Theoretical ab initio study of the protomeric tautomerism of 2-hydroxypyrimidine, 4-hydroxypyrimidine, and their derivatives

We investigated the gas-phase protomeric tautomerism of a series of monosubstituted derivatives of two parent compounds, 2-hydroxypyrimidine and 4-hydroxypyrimidine (substituted at the C(4) and C(2) positions, respectively, by H, NH₂, OH, SH, and SCH₃). We used the ab initio Hartree-Fock method, the many-body perturbation theory (MBPT), and the coupled cluster (CC) method with the double-ζ Gaussian basis augmented with polarization functions to calculate the electronic contribution to the molecular total energy. The energy of the zero-point nuclear vibrations was obtained within the harmonic approximation by means of the SCF/3-21G* analytical energy derivatives. For each molecule we considered several tautomeric forms corresponding to different protonation sites: at the ring nitrogen atoms and the exocyclic oxygen atom. We estimated the relative temperature-dependent distribution of various tautomeric forms in the gas phase and predicted the environmental influence on the tautomeric equilibrium. We show that the commonly applied MBPT(2) theory for the evaluation of the electron correlation effects should be supplemented by an estimation of the higher order electron correlation effects. For all investigated systems, they appear to favor the oxo tautomeric forms by 1-4 kJ mol^-1. In all cases studied in the present paper we achieved a qualitative agreement with the conclusions based on the recent low-temperature matrix-isolation IR spectra. We lend support to the experimentally derived conclusion that 2-hydroxypyrimidine should exist in the gas phase (or in the weakly polar environment) almost exclusively in the hydroxy tautomeric form. The theoretically derived equilibrium constant is equal to K(oxo/hydroxy) = 0.01 at T = 500 K. A coexistence of the hydroxy and oxo forms, with a clear predominance of the hydroxy form, should characterize the cytosine (K = 0.37), isocytosine (K = 0.15), and S-methylated 4-thiouracil (K = 0.17) vapors. A nearly equimolar hydroxy:oxo mixture should correspond to the gas-phase 4-hydroxypynmidme (K = 1.04) and S-methylated 2-thiouracil (K = 1.08). According to our estimation of the environment effects, the hydroxy-oxo tautomeric equilibrium should be strongly shifted toward the oxo form in polar solvents. The tautomeric rearrangement corresponding to proton transfer between the ring nitrogen atoms (N(1)-H to N(3)-H and vice versa) appears to be highly unfavorable in the gas phase. On the other hand, such a process can easily occur in polar solvents due to an additional strong (mostly electrostatic) solvent stabilization of the energetically unfavored tautomeric form.