Exploring the Behaviour of 13C-19F Coupling Interactions in 13C-NMR Spectra of Bio-relevant Fluorinated Organic Molecules: Case Studies#

Abstract:

Fluorinated compounds are essential in modern chemistry, especially in drug design, where fluorine enhances metabolic stability and lipophilicity, enabling the development of more effective therapeutics with improved pharmacological properties. The presence of a fluorine atom in an organic molecule gives rise to observable 13C-19F coupling in 13C{1H} NMR spectroscopy, offering valuable structural insight. The magnitude of the coupling constant (JCF) varies significantly and leads to characteristic splitting of 13C-signals, although the precise contribution of individual factors is often complex and not easily delineated. This review surveys the variations in 13C-19F coupling constants across fluorinated bioactive compounds, highlighting the different types and ranges of observed JCF values and their corresponding 13C NMR splitting patterns. The coupling constants are generally influenced by structural, electronic, and external factors such as solvent and temperature, although the precise contribution of individual parameters is often difficult to define. A total of 45 different types of reported fluorinated molecules have been screened as targeted case studies, and these are highlighted along with their respective JCF data, presented in tabular form, and carbon signals assigned based on coupling constants. By comparing trends across various structural classes, this review provides a comprehensive understanding of 13C-19F couplings, serving as a practical guide for the rational design and optimization of fluorine-containing molecules.