# Accurate Prediction of pKb in Amines: Validation of the CAM-B3LYP/6-311+G(d,p)/SMD Model

## TL;DR

This paper presents a reliable method to predict pKb values in amines using a DFT-based model, improving accuracy for secondary and tertiary amines.

## Contribution

The study introduces a revised DFT method that includes a third water molecule for accurate pKb prediction in secondary and tertiary amines.

## Key findings

- Including a third water molecule at the reaction center improves pKb prediction accuracy for secondary and tertiary amines.
- The revised method achieves a minimum average error (MAE) of less than 0.4 across a wide range of amines.
- The method is a simple and direct DFT approach using CAM-B3LYP/SMD/6-311G+(d,p) without post facto modifications.

## Abstract

Amines play several key roles in chemistry and biology
and are
involved in numerous industrial processes, often with significant
economic impacts. Recently, amines are also garnering interest as
catalysts for polymer synthesis and for CO2 fixation, incentivizing
the need to rapidly design and screen new amino compounds. Hence,
developing reliable methods to predict their physicochemical properties,
e.g., the base dissociation constant (pKb), is pivotal. Here, a density
functional theory (DFT)-based approach was employed to compute the
pKb of substituted amines, exploring the impact of several key parameters,
including (i) the number of explicit water molecules at the reaction
center, (ii) the van der Waals (vdW) surface, and (iii) solvent polarizability.
In previous work, it was determined that including two explicit water
molecules at the reaction center resulted in highly accurate pKb estimates
for primary amines. Here, we find that including a third water molecule
at the reaction center is essential for accurate pKb for secondary
and tertiary amines. The revised methodology was then applied to a
wider selection of amines, obtaining a minimum average error (MAE)
< 0.4. This result represents an extension of our “easy-to-use
method,” a simple and direct DFT approach exploiting CAM-B3LYP/SMD/6-311G+(d,p)
to compute pKb without post facto modifications.