Prediction of microscopic protonation constants of polybasic molecules via computational methods: A complete microequilibrium analysis of spermine

Abstract

For the first time, a simple methodology is reported for theoretical calculation of microscopic protonation constants of polybasic molecules in solution. Density functional theory study was used for complete microequilibrium analysis of spermine, H 2 N(CH 2 ) 3 NH(CH 2 ) 4 NH(CH 2 ) 3 NH 2 , a linear tetraamine with 16 known microspecies. A general thermodynamic cycle is proposed to calculate protonation microconstants of polybasic molecules using calculated micro-DG values in aqueous solution. The microscopic protonation constants were determined with considering both the most abundant and most stable conformers for all microspecies. The results show that the microscopic protonation constants derived from the most abundant conformers (i.e., linear conformers in which the intramolecular hydrogen bonding does not exist) are in good agreement with the corresponding available experimental data.

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

“…it is less stable) than the one selected from the Epath. A similar discrepancy between Gibbs free energy and electronic energy based selection of LECs has been reported by Salehzadeh et al [16] in their study of micro protonation constants of spermine.…”

“…Many papers have focused on theoretical prediction of protonation constants for diverse biologically important compounds such as amines, amides, carboxylic acids, bicarbonates and proteins, amongst others [11,[16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34].…”

“…These TCs involve a two-stage process; (i) full gas-phase energy minimization of components involved in the protonation reaction, followed by (ii) a single point calculation in solvent (water) from which G (aq) is computed and used to calculate protonation constants at room temperature [12,13,16]. Typically, the TC-based methods are able to give protonation constants within 2 log units of experimental value for neutral or singly charged molecules but this accuracy depreciates as the charge on the studied molecule increases [9].…”

“…In other cases, results obtained from TCs have been empirically corrected using parameters obtained from linear regression analysis of experimentally measured protonation constants. [16] In some instances, these modifications have made the prediction of protonation constants to within 1-2 log units possible, though this is still far from what is obtainable experimentally.…”

A theoretical study on the importance of steric effects, electronic properties, interaction and solvation energies in the ‘host–guest’ chemistry of protonated azacryptands and halide anions

“…In our previous works we have been successful in calculating the macroscopic and even microscopic protonation constants of polybasic molecules. 18 We have also been successful in predicting the formation constants of metal complexes of a series of tripodal tetraamines 19,20 and/or macrocyclic ligands 21 by studying their proton affinities. However, unfortunately, the results of our present calculations using different solvation models at different levels of theory (see Table S1) showed that the calculation of formation constants of present complexes is not simply possible.…”