AbstractThis paper reports the results of experimental work on the aminolysis of penicillin (6‐APA) and monobactam (aztreonam) antibiotics by propylamine or ethanolamine. In general, aztreonam is slightly more reactive than 6‐APA, despite the common assumption that the amide bond should be less activated in monobactams. Intriguingly, when ethanolamine acts as the nucleophile, the corresponding rate law has a kinetic term proportional to [RNH2][RNH3+]. To complement the experimental observations, the rate‐determining free energy barriers in aqueous solution for various mechanistic pathways were computed by standard quantum chemical methodologies. From previous theoretical work it was assumed that the aminolysis of β‐lactams proceeds through mechanisms in which either a water molecule or a second amine molecule may act as bifunctional catalysts, assisting proton transfer from the attacking amine molecule to the leaving amino group. The energy barriers as computed have moderate values (ca