Abstract

This dissertation focuses on the development and application of high-resolution ion mobility-mass spectrometry (IMS-MS) methodologies for gas-phase separation and structural characterization of small molecules, with particular emphasis on epimers, positional isomers, and protomers. In addition to structural separations, this work investigates fundamental aspects of gas-phase ion chemistry using IMS-MS in combination with collision-induced ion activation and dissociation techniques. Advanced separations were performed using cyclic traveling-wave ion mobility spectrometry (cyclic TWIMS), implemented in a commercial cyclic ion mobility-mass spectrometry (cIMS) platform, to systematically evaluate both the capabilities and limitations of high-resolution IMS in resolving subtle structural differences. Initial studies demonstrated that, despite the enhanced resolving power of cyclic TWIMS, specific epimeric and positional isomeric systems cannot be fully resolved as protonated monomeric ions. To overcome these limitations, ion-manipulation strategies, such as molecular self-association and host-guest complexation with the macrocyclic host β-cyclodextrin, were employed. These approaches enabled improved differentiation of isomers. Separation of protonated methasone dimers produced well-resolved mobiligram features that enabled relative epimer quantification. In addition, host-guest complexation of phenyl pyridyl urea positional isomers yielded mobility separations orthogonal to those observed for protonated ions. Differences in host-guest binding strengths were further examined using collision-induced dissociation. Beyond separations of isomers, this work investigates the gas-phase behavior of sodiated cyclodextrin ions and provides evidence for potential ring-opening processes occurring prior to fragmentation. This work also examines ion activation processes occurring before ion mobility separation, revealing that extended cyclic IMS separation sequences can lead to ion accumulation and unintended activation due to space-charge effects. Finally, protomer-specific fragmentation was explored using the pharmaceutical compound quizartinib, demonstrating that cIMS can be used to reveal nuances in gas-phase ion chemistry. Overall, this dissertation highlights how advanced ion mobility techniques, with or without targeted ion manipulation, enhance the analytical capabilities of IMS-MS for structural characterization of complex molecular systems.

Degree

PhD

College and Department

Computational, Mathematical, and Physical Sciences; Chemistry and Biochemistry

Rights

https://lib.byu.edu/about/copyright/

Date Submitted

2026-04-13

Document Type

Dissertation

Keywords

cyclic ion mobility-mass spectrometry, isomer separation, host-guest chemistry, tandem mass spectrometry, gas-phase ion chemistry

Language

english

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