Fluorine-19 nuclear magnetic resonance spectroscopy

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A sample 19F NMR spectrum of a simple organic compound. Integrations are shown under each peak. 19F-NMR yne-6AmF5.svg
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. 19FNMR C6F3H2Br.png
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

Operational details

19F has a nuclear spin (I) of 12 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.

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]
CFCl3C6H5FPhCF3C6F6CF3CO2H
Solvent[ppm][ppm][ppm][ppm][ppm]
CDCl3 0.65-112.96-62.61-161.64-75.39
CD2Cl20.02-113.78-62.93-162.61-75.76
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
-Rδ (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
-Rδ (ppm)
H-144
CH3-110
CH2CH3-120
CF3-141
CF2CF3-138
C(=O)OH-127
19F Chemical Shifts of FH2C-R Groups
-Rδ (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 for estimation of 19F chemical shfits:

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 RZcisZtransZgem
-H-7.4-31.349.9
-CH3-6.0-43.09.5
-CH=CH2------47.7
-Ph-15.7-35.138.7
-CF3-25.3-40.754.3
-F000
-Cl-16.5-29.4---
-Br-17.7-40.0---
-I-21.3-46.317.4
-OCH2CH3-77.5---84.2
Interaction Factors for Fluoroalkene Substituents
SubstituentSubstituentScis/transScis/gemStrans/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-7.5-10.612.5
-CF3-CF3-5.9-5.3-4.7
-CF3-CH317.0------
-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:

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
SubstituentZorthoZmetaZpara
-CH3-3.9-0.4-3.6
-CH=CH2-4.40.7-0.6
-F-23.22.0-6.6
-Cl-0.33.5-0.7
-Br7.63.50.1
-I19.93.61.4
-OH-23.50-13.3
-OCH3-18.9-0.8-9.0
-NH2-22.9-1.3-17.4
-NO2-5.63.89.6
-CN6.94.110.1
-SH10.00.9-3.5
-CH(=O)-7.42.110.3
-C(=O)CH32.51.87.6
-C(=O)OH2.31.16.5
-C(=O)NH20.5-0.83.4
-C(=O)OCH33.33.87.1
-C(=O)Cl3.43.512.9

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

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

Related Research Articles

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In nuclear magnetic resonance (NMR) spectroscopy, the chemical shift is the resonant frequency of an atomic nucleus relative to a standard in a magnetic field. Often the position and number of chemical shifts are diagnostic of the structure of a molecule. Chemical shifts are also used to describe signals in other forms of spectroscopy such as photoemission spectroscopy.

<span class="mw-page-title-main">Nuclear magnetic resonance spectroscopy</span> Laboratory technique

Nuclear magnetic resonance spectroscopy, most commonly known as NMR spectroscopy or magnetic resonance spectroscopy (MRS), is a spectroscopic technique based on re-orientation of atomic nuclei with non-zero nuclear spins in an external magnetic field. This re-orientation occurs with absorption of electromagnetic radiation in the radio frequency region from roughly 4 to 900 MHz, which depends on the isotopic nature of the nucleus and increased proportionally to the strength of the external magnetic field. Notably, the resonance frequency of each NMR-active nucleus depends on its chemical environment. As a result, NMR spectra provide information about individual functional groups present in the sample, as well as about connections between nearby nuclei in the same molecule. As the NMR spectra are unique or highly characteristic to individual compounds and functional groups, NMR spectroscopy is one of the most important methods to identify molecular structures, particularly of organic compounds.

Carbon-13 (C13) nuclear magnetic resonance is the application of nuclear magnetic resonance (NMR) spectroscopy to carbon. It is analogous to proton NMR and allows the identification of carbon atoms in an organic molecule just as proton NMR identifies hydrogen atoms. 13C NMR detects only the 13
C
isotope. The main carbon isotope, 12
C
does not produce an NMR signal. Although ca. 1 mln. times less sensitive than 1H NMR spectroscopy, 13C NMR spectroscopy is widely used for characterizing organic and organometallic compounds, primarily because 1H-decoupled 13C-NMR spectra are more simple, have a greater sensitivity to differences in the chemical structure, and, thus, are better suited for identifying molecules in complex mixtures. At the same time, such spectra lack quantitative information about the atomic ratios of different types of carbon nuclei, because nuclear Overhauser effect used in 1H-decoupled 13C-NMR spectroscopy enhances the signals from carbon atoms with a larger number of hydrogen atoms attached to them more than from carbon atoms with a smaller number of H's, and because full relaxation of 13C nuclei is usually not attained, and the nuclei with shorter relaxation times produce more intense signals.

<span class="mw-page-title-main">Proton nuclear magnetic resonance</span> NMR via protons, hydrogen-1 nuclei

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<span class="mw-page-title-main">Phosphorus-31 nuclear magnetic resonance</span> Spectroscopy technique for molecules containing phosphorus

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<span class="mw-page-title-main">Hexafluorobenzene</span> Chemical compound

Hexafluorobenzene, HFB, C
6
F
6
, or perfluorobenzene is an organofluorine compound. In this derivative of benzene, all hydrogen atoms have been replaced by fluorine atoms. The technical uses of the compound are limited, although it has some specialized uses in the laboratory owing to distinctive spectroscopic properties.

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References

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  4. Harris, Robin Kingsley; Mann, Brian E. NMR and the periodic table. p. 13. ISBN   0123276500.
  5. 1 2 3 4 5 6 7 8 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.
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  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.{{cite book}}: CS1 maint: multiple names: authors list (link)
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  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.
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  12. 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.