Real-Time and In Situ Monitoring of Transmetalation of Grignard with Manganese(II) Chloride by Raman Spectroscopy

The introduction of the nontoxic, inexpensive manganese­(II) chloride (MnCl2) salt in Grignard methylation to facilitate the transmetalation in reaction solvents of anisole and 2-methyl tetrahydrofuran (2-MeTHF) has provided unique reactivity and stereoselectivity under mild reaction conditions. However, because MnCl2 is insoluble in anisole and 2-MeTHF, the transmetalation initiation can be slow with the Grignard reagent without adequate milling of MnCl2. In addition, the reaction mechanism of manganese involvement and the potential synergies brought by MnCl2 are unclear. To date, methods to monitor the transmetalation reaction are scarce. The air/moisture sensitivity of this reaction poses significant challenges for standard analytical technologies. In this work, a Raman analyzer with an in situ probe was used to monitor the reaction species, including those arising from the organometallic species in real time and unambiguously. The results demonstrate how Raman spectroscopy is able to elucidate the transmetalation mechanism and detect the formation of the product in real time to follow the reaction successfully.