Nitrones are useful dipoles in both synthesis and in bioorthogonal transformations to report on biological phenomena. In bioorthogonal reactions, nitrones are both small and relatively easy to incorporate into biomolecules, while providing versatility in their ability to harbor different substituents that tune their reactivity. Herein, we examine the reactivities of some common and useful nitrone cycloadditions using density functional theory (DFT) and the distortion/interaction (D/I) model. The data show that relative reactivities can be predicted using these approaches, and useful insights gained further enchancing reactivities of both nitrones and their dipolarophile reaction partners. We find that D/I is a useful guide to understanding and predicting reactivities of cycloadditions involving nitrones.