Conformation/Tautomerization effect on the pK_a values of lumazine and 6-thienyllumazine

摘要

Density functional theory [B3LYP/6-311+G(d,p)] was used in combination with the conductor-like polarizable continuum model (CPCM) solvation model to investigate the relative stability and site-specific p_a~(Kij) values of neutral and ionized tautomers of lumazine (LM) and 6-thienylLM (TLM). Two types of populations should be taken into consideration when calculating the p_a~(Kij), tautomers, and conformers. The major tautomer of neutral LM in aqueous solution is 13-LM (the 13 notation refers to the acidic protons being in positions 1 and 3 of LM) TLM has decreased acidity at N_8 relative to LM. Further, the trans conformer of TLM is more acidic than cis. Similar to the case of LM, for TLM, N_1 is more acidic than N_3 in the uracil part. However, N_8 is predicted to be a stronger acid than N_1 for TLM. This acidity enhancement is essentially because of a specific stabilization of the anion when the thienyl group replaces H. Two factors are responsible for the acidity strength of N_8: The thienyl ring upon deprotonation acts inductively as an electron-withdrawing group, and the excess electron density is dispersed better when the system is trans and contains second-row atoms. Accurate pK_a calculation requires that all conformers/tautomers be included into the calculation.