DFT-GIAO ¹⁹F NMR Chemical Shift Prediction Using B3LYP/pcSseg-3: Application to Augment Structure Elucidation of Drug-like Organic Molecules

Accurate calculation of ¹⁹F chemical shifts for CF₃, CF₂, and CF fluorine types using density functional theory-gauge including invariant atomic orbitals (DFT-GIAO) approximation is described. Six methods, B3LYP/cc-pVDZ, B3LYP/pcSseg-3, ωB97X-D/cc-pVDZ, ωB97X-D/pcSseg-3, B3LYP/6-31+G(d,p), and PBE1PBE/Def2TZVP were evaluated for speed and accuracy. Based on our findings B3LYP/cc-pVDZ and B3LYP/pcSseg-3 were selected for systematic investigation and comparison. A conformational search followed by geometry optimization at the B3LYP/cc-pVDZ level of theory was carried out and the conductor like polarizable continuum mode (CPCM) was used to simulate solvation effects in DMSO. The methods were validated across 1265 fluorine containing organic compounds with a diverse set of structural scaffolds. General linear scaling (GLS) terms were calculated for the three different fluorine types using B3LYP/cc-pVDZ and B3LYP/pcSseg-3. The results showed that both methods accurately predicted ¹⁹F chemical shifts for CF₃ and CF; however, B3LYP/pcSseg-3 outperformed B3LYP/cc-pVDZ for CF₂ moieties with linearity coefficients <i>R</i>² = 0.97 and <i>R</i>² = 0.92, respectively. Comparison of experimental and calculated ¹⁹F isotropic chemical shifts produced rapid and reliable assignment of the correct structure when experimental data alone was ambiguous or inconclusive. These DFT methods consistently showed accurate stereochemistry distinction for CF chiral centers in diastereomers.