Diagnostic gas-phase ion-molecule reactions serve as a powerful alternative to collision-activated dissociation for the structural elucidation of analytes when using tandem mass spectrometry. The use of such ion-molecule reactions has been demonstrated to provide a robust tool for the identification of specific functional groups in unknown ionized analytes, differentiation of isomeric ions, and classification of unknown ions into different compound classes. During the past several years, considerable efforts have been dedicated to exploring various reagents and reagent inlet systems for functional-group selective ion-molecule reactions with protonated analytes. This review provides a comprehensive coverage of literature since 2006 on general and predictable functional-group selective ion-molecule reactions of protonated analytes, including simple monofunctional and complex polyfunctional analytes, whose mechanisms have been explored computationally. Detection limits for experiments involving high-performance liquid chromatography coupled with tandem mass spectrometry based on ion-molecule reactions and the application of machine learning to predict diagnostic ion-molecule reactions are also discussed.
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