By confining a reactant inside electrostatically tuned molecular cages, chemists have performed acid catalysis in basic solution (Science 2007, 316, 85). Michael D. Pluth, Robert G. Bergman, and Kenneth N. Raymond of the University of California, Berkeley, show that a water-soluble, tetrahedral metal-ligand assembly (shown, metal ions are green) thermodynamically drives the protonation of a guest molecule (space-filling model) trapped inside its highly charged cavity. The researchers exploit this host-induced shift in the guest's ability to accept a proton to do acid catalysis in basic solution. In the presence of catalytic amounts of the host, orthoformates [HC(OR)3, R = alkyl] in basic solution are trapped inside and protonated by water, resulting in rapid hydrolysis of the otherwise stable-to-base orthoformate. A similar strategy could be used to hydrolyze other acid-sensitive molecules in basic environments, the researchers note. The host's ability to select appropriately sized substrates is of particular interest, they add, because size selectivity is "often used by nature but rarely incorporated into standard homogeneous or heterogeneous catalysis."