Enantiotopic nuclei

As was already mentioned, the phenomenon of nonequivalence of NMR spectra of enantiomers in chiral solvents is a basis for the determination of enantiomeric purity of a variety of chiral sulfur compounds. This method, developed by Pirkle, has the advantage over other methods of being absolute that is, the chemical shift difference between enantiotopic nuclei induced by the chiral solvent increases with increasing optical purity of the solvent, whereas the relative intensities of the signals that are used to measure the enantiomeric composition of the solute are not affected. 

NMR spectroscopy the NMR spectrum of the sample in the presence of a chiral solvating agent (see Section 3.1.4.1.) or a chiral paramagnetic lanthanide shift reagent (see Section 3.1.4.2.2.) is recorded. The determination of enantiomeric purity rests on the nonequivalence of externally enantiotopic nuclei which are rendered externally diastereotopic in a non-racemic chiral environment. 

It is important to note that enantiotopic nuclei, i.e., nuclei that are related by reflection symmetry, are rendered diastereotopic in a chiral environment. Thus, in contrast to homotopic nuclei, i.c., nuclei that are related by an axis of rotation, isochronous (enantiotopic) nuclei can be transformed into anisochronous (diastereotopic) nuclei via desymmetrization with chiral reagents or in chiral environments. 

It should be noted that the vinyl and methyl proton resonances of the Z-isomer [i.e., of the achiral tetracarbonylirondimethyl (Z)-butenedioate complex] are also discriminated in the presence of Eutbfc), because the internally enantiotopic nuclei are rendered diastereotopic in the presence of the nonracemic LSR81. The vinyl protons of the. E-isomer show two lines (external diastereotopism) while the vinyl protons of the Z-isomer exhibit an AB-system (internal diastereotopism)5. 

Since nuclear magnetic resonance is a scalar probe, enantiotopic nuclei are isochronous (i.e. have the same chemical shift) in achiral media. Such nuclei, however, become diastereotopic in chiral media and thus, in principle (though often not in practice) anisochronous. Among many examples 26,27) are the enantiotopic methyl protons of dimethyl sulfoxide, CH3SOCH3, which are shifted with respect to each other by 0.02 ppm 26c) in solvent QH5CHOHCF3. (Surprisingly the 13C signals of the... 

These two structures are, in fact, non-superimposable mirror images, though you may wish to verify this by constructing molecular models of each one. We can summarize by saying that all enantiotopic nuclei are symmetry equivalent (by virtue of a a plane) but not all symmetry-equivalent nuclei are enantiotopic. To prove this, carry out the isotope substitution test on the equivalent nuclei in structures 4-1 through 4-5 and confirm that no two are enantiotopic. 

Therefore, the two circled hydrogens in 4-9 are said to be diastereotopically related, or simply diastereotopic. They are not equivalent. And this relationship persists even though rotation of the C -C bond is fast on the NMR time scale. Here is the all-important bottom line While NMR normally cannot distinguish between enantiotopic nuclei (but see Section 10.7.3), NMR can distinguish between diastereotopic nuclei (at least in principle). 

EXAMPLE 4.6 (a) Indicate all homotopic nuclei, enantiotopic nuclei, and diastereotopic nuclei in structure 4-10. You may assume rapid rotation of all bonds, (b) How many H and 13C NMR signals would you predict for the compound ... 

In Section 4.3 we mentioned two important stereochemical terms, enantiomers and enantiotopic nuclei. Enantiomers are structures related as the left hand is related to the right nonsuperimposable mirror images. Any chiral (dissymmetric) molecule can exist in two (and only two) enantiomeric forms. For example, chiral alcohol 10-11 has two enantiomeric configurations, labeled R and S.10 Enantiotopic nuclei are those related by a plane of symmetry. The methylene hydrogens of benzyl alcohol (10-12) are enantiotopic and are labeled pro-R and pro-S10 ... 

Here is the most important thing to remember about enantiotopic nuclei They have identical physical, chemical, and spectroscopic properties and are therefore indistinguishable by NMR under normal conditions. Likewise, enantiomers have identical physical, chemical, and spectroscopic properties and are indistinguishable by NMR under normal conditions. (Enantiomers can be distinguished by a technique... 

Enantiomers and enantiotopic nuclei normally exhibit identical NMR spectra. However, if such molecules are immersed in an asymmetric medium (e.g., a chiral shift reagent or chiral solvent), the signals for each enantiomer (or each enantiotopic nucleus) will be resolved. 

These both key intermediates were opened with H2S in the presence of diisopro-pylamine. This reaction is known to proceed with full retention of configuration. Therefore we assume, that the obtained thiols 210 and 211 are of the assigned absolute stereochemistry. The optical purity of each enantiomer was directly determined from the relative peak areas and senses of nonequivalence of the resonances of enantiotopic nuclei in chiral solvent, e. g. Eu(TBC)3. We observe optical purities for 210p = 85% and for 211 p = 75%. The addition of 210 to the optically active 212 gave after column chromatography the desired 8 R, 11 R, 12 R, 15 S-13-thiaprostanoid E 213. 

Enantiotopic nuclei or groups are capable of fulfilling all or, at least, most of the foregoing symmetry-related expectations. Their chemical shifts depend, in addition, on both the medium in which the NMR experiment is conducted and the spectral resolution of the spectrometer. The latter is influenced by, for example, the magnetic-field strength. Enantiotopic groups are isochronous in achiral or racemic media and constitute A2,X2, etc., systems. Moreover, they are potentially anisochronous in chiral media. 

Applying the same substitution process to and H 2 gives enantiomeric representations, as seen in Figure 8.22b, and the two hydrogen atoms are described as being enantiotopic. Enantiotopic nuclei are also chemically equivalent and will have the same chemical shift, provided they are in an achiral environment, such as that provided by the solvents commonly used in NMR studies. It is left as an exercise to demonstrate that the hydrogen atoms of type Hj, are also enantiotopic. 

One of the most common methods employed for analysis of chiral compounds is NMR spectroscopy [82, 83]. Enantiomers cannot be discriminated in an achiral medium because the resonances of enantiotopic nuclei are isochronous. However, diastereoisomers may be distinguished as the nuclei resonances are anisochronous. In NMR, nuclei can be classified as isochronous or anisochronous. Where diastereotopic protons show the same chemical shift, they are said to be equivalent or isochronous, and where they have different chemical shifts, the protons are described as anisochronous [84]. As long as there is a large enough... 

---