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

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 (CCSHe/ΔCCSHe) of 190 for a path length of 9 m, corresponding to nitrogen-based resolutions (CCSN2/ΔCCSN2) 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.