Fluorine-19 nuclear magnetic resonance spectroscopy

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]

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]^[a] 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 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.^[9] Some representative values for use in this equation are provided in the table below:^[10]

SSCS values for fluoroalkene substituents
Substituent R	Z_cis	Z_trans	Z_gem
−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	S_cis/trans	S_cis/gem	S_trans/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 $\delta _{F}~[{\text{ppm}}]=-113.9+\Sigma Z_{\text{ortho}}+\Sigma Z_{\text{meta}}+\Sigma Z_{\text{para}},$ 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:^[10]

SSCS values for fluorobenzene substituents
Substituent	Z_ortho	Z_meta	Z_para
−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.

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.^[12]

Notes

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

References

^ Claridge, Timothy (2016). High Resolution NMR Techniques in Organic Chemistry. Oxford, United Kingdom: Elsevier. pp. 428–429. ISBN 978-0-08-099986-9.
^ Martino, R.; Gilard, V.; Malet-Martino, M. (2008). NMR Spectroscopy in Pharmaceutical Analysis. Boston: Elsevier. p. 371. ISBN 978-0-444-53173-5.
^ H. Friebolin "Basic One- and Two-Dimensional NMR Spectroscopy", Wiley-VCH, Weinheim, 2011. ISBN 978-3-527-32782-9
^ Harris, Robin Kingsley; Mann, Brian E. NMR and the periodic table. p. 13. ISBN 0123276500.
^ ^a ^b ^c ^d ^e ^f ^g ^h Rosenau, Carl Philipp; Jelier, Benson J.; Gossert, Alvar D.; Togni, Antonio (2018-05-16). "Exposing the Origins of Irreproducibility in Fluorine NMR Spectroscopy". Angewandte Chemie International Edition. 57 (30): 9528–9533. doi:10.1002/anie.201802620. ISSN 1433-7851. PMID 29663671.
^ 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.
^ 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.{{cite book}}: CS1 maint: multiple names: authors list (link)
^ ^a ^b 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.
^ 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.
^ ^a ^b ^c 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.
^ ^a ^b ^c 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.
^ Hermann, Petr; Blahut, Jan; Kotek, Jan; Herynek, Vit (2021). "Chapter 8. Paramagnetic Metal Ion Probes for ¹⁹F Magnetic Resonance Imaging". Metal Ions in Bio-Imaging Techniques. Springer. pp. 239–270. doi:10.1515/9783110685701-014. S2CID 233704089.

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

[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. p. 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. NMR and the periodic table. p. 13. ISBN 0123276500.

[:3-6] ^ ^a ^b ^c ^d ^e ^f ^g ^h Rosenau, Carl Philipp; Jelier, Benson J.; Gossert, Alvar D.; Togni, Antonio (2018-05-16). "Exposing the Origins of Irreproducibility in Fluorine NMR Spectroscopy". Angewandte Chemie International Edition. 57 (30): 9528–9533. doi:10.1002/anie.201802620. ISSN 1433-7851. PMID 29663671.

[7] 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.

[8] 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.{{cite book}}: CS1 maint: multiple names: authors list (link)

[:0-9] 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.

[10] 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.

[:1-11] 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.

[:2-12] 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.

[13] Hermann, Petr; Blahut, Jan; Kotek, Jan; Herynek, Vit (2021). "Chapter 8. Paramagnetic Metal Ion Probes for ¹⁹F Magnetic Resonance Imaging". Metal Ions in Bio-Imaging Techniques. Springer. pp. 239–270. doi:10.1515/9783110685701-014. S2CID 233704089.

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