Fluorine-19 nuclear magnetic resonance spectroscopy

A sample 19F NMR spectrum of a simple organic compound. Integrations are shown under each peak.

19F NMR spectrum of 1-bromo-3,4,5-trifluorobenzene. The expansion shows the spin–spin coupling pattern arising from the para-fluorine coupling to the 2 meta-fluorine and 2 ortho proton nuclei.

Fluorine-19 nuclear magnetic resonance spectroscopy (fluorine NMR or ¹⁹F NMR) is an analytical technique used to detect and identify fluorine-containing compounds. ¹⁹F is an important nucleus for NMR spectroscopy because of its receptivity and large chemical shift dispersion, which is greater than that for proton nuclear magnetic resonance spectroscopy.

Operational details

¹⁹F has a nuclear spin (I) of 1⁄2 and a high gyromagnetic ratio. Consequently, this isotope is highly responsive to NMR measurements. Furthermore, ¹⁹F comprises 100% of naturally occurring fluorine. The only other highly sensitive spin ⁠1/2⁠ NMR-active nuclei that are monoisotopic (or nearly so) are ¹H and ³¹P. Indeed, the ¹⁹F nucleus is the third most receptive NMR nucleus, after the ³H nucleus and ¹H nucleus.

The ¹⁹F NMR chemical shifts span a range of about 800 ppm. For organofluorine compounds the range is narrower, being about −50 to −70 ppm (for CF₃ groups) to −200 to −220 ppm (for CH₂F groups). The very wide spectral range can cause problems in recording spectra, such as poor data resolution and inaccurate integration.

It is also possible to record decoupled ¹⁹F{¹H} and ¹H{¹⁹F} spectra and multiple bond correlations ¹⁹F-¹³C HMBC and through space HOESY spectra.

Chemical shifts

¹⁹F NMR chemical shifts in the literature vary strongly, commonly by over 1 ppm, even within the same solvent. Although the reference compound for ¹⁹F NMR spectroscopy, neat CFCl₃ (0 ppm), has been used since the 1950s, clear instructions on how to measure and deploy it in routine measurements were not present until recently. An investigation of the factors influencing the chemical shift in fluorine NMR spectroscopy revealed the solvent to have the largest effect (Δδ = ±2 ppm or more). A solvent-specific reference table with 5 internal reference compounds has been prepared (CFCl₃, C₆H₅F, PhCF₃, C₆F₆ and CF₃CO₂H) to allow reproducible referencing with an accuracy of Δδ = ±30 ppb. As the chemical shift of CFCl₃ is also affected by the solvent, care must be taken when using dissolved CFCl₃ as reference compound with regards to the chemical shift of neat CFCl₃ (0 ppm). Example of chemical shifts determined against neat CFCl₃:

Excerpt of referencing table against neat CFCl₃ [ppm]

	CFCl3	C6H5F	PhCF3	C6F6	CF3CO2H
Solvent	[ppm]	[ppm]	[ppm]	[ppm]	[ppm]
CDCl3	0.65	−112.96	−62.61	−161.64	−75.39
CD2Cl2	0.02	−113.78	−62.93	−162.61	−75.76
C6D6	−0.19	−113.11	−62.74	−163.16	−75.87
Acetone-d6	−1.09	−114.72	−63.22	−164.67	−76.87

For a complete list the reference compounds chemical shifts in 11 deuterated solvents the reader is referred to the cited literature.

A concise list of appropriately referenced chemical shifts of over 240 fluorinated chemicals has also been recently provided.

Chemical shift prediction

¹⁹F NMR chemical shifts are more difficult to predict than ¹H NMR shifts. Specifically, ¹⁹F NMR shifts are strongly affected by contributions from electronic excited states whereas ¹H NMR shifts are dominated by diamagnetic contributions.

Fluoromethyl compounds

¹⁹F chemical shifts of F₃C−R groups

−R	δ (ppm)
H	−78
CH3	−62
CH2CH3	−70
CH2NH2	−72
CH2OH	−78
CH=CH2	−67
C≡CH	−56
CF3	−89
CF2CF3	−83
F	−63
Cl	−29
Br	−18
I	−5
OH	−55
NH2	−49
SH	−32
C(=O)Ph	−58
C(=O)CF3	−85
C(=O)OH	−77
C(=O)F	−76
C(=O)OCH2CH3	−74

¹⁹F chemical shifts of F₂CH−R groups

−R	δ (ppm)
H	−144
CH3	−110
CH2CH3	−120
CF3	−141
CF2CF3	−138
C(=O)OH	−127

¹⁹F chemical shifts of FH₂C−R groups

−R	δ (ppm)
H	−268
CH3	−212
CH2CH3	−212
CH2OH	−226
CF3	−241
CF2CF3	−243
C(=O)OH	−229

Fluoroalkenes

For vinylic fluorine substituents, the following formula allows estimation of ¹⁹F chemical shfits: $$\delta _{C=CF}~[{\text{ppm}}]=-133.9+Z_{\text{cis}}+Z_{\text{trans}}+Z_{\text{gem}}+S_{\text{cis/trans}}+S_{\text{cis/gem}}+S_{\text{trans/gem}},$$ where Z is the statistical substituent chemical shift (SSCS) for the substituent in the listed position, and S is the interaction factor. Some representative values for use in this equation are provided in the table below:

SSCS values for fluoroalkene substituents

Substituent R	Zcis	Ztrans	Zgem
−H	−7.4	−31.3	49.9
−CH3	−6.0	−43.0	9.5
−CH=CH2	—	—	47.7
−Ph	−15.7	−35.1	38.7
−CF3	−25.3	−40.7	54.3
−F	0	0	0
−Cl	−16.5	−29.4	—
−Br	−17.7	−40.0	—
−I	−21.3	−46.3	17.4
−OCH2CH3	−77.5	—	84.2

Interaction factors for fluoroalkene substituents

Substituent	Substituent	Scis/trans	Scis/gem	Strans/gem
−H	−H	−26.6	—	2.8
−H	−CF3	−21.3	—	—
−H	−CH3	—	11.4	—
−H	−OCH2CH3	−47.0	—	—
−H	−Ph	−4.8	—	5.2
−CF3	−H	−7.5	−10.6	12.5
−CF3	−CF3	−5.9	−5.3	−4.7
−CF3	−CH3	17.0	—	—
−CF3	−Ph	−15.6	—	−23.4
−CH3	−H	—	−12.2	—
−CH3	−CF3	—	−13.8	−8.9
−CH3	−Ph	—	−19.5	−19.5
−OCH2CH3	−H	−5.1	—	—
−Ph	−H	—	—	20.1
−Ph	−CF3	−23.2	—	—

Fluorobenzenes

When determining the ¹⁹F chemical shifts of aromatic fluorine atoms, specifically phenyl fluorides, there is another equation that allows for an approximation. Adopted from "Structure Determination of Organic Compounds," this equation is $$\delta _{F}~[{\text{ppm}}]=-113.9+\Sigma Z_{\text{ortho}}+\Sigma Z_{\text{meta}}+\Sigma Z_{\text{para}},$$ where Z is the SSCS value for a substituent in a given position relative to the fluorine atom. Some representative values for use in this equation are provided in the table below:

SSCS values for fluorobenzene substituents

Substituent	Zortho	Zmeta	Zpara
−CH3	−3.9	−0.4	−3.6
−CH=CH2	−4.4	0.7	−0.6
−F	−23.2	2.0	−6.6
−Cl	−0.3	3.5	−0.7
−Br	7.6	3.5	0.1
−I	19.9	3.6	1.4
−OH	−23.5	0	−13.3
−OCH3	−18.9	−0.8	−9.0
−NH2	−22.9	−1.3	−17.4
−NO2	−5.6	3.8	9.6
−CN	6.9	4.1	10.1
−SH	10.0	0.9	−3.5
−CH(=O)	−7.4	2.1	10.3
−C(=O)CH3	2.5	1.8	7.6
−C(=O)OH	2.3	1.1	6.5
−C(=O)NH2	0.5	−0.8	3.4
−C(=O)OCH3	3.3	3.8	7.1
−C(=O)Cl	3.4	3.5	12.9

The data shown above are only representative of some trends and molecules. Other sources and data tables can be consulted for a more comprehensive list of trends in ¹⁹F chemical shifts. Something to note is that, historically, most literature sources switched the convention of using negatives. Therefore, be wary of the sign of values reported in other sources.

Spin–spin coupling

¹⁹F-¹⁹F coupling constants are generally larger than ¹H-¹H coupling constants. Long range ¹⁹F-¹⁹F coupling, (²J, ³J, ⁴J or even ⁵J) are commonly observed. Generally, the longer range the coupling, the smaller the value. Hydrogen couples with fluorine, which is very typical to see in ¹⁹F spectrum. With a geminal hydrogen, the coupling constants can be as large as 50 Hz. Other nuclei can couple with fluorine, however, this can be prevented by running decoupled experiments. It is common to run fluorine NMRs with both carbon and proton decoupled. Fluorine atoms can also couple with each other. Between fluorine atoms, homonuclear coupling constants are much larger than with hydrogen atoms. Geminal fluorines usually have a J-value of 250-300 Hz. There are many good references for coupling constant values. The citations are included below.

Magnetic resonance imaging

¹⁹F magnetic resonance imaging (MRI) is a viable alternative to ¹H MRI. The sensitivity issues can be overcome by using soft nanoparticles. Application include pH-, temperature-, enzyme-, metal ion- and redox responsive- contrast agents. They can also be used for long-term cell labelling.