The computational determination of pKa values receives increasing popularity. It replaces time consuming titration methods and allows for a prediction of values in target molecules and considers additional functional groups. The correlation of predicted vs experimental values improved significantly when solvent models, such as PCM and SMD were incorporated and benchmark studies for selecting the ideal functional/basis set combination let to further improvement.[1] Based on the large volume of available experimental data, acids and bases with pKa values between 0 to 14, such as carboxylic acids (-COOH), phenols (-OH), and amines (-NR2), were most investigated. However, it was found that the determination of pKa values in aqueous media shows high systematic errors if ‘naked’ molecules and anions were investigated, whereas the incorporation of explicit molecules of water improved the correlation.[2]
The calculation of CH acidities for common functionalised aromatics, such as benzenes, pyridines and ferrocenes in non-aqueous media remains a challenge. Compared to carboxylic acids with distinct reactive sites, CH-acidic (hetero)aromatic compounds contain several reactive sites of similar reactivity, which cannot be determined experimentally. Several studies report about a miss-match between functionalization at the ‘most acidic site’, determined by DFT, and experimental findings, which remained mostly unquestioned. During our studies of the anionic Fries rearrangement[3] we noticed a similar miss-match, which we revised by considering C–Li bonding and is presented herein.