Online Stereochemical Process Monitoring by Molecular Rotational Resonance Spectroscopy

A molecular rotational resonance (MRR) spectrometer designed to monitor the product composition of an asymmetric continuous flow reaction online is presented. The MRR technique is highly sensitive to small changes in molecular structure and, as such, is capable of rapidly quantifying isomers as well as other impurities in a complex mixture, without chromatographic separation or chemometrics. The spectrometer in this study operates by automatically drawing a portion of the reaction solution into a reservoir, volatizing it by heating, and measuring the highly resolved MRR spectra of each of the components of interest in order to determine their relative quantity in the mixture. The reaction under study was the hydrogenation of artemisinic acid, an intermediate step in the semisynthesis of the antimalarial drug artemisinin. Four analytes were characterized in each measurement: the starting material, the product, a diastereomer of the product, and an overreduction byproduct that was not directly quantifiable by either HPLC or NMR methods. The MRR instrument has a measurement cycle time of approximately 17 min for this analysis and can run for several hours without any user interaction.