Predicting pKa in Implicit Solvents: Current Status and Future Directions

Abstract

Computational prediction of condensed phase acidity is a topic of much interest in the field today. We introduce the methods available for predicting gas phase acidity and pKas in aqueous and non-aqueous solvents including high-level electronic structure methods, empirical linear free energy relationships (LFERs), implicit solvent methods, explicit solvent statistical free energy methods, and hybrid implicit–explicit approaches. The focus of this paper is on implicit solvent methods, and we review recent developments including new electronic structure methods, cluster-continuum schemes for calculating ionic solvation free energies, as well as address issues relating to the choice of proton solvation free energy to use with implicit solvation models, and whether thermodynamic cycles are necessary for the computation of pKas. A comparison of the scope and accuracy of implicit solvent methods with ab initio molecular dynamics free energy methods is also presented. The present status of the theory and future directions are outlined.

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

“…log K values, among them (i) an inherent property of error cancellation which is typical for CRn (or isodesmic reaction in general), (ii) structural similarity of and charge distribution on the studied and reference molecules and (iii) simplicity of the continuum solvation model (CSM) used, [12,13] which performs well when used at the level of theory for which it was parameterized [9]. Many existing computational methodologies can be seen as well established (or routine) now in the field and they are described in details in recent reviews by Ho and Coote [9,10] and Casasnovas et al [8] In spite of unquestionable successes in this area, it is somewhat surprising that there is still little [39] (in case of diamines) or no information about the theoretical prediction of protonation constants of polyamines, such as, e.g., tetramines.…”

“…Many existing computational methodologies can be seen as well established (or routine) now in the field and they are described in details in recent reviews by Ho and Coote [9,10] and Casasnovas et al [8] In spite of unquestionable successes in this area, it is somewhat surprising that there is still little [39] (in case of diamines) or no information about the theoretical prediction of protonation constants of polyamines, such as, e.g., tetramines. This observation might be attributed to specific properties of polyamines, particularly with more than two N-atoms:…”

“…Proton transfer is one of the most important processes in chemical and biochemical systems [8][9][10][11][12][13]. Consequently, the ability of a molecule to accept or donate a proton is crucial and fundamental to our understanding of the pathways/mechanisms for several important reactions in living systems [9,12].…”

“…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]. There are several sources of errors which contribute to an inherent uncertainty of results obtained from TCs, such as (i) uncertainty in the solvation free energy of a proton, (ii) inaccuracy in evaluating the solvation free energy of ionic species by continuum solvation models (this might range between 0.5-1 kcal/mol for neutral molecules and 3-4 kcal/mol for ions) [8] and (iii) errors inherent in state-of-the-art quantum chemistry methods (about 1 kcal/mol) [8] used to compute free energies in the gas phase.…”

“…Consequently, the ability of a molecule to accept or donate a proton is crucial and fundamental to our understanding of the pathways/mechanisms for several important reactions in living systems [9,12]. Several experimental techniques, such as mass spectrometry and ioncyclotron resonance techniques in the gas phase as well as UV-visible spectroscopy, potentiometry, and NMR titration procedures in the solvent phase, have been used to obtain protonation constants [8,10,12].…”