TAUTOMERIC EQUILIBRIA OF 3-HYDROXYPYRAZOLE IN THE GAS-PHASE AND IN SOLUTION - A THEORETICAL-STUDY COMBINING AB-INITIO QUANTUM-MECHANICS AND MONTE-CARLO SIMULATION METHODS

Ab initio geometry optimizations were carried out with the inclusion of electron correlation at the second-order Moller-Plesset (MP2) level for eight tautomers of 3-hydroxypyrazole, and some important structural features due to electron correlation effects are discussed. To obtain a more definitive estimate of the relative stabilities for the five major tautomeric forms A, B1, B2, F, and G in the gas phase, energy calculations were performed at various levels of electron correlation up to coupled-cluster single and double excitation (CCSD) and with a hierarchy of basis sets up to 6-311+G(3df,2p). The effects of basis set and electron correlation are profound due to the slow convergence of the relative energies. Combining our best estimate of the relative energies with zero-point vibrational energy corrections, thermal corrections, and entropic contributions, we conclude that B1 is the most stable form in the gas phase and G the least stable one with a free energy of 7.6 kcal/mol higher than that of B1. The tautomeric equilibria in a polar solvent with epsilon = 40 and in water with epsilon = 78.3 were studied using the self-consistent reaction field (SCRF) theory. The inability of the ab initio continuum model to treat first-hydration-shell effects, which are dominated by hydrogen bonding, resulted in a significant underestimate of the hydration free energy for G. In an effort to include both the solute polarization and the first-hydration-shel1 effects, we combined Monte Carlo simulation/statistical perturbation theory (MC/SPT) with the SCRF method to investigate the hydration effects on the system. Partial charges that correspond to the relaxed charge distribution in a polar medium with epsilon = 78.3 were used in the MC simulations, together with standard OPLS Lennard-Jones parameters. The calculated relative free energies indicate G to be the most stable tautomer in aqueous solution, in agreement with the experimental estimate. It is concluded that both solute polarization and the first-hydration-shell effects are important, and neither of them must be neglected. We also studied the sigmatropic rearrangements of A to B1, A to F, and G to B1. Geometry optimizations for the corresponding transition structures were carried out at the HF/6-31G(**) and MP2/6-31G(**) levels, and the energy barriers were estimated at the MP4(SDQ)/6-311G(**) level. The transition structure AB shows aromatic character with the migrating hydrogen moving out of the molecular plane by 55 degrees. The most severe geometry distortion was observed for the AF transition structure, where the O-C-C angle contracted by more than 15 degrees and the oxygen atom moved 22 degrees out of the plane. It was found that the barrier height from A to B1 is comparable to that from G to B1, while F is well separated from other tautomers by forbidding energy barriers in the gas phase.