¹⁹Fluorine NMR

NMR Reference: CCl₃F was used as a standard reference sample. Its absolute frequency is 94.094011 MHz, relative to a TMS of 100.00 MHz. NMR Parameters: The fluorine-19 (¹⁹F) chemical shift range is 1300 ppm. There are a large number of constant coupling values available for any ¹⁹F-X spin system. The most reported coupling constant measurements are ¹H-¹⁹F and ¹⁹F-¹⁹F.

Isotope	Natural Abundance (%)	Nuclear Spin (I)	Magnetogyric ratio (107*rad/T*s)	Quadruple moment (1028*Q/m2)	Resonance frequency (MHz) at 11.744T (500 MHz for 1H)	Relative sensitivity (1H=1.00)	Absolute sensitivity (1H=1.00)
19F	100	1/2	25.18148	0	470.385	0.83	0.83

Theoretical Basis of ¹⁹F NMR

¹⁹F NMR is based on the interaction of the magnetic moment of the fluorine nucleus with an external magnetic field. The fluorine isotope, ¹⁹F, has a nuclear spin of 1/2 and a relatively high gyromagnetic ratio, which results in a strong and well-resolved NMR signal. In a magnetic field, the energy levels of the nuclear spins split according to the chemical shift, allowing the detection of specific resonance frequencies. The chemical shift, which is usually expressed in parts per million (ppm), is determined by the electronic conditions of the fluorine atom (such as electronegativity, bond type, and molecular symmetry).

These ¹⁹F NMR spectra are highly resolvable because the chemical shifts between fluorinated species are vastly different from hydrogen and carbon nuclei, making them possible to analyze with high accuracy in complicated solutions. Additionally, because most fluorinated molecules don't contain proton couplings, the spectra are clear and easily read.

For more NMR information on ¹⁹F see: ¹⁹F NMR Chemical Shift Table and ¹⁹F Coupling Constants Table

Applications of ¹⁹F NMR

Structural Elucidation of Fluorine-Containing Compounds

The most common use of ¹⁹F NMR is to investigate the structure of fluorine molecules. As fluorine atoms are added to organic molecules, they cause peculiar shifts based on where and how they bond to the molecule. A fluorine atom tethered to an sp²-hybridized carbon (e.g., in fluoroaromatics) has a different chemical shift than a fluorine atom tethered to an sp³-hybridized carbon. This is very useful for the molecular structure and functional groups of the compound.

For fluoroalkyl groups, for instance, ¹⁹F NMR can tell us with great precision about the surrounding bonding environment: -CF₃, -CF₂H and -CF₂X (where X is another substituent group). Splitting and shift can be mapped onto the environment, and this is how compounds can be identified.

Pharmaceutical and Medicinal Chemistry

¹⁹F NMR in pharmaceutical chemistry is used to develop fluorine drugs. Fluorine can be added to drug molecules to make them more metabolically stable, lipophilic and bioactive. The stable and conformational changes of fluorinated drugs, such as their binding to receptors or enzymes, can be tracked by ¹⁹F NMR.

And ¹⁹F NMR is used in drug metabolism and biodistribution. Because fluorine atoms are typically not found in biological molecules, adding ¹⁹F to drug candidates gives us a direct way to observe their behaviour in vivo. In PET (positron emission tomography) imaging, for instance, ¹⁸F-labelled substances are often studied with ¹⁹F NMR in order to determine their biological fate.

Fig.1 ¹⁹F NMR (470.67 MHz) spectra of fluorine-labeled oligonucleotides in single-stranded (ss) and double-stranded (ds) form^[1].

Quantification of Fluorine-Containing Compounds

¹⁹F NMR is very sensitive to measuring fluorinated molecules (crucial for synthetic chemistry and pharma quality control). The approach gives a linear correlation between the intensity of the NMR signal and the amount of the fluorine-containing compound. It is therefore able to be used for exact purification measurement, particularly when measuring fluorine levels in bulk materials (e.g. polymers or bulk chemical reactions).

This quantitative aspect is especially useful in the synthesis of fluorocarbons, because the dynamics of the reaction can be followed by observing the intensity of the fluorine signal. The same applies to optimising reaction conditions or constructing more efficient synthetic routes.

Polymer Chemistry and Material Science

Fluorine-based polymers like polytetrafluoroethylene (PTFE) or perfluorinated ionomers are common materials in advanced structures because of their chemical inertness and thermal stability. These polymers are then characterized with ¹⁹F NMR spectroscopy to study their structure and dynamics. The method also gives us a window on how fluorine atoms are spread in polymer chains so that we can look at copolymer compositions and see the amorphous and crystallized states of the polymer.

It is also possible to employ ¹⁹F NMR to study the reactions of fluorinated compounds with non-fluorinated compounds, such as solvents or reinforcements. That data is essential to creating tailored-performance materials.

Methodological Considerations

¹⁹F NMR is a very useful tool, but it's not effective without the right experimental setup. The spectrometer needs to be calibrated for fluorine nuclei's sensitive nature in low concentrations. Moreover, ¹⁹F NMR measurements should be conducted in high-field NMR machines so that they are as precise and as less signal-overlapping as possible (particularly in fluorinated complex mixtures).

The interaction of fluorine with other nuclei also produces multiplet splitting, which should be taken into account when spectra are compared. Couling with nearby nuclei (¹H or ¹³C) can interfere with the spectra, but this can be corrected with the right pulse sequences and experimental setup (decoupling, 2D NMR spectroscopy).

Fig.2 CFCl₃ calibrated tertiary reference material suitable for ¹⁹F NMR reference in various deuterated solvents^[2].

References

1. Baranowski M. R., et al. (2020). "5'-Fluoro(di)phosphate-labeled Oligonucleotides are Versatile Molecular Probes for Studying Nucleic Acid Secondary Structure and Interactions by ¹⁹F NMR." Nucleic Acids Research, 48(15), 8209-8224.
2. Rosenau C. P., et al. (2018). "Exposing the Origins of Irreproducibility in Fluorine NMR Spectroscopy." Nucleic Acids Research, 57(30), 9528-9533.