pKa calculations of aliphatic amines, diamines, and aminoamides via density functional theory with a Poisson-Boltzmann continuum solvent model

In order to make reliable predictions of the acid-base properties of macroligands with a large number of ionizable sites such as dendrimers, one needs to develop and validate computational methods that accurately estimate the acidity constants (pK(a)) of their chemical building blocks. In this article, we couple density functional theory (B3LYP) with a Poisson-Boltzmann continuum solvent model to calculate the aqueous pK(a) of aliphatic amines, diamines, and aminoamides, which are building blocks for several classes of dendrimers. No empirical correction terms were employed in the calculations except for the free energy of solvation of the proton (H+) adjusted to give the best match with experimental data. The use of solution-phase optimized geometries gives calculated pK(a) values in excellent agreement with experimental measurements. The mean absolute error is < 0.5 pK(a) unit in all cases. Conversely, calculations for diamines and aminoamides based on gas-phase geometries lead to a mean absolute error > 0.5 pK(a) unit compared to experimental measurements. We find that geometry optimization in solution is essential for making accurate pK(a) predictions for systems possessing intramolecular hydrogen bonds.