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.