Correlation of Dissociation Constants of 2- and 2,6-Substituted Anilines in Water by Methods Based on the Similarity Principle and Quantum-Chemistry Calculations

Abstract

In the context of studies of the ortho effect, two series of 2-monosubstituted (H, CH 3 , CF 3 , OH, CH 3 O, F, Cl, NH 2 , CN, NO 2 ) and 2,6-disubstituted anilines (containing all combinations of CH 3 , CH 3 O, Cl, and NO 2 substituents) were chosen for this work. Commercially unavailable derivatives were synthesized, and dissociation constants in water were determined for those substances for which the proper measurements had not yet been carried out. A critical compilation of pK a literature data has been summarized and compared with the authors' own data. The analysis and interpretation of the ortho substitution effect and its manifestation in the dissociation constants of the studied anilines (as log K a ) was based on two different approachess correlation analysis (similarity principle) and quantum-chemistry calculations. The classical correlation equation with substituent constants σ I and σ R was extended by the parameter υ describing the steric effects, but the correlation was not close enough (s ) 0.514, R ) 0.986). The AISE theory (alternative interpretation of substituent effects), extended by parameter υ for the steric effects description, significantly improved the correlation (s ) 0.139, R ) 0.9991). The B3LYP/6-311G(d,p) method was used for the calculation of physicalchemical properties of protonated and nonprotonated forms of aniline derivatives. Quantum chemically calculated properties were correlated with experimental data. The data mining regression method showed that the statistically most suitable interpreting variables are the Gibbs energy of the dissociation equilibrium (∆G eq ) and the sum of the natural charges of the nonprotonated amino group hydrogen atoms (Q n (∑H)) and the dipole moment of the aniline protonated form (µ + ). This correlation is closer (s ) 0.316, R ) 0.995) than that based on the similarity principle. The correlation with quantum-chemical characteristics indicates a close interrelation of the dissociation constant with the energy of the equilibrium participants and the delocalization energy of the nonprotonated form of aniline. The meaning of the ∑H quantity in the correlation relation is related to the presence of a nitro substituent (intramolecular hydrogen bond with the reaction center). The dipole moment of the aniline protonated form µ + is in relation with nonspecific solvation in an aqueous medium.

The role of the Frontier orbitals in acid–base chemistry of organic amines probed by ab initio and chemometric techniques

“…On the other hand, the solvent effects were neglected in other works correlating MO energies with acid/base parameters values [10,14]. That approximation seems valid for some aromatic systems previously studied (anilines [10], phenols [12], and azines [15]), in which sizes and geometries do not vary strongly. For these reasons, the entropy term may be roughly the same along each of these compound families and the solvent effects will also be considered.…”

“…Numerous works have shown how well pK b values correlate with quantum descriptors; the average local ionization potential [35,36], atomic charges and interatomic distances [14,37], and the HOMO energy [10,13,15] are the most common quantum descriptors used.…”

“…However, for a number of other compounds, HOMO energies do not show good correlation with acid/base parameter values, and other quantum parameters, such as dipole moments, bond orders, atomic charges on hydrogen, and bond lengths, have to be included in multiple linear regression analysis to improve the correlation [10][11][12][13][14][15]. This procedure weakens the familiar idea that donor-acceptor reactions are driven by Frontier orbital energies.…”

“…However, the theoretical calculation of acid-base parameters, especially in solution, is a great challenge for quantum chemists [8]. Turning to gas phase, the proton affinity (PA) is the most useful acid-base parameter and many works have shown how PA values correlate with quantum descriptors [9][10][11][12][13]. The PA of a molecule is a measure of its gas-phase basicity.…”

A Novel Method for Assessing Drug Degradation Product Safety Using Physiologically-Based Pharmacokinetic Models and Stochastic Risk Assessment

“…The acidity of the hydroxyl function is depressed by the presence of an amino group on the benzene ring and the amino group behaves as a weak base. The physicochemical parameters such as p K a and log P values, which are necessary for the prediction of tissue to plasma partition coefficients, were taken from literature . This group of small molecule compounds (p K a = 4–5) are soluble in aqueous media and rapidly absorbed, hence, at low doses in humans, they are expected to have complete absorption following oral administration.…”