Example H NMR spectrum (1-dimensional) of a mixture of mentholenantiomers plotted as signal intensity (vertical axis) vs. chemical shift (in ppm on the horizontal axis). Signals from spectrum have been assigned hydrogen atom groups (a through j) from the structure shown at upper left.
Proton nuclear magnetic resonance (proton NMR, hydrogen-1 NMR, or 1H NMR) is the application of nuclear magnetic resonance in NMR spectroscopy with respect to hydrogen-1nuclei within the molecules of a substance, in order to determine the structure of its molecules.[1] In samples where natural hydrogen (H) is used, practically all the hydrogen consists of the isotope1H (hydrogen-1; i.e. having a proton for a nucleus).
Historically, deuterated solvents were supplied with a small amount (typically 0.1%) of tetramethylsilane (TMS) as an internal standard for referencing the chemical shifts of each analyte proton. TMS is a tetrahedral molecule, with all protons being chemically equivalent, giving one single signal, used to define a chemical shift = 0 ppm. [2] It is volatile, making sample recovery easy as well. Modern spectrometers are able to reference spectra based on the residual proton in the solvent (e.g. the CHCl3, 0.01% in 99.99% CDCl3). Deuterated solvents are now commonly supplied without TMS.
Deuterated solvents permit the use of deuterium frequency-field lock (also known as deuterium lock or field lock) to offset the effect of the natural drift of the NMR's magnetic field . In order to provide deuterium lock, the NMR constantly monitors the deuterium signal resonance frequency from the solvent and makes changes to the to keep the resonance frequency constant.[3] Additionally, the deuterium signal may be used to accurately define 0 ppm as the resonant frequency of the lock solvent and the difference between the lock solvent and 0 ppm (TMS) are well known.
Proton NMR spectra of most organic compounds are characterized by chemical shifts in the range +14 to -4 ppm and by spin–spin coupling between protons. The integration curve for each proton reflects the abundance of the individual protons.
Simple molecules have simple spectra. The spectrum of ethyl chloride consists of a triplet at 1.5 ppm and a quartet at 3.5 ppm in a 3:2 ratio. The spectrum of benzene consists of a single peak at 7.2 ppm due to the diamagnetic ring current.
Together with carbon-13 NMR, proton NMR is a powerful tool for molecular structure characterization.
Chemical shifts
Chemical shift values, symbolized by δ, are not precise, but typical– they are to be therefore regarded mainly as a reference. Deviations are in ±0.2ppm range, sometimes more. The exact value of chemical shift depends on molecular structure and the solvent, temperature, magnetic field in which the spectrum is being recorded and other neighboring functional groups. Hydrogen nuclei are sensitive to the hybridization of the atom to which the hydrogen atom is attached and to electronic effects. Nuclei tend to be deshielded by groups that withdraw electron density. Deshielded nuclei resonate at higher δ values, whereas shielded nuclei resonate at lower δ values.
Examples of electron withdrawing substituents are −OH, −OCOR, −OR, −NO2 and halogens. These cause a downfield shift of approximately 2–4ppm for H atoms on Cα (an aliphaticC atom directly bonded to the substituent in question) and of less than 1–2ppm for H atoms on Cβ (an aliphatic C atom bonded to Cα). Carbonyl groups, olefinic fragments and aromatic rings contribute sp2 hybridized carbon atoms to an aliphatic chain. This causes a downfield shift of 1–2ppm at Cα.
Note that labile protons (−OH, −NH2, −SH) have no characteristic chemical shift. However, such resonances can be identified by the disappearance of a peak when reacted with D2O, as deuterium will replace a protium atom. This method is called a D2O shake. Acidic protons may also be suppressed when a solvent containing acidic deuterium ions (e.g. methanol-d4) is used. An alternate method for identifying protons that are not attached to carbons is the heteronuclear single quantum coherence (HSQC) experiment, which correlates protons and carbons that are one bond away from each other. A hydrogen that is not attached to a carbon can be identified because it does not have a crosspeak in the HSQC spectrum.
Functional group
CH3
CH2
CH
CH2R
0.8
1.3
1.6
C=C
1.6
2.0
2.6
C≡C
1.7
2.2
2.8
C6H5
2.3
2.6
2.9
F
4.3
4.4
4.8
Cl
3.0
3.4
4.0
Br
2.7
3.4
4.1
I
2.2
3.2
4.2
OH
3.3
3.5
3.8
OR
3.3
3.4
3.7
OC6H5
3.8
4.0
4.3
OCOR
3.6
4.1
5.0
OCOC6H5
3.9
4.2
5.1
OCOCF3
4.0
4.4
—
CHO
2.2
2.4
2.5
COR
2.1
2.2
2.6
COOH
2.1
2.3
2.6
COOR
2.0
2.3
2.5
CONR2
2.0
2.1
2.4
CN
2.1
2.5
3.0
NH2
2.5
2.7
3.0
NR2
2.2
2.4
2.8
NRC6H5
2.6
3.0
3.6
NR3+
3.0
3.1
3.6
NHCOR
2.9
3.3
3.7
NO2
4.1
4.2
4.4
SR
2.1
2.5
3.1
SOR
2.6
3.1
—
=O (aliphatic aldehyde)
—
—
9.5
=O (aromatic aldehyde)
—
—
10
M−H (metal hydride)
—
—
−5 to −15
Signal intensity
H NMR spectrum predicted for 1,4-dimethylbenzene. Under ideal conditions, the ratio of integrated signal of protons A and B is related to the structure of this molecule.
The integrated intensities of NMR signals are, ideally, proportional to the ratio of the nuclei within the molecule.[4] Together with chemical shift and coupling constants, the integrated intensities allow structural assignments. For mixtures, the signal intensities can be used to determine molar ratios. These considerations are valid only when sufficient time is allowed for full relaxation of the affected signals, as determined by their T1 values. A further complication arises from the difficulty of integrating signals of very different line shapes.
Spin–spin couplings
Example H NMR spectrum (1-dimensional) of ethyl acetate plotted as signal intensity vs. chemical shift. There are three different types of H atoms in ethyl acetate regarding NMR. The hydrogens (H) on the CH3COO− (acetate) group are not coupling with the other H atoms and appear as a singlet, but the −CH2− and −CH3 hydrogens of the ethyl group (−CH2CH3) are coupling with each other, resulting in a quartet and triplet respectively.
In addition to chemical shift, NMR spectra allow structural assignments by virtue of spin–spin coupling (and integrated intensities). Because nuclei themselves possess a small magnetic field, they influence each other, changing the energy and hence frequency of nearby nuclei as they resonate—this is known as spin–spin coupling. The most important type in basic NMR is scalar coupling. This interaction between two nuclei occurs through chemical bonds, and can typically be seen up to three bonds away (3-J coupling), although it can occasionally be visible over four to five bonds, though these tend to be considerably weaker.
H NMR spectrum of a solution of HD (labeled with red bars) and H2 (blue bar). The 1:1:1 triplet for HD arises from heteronuclear (different isotopes) coupling.
The effect of scalar coupling can be understood by examination of a proton which has a signal at 1ppm. This proton is in a hypothetical molecule where three bonds away exists another proton (in a CH−CH group, for instance), the neighbouring group (a magnetic field) causes the signal at 1ppm to split into two, with one peak being a few hertz higher than 1ppm and the other peak being the same amount lower than 1ppm. These peaks each have half the area of the former singlet peak. The magnitude of this splitting (difference in frequency between peaks) is known as the coupling constant. A typical coupling constant value for aliphatic protons would be 7Hz.
The coupling constant is independent of magnetic field strength because it is caused by the magnetic field of another nucleus, not the spectrometer magnet. Therefore, it is quoted in hertz (frequency) and not ppm (chemical shift).
In another molecule a proton resonates at 2.5ppm and that proton would also be split into two by the proton at 1ppm. Because the magnitude of interaction is the same, the splitting would have the same coupling constant 7Hz apart. The spectrum would have two signals, each being a doublet. Each doublet will have the same area because both doublets are produced by one proton each.
The two doublets at 1 ppm and 2.5 ppm from the fictional molecule CH−CH are now changed into CH2−CH:
The total area of the 1 ppm CH2 peak will be twice that of the 2.5ppm CH peak.
The CH2 peak will be split into a doublet by the CH peak—with one peak at 1ppm + 3.5Hz and one at 1ppm − 3.5Hz (total splitting or coupling constant is 7Hz).
In consequence the CH peak at 2.5 ppm will be split twice by each proton from the CH2. The first proton will split the peak into two equal intensities and will go from one peak at 2.5ppm to two peaks, one at 2.5ppm + 3.5Hz and the other at 2.5ppm − 3.5Hz—each having equal intensities. However, these will be split again by the second proton. The frequencies will change accordingly:
The 2.5 ppm + 3.5Hz signal will be split into 2.5ppm + 7Hz and 2.5ppm.
The 2.5 ppm − 3.5Hz signal will be split into 2.5ppm and 2.5ppm − 7Hz.
The net result is not a signal consisting of 4 peaks but three: one signal at 7Hz above 2.5ppm, two signals occur at 2.5ppm, and a final one at 7Hz below 2.5ppm. The ratio of height between them is 1:2:1. This is known as a triplet and is an indicator that the proton is three-bonds from a CH2 group.
This can be extended to any CHn group. When the CH2−CH group is changed to CH3−CH2, keeping the chemical shift and coupling constants identical, the following changes are observed:
The relative areas between the CH3 and CH2 subunits will be 3:2.
The CH3 is coupled to two protons into a 1:2:1 triplet around 1ppm.
The CH2 is coupled to three protons.
Something split by three identical protons takes a shape known as a quartet, each peak having relative intensities of 1:3:3:1.
A peak is split by n identical protons into components whose sizes are in the ratio of the nth row of Pascal's triangle:
n
Name
Row
0
singlet
1
1
doublet
1 1
2
triplet
1 2 1
3
quartet
1 3 3 1
4
quintet
1 4 6 4 1
5
sextet
1 5 10 10 5 1
6
septet
1 6 15 20 15 6 1
7
octet
1 7 21 35 35 21 7 1
8
nonet
1 8 28 56 70 56 28 8 1
Because the nth row has n + 1 components, this type of splitting is said to follow the "n+1 rule": a proton with n neighbors appears as a cluster of n+1 peaks.
With 2-methylpropane, (CH3)3CH, as another example: the CH proton is attached to three identical methyl groups containing a total of 9 identical protons. The C−H signal in the spectrum would be split into 10 peaks according to the n+1 rule of multiplicity. Below are NMR signals corresponding to several simple multiplets of this type. Note that the outer lines of the nonet (which are only 1/8 as high as those of the second peak) can barely be seen, giving a superficial resemblance to a septet.
When a proton is coupled to two different protons, then the coupling constants are likely to be different, and instead of a triplet, a doublet of doublets will be seen. Similarly, if a proton is coupled to two other protons of one type, and a third of another type with a different, smaller coupling constant, then a triplet of doublets is seen. In the example below, the triplet coupling constant is larger than the doublet one. By convention the pattern created by the largest coupling constant is indicated first and the splitting patterns of smaller constants are named in turn. In the case below it would be erroneous to refer to the quartet of triplets as a triplet of quartets. The analysis of such multiplets (which can be much more complicated than the ones shown here) provides important clues to the structure of the molecule being studied.
The simple rules for the spin-spin splitting of NMR signals described above apply only if the chemical shifts of the coupling partners are substantially larger than the coupling constant between them. Otherwise there may be more peaks, and the intensities of the individual peaks will be distorted (second-order effects).
Hetero-nuclear coupling
If there are other NMR-active nuclei present in a molecule, spin–spin coupling will be observed between the hetero-atoms and the protons. This occurs most frequently in compounds that contain phosphorus or fluorine, as they are both spin-1/2 nuclei of 100% abundance. For example, the 1H signals for the protons in fluoromethane are split into a doublet by the fluorine atom; conversely, the fluorine-19 NMR spectrum of this compound shows a quartet due to being split by the three protons. Typical 2J coupling constants between fluorine and protons are 48Hz or so; the strength of coupling declines to 2Hz in 4J coupling.[5]
Even larger coupling constants may be seen in phosphines, especially if the proton is directly bonded to the phosphorus. Coupling constants for these protons are often as large as 200Hz, for example, in diethylphosphine, where the 1J P−H coupling constant is 190Hz.[6] These coupling constants are so large that they may span distances in excess of 1ppm (depending on the spectrometer), making them prone to overlapping with other proton signals in the molecule.
Carbon satellites and spinning sidebands
Occasionally, small peaks can be seen shouldering the main 1H NMR peaks. These peaks are not the result of proton-proton coupling, but result from the coupling of 1H atoms to an adjoining carbon-13 (13C) atom. These small peaks are known as carbon satellites as they are small and appear around the main 1H peak i.e. satellite (around) to them. Carbon satellites are small because only very few of the molecules in the sample have that carbon as the rare NMR-active 13C isotope. As always for coupling due to a single spin-1/2 nucleus, the signal splitting for the H attached to the 13C is a doublet. The H attached to the more abundant 12C is not split, so it is a large singlet. The net result is a pair of evenly spaced small signals around the main one. If the H signal would already be split due to H–H coupling or other effects, each of the satellites would also reflect this coupling as well (as usual for complex splitting patterns due to dissimilar coupling partners). Other NMR-active nuclei can also cause these satellites, but carbon is most common culprit in the proton NMR spectra of organic compounds.
Sometimes other peaks can be seen around 1H peaks, known as spinning sidebands and are related to the rate of spin of an NMR tube. These are experimental artifacts from the spectroscopic analysis itself, not an intrinsic feature of the spectrum of the chemical and not even specifically related to the chemical or its structure.
Carbon satellites and spinning sidebands should not be confused with impurity peaks.[7]
Deuterium (hydrogen-2, symbol 2H or D, also known as heavy hydrogen) is one of two stable isotopes of hydrogen; the other is protium, or hydrogen-1, 1H. The deuterium nucleus, called a deuteron, contains one proton and one neutron, whereas the far more common 1H has no neutrons. Deuterium has a natural abundance in Earth's oceans of about one atom of deuterium in every 6,420 atoms of hydrogen. Thus, deuterium accounts for about 0.0156% by number (0.0312% by mass) of all hydrogen in the ocean: 4.85×1013 tonnes of deuterium – mainly as HOD (or 1HO2H or 1H2HO) and only rarely as D2O (or 2H2O) – in 1.4×1018 tonnes of water. The abundance of 2H changes slightly from one kind of natural water to another (see Vienna Standard Mean Ocean Water).
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.
Nuclear magnetic resonance spectroscopy of proteins is a field of structural biology in which NMR spectroscopy is used to obtain information about the structure and dynamics of proteins, and also nucleic acids, and their complexes. The field was pioneered by Richard R. Ernst and Kurt Wüthrich at the ETH, and by Ad Bax, Marius Clore, Angela Gronenborn at the NIH, and Gerhard Wagner at Harvard University, among others. Structure determination by NMR spectroscopy usually consists of several phases, each using a separate set of highly specialized techniques. The sample is prepared, measurements are made, interpretive approaches are applied, and a structure is calculated and validated.
The heteronuclear single quantum coherence or heteronuclear single quantum correlation experiment, normally abbreviated as HSQC, is used frequently in NMR spectroscopy of organic molecules and is of particular significance in the field of protein NMR. The experiment was first described by Geoffrey Bodenhausen and D. J. Ruben in 1980. The resulting spectrum is two-dimensional (2D) with one axis for proton (1H) and the other for a heteronucleus, which is usually 13C or 15N. The spectrum contains a peak for each unique proton attached to the heteronucleus being considered. The 2D HSQC can also be combined with other experiments in higher-dimensional NMR experiments, such as NOESY-HSQC or TOCSY-HSQC.
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 stereochemistry, topicity is the stereochemical relationship between substituents and the structure to which they are attached. Depending on the relationship, such groups can be heterotopic, homotopic, enantiotopic, or diastereotopic.
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.
Deuterated chloroform, also known as chloroform-d, is the organic compound with the formula CDCl3. Deuterated chloroform is a common solvent used in NMR spectroscopy. The properties of CDCl3 and ordinary CHCl3 (chloroform) are virtually identical.
Nuclear magnetic resonance (NMR) in the geomagnetic field is conventionally referred to as Earth's field NMR (EFNMR). EFNMR is a special case of low field NMR.
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.
Fluorine-19 nuclear magnetic resonance spectroscopy 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.
Carbohydrate NMR spectroscopy is the application of nuclear magnetic resonance (NMR) spectroscopy to structural and conformational analysis of carbohydrates. This method allows the scientists to elucidate structure of monosaccharides, oligosaccharides, polysaccharides, glycoconjugates and other carbohydrate derivatives from synthetic and natural sources. Among structural properties that could be determined by NMR are primary structure, saccharide conformation, stoichiometry of substituents, and ratio of individual saccharides in a mixture. Modern high field NMR instruments used for carbohydrate samples, typically 500 MHz or higher, are able to run a suite of 1D, 2D, and 3D experiments to determine a structure of carbohydrate compounds.
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 disturbed 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. High-resolution 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 should not be confused with solid state NMR, which aims at removing the effect of the same couplings by Magic Angle Spinning techniques.
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.
In the context of nuclear magnetic resonance (NMR), the term magnetic inequivalence refers to the distinction between magnetically active nuclear spins by their NMR signals, owing to a difference in either chemical shift or spin–spin coupling (J-coupling). Since chemically inequivalent spins are expected to also be magnetically distinct, and since an observed difference in chemical shift makes their inequivalence clear, the term magnetic inequivalence most commonly refers solely to the latter type, i.e. to situations of chemically equivalent spins differing in their coupling relationships.
References
↑ R. M. Silverstein, G. C. Bassler and T. C. Morrill, Spectrometric Identification of Organic Compounds, 5th Ed., Wiley, 1991.
↑ Baccolini, Graziano; Boga, Carla; Mazzacurati, Marzia; Sangirardi, Federico (2006-04-01). "High Atom-Economical One-Pot Synthesis of Secondary Phosphines and Their Borane Complexes Using Recycling Phosphorus Donor Reagent". Organic Letters. 8 (8): 1677–1680. doi:10.1021/ol060284d. ISSN1523-7060. PMID16597139.
↑ Gottlieb HE; Kotlyar V; Nudelman A (October 1997). "NMR Chemical Shifts of Common Laboratory Solvents as Trace Impurities". J. Org. Chem. 62 (21): 7512–7515. doi:10.1021/jo971176v. PMID11671879.
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