In this paper we report enhanced reactivity of the D5h isomers in comparison with the more common Ih isomers of Sc3N@C80 and Lu3N@C80 toward Diels−Alder and 1,3-dipolar tritylazomethine ylide cycloaddition reactions. Also, the structure of the D5h isomer of Sc3N@C80 has been determined through single-crystal X-ray diffraction on D5h-Sc3N@C80·Ni(OEP)·2benzene (OEP = octaethylporphyrin). The Sc3N portion of D5h-Sc3N@C80 is strictly planar, but the plane of these four atoms is tipped out of the noncrystallographic, horizontal mirror plane of the fullerene by 30°. The combination of short bond length and high degree of pyramidization for the central carbon atoms of the pyracylene sites situated along a belt that is perpendicular to the C5 axis suggests that these are the sites of greatest reactivity in the D5h isomer of Sc3N@C80. Consistent with the observation of higher reactivity observed for the D5h isomers, cyclic voltammetry and molecular orbital (MO) calculations demonstrate that the D5h isomers have slightly smaller energy gaps than those of the Ih isomers. The first mono- and bis-adducts of D5h Sc3N@C80 have been synthesized via 1,3-dipolar cycloaddition of tritylazomethine ylide. The NMR spectrum for the monoadduct 2b is consistent with reaction at the 6,6-ring juncture in the pyracylene unit of the D5h Sc3N@C80 cage and is the thermodynamically stable isomer. On the other hand, monoadduct 2a undergoes thermal conversion to other isomeric monoadducts, and three possible structures are proposed.