19 F NMR chemical shifts are sensitive to remote functional group variations

Covalently identical ortho-F nuclei display dual 19 F NMR signals in di-ortho-F substituted N-phenyl gamma- lactams. We found that the deshielding 19 F signal (delta down) was significantly affected by C9-substituent, especially when C9 -substituents are steric bulky. Notably, the deshielded 19 F chemical shift is sen-sitive to chirality variations at C9-alkyls, while the shielded 19 F NMR signal delta up manifests negligible changes among various C9-alkyl derivatives. Calculated molecular electrostatic surface potentials (ESPs) were used to interpret the experimental observations. 19 F NMR signal assignments in an exemplary ro-tameric molecule are presented based on our understanding on structure -19 F shielding relationship. Our work described here provides basics to deciphering 19 F shielding in biologically important molecules and drugs, and to use of 19 F chemical shifts in monitoring molecular dynamics and conformations. (c) 2023 Elsevier B.V. All rights reserved.

Automated summary

In di-ortho-F substituted N-phenyl gamma-lactams, covalently identical ortho-F nuclei exhibit dual 19F NMR signals. The deshielding 19F signal (delta down) is significantly influenced by C9-substituent, particularly when C9-substituents are steric bulky. Notably, the deshielded 19F chemical shift is sensitive to chirality variations at C9-alkyls, while the shielded 19F NMR signal delta up shows negligible changes among various C9-alkyl derivatives. Calculated molecular electrostatic surface potentials (ESPs) were used to explain the experimental observations. 19F NMR signal assignments in an exemplary rotameric molecule are provided based on the understanding of the structure-19F shielding relationship. Our work lays the foundation for deciphering 19F shielding in biologically important molecules and drugs, as well as utilizing 19F chemical shifts to monitor molecular dynamics and conformations.