Fluorine-19 nuclear magnetic resonance spectroscopy

19F has a nuclear spin (I) of 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 NMR-active nuclei that are monoisotopic (or nearly so) are 1H and 31P. 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. Although the reference compound for 19F NMR spectroscopy, neat CFCl3 (0 ppm), has been used since the 1950s, clear instructions on how to measure and deploy it in routine measurements were not present until recently. Fluoromethyl compounds Fluoroalkenes For vinylic fluorine substituents, the following formula allows estimation of 19F chemical shifts: \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. Some representative values for use in this equation are provided in the table below: 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," 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: 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. == 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. 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. There are many good references for coupling constant values. 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. 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. 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. 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. For example, it has been used to study in vivo pharmacokinetics and metabolism of 5-fluorouracil. The estimates of biological half-life of fleroxacin using in vivo 19F MRS (14.2 ± 2.4) were well in line with those determined with other methods. A fluorinated polymer poly(2,2-difluoroethyl)acrylamide showed a biological half-life ≈200 days using in vivo 19F MRS, in line with estimated provides with in vivo fluorescence imaging (150 ± 20 days). Analogously, 19F MRS/MRI has been used to track the in vivo degradation of fluorinated materials. ==Notes==