Computational Determination of pKa Values for Weak C–H Acids/Lithiated Species

The accurate computational prediction of pKa values for weak C–H acids, particularly in the context of lithiation reactions, remains a challenge due to the complex solvation and aggregation behavior of organolithium species. This study introduces a refined approach using lithiated species ArLiL2(L = solvent) rather than “naked” anions to improve the calculation of pKa values of weak CH acids for five groups of aromatic substrates. Density functional theory calculations incorporating solvation and aggregation effects reveal that this method aligns better with experimental regioselectivities, especially for substrates bearing ortho-directing groups. Comparative analyses across a range of functionalized ferrocene and dithiane derivatives demonstrate that the lithiated approach significantly reduces discrepancies in the regioselectivity and absolute pKa values observed from traditional anionic models. Furthermore, correlation of the calculated pKa values with redox potentials of the ferrocenyl motifs allowed for the prediction of reactivity trends during anionic-Fries rearrangements, enhancing predictive power and reassessing the ortho-directing properties of commonly used directing groups. The proposed model provides synthetic chemists with a more reliable tool for evaluating CH acidity that is aligned with experimental results during lithiation-based functionalization and helps predict the outcome of a deprotonation reaction. It is also less susceptible to solvent effects and shows smaller absolute errors in a DLPNO–CCSD(T) calculation and wall times compared to double-hybrid functionals.