Cation binding effect on imidazole tautomerism

Binding of Zn²⁺ to imidazole (Im) and methyl imidazole (MeIm) is studied by ab initio methods as a model for the effect of cation binding on tautomeric energies. Gradient energy optimized conformations were obtained for all neutral and ionic structures, including the deprotonated molecules and the ylides. The N3H tautomer of MeIm is calculated to be more stable than N1H by about 1 kcal/mole. However, binding of a Zn²⁺ cation to the available nitrogen site is found to reverse the order of binding, leaving N1H more stable by 1 kcal/mole. Binding of Zn²⁺ produces a significant perturbation in the electronic structure, a smaller shift in the equilibrium conformation of the imidazole ring, and only a small absolute shift in the relative tautomer energies. Methyl substitution at C5 has a small effect on both conformation and energetics. A high‐energy ylide tautomer is produced by moving the proton bound to C2 to the N1 atom. The binding of Zn²⁺ to the C2 site is substantially stronger than to the N1 site, yielding nearly isoenergetic ZnIm²⁺ conformations for binding to either N or C atoms. For the deprotonated salts the lowest energy conformation has the C2N3 bond bridged by Zn²⁺.