Computational Screening of New Orthogonal Metal-Free Dipolar Cycloadditions of Mesomeric Betaines.

Computational strategies have gained increasing impact in the de novo design of large molecular sets targeted to a desired application. Herein, DFT-assisted theoretical analyses of cycloadditions, involving mesoionic dipoles and strained cycloalkynes, unveil a series of unexplored mesomeric betaines as vastly superior candidates for orthogonal applications. Thus, isosydnones; thiosydnones; and a six-membered homolog, 6-oxo-1,3-oxazinium-4-olate, exhibit enhanced reactivity with respect to sydnone, which is the archetypal mesoionic ring employed so far in orthogonal chemistry. These compounds were found by assessing energy barriers and transition structures, which are largely governed by electron fluxes from dipolarophile to dipole and noncovalent interactions. Charge-transfer analysis also accounts for previous experimental and theoretical results gathered in the literature, and provides a rationale for further substitution variations. The above naked dipoles release only CO2 as a byproduct through retro-Diels-Alder of the resulting cycloadducts. These results should invite practitioners to look at such underestimated dipoles and could also help to minimize the number of experiments.