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Bsc Chemistry Subject Chemistry Paper No and Title 1: ORGANIC CHEMISTRY- I (Nature of Bonding and Stereochemistry) Module No and 19; Prostereoisomerism (Prochirality) Title Module Tag CHE_P1_M19 CHEMISTRY Paper No. 1: ORGANIC CHEMISTRY- I (Nature of Bonding and Stereochemistry) Module No. 19: Prostereoisomerism (Prochirality) TABLE OF CONTENTS 1. Learning Outcomes 2. Introduction 2.1 Molecular Symmetry and Chirality 2.2 What is prochirality? 3. Homotopic and Heterotopic Ligands and Faces 3.1 Topicity of Ligands and Faces 3.2 Homotopic Ligands and Faces 3.3 Heterotopic Ligands and Faces 4. Summary CHEMISTRY Paper No. 1: ORGANIC CHEMISTRY- I (Nature of Bonding and Stereochemistry) Module No. 19: Prostereoisomerism (Prochirality) 1. Learning Outcomes After studying this module, you shall be able to Understand the connection between molecular symmetry and chirality. Differentiate between chiral and prochiral molecule. Know the difference between homotopic and heterotopic ligands and faces. To identify the prochirality in molecules. Identify the different type of stereotopic ligands and faces in the molecules. 2. Introduction 2.1 Molecular Symmetry and Chirality A molecule (or an object) can have only one mirror image. If the image is superimposable on the original, the molecule is called achiral. On the other hand, if it is not superimposable on the original, the molecule and its mirror image form two distinct species called enantiomers, giving rise to a type of stereoisomerism known as enantiomerism. Such molecules are called chiral and the two enantiomers are said to differ in their sense of chirality or handedness in the same way as right hand differs from the left hand. Three terms have almost been used interchangeably to describe molecules, which show enantiomerism: asymmetric, dissymmetric, and chiral. The term chiral is synonymous with dissymmetric (Elliel and Wheland, 1962) although the former is now getting wider currency. The term asymmetric (asymmetry) has a slightly different connotation in the sense that symmetry elements are absent except for the trivial C1 axis. The following diagram clarifies the situation. CHEMISTRY Paper No. 1: ORGANIC CHEMISTRY- I (Nature of Bonding and Stereochemistry) Module No. 19: Prostereoisomerism (Prochirality) 2.2 What is Prochirality? Molecules which display chirality are called chiral e.g., (S)-(+)-lactic acid is chiral. Chirality as explained and depicted above is associated with this type of molecules is known as centre of chirality and chiral centre at C2 carbon (Figure 1). Some other type of chirality also presents in molecules which do not have chiral centres, but they show chirality due to disymmetrisation of axis and plane. Fig. 1: Chiral and prochiral molecule In propionic acid (2), replacement of HA or HB by the OH gives a (S)-(+)-lactic acid (1) or (R)-(- )-lactic acid. The protons HA and HB of the propionic acid are the hetero (different) topic (place). The molecule 2 is prochiral means this can be converted to chiral compound 1 by replacing its ligands (HA or HB) by the different ligands (OH). The carbon C2 is called as prochiral centre (Figure 2). CHEMISTRY Paper No. 1: ORGANIC CHEMISTRY- I (Nature of Bonding and Stereochemistry) Module No. 19: Prostereoisomerism (Prochirality) The term chirality in stereoisomerism should similarly be replaced by the term prochirality in prostereoisomerism. It would mean that if two homomorphic ligands at a prochiral centre (or axis or plane) be made different, a chiral centre (or axis or plane) would result. Just as a stereogenic centre may not necessarily be a chiral centre, a prostereogenic centre may not necessarily be a prochiral centre, i.e., a centre may be prostereogenic without being prochiral. Fig. 2: Prochiral centre in propionic acid Substitution is the one of the common way to interconverting the organic molecules. The lactic acid in principle can be synthesized by the addition of methylmagnesium bromide to carbonyl of the glyoxyalic acid (may be necessary to protect acid group as ester). If the attack of the Grignard reagent on the front face of the carbonyl gives a (S)-lactic acid and attack on the rear face gives (R)-lactic acid. Thus, the carbonyl group in glyoxylic acid also prochiral and present as two heterotopic faces (Figure 3). Fig. 3: Attack of Grignard reagent to front and rear faces of carbonyl group of the glyoxylic acid CHEMISTRY Paper No. 1: ORGANIC CHEMISTRY- I (Nature of Bonding and Stereochemistry) Module No. 19: Prostereoisomerism (Prochirality) History Historically, the first significant observation involving was the decarboxylation of methylethylmalonic acid (4) to α-methylbutyric acid (5) in the presence of brucine (6) as a chiral source (Figure 4). The C2 carbon in α-methylbutyric acid is a chiral centre; the C2 carbon in the malonic acid precursor is a prochiral centre. The product (Figure 4) is optically active; indeed, this is one of the first recorded asymmetric syntheses. Clearly the superficial impression that the two carboxyl groups of the starting malonic acid are equivalent, in principle is distinguished in the presence of the chiral catalyst brucine (Figure 4). COOH H COOH Brucine, H3C C2 C2H5 H3C C2 C2H5 + H3C C2 C2H5 -CO2 COOH COOH H 4 (S)-5, 55% (R)-5, 45% 6 Fig. 4: Asymmetric decarboxylation of methylethylmalonic acid (4) promoted by Brucine(6) 3. Homotopic and Heterotopic Ligands and Faces 3.1 Topicity of Ligands and Faces CHEMISTRY Paper No. 1: ORGANIC CHEMISTRY- I (Nature of Bonding and Stereochemistry) Module No. 19: Prostereoisomerism (Prochirality) A ligand cannot 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. 3.2 Homotopic Ligands and Faces Some of the apparently identical ligands are not equivalent towards enzyme or in their NMR signals. How we will decide whether the nuclei (ligand) are equivalent? There are two criteria- (i) Substitution criterion and (ii) Symmetry criterion. Similarly addition and symmetry criterion serve to test the equivalency of faces. 3.1.1 Substitution and addition criterion Two homomorphic (homos means same and morph means form) ligands are homotopic if the replacement of first one and then the other by different ligand leads to the same structure. Two hydrogen atoms of the methylene bromide (7) are homotopic because replacement of either by chlorine gives the same CHBr2Cl (8) (Figure 5). Fig. 5: Homotopic ligands in methylene bromide CHEMISTRY Paper No. 1: ORGANIC CHEMISTRY- I (Nature of Bonding and Stereochemistry) Module No. 19: Prostereoisomerism (Prochirality) The three hydrogen atoms in acetic acid (9) are homotopic because replacement of any one of them by fluorine gives one and same fluoroacetic acid (10) (Figure 6). Superimposable molecules (by the rotation of CH2F group) Fig. 6: Homotopic ligands in acetic acid Methine hydrogen atoms in (R)-tartaric acid (11) are homotopic because replacement of either of them e.g., by deuterium gives the same (2R, 3R)-tartaric-2-d acid (12) (Figure 7). Fig. 7: Homotopic ligands in (1R, 2R)-tartaric acid CHEMISTRY Paper No. 1: ORGANIC CHEMISTRY- I (Nature of Bonding and Stereochemistry) Module No. 19: Prostereoisomerism (Prochirality) A. Homotopic faces Two faces of molecules (usually but not invariably faces of double bond) are homotopic when addition of the same reagent to either face gives the same addition product. For example reduction of acetone (13) with NaBH4 will give same reduced product 2-propanol (14) by the attack of front face or the rear face (Figure 8). Fig. 8: Homotopic face of acetone Two faces of ethylene (15) are homotopic and attack of bromine on either the face give the 1,2- dibromoethane (16) as a product (Figure 9). Fig. 9: Homotopic face of ethylene The faces of carbonyl group in acetone and faces of alkene in ethylene are homotopic because by the addition of reagent on both the faces giving the same products. 3.1.2 Symmetry criterion Other criteria to find out the homotopic ligands and faces are symmetry criteria. Ligands are homotopic if they can interchange places through the operation of Cn symmetry axis. CHEMISTRY Paper No. 1: ORGANIC CHEMISTRY- I (Nature of Bonding and Stereochemistry) Module No. 19: Prostereoisomerism (Prochirality) 1. The bromine atoms in the methylene bromide (symmetry point group C2v) are homotopic since they exchange places through 180° turn around C2 axis (Figure 10). Fig. 10: Rotation through C2 axis of methylene bromide It is important to note that presence of a symmetry axis in a molecule does not guarantee that the homomorphic ligands will be homotopic. In the 1,3-dioxolane (17) in its average planar conformation, the hydrogen at C2 are homotopic, they are interchangeable by operation C2. On the other hand the geminal hydrogen atoms at C4 and C5 are not interconverted by C2-symmetry operation so these are heterotopic (HA with respect to HB and HC with respect to HD). However HA and HD are homotopic (interchanged by C2 axis) also HB and HC are homotopic (Figure 11). Fig. 11: Homotopic and heterotopic ligands in 1,3-dioxalane CHEMISTRY Paper No. 1: ORGANIC CHEMISTRY- I (Nature of Bonding and Stereochemistry) Module No. 19: Prostereoisomerism (Prochirality) Allene also has the D2d point group and by the rotation of C2 axes the ligands on the terminal carbons are the homotopic. HA and HB are the homotopic ligands (Figure 12). Fig. 12: Homotopic ligands in allene Similarly the ortho hydrogen atoms of the biphenyls are homotopic because of the rotation of the C2 axis these are also interchangeable (Figure 13). Fig. 13: Homotopic ligands in biphenyls Faces of double bonds are similarly homotopic when they can be interchanged by operation of a symmetry axis. Acetone (20) (D2h point group) has two faces and can be interchanged by operation of two of the three C2 axes.
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