Fluorine-19 nuclear magnetic resonance spectroscopy

Short description: Analytical technique

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.[1][2][3]

## Contents

* 1 Operational details
* 2 Chemical shifts
* 2.1 Chemical shift prediction
* 2.2 Fluoromethyl compounds
* 2.3 Fluoroalkenes
* 2.4 Fluorobenzenes
* 3 Spin–spin coupling
* 4 Biochemical and medical applications
* 4.1 In vivo magnetic resonance spectroscopy and imaging (19F MRS / MRI)
* 5 Notes
* 6 References

## 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.[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 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.[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]

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.[5]

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

### 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.[8]

### 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 shifts: δC=CF[ppm]=−133.9+Zcis+Ztrans+Zgem+Scis/trans+Scis/gem+Strans/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

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|
|

−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,"[10] this equation is δF[ppm]=−113.9+ΣZortho+ΣZmeta+ΣZpara, 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]

## 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.[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.

## Biochemical and medical applications

Fluorine-19 has often been employed to examine the structure and dynamics of fluorine-labeled proteins. The following fluorinated amino acids have been incorporated into proteins: 3- and 4-fluorophenylalanine, 6- and 5-fluorotryptophan and 3-fluorotyrosine, 5-fluoroleucine, trifluoroethylglycine, trifluoro- and difluoromethionine, and 2-fluorohistidine. Substitution, mediated often ribosomally, is facilitated because H and F are similar in size, even though C-F bonds are somewhat longer.[12][13]

### In vivo magnetic resonance spectroscopy and imaging (19F MRS / MRI)

In vivo magnetic resonance spectroscopy is a technique that closely resembles the laboratory NMR, but the sample is contained within a living organism (in vivo). In turn, magnetic resonance imaging is more complex technique that can provide the spatial distribution of the study MR signal throughout the body. Most commonly, MRI acquires 1H signal, but it can also acquire any other nuclide with non-zero spin number.

Natural fluorine is monoisotopic - its only non-radioactive nuclide (19F) has spin number 1/2 and a very high gyromagnetic ratio (ca. 93% of that of 1H). Because of this, 19F MRS/MRI can be acquired relatively easily even with the same hardware as 1H MRS/MRI.[14]

The natural fluorine background in the body is negligible; most of the body's fluorine is found in teeth and bones, where it has very short T2 relaxation times and so is virtually invisible to most 19F MRI/MRS techniques.[15] For this reason, 19F MRI/MRS suffers from no background interference and can be used to monitor fluorinated xenobiotics (artificial compounds).

In vivo 19F MRI/MRS are not common techniques, but these methods can both quantify and locate the fluorinated drug, as well as differentiate its metabolic states.[16][17] For example, it has been used to study in vivo pharmacokinetics and metabolism of 5-fluorouracil.[18] The estimates of biological half-life of fleroxacin using in vivo 19F MRS (14.2 ± 2.4)[19] were well in line with those determined with other methods.[20] A fluorinated polymer poly(2,2-difluoroethyl)acrylamide showed a biological half-life ≈200 days using in vivo 19F MRS,[21] in line with estimated provides with in vivo fluorescence imaging (150 ± 20 days).[22] Analogously, 19F MRS/MRI has been used to track the in vivo degradation of fluorinated materials.[23]

## Notes

1. ↑ The nuclei 89Y, 103Rh and 169Tm are also monoisotopic and spin ⁠1/2⁠, but have very low magnetogyric ratios.

## References

1. ↑ Claridge, Timothy (2016). High Resolution NMR Techniques in Organic Chemistry. Oxford, United Kingdom: Elsevier. pp. 428–429. ISBN 978-0-08-099986-9.
2. ↑ Martino, R.; Gilard, V.; Malet-Martino, M. (2008). NMR Spectroscopy in Pharmaceutical Analysis. Boston: Elsevier. pp. 371. ISBN 978-0-444-53173-5.
3. ↑ H. Friebolin "Basic One- and Two-Dimensional NMR Spectroscopy", Wiley-VCH, Weinheim, 2011. ISBN 978-3-527-32782-9
4. ↑ Harris, Robin Kingsley; Mann, Brian E. (1978). NMR and the periodic table. Academic Press. p. 13. ISBN 0123276500.
5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 5.7 Rosenau, Carl Philipp; Jelier, Benson J.; Gossert, Alvar D.; Togni, Antonio (2018-05-16). "Exposing the Origins of Irreproducibility in Fluorine NMR Spectroscopy" (in en). Angewandte Chemie International Edition 57 (30): 9528–9533. doi:10.1002/anie.201802620. ISSN 1433-7851. PMID 29663671. Bibcode: 2018ACIE...57.9528R.
6. ↑ Harris, R. K. (2001). "NMR nomenclature. Nuclear spin properties and conventions for chemical shifts (IUPAC Recommendations 2001)". Pure and Applied Chemistry 73 (11): 1795–1818. doi:10.1351/pac200173111795.
7. ↑ H., Dungan, Claude (1970). Compilation of reported F19 NMR chemical shifts, 1951 to mid-1967. Van Wazer, John R.. New York: Wiley-Interscience. ISBN 0471226505. OCLC 88883. https://archive.org/details/compilationofrep0000dung.
8. ↑ 8.0 8.1 Silverstein, Robert M.; Webster, Francis X.; Kiemle, David J. (2005). Spectrometric Identification of Organic Compounds (7th ed.). Hoboken, NJ: John Wiley & Sons, Inc.. pp. 323–326. ISBN 978-0-471-39362-7. https://archive.org/details/spectrometricide00silv_456.
9. ↑ Jetton, R. E.; Nanney, J. R.; Mahaffy, C. A. L. The prediction of the 19F NMR signal positions of fluoroalkenes using statistical methods, J. Fluorine Chem. 1995, 72, 121.
10. ↑ 10.0 10.1 10.2 Pretsch, Ernö; Bühlmann, Philippe; Badertscher, Martin (2009). Structure Determination of Organic Compounds (4th ed.). Berlin, Germany: Springer. pp. 243–259. ISBN 978-3-540-93809-5. https://archive.org/details/structuredetermi00pret.
11. ↑ 11.0 11.1 11.2 Dolbier, W. R. (2009) An Overview of Fluorine NMR, in Guide to Fluorine NMR for Organic Chemists, John Wiley & Sons, Inc., Hoboken, NJ, USA. doi:10.1002/9780470483404.ch2.
12. ↑ Gerig, J.T. (1994). "Fluorine NMR of Proteins". Progress in Nuclear Magnetic Resonance Spectroscopy 26: 293-370. doi:10.1016/0079-6565(94)80009-X. Bibcode: 1994PNMRS..26..293G.
13. ↑ Marsh, E.N.G. Suzuki, Yuta (2014). "Using 19F NMR to Probe Biological Interactions of Proteins and Peptides". ACS Chemical Biology 9 (6): 1242-1250. doi:10.1021/cb500111u. PMID 24762032.
14. ↑ Keupp, Jochen; Rahmer, Jürgen; Grässlin, Ingmar; Mazurkewitz, Peter C.; Schaeffter, Tobias; Lanza, Gregory M.; Wickline, Samuel A.; Caruthers, Shelton D. (2011). "Simultaneous dual-nuclei imaging for motion corrected detection and quantification of 19 F imaging agents". Magnetic Resonance in Medicine 66 (4): 1116–1122. doi:10.1002/mrm.22877. ISSN 0740-3194. PMID 21394779.
15. ↑ Code, R. F.; Harrison, J. E.; Mcneill, K. G.; Szyjkowski, M. (1990). "In vivo 19 f spin relaxation in index finger bones". Magnetic Resonance in Medicine 13 (3): 358–369. doi:10.1002/mrm.1910130303. ISSN 0740-3194. PMID 2325536. https://onlinelibrary.wiley.com/doi/10.1002/mrm.1910130303. Retrieved 2025-08-09.
16. ↑ Wolf, Walter; Presant, Cary A; Waluch, Victor (2000). "19F-MRS studies of fluorinated drugs in humans". Advanced Drug Delivery Reviews 41 (1): 55–74. doi:10.1016/S0169-409X(99)00056-3. PMID 10699305. https://linkinghub.elsevier.com/retrieve/pii/S0169409X99000563. Retrieved 2025-08-09.
17. ↑ Wade, K.E.; Wilson, I.D.; Troke, J.A.; Nicholson, J.K. (1990). "19F and 1H magnetic resonance strategies for metabolic studies on fluorinated xenobiotics: Application to flurbiprofen [2-(2-fluoro-4-biphenylyl)propionic acid"]. Journal of Pharmaceutical and Biomedical Analysis 8 (5): 401–410. doi:10.1016/0731-7085(90)80067-Y. PMID 2081200. https://linkinghub.elsevier.com/retrieve/pii/073170859080067Y. Retrieved 2025-08-09.
18. ↑ Kar, R.; Cohen, R. A.; Terem, T. M.; Nahabedian, M. Y.; Wile, A. G. (1986). "Pharmacokinetics of 5-fluorouracil in rabbits in experimental regional chemotherapy". Cancer Research 46 (9): 4491–4495. ISSN 0008-5472. PMID 3731104.
19. ↑ Jynge, Per; Skjetne, Tore; Gribbestad, Ingrid; Kleinbloesem, Cornelis H; Hoogkamer, Hans F W; Antonsen, Ole; Bakøy, Ole E; Furuheim, Knut M et al. (1990). "In vivo tissue pharmacokinetics by fluorine magnetic resonance spectroscopy: A study of liver and muscle disposition of fleroxacin in humans". Clinical Pharmacology and Therapeutics 48 (5): 481–489. doi:10.1038/clpt.1990.183. ISSN 0009-9236. PMID 2121409. http://doi.wiley.com/10.1038/clpt.1990.183. Retrieved 2025-08-09.
20. ↑ Blouin, R A; Hamelin, B A; Smith, D A; Foster, T S; John, W J; Welker, H A (1992). "Fleroxacin pharmacokinetics in patients with liver cirrhosis". Antimicrobial Agents and Chemotherapy 36 (3): 632–638. doi:10.1128/AAC.36.3.632. ISSN 0066-4804. PMID 1622175.
21. ↑ Kolouchova, Kristyna; Jirak, Daniel; Groborz, Ondrej; Sedlacek, Ondrej; Ziolkowska, Natalia; Vit, Martin; Sticova, Eva; Galisova, Andrea et al. (2020). "Implant-forming polymeric 19F MRI-tracer with tunable dissolution". Journal of Controlled Release 327: 50–60. doi:10.1016/j.jconrel.2020.07.026. PMID 32730953. https://linkinghub.elsevier.com/retrieve/pii/S0168365920304107. Retrieved 2025-08-09.
22. ↑ Groborz, Ondřej; Kolouchová, Kristýna; Pankrác, Jan; Keša, Peter; Kadlec, Jan; Krunclová, Tereza; Pierzynová, Aneta; Šrámek, Jaromír et al. (2022). "Pharmacokinetics of Intramuscularly Administered Thermoresponsive Polymers". Advanced Healthcare Materials 11 (22). doi:10.1002/adhm.202201344. ISSN 2192-2640. PMID 36153823.
23. ↑ Kolouchova, Kristyna; Herynek, Vit; Groborz, Ondrej; Karela, Jiří; Van Damme, Lana; Kucka, Jan; Šafanda, Adam; Bui, Quang Hiep et al. (2024-05-14). "19 F MRI In Vivo Monitoring of Gelatin-Based Hydrogels: 3D Scaffolds with Tunable Biodegradation toward Regenerative Medicine". Chemistry of Materials 36 (9): 4417–4425. doi:10.1021/acs.chemmater.3c03321. ISSN 0897-4756. https://pubs.acs.org/doi/10.1021/acs.chemmater.3c03321. Retrieved 2025-08-10.

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