Ab Initio and Density Functional Calculations of¹⁹F NMR Chemical Shifts for Models of Carbonic Anhydrase Inhibitors

Abstract

Ab initio (HF) and density functional theory (DFT) calculations of 19 F NMR chemical shifts were performed for models of fluoroaromatic inhibitors of carbonic anhydrase II (CA). DFT gave slightly better agreement with the experimentally measured chemical shifts of the actual inhibitors, suggesting that intramolecular dispersion does contribute significantly to the chemical shifts in these molecules. HF and DFT calculations for the stacked complex of hexafluorobenzene with benzene gave excellent agreement with experimental 19 F chemical shifts in this system. The fact that both approaches to this calculation were successful suggests that intermolecular dispersion is not an important contributor to 19 F chemical shifts in this system. Electron transfer and electrostatics must, therefore, be responsible for the changes in the 19 F NMR spectra observed on complexation. Finally, an unsuccessful attempt was made to apply HF and DFT methods to the calculation of the 19 F chemical shift of a pentafluorobenzyl-derived CA inhibitor bound to the protein in close proximity to a phenylalanine residue. A model of the inhibitor's aromatic ring interacting with the protein's aromatic residue gave a calculated chemical shift change that was much greater than that observed experimentally. Effects on the chemical shift from the field due to atoms omitted from the calculation, as well as from extensive rovibrational freedom, cannot easily be addressed in calculations of these large systems and are the likely reasons for the failure of these calculations.

Dissecting the paradoxical effects of hydrogen bond mutations in the ketosteroid isomerase oxyanion hole

“…4A) suggests that the ortho-F atom is approximately 4.5 Å from the phenyl ring of Phe16. Previous ab initio and density functional theory calculations of 19 F NMR shielding contributions from a benzene ring positioned near hexafluorobenzene, however, reported negligible shielding contributions at separation distances greater than 4.0 Å (27). Thus, ring current effects from Phe16 are not expected to contribute significantly to chemical shift differences of the fluorine nucleus in Tyr16Phe versus Tyr16Ser.…”

An approach to evaluation of 19F‐NMR chemical shifts via basis functions analysis in fluorinated small compounds

“…Reasons for use of these methods were both our trial calculations for 19 F nuclei and previous reported calculations by other researches. In recent years, several groups have reported an excellent correlation and good agreement with experimental data using acceptable basis sets for 19 F‐NMR properties (31–35). All the studied molecules with the experimental values were collected in Table 3.…”

Computational 19F NMR. 1. General features

“…Some early computational work (aimed at benchmarking and validation) included F 2 as test molecule, which proved to be challenging [26][27][28]. Interest in modeling 19 F shifts has steadily continued, and several papers have appeared in the last decade aimed at general structural issues, solution chemistry and physical organic chemistry, [29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46] solid-state issues (especially the prediction of chemical shift tensors), [47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63][64] J-couplings [65][66][67][68][69][70][71][72]…”