Conformation/Tautomerization effect on the pK a values of lumazine and 6‐thienyllumazine

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 K a ijvalues 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 K a ij , 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. Copyright © 2014 John Wiley & Sons, Ltd.