Enantiotopic and Diastereotopic Atoms, Groups, and Faces - Stereochemistry and Conformation - Introduction - March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th Edition (2013)

March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th Edition (2013)

Part I. Introduction

Chapter 4. Stereochemistry and Conformation

4.L. Enantiotopic and Diastereotopic Atoms, Groups, and Faces259

Many molecules contain atoms or groups that appear to be equivalent, but a close inspection will show them to be actually different. We can test whether two atoms are equivalent by replacing each of them in turn with some other atom or group. If the new molecules created by this process are identical, the original atoms are equivalent; otherwise they are not. There are three cases.

1. In the case of malonic acid [CH2(COOH)2], propane (CH2Me2), or any other molecule of the form CH2Y2,260 replacing either of the CH2 hydrogens by a group Z will give the identical compound. The two hydrogens are thus equivalent. Equivalent atoms and groups need not, of course, be located on the same carbon atom. For example, all the chlorine atoms of hexachlorobenzene are equivalent as are the two bromine atoms of 1,3-dibromopropane.

2. In the case of ethanol, replacing one of the CH2 hydrogens by a group Z will give one enantiomer of the compound ZCHMeOH (91), while replacement of the other hydrogen gives the other enantiomer (92). Since the two compounds that result upon replacement of H by Z (91 and 92) are not identical but enantiomeric, the hydrogens are not equivalent. Two atoms or groups that upon replacement with a third group give enantiomers are defined as enantiotopic. In any symmetrical environment, the two hydrogens behave as equivalent, but in a dissymmetrical environment they may behave differently. For example, in a reaction

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with a chiral reagent they may be attacked at different rates. This has important consequences in enzymatic reactions,261 since enzymes are capable of much greater discrimination than ordinary chiral reagents. An example is found in the Krebs cycle, in biological organisms, where oxaloacetic acid (93) is converted to α-oxoglutaric acid (95) by a sequence that includes citric acid (94) as an intermediate. When 93 is labeled with 14C at the 4 position, the label is found only at C-1 of 95, despite the fact that 94 is not chiral. The two

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CH2COOH groups of 94 are enantiotopic and the enzyme easily discriminates between them.262 Note that the X atoms or groups of any molecule of the form CX2WY are always enantiotopic if neither W nor Y is chiral. However, enantiotopic atoms and groups may also be found in other molecules (e.g., the hydrogen atoms in 3-fluoro-3-chlorocyclopropene, 96). In this case, substitution of an H by a group Z makes the C-3 atom asymmetric and substitution at C-1 gives the opposite enantiomer from substitution at C-2.

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The term prochiral263 is used for a compound or group that has two enantiotopic atoms or groups (e.g., CX2WY). That atom or group X that would lead to an R compound if preferred to the other is called pro-(R). The other is pro-(S); for example,

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3. Where two atoms or groups in a molecule are in such positions that replacing each of them in turn by a group Z gives rise to diastereomers, the atoms or groups are called diastereotopic. Some examples are the CH2 groups of 2-chlorobutane (97), vinyl chloride (98), and chlorocyclopropanone (99), as well as the two alkenyl hydrogens

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of 100. Diastereotopic atoms and groups are different in any environment, chiral or achiral. These hydrogens react at different rates with achiral reagents, but an even more important consequence is that in NMR spectra, diastereotopic hydrogens theoretically give different peaks and split each other. This is in sharp contrast to equivalent or enantiotopic hydrogens, which are indistinguishable in the NMR, except when chiral solvents are used, in which case enantiotopic (but not equivalent) protons give different peaks.264 The term isochronous is used for hydrogens that are indistinguishable in the NMR.265 In practice, the NMR signals from diastereotopic protons are often found to be indistinguishable, but this is merely because they are very close together. Theoretically they are distinct, and they have been resolved in many cases. When they appear together, it is sometimes possible to resolve them by the use of lanthanide shift reagents (Sec. 4.J) or by changing the solvent or concentration. Note that X atoms or groups (CX2WY) are diastereotopic if either W or Y is chiral.

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Just as there are enantiotopic and diastereotopic atoms and groups, enantiotopic and diastereotopic faces in trigonal molecules may be distinguished. Again, there are three cases: (1) In formaldehyde or acetone (101), attack by an achiral reagent A from either face of the molecule gives rise to the same transition state and product; the two faces are thus equivalent and there is only one product. (2) In 2-butanone (102) or acetaldehyde, attack by an achiral A at one face gives a chiral transition state and the enantiomeric products arise from attack at one or the other face. Such faces are enantiotopic. Attack at an enantiotopic face by a chiral reagent will generate another stereogenic center, which gives diastereomers that may not be formed in equal amounts. (3) In a case like 103, the two faces are obviously not equivalent and are called diastereotopic. Enantiotopic and diastereotopic faces can be named by an extension of the CIP system (Sec. 4.E.i).263 If the three groups as arranged by the sequence rules have the order X > Y > Z, that face in which the groups in this sequence are clockwise (as in 104) is the Re face (from Latin rectus), whereas 105 shows the Si face (from Latin sinister).

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Note that new terminology has been proposed.266 The concept of sphericity is used, and the terms homospheric, enantiospheric, and hemispheric have been coined to specify the nature of an orbit (an equivalent class) assigned to a coset representation.267 Using these terms, prochirality can be defined: If a molecule has at least one enantiospheric orbit, the molecule is defined as being prochiral.258