Correlation between Thermodynamics and Collision Cross Sections in Ion–Modifier Clustering: Experimental and Theoretical Insights into Nitroaromatic Isomer Separation by Corona Discharge Drift Tube Ion Mobility Spectrometry

Using drift gas modifiers in ion mobility spectrometry (IMS) can significantly improve peak resolution by altering ion cluster characteristics, such as geometry, polarity, and collision cross section (CCS), factors critical to ion separation in drift tube IMS (DTIMS). Isomeric compounds often yield overlapping peaks in DTIMS, requiring enhanced separation strategies. In this study, a series of alcohol-based and acetonitrile modifiers were evaluated for their ability to resolve nitroaromatic isomers. Additionally, the behavior of analyte–modifier cluster in the negative mode of DTIMS was investigated on the cluster formation with particular emphasis on the influence of structural and functional group variations as well as thermodynamic factors. To characterize the isomer separation, different clustering states, defined by the number of modifier molecules per analyte, were proposed. Thermodynamic stabilities of these clusters were evaluated via Gibbs free energy (Δ G ) calculations, and charge transfer analyses were conducted to probe changing cluster polarity. These results along with theoretical and experimental CCS values were compared with the practical separation trend. The results revealed agreement between theoretical predictions and observed separations, particularly regarding the optimal number of modifier molecules required for effective resolution. As a result, establishing correlations among these parameters is essential for more accurate characterization of ion–modifier interactions within the drift region.