Fluorine-19 nuclear magnetic resonance spectroscopy

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.[4][lower-alpha 1] 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 ca. 800 ppm. For organofluorine compounds the range is narrower, being ca. -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.

¹⁹F NMR chemical shifts in the literature vary strongly, commonly by over 1 ppm, even within the same solvent.[5] Although the reference compound for ¹⁹F NMR spectroscopy, neat CFCl₃ (0 ppm),[6] has been used since the 1950s,[7] clear instructions on how to measure and deploy it in routine measurements were not present until recently.[5] 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).[5] 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.[5] 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).[5] Example of chemical shifts determined against neat CFCl₃:[5]

For a complete list the reference compounds chemical shifts in 11 deuterated solvents the reader is referred to the cited literature.[5]

A concise list of appropriately referenced chemical shifts of over 240 fluorinated chemicals has also been recently provided.[5]

Fluoroalkenes

For vinylic fluorine substituents, the following formula allows for estimation of ¹⁹F chemical shfits:

$${\displaystyle \delta _{C=CF}~(ppm)=-133.9+Z_{cis}+Z_{trans}+Z_{gem}+S_{cis/trans}+S_{cis/gem}+S_{trans/gem}}$$

where Z is the statistical substituent chemical shift (SSCS) for the substituent in the listed position, and S is the interaction factor.[9] Some representative values for use in this equation are provided in the table below:[10]

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 Fluroalkene 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,"[10] this equation is:

$${\displaystyle \delta _{F}~(ppm)=-113.9+\Sigma Z_{ortho}+\Sigma Z_{meta}+\Sigma Z_{para}}$$

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:[10]

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.[8]

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.[11] 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.[11] There are many good references for coupling constant values.[11] The citations are included below.

Most commonly ¹⁹F NMR spectroscopy is used to analyze the structure of organofluorine compounds. Representative targets of this method are the many pharmaceuticals that contain C-F bonds. The technique is also used to analyze fluoride salts.[12]