Selectivity Beyond Mass: Real‐Time Isomer Separation Using SLIM IMS Coupled to PTR‐MS

ABSTRACT Proton‐transfer‐reaction—mass spectrometry (PTR‐MS) provides real‐time analysis of volatile organic compounds (VOCs) relevant to atmospheric research, food and flavor characterization, industrial process control, and medical applications. However, PTR‐MS is inherently limited in its ability to resolve isomers of molecules with the same mass‐to‐charge ratio ( m/z ). To address this selectivity constraint, we coupled a time‐of‐flight (TOF) based PTR‐MS setup with a “Structures for Lossless Ion Manipulations Ion Mobility Spectrometry” (SLIM IMS) module. The integration of SLIM IMS introduces an additional separation dimension without compromising the real‐time capability of PTR‐MS. A custom designed SLIM device enabled efficient confinement and transmission of low mass ions ( m/z < 300), which are typically analyzed in PTR‐MS. The developed system achieved helium‐based ion mobility resolutions (CCS He /ΔCCS He ) of 190 for a path length of 9 m, corresponding to nitrogen‐based resolutions (CCS N2 /ΔCCS N2 ) of approximately 600. On average 65% of the ions transmitted in straight‐through mode were still detected after accumulation and transport through the 9‐m serpentine IMS structure. Limits of detection were determined to be in the low parts‐per‐trillion by volume (pptv) range. The enhanced resolving power of the PTR‐SLIM‐TOF was demonstrated by the successful separation of the protonated isomeric system 3‐methyl‐2‐butanone and 2‐pentanone ( m/z 87.080) within multiple IMS laps. Furthermore, as a real‐life test, the headspace above freshly brewed coffee was analyzed. Separation of the isomeric flavor compounds, 2‐ethyl‐3‐methylpyrazine, 2,3,5‐trimethylpyrazine, and 2‐ethyl‐5(6)‐methylpyrazine was confirmed by introducing reference samples. These results demonstrate that coupling PTR‐TOF‐MS with SLIM‐IMS substantially enhances compound selectivity while retaining the real‐time and sensitivity capabilities of PTR‐MS. The PTR‐SLIM‐TOF platform represents a significant advancement in ion mobility assisted mass spectrometry for high‐throughput chemical analysis across diverse scientific and industrial applications.