A Rigorous Test for SPARC's Chemical Reactivity Models: Estimation of More Than 4300 Ionization pK_as

Abstract

Ionization pK,s for a large set of molecules were calculated using reactivity models developed in the computer program SPARC. SPARC uses relatively simple computational algorithms based on fundamental chemical structure theory to estimate ionization pK,s of organic molecules strictly from molecular structure. Molecular structures are broken at each essential single bond into functional units with intrinsic properties. Reaction centers (acid or base) are identified and the impact of appended molecular structure on ionization p& is quantified by perturbation theory. Resonance, electrostatic, solvation and H-bonding models have been developed and tested on 4338pK,s for 3685 compounds. The RMS deviation for the acids and the amino reaction center was 0.36 pK, units whereas that for the in-ring N and = N reaction centers was 0.41. Microscopic ionization constants, zwitterionic constants, isoelectric points, and molecular speciation as a function of pH can be calculated using the SPARC models. solubility, partitioning phenomena, and chemical reactivity are all highly dependent upon the state of ionization in the solution phase. The ionization pK, of an organic compound is vital to environmental exposure assessment because it can be used to define the degree of ionization and the propensity for sorption to soil and sediment by cation exchange. This, in turn, can determine mobility, reaction kinetics, bioavailability, complexation, etc. In addition to being highly significant in evaluating environmental fate and effects, acid-base ionization equilibria provide an excellent arena for testing the electrostatic effects models in the computer program SPARC. Because the gain or loss of protons results in a change in molecular charge, these processes are extremely sensitive to electric field effects within the molecule. The object of this study was to test these reactivity models utilizing the large pK, databases that are available. These databases are relatively reliable (f a few tenths of a pK, unit) for smaller more soluble molecules.Numerous investigators have attempted to predict ionization pK,s using various approaches such as ab initio [I, 21 and semiempirical [3,4] methods. The energy differences between the protonated state and the unprotonated state are small compared to the total binding energy of the reactant involved. This presents a problem for ab initio computational methods that calculate absolute energy values. Computing the relatively small energy differences needed for the analysis of chemical reactivity from absolute energies requires extremely accurate calculations. Hence, the aforementioned calculations were limited to a small subclass of molecules. A more aggressive attempt has been made by Klopman et. al., [5,6]. They estimated the p&s for some 2400 molecules (? = 0.846) based on QSAR using the Multi-CASE program. Despite the relatively large number of pK,s calculated their calculator was limited to the estimation of the first pK, [6]. Recently, we described our approach to predict numerous physical pr...

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