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]
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 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.
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]
| 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]
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]
| -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 |
| -R | δ (ppm) |
|---|---|
| H | -144 |
| CH3 | -110 |
| CH2CH3 | -120 |
| CF3 | -141 |
| CF2CF3 | -138 |
| C(=O)OH | -127 |
| -R | δ (ppm) |
|---|---|
| H | -268 |
| CH3 | -212 |
| CH2CH3 | -212 |
| CH2OH | -226 |
| CF3 | -241 |
| CF2CF3 | -243 |
| C(=O)OH | -229 |
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]
| Substituent R | Zcis | Ztrans | Zgem |
|---|---|---|---|
| -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 |
| 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 | --- | --- |
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]
| 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]
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.
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]
The nuclear Overhauser effect (NOE) is the transfer of nuclear spin polarization from one population of spin-active nuclei to another via cross-relaxation. A phenomenological definition of the NOE in nuclear magnetic resonance spectroscopy (NMR) is the change in the integrated intensity of one NMR resonance that occurs when another is saturated by irradiation with an RF field. The change in resonance intensity of a nucleus is a consequence of the nucleus being close in space to those directly affected by the RF perturbation.
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.
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.
Proton nuclear magnetic resonance is the application of nuclear magnetic resonance in NMR spectroscopy with respect to hydrogen-1 nuclei within the molecules of a substance, in order to determine the structure of its molecules. In samples where natural hydrogen (H) is used, practically all the hydrogen consists of the isotope 1H.
Two-dimensional nuclear magnetic resonance spectroscopy is a set of nuclear magnetic resonance spectroscopy (NMR) methods which give data plotted in a space defined by two frequency axes rather than one. Types of 2D NMR include correlation spectroscopy (COSY), J-spectroscopy, exchange spectroscopy (EXSY), and nuclear Overhauser effect spectroscopy (NOESY). Two-dimensional NMR spectra provide more information about a molecule than one-dimensional NMR spectra and are especially useful in determining the structure of a molecule, particularly for molecules that are too complicated to work with using one-dimensional NMR.
In nuclear chemistry and nuclear physics, J-couplings are mediated through chemical bonds connecting two spins. It is an indirect interaction between two nuclear spins that arises from hyperfine interactions between the nuclei and local electrons. In NMR spectroscopy, J-coupling contains information about relative bond distances and angles. Most importantly, J-coupling provides information on the connectivity of chemical bonds. It is responsible for the often complex splitting of resonance lines in the NMR spectra of fairly simple molecules.
The residual dipolar coupling between two spins in a molecule occurs if the molecules in solution exhibit a partial alignment leading to an incomplete averaging of spatially anisotropic dipolar couplings.
In vivo magnetic resonance spectroscopy (MRS) is a specialized technique associated with magnetic resonance imaging (MRI).
Carbon satellites in physics and spectroscopy, are small peaks that can be seen shouldering the main peaks in the nuclear magnetic resonance (NMR) spectrum. These peaks can occur in the NMR spectrum of any NMR active atom where those atoms adjoin a carbon atom. However, Carbon satellites are most often encountered in proton NMR.
Phosphorus-31 NMR spectroscopy is an analytical chemistry technique that uses nuclear magnetic resonance (NMR) to study chemical compounds that contain phosphorus. Phosphorus is commonly found in organic compounds and coordination complexes, making it useful to measure 31- NMR spectra routinely. Solution 31P-NMR is one of the more routine NMR techniques because 31P has an isotopic abundance of 100% and a relatively high gyromagnetic ratio. The 31P nucleus also has a spin of 1/2, making spectra relatively easy to interpret. The only other highly sensitive NMR-active nuclei spin 1/2 that are monoisotopic are 1H and 19F.
Nuclear magnetic resonance decoupling is a special method used in nuclear magnetic resonance (NMR) spectroscopy where a sample to be analyzed is irradiated at a certain frequency or frequency range to eliminate or partially the effect of coupling between certain nuclei. NMR coupling refers to the effect of nuclei on each other in atoms within a couple of bonds distance of each other in molecules. This effect causes NMR signals in a spectrum to be split into multiple peaks. Decoupling fully or partially eliminates splitting of the signal between the nuclei irradiated and other nuclei such as the nuclei being analyzed in a certain spectrum. NMR spectroscopy and sometimes decoupling can help determine structures of chemical compounds.
Nuclear magnetic resonance (NMR) is a physical phenomenon in which nuclei in a strong constant magnetic field are perturbed by a weak oscillating magnetic field and respond by producing an electromagnetic signal with a frequency characteristic of the magnetic field at the nucleus. This process occurs near resonance, when the oscillation frequency matches the intrinsic frequency of the nuclei, which depends on the strength of the static magnetic field, the chemical environment, and the magnetic properties of the isotope involved; in practical applications with static magnetic fields up to ca. 20 tesla, the frequency is similar to VHF and UHF television broadcasts (60–1000 MHz). NMR results from specific magnetic properties of certain atomic nuclei. Nuclear magnetic resonance spectroscopy is widely used to determine the structure of organic molecules in solution and study molecular physics and crystals as well as non-crystalline materials. NMR is also routinely used in advanced medical imaging techniques, such as in magnetic resonance imaging (MRI). The original application of NMR to condensed matter physics is nowadays mostly devoted to strongly correlated electron systems. It reveals large many-body couplings by fast broadband detection and it should not to be confused with solid state NMR, which aims at removing the effect of the same couplings by Magic Angle Spinning techniques.
Nuclear magnetic resonance spectroscopy of stereoisomers most commonly known as NMR spectroscopy of stereoisomers is a chemical analysis method that uses NMR spectroscopy to determine the absolute configuration of stereoisomers. For example, the cis or trans alkenes, R or S enantiomers, and R,R or R,S diastereomers.
Hexafluorobenzene, HFB, C
6F
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.
Nucleic acid NMR is the use of nuclear magnetic resonance spectroscopy to obtain information about the structure and dynamics of nucleic acid molecules, such as DNA or RNA. It is useful for molecules of up to 100 nucleotides, and as of 2003, nearly half of all known RNA structures had been determined by NMR spectroscopy.
Paramagnetic nuclear magnetic resonance spectroscopy refers to nuclear magnetic resonance (NMR) spectroscopy of paramagnetic compounds. Although most NMR measurements are conducted on diamagnetic compounds, paramagnetic samples are also amenable to analysis and give rise to special effects indicated by a wide chemical shift range and broadened signals. Paramagnetism diminishes the resolution of an NMR spectrum to the extent that coupling is rarely resolved. Nonetheless spectra of paramagnetic compounds provide insight into the bonding and structure of the sample. For example, the broadening of signals is compensated in part by the wide chemical shift range (often 200 ppm in 1H NMR). Since paramagnetism leads to shorter relaxation times (T1), the rate of spectral acquisition can be high.
Protein chemical shift prediction is a branch of biomolecular nuclear magnetic resonance spectroscopy that aims to accurately calculate protein chemical shifts from protein coordinates. Protein chemical shift prediction was first attempted in the late 1960s using semi-empirical methods applied to protein structures solved by X-ray crystallography. Since that time protein chemical shift prediction has evolved to employ much more sophisticated approaches including quantum mechanics, machine learning and empirically derived chemical shift hypersurfaces. The most recently developed methods exhibit remarkable precision and accuracy.
Nitrogen-15 nuclear magnetic resonance spectroscopy is a version of nuclear magnetic resonance spectroscopy that examines samples containing the 15N nucleus. 15N NMR differs in several ways from the more common 13C and 1H NMR. To circumvent the difficulties associated with measurement of the quadrupolar, spin-1 14N nuclide, 15N NMR is employed in samples for detection since it has a ground-state spin of ½. Since14N is 99.64% abundant, incorporation of 15N into samples often requires novel synthetic techniques.
Platinum-195 nuclear magnetic resonance spectroscopy is a spectroscopic technique which is used for the detection and characterisation of platinum compounds. The sensitivity of the technique and therefore its diagnostic utility have increased significantly starting from the 1970s, with 195Pt NMR nowadays considered the method of choice for structural elucidation of Pt species in solution.
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