The Antagonist Effect of Nitrogen Lone Pair: 3 JHF versus 5 JHF.

The long-range scalar coupling constant between proton and fluorine nuclei, 5 JHF , is observed to be larger than 3 JHF 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 JHF values. Spectral aliased pure shift heteronuclear single quantum coherence spectroscopy (SAPS-HSQC) is applied to determine the relative sign between the JCF and JHF scalar couplings. Theoretical calculations show that the 3 JHF and 5 JHF coupling constants can be described mainly by a Fermi contact (FC) transmission mechanism. A decomposition analysis of JHF 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 5 JHF compared to 3 JHF . Our analysis indicates that delocalization of LPN has a positive contribution to the long-range coupling, while a negative one is observed for 3 JHF .