The Antagonist Effect of Nitrogen Lone Pair: ³J_HF versus ⁵J_HF

The long-range scalar coupling constant between proton and fluorine nuclei, ⁵J_HF, is observed to be larger than ³J_HF in the pyrimidinyl moiety of voriconazole. A set of smaller molecules is chosen (fluorobenzene, N-methyl-2-fluoropyridine, N-methyl-3-fluoropyridine, 3-fluoropyridine, 5-pyrimidine, and 2-fluoropyridine) to evaluate the influence of the nitrogen atom in the experimental J_HF values. Spectral aliased pure shift heteronuclear single quantum coherence spectroscopy (SAPS-HSQC) is applied to determine the relative sign between the J_CF and J_HF scalar couplings. Theoretical calculations show that the ³J_HF and ⁵J_HF coupling constants can be described mainly by a Fermi contact (FC) transmission mechanism. A decomposition analysis of J_HF in terms of localized molecular orbital (LMO) contributions allows us to determine that the interaction involving the nitrogen lone pair (LPN) is the main reason for the larger ⁵J_HF compared to ³J_HF. Our analysis indicates that delocalization of LPN has a positive contribution to the long-range coupling, while a negative one is observed for ³J_HF.