Application Note 4

Application of a high performancebenchtop NMR spectrometer for 19F
NMR spectroscopy
Background
Fluorine is an important element in industrial
chemistry and has applications in a wide range ofindustries, such as pharmaceuticals, agrochemicals,
polymers, surfactants and solvents. It is estimatedthat more than 20% of all pharmaceuticalcompounds contain fluorine. This includes some of
the commercially important drugs such as Prozac(fluoxetine) and Paxil (paroxetine). Nuclear Magnetic
Resonance (NMR) spectroscopy is a valuable
technique for the measurement of compounds
containing fluorine especially organo-fluorinecompounds. After the proton (1H) and carbon-13(13C) NMR, fluorine-19 (19F) is the most common
nucleus studied by this technique. 19F nuclei have anuclear spin of ½, have a high gyromagnetic ratio,
and have 100% natural abundance, ensuring they
have a high receptivity for NMR measurements. The19F resonance frequency in a 1.4 T magnetic field,
such as X–Pulse, is 56.2 MHz which is sufficiently
close to the resonance frequency of 1H, that protonand fluorine-19 spectra can be measured using thesame probe.

Measuring 19F spectra on X–Pulse
X–Pulse is a high performance broadband benchtop
NMR spectrometer that does not require external
services, such as liquid cryogens or compressed air,and can be placed in the laboratory rather than in a
specialised NMR facility. Spectra can be collected
within a couple of minutes using standard 5 mm
NMR tubes.

A series of spectra have been collected todemonstrate the 19F and 1H capability andperformance of the instrument using the sameprobe.
aα,αa,aα-Trifluorotoluene is a useful referencematerial for 19F NMR spectroscopy and can beused as an internal standard in a similar way
to tetramethylsilane (TMS) is for 1H and 13C
measurements. The 1H and 19F spectra of αa,αa,αatrifluorotoluene are shown in figure 1.

Figure 2: 19F spectrum of a mixture of αa,aα,aα-trifluorotolueneand 2,2,2-trifluoroethanol

Figure 1: 1H (top, purple) and 19F (bottom, sea green)
spectra of αa,αa,aα-trifluorotoluene

The 19F spectrum, shown in figure 1, consists ofa single peak since the three fluorine nuclei are
chemically and magnetically equivalent, and are
not in close proximity to any of the protons in themolecule. The 1H spectrum is more complex since
the hydrogen nuclei on the aromatic ring are notequivalent and the resulting homonuclear couplings
give rise multiple overlapping signals, appearing as asingle multiplet.

Figure 3 shows the 1H and 19F spectra of thecompound 5-bromo-1,2,3-trifluorobenzene. The1
H spectrum consists of a single multiplet of peaks
resulting from the two equivalent 1H nuclei and theircouplings with the chemically and magneticallyinequivalent 19F nuclei within the molecule. The 19F
spectrum consists of two resonances, each of which
are multiplets due to the two different chemical
environments of the 19F nuclei. The resonance at −132ppm arises from the fluorines in the meta positions of
the molecule while the resonance at −161 ppm arises
from the fluorine in the para position.

The spectrum shown in figure 2 is a mixture of two
fluorine containing chemicals; αa,αa,aα-trifluorotoluene(TFT) and 2,2,2-trifluoroethanol. TFT is often used
as a reference material for 19F spectra; since itappears as a strong, single peak with a chemical
shift of −62.6 ppm relative to the standard 19F NMR
chemical shift reference compound, CFCl3, at 0 ppm.
(Angew. Chem. Int. Ed., 2018, 57, 9528-9533) It is a single peak as thestructure consists of three equivalent fluorine nuclei
isolated from any other nuclei that would couple toit. By comparison the peak in the spectrum due totrifluoroethanol, at −77.1 ppm, is split into a triplet.
This is due to the fact that the 19F nuclei couples withthe two equivalent 1H nuclei on the adjacent carbon
atom in the molecule, just as 1H nuclei would couple
with other neighbouring 1H nuclei in the molecule.

Figure 3: 1H (top, purple) and 19F (bottom, sea green)
spectra of 5-bromo-1,2,3-trifluorobenzene

Each of these resonances shows a complex coupling
pattern due to the other nuclei on the aromaticring. Most easily recognisable is the triplet of triplet
pattern at −162 ppm, arising because the fluorine
in the para position is coupled to two equivalent
fluorines in the meta positions and two equivalenthydrogens in the ortho positions.
Finally, a comparison has been made of the 19F
spectra of two different positional isomers ofbromotrifluorobenzene. Figure 4 shows the 19F
spectra of 5-bromo-1,2,3-trifluorobenzene and1-bromo-2,4,5-trifluorobenzene.

In contrast to the spectrum of 5-bromo-1,2,3trifluorobenzene, the spectrum of 1-bromo-2,4,5trifluorobenzene shows three 19F resonances
because each of the fluorines on the ring are indifferent chemical environments. They all appear as
a doublet of doublets of doublets of doublets, sinceeach is coupled to two inequivalent fluorines andtwo inequivalent hydrogens.

Figure 4: 19F spectra of 5-bromo-1,2,3-trifluorobenzene (top, sea green) and 1-bromo-2,4,5-trifluorobenzene (bottom,deep sky)Summary
The data presented here displays that benchtop
NMR is a valuable analytical tool formeasuring 19F spectra and provides useful
information for fluorine chemistry. WithX-Pulse it is possible to measure both 19F and1
H spectra of a sample within a couple ofminutes using the same probe.

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