Using Benchtop 19F NMR to Evaluate Fluoroorganic Compounds

Fluorine-19 NMR brings a new dimension to the analysis group of fluorine-containing compounds. The wider chemical shift range in ¹⁹F NMR makes it possible to resolve each fluorine-containing functional group and the routinely large variable magnitude of ¹H-¹⁹F and ¹⁹F-¹⁹F coupling sheds more light on structural effects. Analysis is also simplified by highly resolved resonance lines and first-order coupling.

Introduction

Fluorine (¹⁹F) is known to play an integral role in agrochemical, pharmaceutical, and medicinal chemistry because the fluorine atoms placed judiciously in a molecule can have a major impact on both its physical and chemical properties. While there is minimal steric impact of substituting a hydrogen (¹H) atom with fluorine, the withdrawal of electrons and the inductive field effects caused by a single fluorine nucleus are very intense, influencing a number of properties such as polarity, lipophilicity, and acidity.

Figure 1 shows examples of fluoroorganic compounds having varying degree of fluorination and structural complexity. Fluorine-based biologically active agrochemical and pharmaceutical compounds are usually “lightly” fluorinated and contain one or a few fluorine-containing substituents. However, electronic liquids are oligo perfluorocarbon compounds that are chemically inert and are generally used in low temperature heat transfer applications or as lubricants.

Figure 1. Chemical structures of the fluoroorganic compounds used in this study. (1) Fluorobenzene; (2) 4-fluorobenzyl bromide; (3) [4-(trifluoromethyl)phenyl]methanamine; (4) perfluoro-n-butyl ethylene, trade name Zonyl^® PFBE; and (5) 2H,3H-decafluoropentane, trade name Vertrel^® XF.

After ¹H and ¹³C, ¹⁹F is one of the most researched nuclide in NMR spectroscopy. ¹⁹F NMR provides a number of advantages:

1. With regards to lightly fluorinated bioactive molecules, the fairly small number of fluorine atoms produce a fewer number of signals which enable easy interpretation of spectra.
2. Fluorine binds strongly to other ¹⁹F nuclides placed as far as six bonds away, and also binds to adjacent carbon atoms and ¹H nuclei. Therefore, the resulting ¹⁹F NMR spectrum is data-rich in both molecular structure and relevant chemical environment.
3. The ¹⁹F NMR spectra are generally first-order in nature because spin-spin coupling obeys the n+1 rule for multiplicity.
4. ¹⁹F is the most electronegative element on the periodic table and exhibits large shift dispersion (from -300 ppm to 400 ppm), leading to considerably larger chemical shifts in ¹⁹F spectra than in ¹H ones as well as a significantly smaller probability of peak overlapping.

In order to show the wealth of ¹⁹F spectral data, this article presents the ¹⁹F NMR spectra of a range of commercially available fluoroorganic compounds, acquired with a Thermo Fisher Scientific picoSpin 80 ¹⁹F NMR spectrometer.

Experiment

A picoSpin 80 NMR spectrometer – a pulsed, Fourier transform ¹⁹F NMR permanent magnet instrument integrated with a capillary cartridge probe – was used to acquire spectra. The spectrometer was adjusted to the fluorine Larmor frequency of 77 MHz in order to obtain the highest sensitivity. The capillary cartridge of the spectrometer was equipped with micro-fluidic outlet and inlet connectors that enable injecting a liquid sample into the RF coil of the spectrometer. Teflon/Quartz capillary tubing with an overall flowpath volume of 40 microliters (μL) tubing constituted the fluid path. Through manual injection, liquid samples were introduced with a 22-gauge blunt tip needle and a disposable 1 mL syringe. As an internal shift reference, hexafluorobenzene (HFB, C₆F₆) was added to the fluorinated samples at a concentration of 1% (v/v). Being a high fluorine density compound, HFB provides a robust fluorine signal and has a chemical shift value of -164 ppm. Since fluorine compounds require solubility and a large shift dispersion, other reference compounds are also utilized to capture the entire range of potential chemical shifts. These compounds include ethyl trifluoroacetate (-75.8 ppm), trifluoroacetic acid (-76.2 ppm), trifluoromethylbenzene (-63.2 ppm), and fluorotrichloromethane (0 ppm).

The following acquisition parameters were used to acquire spectra:

• a 90° RF excitation pulse
• a 1000 ms acquisition time
• a 10 second recycle delay

The large chemical shift dispersion in the ¹⁹F spectrum was captured by tuning the spectral width. Signal averaging was used to acquire all the spectra. The resultant spectral data were then stored in a JCAMP-DX file format and subsequently processed by feeding into MestreLab Research’s Mnova™ NMR analysis program. Across all the spectra, standardized data processing was applied which mainly included zero filling, filtering using exponential Apodization, and phase correction.

Results and discussion

Examples of lightly fluorinated compounds

Figure 2 shows the ¹⁹F NMR spectra of one trifluoromethylsubstituted phenylmethylamine and two mono-substituted aromatic fluoroorganic compounds. Fluorine substituents present on the aromatic ring absorb in the same region, i.e., between -200 ppm and -100 ppm. This is because shielding zones caused by the ring currents in the benzene ring do not have a major impact on the fluorine atoms. Aromatic experiences ³J_FH and ⁴J_FH coupling is changed to ring protons by mono-fluorine, leading to complex but distinct multiplets. By contrast, the trifluoromethyl group (CF₃) in compound 3 seems to be a singlet.

Figure 2. Full ¹⁹F NMR spectra of, from top down, fluorobenzene (compound 1), 4-fluorobenzyl bromide (compound 2), and [4-(trifluoromethyl)phenyl]methanamine (compound 3).

It must be noted that J coupling is an indirect, through-bond scalar coupling that occurs between nuclei of like spin. The number of bonds isolating the coupled nuclei is indicated by the superscripts preceding the J term, for example, ²J, ³J, or ⁴J. Furthermore, ³J coupling is generally seen in ¹H NMR, while coupling 2-6 bonds away is commonly seen in ¹⁹F NMR. The type of nuclei coupled together is indicated by the subscripts, for example, J_HH, J_FF, or J_FH. It is the coupling constants that give important information on which nuclei are proximal to one another. The signal intensity of uncoupled nuclei is split by the coupled nuclei, resulting in a multiplet signal. The well-defined multiplicity, which follows the n+1 rule for first-order coupling, indicates the number of neighboring coupled nuclei, n.

An example of a fluorotelomer

Fluorotelomers, an example of fluorocarbon-based oligomers, are produced through radical polymerization. They are utilized as flame retardants in a wide range of manufacturing processes and also as non-conductive coatings because of their lipophobicity. Since fluorotelomers are used as surfactants, they form the basis of many perfluorinated carboxylic acids that are prevalent in the environment.

The perfluoro-n-butyl ethylene compound is a fluorotelomer intermediate marketed under the trade name

Zonyl^® PFBE. It includes a fluorocarbon backbone and an ethylene functional group. The fluorine peaks have higher spectral resolution which makes structural determination and multiplet analysis relatively easy, as shown in Figure 3.

Figure 3. Full ¹⁹F NMR spectrum of perfluoro-n-butyl ethylene. Inset: Multiplet analysis of the splitting pattern of individual peaks, with a J-coupling tree and coupling constants overlaid on the spectrum.

The insets demonstrate the J-coupling trees for the well-defined multiplicity peaks (peaks 4, 5, and 6). It is observed that the extent of the ³J_FF coupling constants has the predicted size for symmetric, linear, primary, and secondary fluoroalkyl groups. In the case of peak 3, the fluorine atoms coupling to nearby protons (³J_FH) at C₃ position affects the symmetry at this position, resulting in the loss of a well-defined multiplet.

An example of a hydrofluorocarbon

A wide range of applications, such as lubricants, heat transfer fluids, and precision and optics cleaning make use of hydrofluorocarbon (HFC) electronic fluids. The ¹H and ¹⁹F spectra of 2H,3Hdecafluoropentane—a specialty fluid—are shown in Figures 4 and 5, respectively. 2H,3Hdecafluoropentane is marketed by DuPont™ under the trade name Vertrel^® XF.

In the ¹H spectrum, shown in Figure 4, apart from H-H coupling ³J_HH, both protons undergo a strong ¹H-¹⁹F geminal coupling (²J_FH; coupling of spin ½ nuclei coupled to the same carbon center) to fluorine and also experience vicinal coupling (³J_FH; coupling of spin ½ nuclei on neighboring carbon centers) to nearby fluorine atoms, producing an intricate multiplet splitting pattern. This pattern is made more complicated by the asymmetry of proton substitution at the positions C₂ and C₃ and the somewhat different chemical shifts for both protons. The splitting pattern was then subjected to multiplet analysis which indicates a dddd class, with a ²J_FH coupling constant of 43.4 Hz.

Figure 4. Full ¹H NMR spectrum of 2H,3H-decafluoropentane (C₅H₂F₁₀; neat) with TMS added as a chemical shift reference. Multiplet analysis of the splitting pattern reveals a dddd class; a J-coupling tree and coupling constants are overlaid on the spectrum.

Figure 5 shows the ¹⁹F spectrum, where both primary and secondary alkyl fluorides undergo widely different shielding along the carbon backbone, covering between -220 ppm and -75 ppm and thus enabling a separate analysis of individual fluorine groups. Validation of the intense geminal ²J_FH coupling seen in the ¹H spectrum lies in the multiplet analysis of the complex splitting pattern of fluorine atoms at C₂ and C₃ positions (inset for peaks 2 and 3).

Figure 5. Full ¹⁹F NMR spectrum of 2H,3H-decafluoropentane (C₅H₂F₁₀; neat) with C₆F₆ added as a chemical shift reference. Inset: Expanded view of chemical shift regions showing complex, multiplet splitting patterns arising from ²J_FH and ³J_FH coupling, and molecular asymmetry. J-coupling trees and coupling constants are overlaid on the spectrum.

Conclusions

¹H and ¹³C NMR in structure determination are complimented by fluorine-19 NMR. The wider chemical shift range in ¹⁹F NMR makes it possible to overcome each fluorine-containing functional group, whereas the routinely large variable magnitude of ¹H-¹⁹F and ¹⁹F-¹⁹F coupling offers a better understanding of structural effects. Analysis is also simplified by highly resolved resonance lines and first-order coupling. On the whole, ¹⁹F NMR brings a new dimension to the analysis group of fluorine-containing compounds.

This information has been sourced, reviewed and adapted from materials provided by Thermo Fisher Scientific – Materials & Structural Analysis.

For more information on this source, please visit Thermo Fisher Scientific – Materials & Structural Analysis.