Gas phase ion/molecule reactions are often used in analytical applications to support the analysis of isomers or to identify specific functional groups of organic molecules. Until now, deliberate chemical reactions have not been performed in differential ion mobility spectrometry (DMS) devices except for hydrogen exchange and cluster formation. The present work extends that of Colorado and Brodbelt (Anal Chem 66:2330-5, 1994) on ion/molecule reactions in an ion trap mass spectrometer. In this study, class-specific chemical reactions of 4-quinolone antibiotics with various chemical reagents were used to demonstrate the analytical utility of ion/molecule reactions in a DMS drift cell. For these reactions, dehydrated reactive precursor ions were initially formed and made to undergo annulation reactions with selected reagents within the timescale of the DMS separation. Careful study of the energies required for dissociation of the adducts confirmed the covalent nature of the newly formed bond; thus demonstrating the analytical utility of this approach. Graphical abstract.