View source for Fluorine-19 nuclear magnetic resonance spectroscopy

{{short description|Analytical technique}}
[[File:19F-NMR yne-6AmF5.svg|thumb|A sample 19F NMR spectrum of a simple organic compound. Integrations are shown under each peak.]]
[[File:19FNMR C6F3H2Br.png|thumb|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 '''<sup>19</sup>F NMR''') is an analytical technique used to detect and identify fluorine-containing compounds. <sup>19</sup>F  is an important nucleus for [[NMR spectroscopy]] because of its [[Receptivity (NMR)|receptivity]] and large [[chemical shift]] dispersion, which is greater than that for [[proton nuclear magnetic resonance]] spectroscopy.<ref>{{Cite book |title=High Resolution NMR Techniques in Organic Chemistry |last=Claridge |first=Timothy |publisher=Elsevier |year=2016 |isbn=978-0-08-099986-9 |location=Oxford, United Kingdom |pages=428–429}}</ref><ref>{{Cite book |title=NMR Spectroscopy in Pharmaceutical Analysis |last1=Martino |first1=R. |last2=Gilard |first2=V. |last3=Malet-Martino |first3=M. |publisher=Elsevier |year=2008 |isbn=978-0-444-53173-5 |location=Boston |pages=371}}</ref><ref>H. Friebolin "Basic One- and Two-Dimensional NMR Spectroscopy", Wiley-VCH, Weinheim, 2011.  {{ISBN|978-3-527-32782-9}}</ref>

==Operational details==
[[Fluorine-19|<sup>19</sup>F]] has a [[nuclear spin]] (I) of {{frac|1|2}} and a high [[gyromagnetic ratio]].  Consequently, this [[isotope]] is highly responsive to NMR measurements.  Furthermore, <sup>19</sup>F comprises 100% of naturally occurring fluorine. The only other highly sensitive spin {{sfrac|1|2}} NMR-active nuclei that are monoisotopic (or nearly so) are <sup>1</sup>H and <sup>31</sup>P.<ref>{{cite book|last1=Harris|first1=Robin Kingsley|last2=Mann|first2=Brian E.|title=NMR and the periodic table|page=13|isbn=0123276500}}</ref>{{efn|The nuclei [[Isotopes of yttrium|<sup>89</sup>Y]], [[Isotopes of rhodium|<sup>103</sup>Rh]] and [[Isotopes of thulium|<sup>169</sup>Tm]] are also monoisotopic and spin {{sfrac|1|2}}, but have very low magnetogyric ratios.}}  Indeed, the <sup>19</sup>F nucleus is the third most receptive NMR nucleus, after the <sup>3</sup>H nucleus and <sup>1</sup>H nucleus.

The <sup>19</sup>F NMR chemical shifts span a range of about 800&nbsp;ppm.  For ''organo''fluorine compounds the range is narrower, being about −50 to −70&nbsp;ppm (for CF<sub>3</sub> groups) to −200 to −220&nbsp;ppm (for CH<sub>2</sub>F 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 <sup>19</sup>F{<sup>1</sup>H} and <sup>1</sup>H{<sup>19</sup>F} spectra and multiple bond correlations <sup>19</sup>F-<sup>13</sup>C HMBC and through space HOESY spectra.

== Chemical shifts ==
<sup>19</sup>F NMR chemical shifts in the literature vary strongly, commonly by over 1 ppm, even within the same solvent.<ref name=":3">{{Cite journal |last1=Rosenau |first1=Carl Philipp |last2=Jelier |first2=Benson J. |last3=Gossert |first3=Alvar D. |last4=Togni |first4=Antonio |date=2018-05-16 |title=Exposing the Origins of Irreproducibility in Fluorine NMR Spectroscopy |journal=Angewandte Chemie International Edition |volume=57 |issue=30 |pages=9528–9533 |language=en |doi=10.1002/anie.201802620 |pmid=29663671 |issn=1433-7851}}</ref> Although the reference compound for <sup>19</sup>F NMR spectroscopy, neat [[CFCl3|CFCl<sub>3</sub>]] (0 ppm),<ref>{{Cite journal |last=Harris |first=R. K. |title=NMR nomenclature. Nuclear spin properties and conventions for chemical shifts (IUPAC Recommendations 2001) |journal=Pure and Applied Chemistry |volume=73 |issue=11 |pages=1795–1818 |doi=10.1351/pac200173111795 |year=2001 |doi-access=free}}</ref> has been used since the 1950s,<ref>{{Cite book |url=https://archive.org/details/compilationofrep0000dung |title=Compilation of reported F<sup>19</sup> NMR chemical shifts, 1951 to mid-1967 |last=H. |first=Dungan, Claude |date=1970 |publisher=Wiley-Interscience |others=Van Wazer, John R. |isbn=0471226505 |location=New York |oclc=88883 |url-access=registration}}</ref> clear instructions on how to measure and deploy it in routine measurements were not present until recently.<ref name=":3" /> 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).<ref name=":3" /> A solvent-specific reference table with 5 internal reference compounds has been prepared ([[CFCl3|CFCl<sub>3</sub>]], [[C6H5F|C<sub>6</sub>H<sub>5</sub>F]], [[Trifluorotoluene|PhCF<sub>3</sub>]], [[C6F6|C<sub>6</sub>F<sub>6</sub>]] and [[CF3CO2H|CF<sub>3</sub>CO<sub>2</sub>H]]) to allow reproducible referencing with an accuracy of Δδ = ±30 ppb.<ref name=":3" /> As the chemical shift of CFCl<sub>3</sub> is also affected by the solvent, care must be taken when using dissolved CFCl<sub>3</sub> as reference compound with regards to the chemical shift of neat CFCl<sub>3</sub> (0 ppm).<ref name=":3" /> Example of chemical shifts determined against neat [[CFCl3|CFCl<sub>3</sub>]]:<ref name=":3" />
{| class="wikitable"
|+ Excerpt of referencing table against neat CFCl<sub>3</sub> [ppm]
!
! CFCl<sub>3</sub>
! C<sub>6</sub>H<sub>5</sub>F
! PhCF<sub>3</sub>
! C<sub>6</sub>F<sub>6</sub>
! CF<sub>3</sub>CO<sub>2</sub>H
|-
| Solvent
| [ppm]
| [ppm]
| [ppm]
| [ppm]
| [ppm]
|-
| [[CDCl3|CDCl<sub>3</sub>]]
| 0.65
| −112.96
| −62.61
| −161.64
| −75.39
|-
| CD<sub>2</sub>Cl<sub>2</sub>
| 0.02
| −113.78
| −62.93
| −162.61
| −75.76
|-
| [[C6D6|C<sub>6</sub>D<sub>6</sub>]]
| −0.19
| −113.11
| −62.74
| −163.16
| −75.87
|-
| [[Acetone-d6|Acetone-''d''<sub>6</sub>]]
| −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.<ref name=":3" />

A concise list of appropriately referenced chemical shifts of over 240 fluorinated chemicals has also been recently provided.<ref name=":3" /> 

=== Chemical shift prediction ===
<sup>19</sup>F NMR chemical shifts are more difficult to predict than <sup>1</sup>H NMR shifts. Specifically, <sup>19</sup>F NMR shifts are strongly affected by contributions from electronic excited states whereas <sup>1</sup>H NMR shifts are dominated by diamagnetic contributions.<ref name=":0">{{Cite book |title=Spectrometric Identification of Organic Compounds |url=https://archive.org/details/spectrometricide00silv_456 |url-access=limited |last1=Silverstein |first1=Robert M. |last2=Webster |first2=Francis X. |last3=Kiemle |first3=David J. |publisher=John Wiley & Sons, Inc. |year=2005 |isbn=978-0-471-39362-7 |edition=7th |location=Hoboken, NJ |pages=[https://archive.org/details/spectrometricide00silv_456/page/n340 323]–326}}</ref> 

=== Fluoromethyl compounds ===

{| class="wikitable sortable"
|+  <sup>19</sup>F chemical shifts of F<sub>3</sub>C−R groups
! −R
! δ (ppm)
|-
| H
| −78
|-
| CH<sub>3</sub>
| −62
|-
| CH<sub>2</sub>CH<sub>3</sub>
| −70
|-
| CH<sub>2</sub>NH<sub>2</sub>
| −72
|-
| CH<sub>2</sub>OH
| −78
|-
| CH=CH<sub>2</sub>
| −67
|-
| C≡CH
| −56
|-
| CF<sub>3</sub>
| −89
|-
| CF<sub>2</sub>CF<sub>3</sub>
| −83
|-
| F
| −63
|-
| Cl
| −29
|-
| Br
| −18
|-
| I
| −5
|-
| OH
| −55
|-
| NH<sub>2</sub>
| −49
|-
| SH
| −32
|-
| C(=O)Ph
| −58
|-
| C(=O)CF<sub>3</sub>
| −85
|-
| C(=O)OH
| −77
|-
| C(=O)F
| −76
|-
| C(=O)OCH<sub>2</sub>CH<sub>3</sub>
| −74
|}

{| class="wikitable sortable"
|+ <sup>19</sup>F chemical shifts of F<sub>2</sub>CH−R groups
! −R
! δ (ppm)
|-
| H
| −144
|-
| CH<sub>3</sub>
| −110
|-
| CH<sub>2</sub>CH<sub>3</sub>
| −120
|-
| CF<sub>3</sub>
| −141
|-
| CF<sub>2</sub>CF<sub>3</sub>
| −138
|-
| C(=O)OH
| −127
|}

{| class="wikitable sortable"
|+ <sup>19</sup>F chemical shifts of FH<sub>2</sub>C−R groups
! −R
! δ (ppm)
|-
| H
| −268
|-
| CH<sub>3</sub>
| −212
|-
| CH<sub>2</sub>CH<sub>3</sub>
| −212
|-
| CH<sub>2</sub>OH
| −226
|-
| CF<sub>3</sub>
| −241
|-
| CF<sub>2</sub>CF<sub>3</sub>
| −243
|-
| C(=O)OH
| −229
|}

=== Fluoroalkenes ===

For vinylic fluorine substituents, the following formula allows estimation of <sup>19</sup>F chemical shfits:
<math display="block">
 \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},</math>
where ''Z'' is the statistical substituent chemical shift (SSCS) for the substituent in the listed position, and ''S'' is the interaction factor.<ref>Jetton, R. E.; Nanney, J. R.; Mahaffy, C. A. L. The prediction of the <sup>19</sup>F NMR signal positions of fluoroalkenes using statistical methods, ''J. Fluorine Chem.'' '''1995''', ''72'', 121.</ref> Some representative values for use in this equation are provided in the table below:<ref name=":1">{{Cite book |last1=Pretsch |first1=Ernö |title=Structure Determination of Organic Compounds |url=https://archive.org/details/structuredetermi00pret |url-access=limited |last2=Bühlmann |first2=Philippe |last3=Badertscher |first3=Martin |publisher=Springer |year=2009 |isbn=978-3-540-93809-5 |edition=4th |location=Berlin, Germany |pages=[https://archive.org/details/structuredetermi00pret/page/n254 243]–259}}</ref>
{| class="wikitable sortable"
|+ SSCS values for fluoroalkene substituents
! Substituent R
! ''Z''<sub>cis</sub>
! ''Z''<sub>trans</sub>
! ''Z''<sub>gem</sub>
|-
| −H
| −7.4
| −31.3
| 49.9
|-
| −CH<sub>3</sub>
| −6.0
| −43.0
| 9.5
|-
| −CH=CH<sub>2</sub>
| {{sdash}}
| {{sdash}}
| 47.7
|-
| −Ph
| −15.7
| −35.1
| 38.7
|-
| −CF<sub>3</sub>
| −25.3
| −40.7
| 54.3
|-
| −F
| 0
| 0
| 0
|-
| −Cl
| −16.5
| −29.4
| {{sdash}}
|-
| −Br
| −17.7
| −40.0
| {{sdash}}
|-
| −I
| −21.3
| −46.3
| 17.4
|-
| −OCH<sub>2</sub>CH<sub>3</sub>
| −77.5
| {{sdash}}
| 84.2
|}
{| class="wikitable sortable"
|+ Interaction factors for fluoroalkene substituents
! Substituent
! Substituent
! ''S''<sub>cis/trans</sub>
! ''S''<sub>cis/gem</sub>
! ''S''<sub>trans/gem</sub>
|-
| −H
| −H
| −26.6
| {{sdash}}
| 2.8
|-
| −H
| −CF<sub>3</sub>
| −21.3
| {{sdash}}
| {{sdash}}
|-
| −H
| −CH<sub>3</sub>
| {{sdash}}
| 11.4
| {{sdash}}
|-
| −H
| −OCH<sub>2</sub>CH<sub>3</sub>
| −47.0
| {{sdash}}
| {{sdash}}
|-
| −H
| −Ph
| −4.8
| {{sdash}}
|5.2
|-
| −CF<sub>3</sub>
| −H
| −7.5
| −10.6
| 12.5
|-
| −CF<sub>3</sub>
| −CF<sub>3</sub>
| −5.9
| −5.3
| −4.7
|-
| −CF<sub>3</sub>
| −CH<sub>3</sub>
| 17.0
| {{sdash}}
| {{sdash}}
|-
| −CF<sub>3</sub>
| −Ph
| −15.6
| {{sdash}}
| −23.4
|-
| −CH<sub>3</sub>
| −H
| {{sdash}}
| −12.2
| {{sdash}}
|-
| −CH<sub>3</sub>
| −CF<sub>3</sub>
| {{sdash}}
| −13.8
| −8.9
|-
| −CH<sub>3</sub>
| −Ph
| {{sdash}}
| −19.5
| −19.5
|-
| −OCH<sub>2</sub>CH<sub>3</sub>
| −H
| −5.1
| {{sdash}}
| {{sdash}}
|-
| −Ph
| −H
| {{sdash}}
| {{sdash}}
|20.1
|-
| −Ph
| −CF<sub>3</sub>
| −23.2
| {{sdash}}
| {{sdash}}
|}

=== Fluorobenzenes ===

When determining the <sup>19</sup>F 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,"<ref name=":1" /> this equation is
<math display="block">
 \delta_F~[\text{ppm}] = -113.9 + \Sigma Z_\text{ortho} + \Sigma Z_\text{meta} + \Sigma Z_\text{para},
</math> 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:<ref name=":1" />
{| class="wikitable sortable"
|+ SSCS values for fluorobenzene substituents
! Substituent
! ''Z''<sub>ortho</sub>
! ''Z''<sub>meta</sub>
! ''Z''<sub>para</sub>
|-
| −CH<sub>3</sub>
| −3.9
| −0.4
| −3.6
|-
| −CH=CH<sub>2</sub>
| −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
|-
| −OCH<sub>3</sub>
| −18.9
| −0.8
| −9.0
|-
| −NH<sub>2</sub>
| −22.9
| −1.3
| −17.4
|-
| −NO<sub>2</sub>
| −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)CH<sub>3</sub>
| 2.5
| 1.8
| 7.6
|-
| −C(=O)OH
| 2.3
| 1.1
| 6.5
|-
| −C(=O)NH<sub>2</sub>
| 0.5
| −0.8
| 3.4
|-
| −C(=O)OCH<sub>3</sub>
| 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 <sup>19</sup>F 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.<ref name=":0" />

== Spin–spin coupling ==
<sup>19</sup>F-<sup>19</sup>F coupling constants are generally larger than <sup>1</sup>H-<sup>1</sup>H coupling constants.  Long range <sup>19</sup>F-<sup>19</sup>F coupling, (<sup>2</sup>J, <sup>3</sup>J, <sup>4</sup>J or even <sup>5</sup>J) are commonly observed.  Generally, the longer range the coupling, the smaller the value.<ref name=":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}}.</ref> Hydrogen couples with fluorine, which is very typical to see in <sup>19</sup>F 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.<ref name=":2" />  There are many good references for coupling constant values.<ref name=":2" />  The citations are included below.

==Magnetic resonance imaging==
<sup>19</sup>F [[magnetic resonance imaging]] (MRI) is a viable alternative to <sup>1</sup>H MRI. The sensitivity issues can be overcome by using soft [[nanoparticle]]s. Application include pH-, temperature-, enzyme-, metal ion- and redox responsive- [[contrast agent]]s. They can also be used for long-term cell labelling.<ref>{{cite book |first1=Petr |last1=Hermann |first2=Jan |last2=Blahut |first3=Jan |last3=Kotek |first4=Vit |last4=Herynek |title=Metal Ions in Bio-Imaging Techniques |publisher=Springer |year=2021 |pages=239–270 |chapter=Chapter&nbsp;8. Paramagnetic Metal Ion Probes for <sup>19</sup>F Magnetic Resonance Imaging |doi=10.1515/9783110685701-014 |s2cid=233704089 }}</ref>

==Notes==
{{notelist}}
==References==
<references/>

{{NMR by isotope}}

[[Category:Nuclear magnetic resonance]]
[[Category:Fluorine]]