Competition reaction-based prediction of polyamines' stepwise protonation constants: a case study involving 1,4,7,10-tetraazadecane (2,2,2-tet).

Theoretical prediction of four stepwise protonation constants of 1,4,7,10-tetraazadecane (2,2,2-tet) in correct order and with the smallest (largest) deviation of about 0.1 (−0.8) log unit from experimental values was achieved by an explicit application of a competition reaction (CRn) methodology in discrete-continuum solvation model involving four explicit water molecules. This methodology performs best when (1) tested (L(1)) and reference (L(2)) molecules are structurally similar, (2) lowest energy conformers (LECs, selected from all possible tautomers) are used, and (3) a CRn, which assures a balanced charge distribution between reactants and products, Hn−1L(1) + HnL(2) = HnL(1) + Hn−1L(2), is implemented. A 5-step EEBGB protocol was developed to effectively and in shortest time possibly select LECs (E, B and G stands for electronic-energy-, Boltzmann-distribution- and Gibbs-free-energy-based stepwise selection of conformers). The EEBGB protocol (1) reduced (by 94 %) the number of conformers subjected to the frequency calculations (to obtain G values) from 420 MM-selected to 25 used to compute four protonation constants and (2) is of general purpose as it is applicable to any flexible and polycharged molecules. Moreover, in search for LECs, a rapid pre-screening protocol was developed and tested; it was found efficient for the purpose of this study. Additional research protocols, aimed at even better prediction of protonation constants, are also suggested. [ABSTRACT FROM AUTHOR]