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Inline Analysis Under Reflux
The authors present a simple and safe method to form a Grignard reagent while tracking the reaction progression in situ (at all times), ensuring no accumulation of organic halide, and mitigating the risk of unsafe conditions associated with a stalled reaction and runaway conditions. Typically the strategy of a Grignard reaction is to charge the reactor with Mg and THF, add <10 % organic halide (R-X), raise temperature to reflux, and await initiation (by detecting an exothermic temperature rise). Upon initiation, the remainder of R-X is fed into the reactor. The challenge of this strategy is detecting the exothermic initiation while at reflux conditions, as well as, monitoring the reaction progression to avoid any potential stall conditions that can lead to an exothermic runaway.
In situ mid-infrared FTIR spectroscopy was implemented to monitor the R-X concentration and the Grignard product in real time. This new strategy allowed for instantaneous determination of initiation, reaction kinetics (during feed stage), as well as immediate detection of unsafe conditions.
From a single experiment, an understanding of the complete reaction profile (or behavior) was achieved by collecting in situ mid-infrared data every one minute over a period of 30 minutes. Accumulation of the aryl halide was detected and watching for the subsequent reaction initiation point, allowed operators to safely dose the remainder of aryl halide into the reactor. Product formation and reaction endpoint were also measured in this study. This provided a full understanding of the behavior and mechanics of this reaction for safe scale up and control.
In situ mid-infrared FTIR spectroscopy demonstrated the ability to detect initiation, reaction progression, stall event(s), as well as avoid the exposure of hazardous substances to operators. Real-time monitoring insured continuous validation that the reaction was proceeding correctly.