Two robust hexacationic cages incorporating either urea or isophthalamide motifs were synthesized via a short and high-yielding synthetic pathway using hydrazone condensation reactions in water for the cage forming step. Stability testing revealed that the cages are stable to a range of stimuli in water and in organic solvents. The urea containing cage can bind anions in pure water, and displays strong and selective binding of SO42– over HPO42–. The isophthalamide containing cage binds SO42– only weakly in 1:1 D2O:d6-DMSO but displays strong and cooperative binding of two HPO42– anions. Combined quantum mechanical/annealed molecular dynamics simulations suggest that the remarkable differences in anion selectivity are largely a result of the differing flexibilities of the two cages.