Substituent effects on the physical properties and pKa of aniline

Substituent effects on the electronic structure and pKa of benzoic acid

“…This study of benzoic acids, along with previous studies of anilines 6, 7 and phenols 9, demonstrates that quantum chemical parameters can be used successfully to account for substituent effects. In addition to their ability to quantitatively relate the electronic properties of substituents to their physicochemical effects, an attractive feature of quantum chemical parameters is that they are both flexible and interpretable.…”

“…The Mulliken charges performed well for this series of compounds (Table II), in contrast to their weak performance for a series of anilines studied earlier 7. Among the Mulliken charges examined, the charge on the entire carboxylate group correlated most favorably with the experimental p K a s: The results (Fig.…”

“…Although σ constants provide a valuable practical and heuristic tool, they cannot be expected to work in every case and sometimes yield little mechanistic insight. Recent efforts involving anilines 6–8 and phenols 8, 9 indicate that certain quantum chemical parameters might also serve as useful descriptors for understanding the physical and chemical effects of substituents.…”

High-throughput pKascreening and prediction amenable for ADME profiling

“…Recent studies indicate that a large part of effects of conjugation of drug-like organic compounds is well treated with fairly low-level quantum chemistry calculations [54,[73][74][75]78,95,96]. The example with phenylbutazone was, in this case, chosen to represent a compound group that the authors knew would be difficult for quantum treatment as well.…”

Correlations between quantum chemical indices and the pKas of a diverse set of organic phenols

“…Accordingly, it is important to understand the electronic factors determining the ionizing tendencies in such compounds, and to be able to use this understanding to predict the ionization constants of new or untested compounds. In previous studies, we examined the correlations of a variety of quantum chemical parameters with the experimentally observed aqueous‐phase p K a s of substituted anilines 2–4, phenols 4–6, and benzoic acids 6, 7. These studies of substituent effects on p K a revealed that a number of relatively straightforward electronic properties of the dissociating groups of these compounds showed strong correlations with the variations in the corresponding p K a s. The quantum chemical descriptors employed included atomic and group partial charges, orbital energies, energies of dissociation, and certain properties of the electrostatic potentials.…”