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, H_n−1L⁽¹⁾ + H_nL⁽²⁾ = H_nL⁽¹⁾ + H_n−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 Gibbsfree-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.