Easy to Use DFT Approach for Computational pKa Determination of Carboxylic Acids

Abstract

In pKa computational determination, the challenge in exploring and fostering new methodologies and approaches goes in parallel with the amelioration of computational performances. In this paper a “ready to use methodology” has been compared to other strategies, such as the re‐shaping in solvation cavity (Bondi radius re‐shaping), wanting to assess its reliability in predicting the pKa of a broad list of carboxylic acids. Thus, the functionals B3LYP and CAM‐B3LYP have been selected, using SMD as continuum solvation model. Exploiting our previous results, two water molecules were made explicit on the reaction centre. Data show that our model (CAM‐B3LYP/2H2O) is capable to accurately predict pKa, leading to mean absolute error (MAE) values lower than 0.5. Noteworthy, good results were achieved in computing the pKa of substituents bearing nitro and cyano groups. Focusing on B3LYP, eventually remarkable outputs were obtained only when Bondi correction was applied to the complex with two water molecules. Hence, massive outcomes were obtained in foreseeing the trichloro and trifluoro acetic acid pKa. These findings demonstrated that no complex level of theory nor external factor is required to accurately predict carboxylic acids pKa, with MAE well below 0.5 units.

Towards the “Eldorado” of pKa Determination: A Reliable and Rapid DFT Model

“…To calculate the pKa of the selected benzoic acid derivatives, our previously optimized method was herein adopted [ 1 , 8 ]. In particular, the acid dissociation equilibrium of a generic carboxylic acid (RCO 2 H) and the corresponding reaction free energy (ΔG dep ) can be defined according to Equations (1) and (2), respectively [ 8 ].…”

“…To calculate the pKa of the selected benzoic acid derivatives, our previously optimized method was herein adopted [ 1 , 8 ]. In particular, the acid dissociation equilibrium of a generic carboxylic acid (RCO 2 H) and the corresponding reaction free energy (ΔG dep ) can be defined according to Equations (1) and (2), respectively [ 8 ]. RCO 2 H(H 2 O) 2(sol) + OH − (H 2 O) 2(sol) ⇌ RCO 2 − (H 2 O) 2(sol) + H 2 O(H 2 O) 2(sol) ΔG dep = G RCO2 − + G H2O − G OH − − G RCO2H where G RCO2 − , G H2O , G OH − and G RCO2H are the Gibbs free energies of each species in the presence of two explicit water molecules, in an aqueous solvent.…”

“…B3PW91 shows a non-local correlation function equal to 20%, producing stunning results in determining the H-bond length between oxygen belonging to medium/small organic compounds and water molecules [ 22 ]. CAM-B3LYP has already proven its accountability and reliability in the pKa determination of small organic molecules [ 1 , 8 ], while WB97XD is an RSH-GGA functional, widely used for in silico prediction of organic molecules properties. It usually ensures even greater reliability with respect to CAM-B3LYP, comprising 22% of HF exchange for short-range interactions and 100% HF for long-range interactions.…”

“…Recently, we developed an “easy-to-use” method that allowed us to directly predict the pKa of a series of substituted phenols and carboxylic acids with reliable results [ 1 , 8 ]. Briefly, our methodology requires the introduction of two explicit water molecules at the reaction center, CAM-B3LYP as functional, 6-311G+(d,p) as the basis set and SMD.…”

“…Herein, the reliability of our “easy-to-use method” [ 1 , 8 ] for pKa determination was verified, by screening a panel of functionals belonging to different rungs of Jacob’s ladder. The main goal was to propose other functionals that show similar accuracy and reliability to CAM-B3LYP, with lower computational cost, eventually.…”