Molecular acidity: A quantitative conceptual density functional theory description

Abstract

Accurate predictions of molecular acidity using ab initio and density functional approaches are still a daunting task. Using electronic and reactivity properties, one can quantitatively estimate pKa values of acids. In a recent paper ͓S. B. Liu and L. G. Pedersen, J. Phys. Chem. A 113, 3648 ͑2009͔͒, we employed the molecular electrostatic potential ͑MEP͒ on the nucleus and the sum of valence natural atomic orbital ͑NAO͒ energies for the purpose. In this work, we reformulate these relationships on the basis of conceptual density functional theory and compare the results with those from the thermodynamic cycle method. We show that MEP and NAO properties of the dissociating proton of an acid should satisfy the same relationships with experimental pKa data. We employ 27 main groups and first to third row transition metal-water complexes as illustrative examples to numerically verify the validity of these strong linear correlations. Results also show that the accuracy of our approach and that of the conventional method through the thermodynamic cycle are statistically similar.

Modelling the Correlation Between Molecular Electrostatic Potential and pKa on Sets of Carboxylic Acids, Phenols and Anilines

“…The success of the method consequently depends on the training set used in the program learning process, and the similarity of the studied compounds. 7 A relatively good correlation between the maximum in MEP and the pK a value was found for amines, anilines, carboxylic acids, alcohols, sulfonic acids, and tioles. 12 Furthermore, a good correlation was established recently between pK a and the most positive value of the MEP of benzoic acids and phenols, and between the most negative value of MEP and the local ionization energies of these compounds.…”

“…[2][3][4][5] One of the physico-chemical properties that have recently been shown to be correlated with the MEP is pK a value which describes the acid strength of certain organic acids. [6][7] The background of the correlation is due to the fact that MEP is a quantum-mechanical descriptor influenced by electronic or stereoelectronic properties of the groups in close vicinity to a particular acidic atom. Similarly, NAO (the sum of valence p natural atomic orbitals) has also been used for such calculations and it has been proven that this descriptor is equivalent to MEP.…”

“…Similarly, NAO (the sum of valence p natural atomic orbitals) has also been used for such calculations and it has been proven that this descriptor is equivalent to MEP. 8 Other examples of descriptors in QSAR models that have already been successfully used for determining pKa values are topological 9 , atom type descriptors 10 , and group philicity 11 . The correlation was established by comparing the calculated MEP values via different theoretical methods with the experimentally determined pK a values for the same sets of compounds.…”

Empirical prediction of protein pKavalues with residue mutation

“…More computationally demanding approaches include quantum mechanics/molecular mechanics (MM) 28 type methods, which rely on calculating the pK a with ab initio reactivity indicators [29][30][31] or by directly resorting to the thermodynamic cycle. 32 This approach has also been coupled with free energy perturbation methods, 33,34 where one slowly changes the system from the protonated to the unprotonated state.…”

Lee Pedersen s work in theoretical and computational chemistry and biochemistry

“…In collaboration with Dr. Shubin Liu at UNC-CH, Dr. Pedersen has recently been able to uncover a fundamental correlation of the MEP of electrostatic atoms in a molecule with acidity (i.e. the pKa) and to derive relationships that provide an understanding of why this correlation holds over many orders of magnitude [15,16] .…”