Chiral Derivatization Enables Rapid Differentiation of Enantiomers by High-Resolution Ion Mobility-Mass Spectrometry

Enantiomers continue to represent a significant analytical challenge despite their importance in biological and pharmaceutical analyses. Established approaches (e.g., chiral chromatography) frequently require specialized chiral stationary phases, selectors, or extended separation times. Ion mobility spectrometry (IMS) offers a rapid alternative; however, the collision cross sections (CCS) of enantiomers are identical and therefore preclude separation. In the present work, we demonstrate a simple chiral derivatization strategy for small drug enantiomers. Specifically, Mosher’s chloride is used to interrogate (R/S)-amphetamine and methamphetamine with a total time (reaction and analysis) of less than 2 min. The resulting products are baseline-resolved using structures for lossless ion manipulations (SLIM) high-resolution ion mobility-mass spectrometry (HRIM-MS), despite CCS differences of less than 1.9 and 1.2%, respectively. Conventional reversed-phase liquid chromatography (RP-LC) confirms the purity of the products, as evidenced by the extracted mobility spectra. Finally, the method allowed determination of enantiomeric excess (ee), with a strong linear correlation between prepared and measured values. More broadly, covalent chiral derivatization provides a readily accessible strategy for encoding stereochemical information into analytes prior to rapid gas-phase differentiation.