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

Abstract

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 (i) tested (L(1)) and reference (L(2)) molecules are structurally similar, (ii) lowest energy conformers (LECs, selected from all possible tautomers) are used and (iii) 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 possible select LECs (E, B and G stands for electronic-energy-, Boltzmann-distribution- and Gibbs-free-energy-based stepwise selection of conformers). The EEBGB-protocol (i) 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 (ii) is of general-purpose as it is applicable to any flexible and poly-charged 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.