Homotopic, Enantiotopic, and Diastereotopic Nuclei

Consider now the structure of bromochloromethane, structure 4-7. Careful inspection will reveal the presence of a a plane containing the bromine, carbon, and chlorine atoms and bisecting the H-C-H angle  

Therefore, these two hydrogens are symmetry equivalent (and isochronous) since they are related by reflection in the mirror plane. But because they are not related by any axis of symmetry, they are not homo topic. They are instead referred to as enantiotopic hydrogens, ones related only by a symmetry plane. 

If you have difficulty deciding whether two nuclei are related by a mirror plane, there is another test for whether or not two atoms are enantiotopically related it is called the isotope substitution test. To make the test, mentally substitute first one, then the other, suspected atom with a different isotope, and compare the two resulting structures. If the two structures are enantiomers (i.e., non-superimposable mirror images, as are your left and right hands), the two suspected nuclei are said to be enantiotopically related. In the case of structure 4-7 the two substituted structures would be 4-7A and 4-7B  

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). 

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Students are familiar with the terms applied to relationships between stereoisomeric molecules homomeric molecules (superposable molecules), enantiomeric molecules (nonsuperposable mirror images), and diastereomeric molecules (stereoisomers that are not mirror images of one another). These familiar terms are parallel to the terms that we have introduced above homotopic, enantiotopic, and diastereotopic, which are applied to nuclei or groups within the molecule. 

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 ... 

On the timescale of the NMR experiment, isochrony (chemical shift equivalence) arises from symmetry equivalence of homotopic and enantiotopic nuclei5 17, while anisochrony (chemical shift nonequivalence, JK s <5) arises from symmetry nonequivalence of diastereotopic nuclei. 

Mislow el at.301 have pointed out that the distinction between population difference and intrinsic difference is artificial nuclei are either symmetry related (i.e. interchanged by operation of a symmetry element), in which case they are homotopic or enantiotopic and thus isochronous, or they are not so related, in which case they are diastereotopic or constitutionally heterotopic and therefore anisochronous. While this is certainly correct, the present author believes that the dissection between population and intrinsic difference, like many such dissections in science, is at least pedagogically and possibly in some situations even heuristically useful. 

In each of molecules i and ii in Figure C.l, nuclei a are homotopic in molecule iii, they are enantiotopic and, in iv and v, they are diastereotopic. And yet, enantiotopic ligands a in iii, and diastereotopic ligands a in v, are currently designated by the same pro-R/pro-S prochirality descriptors. Furthermore, different notations are used for diastereotopic ligands of v (pro-R/pro-S), on the one hand, and diastereotopic ligands of iv pro-r/pro-s), on the other. In all the above cases, the existing notations are based on prochirality descriptors. 

Further, in the case of molecules vi and vii, nuclei a are homotopic in viii, they are enantiotopic and in ix and x, they are diastereotopic. And yet, the same pro-E/pro-Z notation is used to designate enantiotopic ligands a in viii, and diastereotopic ligands a in ix and x. Here, the designations utilize prostereotopicity descriptors. Finally, there is no descriptor for homotopic ligands in vi and vii. 

The classical topism concepts are directly applicable to predict the number of distinct environments, and the largest number of distinguishable nuclei. Nuclei in homotopic sites, related by proper symmetry axes, have necessarily the same chemical shifts. Those situated in enantiotopic sites, related by improper, Sn, axes (e.g., inversion centers or symmetry planes) also show identical chemical shifts. However, interactions with chiral entities or the formation of chiral supramolecular complexes (e.g., a helical structure) may destroy preexisting elements, render the sites diastereotopic, and result in the observation of distinct chemical shifts. 

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