Abstract 1 Ion mobility spectrometry (IMS) separates gas-phase ions moving under an electric field according to their size to charge ratio. We used electrospray ionization IMS-mass spectrometry and computational chemistry to study the mobility shifts of the drugs dextromethorphan (Dx) and diphenhydramine (Dy) with the introduction of 2-butanol (B) as a shift reagent (SR) caused by non-covalent adduction of Dx and Dy with B. The binding energies of 2-butanol-ion adducts were calculated using Gaussian 09 at two different levels of theory: M06-2X/6-311 ++(d,p), used to discuss the present results, and B3LYP-GD3/6-311 ++(d,p). We found the reduced mobility (K0) of Dx to decrease by 1.4% and that of Dy by 0.4% when the concentration of 2-butanol changed from 0.14 to 1.4 mmol m− 3 in the buffer gas. This was unexpected from the molecular weights of these compounds, Dx 272.4 g/mol and Dy 256.4 g/mol (small ions suffer large mobility shifts), nor from the apparent steric hindrance on the positive nitrogen in Dx for the adduction of 2-butanol molecules. This hindrance should have produced a smaller mobility shift for Dx than for Dy due to a reduction in clustering with 2-butanol. However, these shifts could be explained on the interaction energies of these ions with 2-butanol. The formation of DxBH+ was favored over that of DyBH+ due to the formation of more stable hydrogen bonds when the adduction occurred in the nitrogen (− 19.9 vs. − 9.4 kcal/mol) or the oxygen atoms (− 32.1 vs. 11.3 kcal/mol), with the outcome that DxH+ showed two favorable adduction sites vs. only one in DyH+. Additionally, an intramolecular N H O bond (− 13 kcal/mol) was formed in DyH+, which hid and stabilized the positive charge by delocalization making it unavailable for adduction with 2-butanol. These results justify the larger mobility shift of DxH+ over DyH+ with the injection of 2-butanol. These experiments are important because they explain the mobility shifts of ions upon the introduction of SRs in the buffer gas in IMS. This may be fundamental for the separation of overlapping peaks and the reduction of false positives when searching for illegal substances and explosives in airports and customs using IMS, which is the preferred method for these procedures.