Evaluation of Different DFT Functionals and Basis Sets for Predicting Proton Affinity and Gas‐Phase Basicity of Small Organic Molecule MALDI Matrices

Abstract Based on density functional theory (DFT), we conducted an in‐depth evaluation of the protonation energies of matrix molecules in matrix‐assisted laser desorption/ionization (MALDI) technology. Various error analysis strategies were employed to explore the discrepancies between theoretical calculations and experimental data. The results showed that, compared to other methods, the M06‐2X functional exhibited lower error and higher linear correlation in predicting the proton affinity and gas‐phase basicity of small organic molecule MALDI matrices, confirming the accuracy and reliability of this functional. Specifically, the mean unsigned error (MUE) for proton affinity under the M06‐2X functional is 2.01, and the MUE for gas‐phase basicity is 2.14. In terms of basis sets, 6–31+G(d,p) performs better than other 3 basis sets. To further validate the reliability of the functional used in molecular structure calculations, the performance of different functionals in predicting the bond length between the amino nitrogen and the adjacent carbon atom in the 4‐nitroaniline (PNA) and 2‐aminobenzoic acid (2‐AA) molecules were compared. The results indicated that most functionals, including M06‐2X, demonstrated good predictive capability.