The fluorine-19 nucleus was recognized early to harbor exceptional properties for NMR spectroscopy. With 100% natural abundance, a high gyromagnetic ratio (83% sensitivity compared to ¹H), a chemical shift that is extremely sensitive to its surroundings and near total absence in biological systems, it was destined to become a favored NMR probe, decorating small and large molecules. However, after early excitement, where uptake of fluorinated aromatic amino acids was explored in a series of animal studies, ¹⁹F-NMR lost popularity, especially in large molecular weight systems, due to chemical shift anisotropy (CSA) induced line broadening at high magnetic fields. Recently, two orthogonal approaches, (i) CF₃ labeling and (ii) aromatic ¹⁹F-¹³C labeling leveraging the TROSY (Transverse Relaxation Optimized Spectroscopy) effect have been successfully applied to study large biomolecular systems. In this perspective, we will discuss the fascinating early work with fluorinated aromatic amino acids, which reveals the enormous potential of these non-natural amino acids in biological NMR and the potential of ¹⁹F-NMR to characterize protein and nucleic acid structure, function and dynamics in the light of recent developments. Finally, we explore how fluorine NMR might be exploited to implement small molecule or fragment screens that resemble physiological conditions and discuss the opportunity to follow the fate of small molecules in living cells.

氟 19 核很早就被认为具有核磁共振波谱的特殊性质。凭借 100% 的自然丰度、高旋磁比（与¹ H 相比，灵敏度为 83%）、对周围环境极其敏感且在生物系统中几乎完全不存在的化学位移，它注定会成为受欢迎的 NMR 探针，装饰小和大分子。然而，在早期的兴奋之后，在一系列动物研究中探索了氟化芳香族氨基酸的摄取，¹⁹ F-NMR 失去了受欢迎程度，特别是在大分子量系统中，这是由于化学位移各向异性 (CSA) 在高磁力下引起谱线展宽。字段。最近，利用 TROSY（横向弛豫优化光谱）效应的两种正交方法（i）CF ₃标记和（ii）芳香族¹⁹ F- ¹³ C 标记已成功应用于研究大型生物分子系统。^{从这个角度来看，我们将讨论有关氟化芳香族氨基酸的令人着迷的早期工作，这些工作揭示了这些非天然氨基酸在生物 NMR 中的巨大潜力，以及19} F-NMR 表征蛋白质和核酸结构、功能和特性的潜力。根据最近的事态发展动态。最后，我们探讨了如何利用氟核磁共振来实现类似于生理条件的小分子或片段筛选，并讨论了跟踪活细胞中小分子命运的机会。