Modeling Flexible Molecules in Solution: A pKa Case Study

Continuum solvation models have been incredibly successful for the computationally efficient study of chemical reactions in solution. However, their development and application has generally been on focused on investigations of small, rigid molecules. Additional factors must be considered when studying large, flexible and multiply ionizable species. These include whether the use of thermocycle or entirely solution-phase approaches are more appropriate for the calculation of solution-phase free energies, which metrics can be used to reliably identify the conformation(s) adopted by flexible molecules in solution, and how errors due to inaccuracies in the prediction of low energy vibrational frequencies can be avoided. Here we explore these issues using the calculation of pKas for a diverse set of amine-containing species as a case study. We show that thermocycle-based approaches should only be applied where there are relatively small structural changes between the gas- and solution-phase molecular geometrie...