Addition of trivalent chromium, Cr­(III), to solutions undergoing electrospray ionization (ESI) enhances protonation and leads to formation of [M + 2H]2+ for peptides that normally produce [M + H]+. This effect is explored using electronic structure calculations at the density functional theory (DFT) level to predict the energetics of various species that are potentially important to the mechanism. Gas- and solution-phase reaction free energies for glycine and its anion reacting with [Cr­(III)­(H2O)6]3+ and for dehydration of these species have been predicted, where glycine is used as a simple model for a peptide. For comparison, calculations were also performed with Fe­(III), Al­(III), Sc­(III), Y­(III), and La­(III). Removal of water from these complexes, as would occur during the ESI desolvation process, results in species that are highly acidic. The calculated pK a of Cr­(III) with a single solvation shell is −10.8, making [Cr­(III)­(H2O)6]3+ a superacid that is more acidic than sulfuric acid (pK a = −8.8). Binding to glycine requires removal of two aqua ligands, which gives [Cr­(III)­(H2O)4]3+ that has an extremely acidic pK a of −28.8. Removal of additional water further enhances acidity, reaching a pK a of −84.7 for [Cr­(III)­(H2O)]3+. A mechanism for enhanced protonation is proposed that incorporates computational and experiment results, as well as information on the known chemistry of Cr­(III), which is substitutionally inert. The initial step involves binding of [Cr­(III)­(H2O)4]3+ to the deprotonated C-terminus of a peptide. As the drying process during ESI strips water from the complex, the resulting superacid transfers protons to the bound peptide, eventually leading to formation of [M + 2H]2+.