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Subject Chemistry

Paper No and Title 1: Organic Chemistry I (Nature of Bonding & Stereochemistry) Module No and Title 23: Enantiotopic & Diastereotopic atoms , groups and faces

Module Tag CHE_P1_M23

TABLE OF CONTENTS

1. Learning Outcomes

2. Introduction

3. Topicity and Prostereoisomerism 4. Homotopic ligand and faces 4.1. Substitution-addition criterion 4.2. Symmetry criterion

5. Stereoheterotopic ligands and faces 5.1. Enantiotopic ligands and faces

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5.1.1. Substitution-addition criterion 5.1.2. Symmetry criterion

5.2. Diastereotopic ligands and faces 5.2.1. Substitution-addition criterion 5.2.2. Symmetry criteron 6. Nomenclature 6.1. Symbols for Stereoheterotopic ligands 6.1.1. Molecule with single prochiral centre 6.1.2. Molecules with pre-pseudoasymmetric centre 6.1.3. Molecules with prochiral axis 6.1.4. Molecules with prochiral plane 6.2. Symbols for Stereoheterotopic faces 6.2.1. Enantiotopic faces 6.2.2. Diastereotopic faces 7. Summary

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1. Learning Outcomes

 Learn what are homotopic and heterotopic ligands.  Understand about the “Topicity” and “Prostereoisomerism”  Study about homotopic ligands and faces by using substitution-addition and symmetric criteria.  Know about enantiotopic ligands and faces by using substitution-addition and symmetric criteria.  Know about diastereotopic ligands and faces by using substitution-addition and symmetric criteria.  Learn the nomenclature of stereoheterotopic ligands and faces.

2. Introduction

As we know, when the atoms or group of atoms in the molecule are superimposable then they are homomorphic. These homomorphic atoms or groups can be distinguished if they are bonded to constitutionally different centres or if they have different spacial relation to the rest of the molecule. This can be clearly understood by taking an example of n- pentane (Figure 1.).

Figure 1. Homotopic and Heterotopic atoms

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In this case the H-atoms at C-2 are constitutionally heterotopic (‘topos’ means ‘place’ in Greek). These C-2 H’s are stereoheterotopic as their spacial relation is different with the rest of the molecule. In this molecule, the plane Me-C-Pr divides it into two halves, the right and the left which are stereochemically distinguishable (enantiomorphic in present case), actually making two H’s stereochemically non equivalent i.e., stereoheterotopic. These H’s can be recognized hypotheically by replacing them with other atoms say Br in this case, this results in two enantiomers as shown in the Figure 1. Similarly, if the replacement is by constitutionally heterotopic ligands this would results to constitutional isomers e.g., if Me or Pr are replaced by chiral groups then it becomes diastereomorphic with respect to the plane and bromination at the C-2 leads to two diastereomers which also makes the two H’s stereoheterotopic. Whereas the geminal H’s of C-3 cannot distinguish two halves, as it resides in Et-C-Et plane which is two-dimentionally achiral. So, the replacement by Br at C-3 gives the identical products. So, these H’s are considered as homotopic. All these are discussed in more detail in later section of this module.

3. Topicity and Prostereoisomerism

In 1967, Mislow and Raban explained the concept of stereoheterotopicity and in 1966 Hanson gave the concept of prochirality which is reviewed by Eliel in 1982. Stereoheterotopicity and prostereoisomerism are related phenomena as the molecules which have stereoheterotopic ligands must exhibits prostereoisomersim (only when the ligands can be reacted on). The term chirality in prostereoisomersim is replaced by the term prochirality. Prochirality is defined as “if two homomorphic ligands at a prochiral centre (or axis or plane) be made different, a chiral center (or axis or plane) would result. In general, a molecule with formula Xaabc represents prochiral centre. As discussed in n- pentane which exhibits prostereoisomersim, with C-2 & C-4 as prostereogenic centres. Like in stereoisomerism we discussed about stereogenic elements such as centres, axes CHEMISTRY PAPER 1: ORGANIC CHEMISTRY- I (Nature of Bonding and Stereochemistry) MODULE 23: Enantiotopic and diastereotopic atoms, groups and faces

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and planes similarly prostereoisomersim is also described in terms of analogous prostereogenic elements, i.e., prostereocentres, prosteroaxes, and prostereoplanes. Also two faces of appropriate molecules may also be stereoheterotopic and reactions on either face would lead to different stereoisomers.

Topicity describe the relationship of two or more homomorphic ligands (or faces) which together constitute a set. Hence, a ligand cannot by itself be called homotopic or heterotopic; in order to use this terminology, a comparison with other homomorphic ligand or ligands present either in the same molecule (internal comparison) or in a different molecule (external comparison) is necessary.

4. Homotopic ligands and faces

Two criteria, namely, substitution-addition criterion and (or) a symmetry criterion are used to determine the relationships of homomorphic ligands and faces (only one test adequate). 4.1 Substitution-addition criterion Two homomorphic ligands are homotopic if substitution of first one and then the other by an atom or a group which is not already attached to the ligating centre gives identical product. For example, all hydrogen atoms in methylene dichloride methyl chloride, ethylene, and allene (Figure 2.) are homotopic. (Substitution of hydrogen atoms in each set gives a single product)

Figure 2. Homotopic ligands

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The two methine hydrogens in (+), - tartaric acid (I) [as also in the (-)-enantiomer] are also homotopic since their respective replacement by deuterium leads to identical product (Figure 3.).

Figure 3. Homotopicity in tartaric acid Two faces of a double bond are homotopic if addition to either face gives identical product, e.g., formation of ethanol by addition of MeMgI to either face of formaldehyde (Figure 4). The two faces of the dialkyl sulphide (IV) are homotopic by the same manner. Alternatively, the two lone pairs may be considered to be homotopic.

Figure 4. Homotopic faces

4.2 Symmetry criterion

Ligands are homotopic (by internal comparison) if they can interchange positions by

rotation around a simple axis Cn ( > n > 1). Thus the two hydrogen in methylene dichloride, the three hydrogens of methyl chloride, and the four hydrogens of ethylene

can interchange positions through rotations around C2, C3 and C2 axes respectively (Figure 2). In allene, the geminal hydrogens are interchangeable in pairs by rotation

around the molecular axis (C2 axis) while the non-geminal hydrogens are interchangeable

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through rotation around the two C2 axis perpendicular to the former. All the four hydrogen atoms are thus homotopic. Similarly, for (+)- tartaric acid the two methine

protons are interchangeable through rotation around a C2 axis either in the eclipsed conformation or in a staggered conformation. This pairs of ligands are, therefore, homotopic. The following points may be noted:

(1) Any achiral or chiral molecule with a Cn axis ( > n >1) must contain at least one set of homotopic.

(2) Molecules belonging to non-axial point groups, such as C1, CS and Ci and also

Cv do not possess any Cn axis cannot have homotopic ligands. (3) For conformationally mobile systems, if the structural change is rapid on the time scale of observation, homomorphic ligands (interchanged under condition of fast rotation) are homotopic (e.g., H’s in cyclohexane). (4) In a rigid molecule, the number of homotopic ligands belonging to a set cannot be greater than (although it may be equal to) its symmetry number (). (5) Faces of double bonds, carbonium ions, and molecules with disubstituted atoms capable of accepting a third ligand (e.g., R-S-R) are homotopic if they interchange

through a C2 axis.

5. Stereoheterotopic ligands

The stereoheterotopic ligands are of two types: enantiotopic if their positions in the molecule are related in mirror-image fashion and diastereotopic if their positions do not bear a mirror-image relationship. 5.1 Enantiotopic ligands and faces Enantiotopic ligands and faces may be recognized by the application of the substitution- addition and symmetry criteria. 5.1.1 Substitution-addition criterion

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Two heterotopic ligands are enantiotopic if replacement of first one and then the other by a different achiral ligand gives rise to two enantiomers. The same goes for addition to enantiotopic faces. Some of the examples are shown below:

Figure 5. Enantiotopic ligands The cases of propionic acid (V), monochloroallene (VI), and paracyclophane (VII)

(Figure 5) (only one pair of enantiotopic H's is shown); replacement of HA and HB one at a time with D leads to enantiomers. Molecules (V)—(VII) provide examples of a prochiral centre, a prochiral axis and a prochiral plane respectively. Addition of a hydride ion to the right face of acetophenone (Figure 6) gives S, while addition to the left face gives R-phenylmethylcarbinol indicating that the two faces are enantiotopic.

R S Figure 6. Enantiotopic Faces

5.1.2. Symmetry criterion

Heterotopic ligands or faces are enantiotopic if they are interchangeable through

operation of symmetry of the second kind, i.e.,  planes and Sn axes. Thus HA and HB in CHEMISTRY PAPER 1: ORGANIC CHEMISTRY- I (Nature of Bonding and Stereochemistry) MODULE 23: Enantiotopic and diastereotopic atoms, groups and faces

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V, VI, and VII (Figure 5.); exchange positions through a  plane. These ligands are therefore, enantiotopic. The enantiotopic faces of acetophenone (Figure 6.) are likewise interchangeable through a  plane coinciding with the plane of the molecules. The following points should be noted in connection with enantiotopicity of ligands: I. Only achiral molecules can have internally enantiotopic ligands (or faces) since the presence, of a symmetry element of the second kind is necessary for interchange.

This excludes all molecules belonging to chiral point groups Cn and Dn (and also

Cv and Ch for a different reason).

II. Molecules with enantiotopic ligands may belong to non-axial point groups, e.g., Ci,

and Cs (in contrast to molecules containing only homotopic ligands) as well as to axial point groups.

III. Molecules with enantiotopic ligands (and faces) are not only prostereogenic but also prochiral. IV. Unlike enantiomers which occur only in pairs, a ligand can be enantiotopic with more than one other ligand. V. Like enantiomers, enantiotopic ligands or faces cannot be distinguished by achiral reagents or in achiral media but are distinguishable by chiral reagents notably by enzymes and by NMR in chiral media.

5.2 Diastereotopic ligands and faces Diastereotopic ligands and faces reside in diastereomeric environments and can be distinguished very often simply by an inspection of the molecular structure. However, application of the substitution-addition and symmetry criteria often makes the task easy.

5.2.1. Substitution-addition criterion

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The hydrogen atoms HA and HB in propene (VIII) and bromocyclobutane (IX) (Figure 7.) on substitution give two diastereomeric products in each case and are, therefore, diastereotopic. Two geminal methylene protons adjacent to a chiral centre are usually diastereotopic as in the molecules represented by the general formula (X). The replacement criterion leads to two chiral diastereomers differing in the configuration at C-2 which correspond to erythro and threo isomers.

VIII IX X Figure 7. Diastereotopic atoms or groups The two faces of the carbonyl group in a molecule of the general formula (Figure 8.) containing a chiral centre are diastereotopic since addition of a hydride to the two faces gives different diastereomers: XI when addition takes place to the left face and XIII when addition takes place to the right face.

XI XII XIII L=Large, M=Medium, S=Small Figure 8. Diastereotopic faces 5.2.2. Symmetry criterion

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Diastereotopic ligands are not related by any symmetry operation and are, therefore, relatively easy to spot.

(i) Chiral molecules belonging Ci point group cannot have homotopic ligands (absence of

Cn ) or enantiotopic ligands (absence of  and Sn) but they may contain diastereotopic ligands or faces. (ii) Frequently, homomorphic ligands at a carbon atom in chiral molecules are in diastereomeric environments and thus diastereotopic. However, this is not true in all

chiral molecules. In fact, molecules belonging to all point groups except Cn and Dv can have diastereotopic ligands. Similarly, both chiral and achiral molecules can have diastereotopic faces. However, such molecules must be non-planar. (iii) Enantiotopic and diastereotopic ligands often coexist e.g., citric acid. (iv) Diastereotopic ligands, in principle, are distinguishable by all physical and chemical (including biochemical) means both in achiral and chiral media. NMR spectroscopy is particularly helpful.

6. Nomenclature

6.1. Symbols for Stereoheterotopic ligands

Just like stereoisomers which differ in their spatial arrangements of their constituent atoms and groups, stereoheterotopic ligands also differ in their spatial relationships. So, it is desirable to give appropriate descriptors to such ligands. Configurational descriptors such as R, S, Z, E, cis and trans which are used to describe stereogenic units may be prefixed with pro and can be used to describe heterotopic ligands attached to analogous prostereogenic units. This system was introduced by Hanson in 1966.

6.1.1. Molecules with one prochiral centre

Molecules with single prochiral centre are represented by the general formula CabXX and depicted by Fischer Plane Projection in two perspectives (A) and (B) (Figure 9.). It CHEMISTRY PAPER 1: ORGANIC CHEMISTRY- I (Nature of Bonding and Stereochemistry) MODULE 23: Enantiotopic and diastereotopic atoms, groups and faces

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is assumed that ligand ‘a’ has higher priority than ligand ‘b’ as determined by the sequence rule while ligand X may have any priority lower, higher, or in between with respect to ‘a’ and ‘b’. Let us assume that X has the lowest priority. In order to assign a descriptor to any of the

paired ligand, say XA, it is arbitrarily given a higher priority than XB without disturbing the priorities of a and b (the unpaired ligands). The chirality rule is now applied to the hypothetical chiral centre which happens to have R configuration (viewed from the side

remote from XB, the lowest ranking group, a→b→XA describes a clockwise direction).

The ligand XA is called pro-R and may be denoted by adding a subscript R, as XR. the

other ligand XB is pro-S (denoted by XS) by default—a conclusion which is alternatively

arrived at by adopting the above procedure but elevating the priority of XB over that of

XA.

Figure 9. pro-S and pro-R descriptor

By applying Hanson’s procedure for assigning pro-R and pro-S symbols is to replaced one of the paired ligands by a heavy isotope, e.g., by D and then apply the chirality rule to the now truly chiral centre. Since the heavier isotope gets over the lighter one, assignment is the same as describe in the previous paragraph. This can be clearly understood by taking an example. (Figure 10.)

Figure 10. Nomenclature of molecule with one prochiral centre

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6.1.2. Molecule with a pro-pseudoasymmetric centre

The two H’s (HA and HB) at C-3 of 2,4-dihydroxyglutaric acid (Figure 11.) are not homotopic, neither they are enantiotopic since they are not interchangeable by the symmetry of any kind (homotopic pairs of ligands). They must, therefore, be

diastereotopic and indeed the substitution criterion (replacement of HA and HB by D) gives two diastereomers (XV) and (XVI) in which C-3 is pseudoasymmetric centre with r and s configuration respectively. The C-3 centre in XIV may, therefore, be called a pro- pseudoasymmetric centre or perhaps more logically (Mislow and Siegel 1984) a

prostereogenic but a prochirotopic centre. HA is Pro-r and HB is Pro-s.

XIV XV XVI Figure 11. Molecule with pro-pseudoasymmetric centre

6.1.3. Molecule with a prochiral axis

Molecules like allenes, biphenyls, and analogues when suitably substituted may have a

pair of stereoheterotopic ligands. To assign descriptor to HA, its priority is elevated over

that of HB (alternatively, HA may be hypothetically replaced by D). Assigning the descriptors to such molecules is to project the molecule on a plane in a similar manner as

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it was done for R and S. If the configuration of the hypothetical chiral axis is R as in

allene then HA is pro-R and so on. Similar procedure is adopted for the biphenyls.

Figure 12. Molecules with prochiral axis

6.1.4. Molecule with a prochiral plane

The assignment of descriptors to heterotopic ligands in molecules with a prochiral plane is best illustrated with an example, the paracyclophane in Figure 13. There are several

pairs of enantiotopic H’s; only one pair, HA and HB is shown (they are not

interchangeable by a Cn axis but by a σ plane). To give a descriptor to HA, it must be

given priority over HB (alternatively it may be replaced by D) so that the bottom methylene C (underlined) becomes the pilot atom and the hypothetical chiral plane has R

configuration; so HA is pro-R (HR). Similarly, when HB is considered, the top methylene

C (underlined) becomes the pilot atom and HB becomes pro-S (HS).

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Figure 13. Paracyclophane

A variety of prostereogenic molecules contains diastereotopic ligands which on substitution give achiral diastereomers, i.e., they do not have prochiral centre or centres. Such ligands may be called pro-Z, pro-E, pro-cis, pro-trans, pro-endo, pro-exo etc. depending on the nature of the diastereomers formed on their substitution.

6.2. Symbols for stereoheterotopic faces

6.2.1. Enantiotopic faces

A different system of nomenclature was given by Prelog and Helmchen (1972) is Re and Si system is used to differentiate heterotopic faces. As we know, enantiotopic faces of molecules are two-dimensionally chiral. If the three ligands arranged in priority order appear clockwise in a face, the face is Re and if they appear anticlockwise, the face is Si as shown in the case of acetaldehyde (XVII) (Figure 14.). If the double bond contains two specifiable trigonal atoms, a face may be uniquely defined by two symbols one for each specifiable atom. This is illustrated with maleic acid (XVIII) (here two face are homotopic) and fumaric acid (XIX) (the two faces are enantiotopic). Olefins of the type (XX) in which one terminal contains two equivalent ligands require, however, only one

symbol Re or Si depending on the priority order of a, b, and =Cd2 (in the figure, the

priority order is a > b > =Cd2)

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XVII XVIII XIX XX Figure 14. Nomenclature of enantiotopic faces

6.2.2. Diastereotopic faces

The two carbonyl faces of 3-hydroxybutanal (Figure 15.) are diastereotopic (presence of a chiral centre). The right face is Re and the left face is Si according to the above procedure to which a further subscript R (the chiral descriptor of C-3) may be added so that the double lettered subscript ReR and SiR are truly diastereotopic.

Figure 15. Nomenclature of diastereotopic faces.

7. Summary

 Homomorphic atoms or groups can be distinguished if they are bonded to constitutionally different centres or if they have different spacial relation to the rest of the molecule.

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 Prochirality is defined as “if two homomorphic ligands at a prochiral centre (or axis or plane) be made different, a chiral center (or axis or plane) would result.  Stereoheterotopicity and prostereoisomerism are related phenomena as the molecules which have stereoheterotopic ligands must exhibits prostereoisomerism.  Like in stereoisomerism, prostereoisomersim is also described in terms of analogous prostereogenic elements, i.e., prostereocentres, prosteroaxes, and prostereoplanes.  Enantiotopic, diastereotopic and homotopic ligands can be recognized by substitution-addition criterion and symmetry criterion.  Configurational descriptors such as R, S, Z, E, cis and trans which are used to describe stereogenic units may be prefixed with pro and can be used to describe heterotopic ligands attached to analogous prostereogenic units.  A different system of nomenclature was given by Prelog and Helmchen (1972) is Re and Si system is used to differentiate heterotopic faces.

CHEMISTRY PAPER 1: ORGANIC CHEMISTRY- I (Nature of Bonding and Stereochemistry) MODULE 23: Enantiotopic and diastereotopic atoms, groups and faces