title: Theoretical studies of the tautomeric equilibria for five-member N-heterocycles in the gas phase and in solution.
abstract: Tautomeric equilibria have been studied for five-member N-heterocycles and their methyl derivatives in the gas phase and in different solvents with dielectric constants of epsilon = 4.7-78.4. The free energy changes differently for tautomers upon solvation as compared to the gas phase, resulting in a shift of the equilibrium constant in solution. Solvents with increasing dielectric constant produce more negative solute-solvent interaction energies and increasing internal energies. The methyl-substituted imidazole and pyrrazole form delicate equilibria between two tautomeric forms. Depending on the solvent, the methyl-substituted triazoles and tetrazole have one or two major tautomers in solution. When estimating the relative solvation free energies by means of an explicit solvent model and using the FEP/MC method, one observes that the preferred tautomers differ in several cases from those predicted by the continuum solvent model. The 1,2-prototropic shift, as an intramolecular tautomerization path, requires about 50 kcal/mol activation energy for imidazole in the gas phase, and this route is also disfavored in a solution. The calculated activation free energy along the intramolecular path is 48-50 kcal/mol in chloroform and water as compared to a literature value of 13.6 kcal/mol for pyrrazole in DMSO. A molecular dynamics computer experiment favors the formation of an imidazole chain in chloroform, making the 1,3-tautomerization feasible along an intermolecular path in nonprotic solvents. In aqueous solution, one strong N-H...Ow hydrogen bond is formed for each species, whereas all other nitrogens in the ring form weaker, N...HwOw type hydrogen bonds. The tetrahydrofuran solvent acts as a hydrogen bond acceptor and forms N-H... Oether bonds. Molecules of the dichloromethane solvent are in favorable dipole-dipole interactions with the solute. The results obtained are useful in the design of N-heterocyclic ligands forming specified hydrogen bonds with protein side chains.
authors.affiliation: Center for Drug Design and Development, The University of Toledo, Toledo, Ohio 43606-3390, USA. pnagy@utnet.utoledo.edu
authors.forename: Peter I
authors.initials: PI
authors.lastname: Nagy
authors.forename: Frederick R
authors.initials: FR
authors.lastname: Tejada
authors.forename: William S
authors.initials: WS
authors.lastname: Messer
mesh_terms: D005740:Gases / Q000737:chemistry; D007093:Imidazoles / Q000737:chemistry*; D008956:Models, Chemical; D015394:Molecular Structure; D012996:Solutions / Q000737:chemistry; D013237:Stereoisomerism
chemical_list: D005740:Gases; D007093:Imidazoles; D012996:Solutions