing an ambient deuterated triglycine sulfate (DTGS) detector to be used and avoiding the need for a sensitive but cryogenic detector.…”