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Sterioisomerism.pptx

  1. 1. Optical Isomerism Mr.P.S.Kore Assistant Professor(Research Scholar) Department of Pharmaceutical Chemistry RCP, Kasegaon. R.C.P.KASEGAON
  2. 2. OPTICALISOMERISM What is OpticalActivity: Optical isomerism is type of stereoisomerism. Optical isomers have the ability to rotate the plane polarized light. This property is often referred as OpticalActivity. A beam of ordinary light consists of electromagnetic waves that oscillate in an infinite number of planes at right angles to the direction of light travel. When a beam of ordinary light is passed through a device called a polarizer, or a Nicol prism (made of calcite or CaCO3), light is found to vibrate in only one plane and is said to be plane-polarized. Light waves in all other planes are blocked out. R.C.P.KASEGAON
  3. 3. Optically Active Compounds When a beam of plane polarized light passes through a solution of certain organic molecules, such as sugar or camphor, the plane of polarization is rotated through an angle α. Not all organic substances exhibit this property, but those that do are said to be optically active. The angle of rotation can be measured with an instrument called a polarimeter. When a solution of known concentration of an optically active material is placed in the polarimeter, the beam of light is rotated either to the right (clockwise) or to the left (anti-clockwise). So the compounds which rotate the plane polarized light (PPL) to the right (clockwise) is said to be the left is said to be while Levorotatory by a Dextrorotatory, and those which rotate the PPL to Levorotatory. Dextrorotatory is indicated by + sign, minus sign (─) (─)-Morphine, for example, is levorotatory, and (+)-sucrose is dextrorotatory. R.C.P.KASEGAON
  4. 4. R.C.P.KASEGAON
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  7. 7. Specific Rotation The extent of rotation depends on the number of optically active molecules encountered by the light beam. This number, in turn, depends on sample concentration and sample path length. If the concentration of sample is doubled, the observed rotation doubles. If the concentration is kept constant but the length of the sample tube is doubled, the observed rotation doubles. In addition, the angle of rotation depends on the wavelength of the light used. To express optical rotations in a meaningful way so that comparisons can be made, we have to choose standard conditions. The specific rotation, [α]D, of a compound is defined as “the observed rotation when light of 589.6 nanometer (nm; 1 nm = 10-9 m) wavelength is used with a sample path length l of 1 decimeter (dm; 1 dm = 10 cm) and a sample concentration c of 1 g/cm3”. R.C.P.KASEGAON
  8. 8. When optical rotation data are expressed in this standard way, the specific rotation, [α]D, is a physical constant characteristic of a given optically active compound. For example, (+)-lactic acid has [α]D = +3.82, and (─)-lactic acid has [α]D = ─3.82. That is, the two enantiomers rotate plane-polarized light to the same extent but in opposite directions. R.C.P.KASEGAON
  9. 9. Elements of Symmetry: Symmetry is when a shape looks identical to its original shape after being flipped or turned. 1. Plane of symmetry(α) 2. Centre of symmetry(i) 3. Axis of symmetry(Cn) 4. Identity (E) 5. Reflection axis symmetry(Sn) R.C.P.KASEGAON
  10. 10. Plane of Symmetry A plane which divides an object to two equal halves is said to be plane of symmetry. For example, coffee cup has a plane of symmetry in comparison with a person’s hand or shoes which lack a plane of symmetry. An object lacking a plane of symmetry is called Chiral or Dissymmetric, while those having a plane of symmetry is referred to as Achiral. R.C.P.KASEGAON
  11. 11. R.C.P.KASEGAON
  12. 12. Plane of symmetry: Tartaric acid contains two chiral centre, but when we apply plane of symmetry which perpendicular to the plane, looks hydroxyl, hydrogen and carboxyl group lies in symmetrical position,. Hence meso tartaric acid contains plane of symmetry and due of plane of symmetry meso tartaric acid is achiral and optically inactive COOH H C H C COOH 2,3-dihydroxysuccinic acid (meso- Tartaric acid) * * OH Plane of symmetry OH R.C.P.KASEGAON
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  14. 14. R.C.P.KASEGAON
  15. 15. Centre of symmetry A centre of symmetry in a molecule is said to exist if a line is drawn from any atom or group to this point and then extended to an equal distance beyond this point meets the identical atom or group. A centre of symmetry is usually present only in an even membered ring. R.C.P.KASEGAON
  16. 16. Axis of symmetry It is called n-fold rotational axis, If the rotation of a molecule about an axis through some angle results in a configuration which is indistinguishable from the original, then the molecule is said to possess a proper rotation axis.  It is denoted as Cn.  n is order of rotation axis. Rotation about an axis by an angle of 360/n R.C.P.KASEGAON
  17. 17. C CH3 H3C CH3 CH3 C CH3 H3C CH3 CH3 C CH3 H3C CH3 CH3 C CH3 H3C CH3 CH3 R.C.P.KASEGAON
  18. 18. 4.Identity [E]:-  This is an operation which brings molecule back to its original orientation.  This operation does nothing. It is simplest of all the symmetry elements.  It is the only element/operation possessed by all molecules.  It is denoted by E. for example:- CHBrFCl R.C.P.KASEGAON
  19. 19. 5.Improperaxisofsymmetryorrotation-reflectionaxisor alternate axisofsymmetry:-  If a molecule is rotated about an axis through some angle and the resulting configuration is reflected in a plane perpendicular to this axis, if new configuration is indistinguishable from the original, then the axis is called an improper axis.  It denoted as ‘Sn’  The symmetry element is denoted as S2. a b 1800 b a a b R.C.P.KASEGAON
  20. 20. R.C.P.KASEGAON
  21. 21. Chiral CarbonAtom A carbon atom which is bonded to four different groups. It is also termed as handedness. Chiral carbon lacks the plane of symmetry and therefore called as dissymmetric orAsymmetric. A chiral object cannot be superimposed on its mirror image. For example, a left hand does not posses a plane of symmetry, and its mirror image is not another left hand but a right hand. The two are not identical and cannot be superimposed. If we lay one hand on the other, the fingers and the thumbs would clash. R.C.P.KASEGAON
  22. 22. Optical Isomerism An optically active compounds exists in two isomeric forms that rotate the plane polarized light in opposite directions. They are called optical isomers and the phenomena is called optical isomerism. The optical rotatory power of two isomers are equal in magnitude but opposite in direction. The equimolar mixture of two isomers will therefore, not rotate the PPL at all and is said to be Racemic Mixture. Optical isomers have the same physical properties: Melting point, boiling point, density etc. They have the same specific rotations but with opposite signs. R.C.P.KASEGAON
  23. 23. Three lactic acids are known. (a) (+)-lactic °acid, (b) (—)-lactic acid, and (c) ± mixture. Since the (±) acid is only a mixture of (+) and (-)-forms, in reality lactic acid exist in two forms, the (+)-lactic acid and the (—)-lactic acid. These two acids are exactly identical in physical and chemical properties but differ in their action on the plane polarized light. So such forms of the same compound which differ only in their optical properties are called Optical isomers and the phenomenon is termed Optical isomerism An optically active compounds exists in two isomeric forms that rotate the plane polarized light in opposite directions. The optical rotatory power of two isomers are equal in magnitude but opposite in direction. R.C.P.KASEGAON
  24. 24. Optical Isomerism of Lactic acid It contains one chiral carbon Three forms of lactic acid are known, of which two are optically active and the third one is optically inactive. (+)-Lactic Acid: Rotate the PPL to the right (clockwise) and is dextrorotatory (-)-Lactic Acid: Rotate the PPL to the left (anti-clockwise) and is levorotatory. (±)-Lactic Acid: Does not rotate PPL and is optically inactive because it is a racemic mixture of (+) and (-) forms R.C.P.KASEGAON
  25. 25. R.C.P.KASEGAON
  26. 26. Conditions for Optical Isomerism Molecule should be dissymmetric. That is, the molecule should not be superimposed on its mirror image. Simply, this dissymmetry results from the presence of a chiral carbon atom. Chiral carbon is the one, which is bonded to four different groups. R.C.P.KASEGAON
  27. 27. The non-superimposable mirror image forms of a chiral carbon are called Enantiomers. They represent two optical isomers (+), and (-). Their opposite rotatory powers are due to the opposite arrangements of groups around a chiral carbon. Note: It is true that molecules containing chiral carbons are optically active, but it is not always so. There are some compounds such as meso-tartaric acid which have chiral carbon but is not optically active. On the other hand, there are some compounds which do not have chiral carbons but are optically active i.e., substituted allenes and biphenyls R.C.P.KASEGAON
  28. 28. OPTICAL ISOMERISM OF TARTARICACID Tartaric acid contains two chiral carbon atoms Four forms of tartaric acid are known, of which two are optically active and two are optically inactive. The two optically active forms are mirror images of each other but not superimposable, that is, they are Enantiomers. R.C.P.KASEGAON
  29. 29. Four forms of Tartaricacid (+)-Tartaric Acid: Rotate the PPL to the right (clockwise) and is dextrorotatory (-)-Tartaric Acid: Rotate the PPL to the left (anti-clockwise) and is levorotatory. meso-Tartaric Acid: It possesses a plane of symmetry and is optically inactive. This optically inactive form is said to be internally compensated; means optical rotation of one chiral carbon is cancelled by that of the other. (±)-Tartaric Acid: Does not rotate PPL and is optically inactive because it is a racemic mixture of (+) and (-) forms R.C.P.KASEGAON
  30. 30. R.C.P.KASEGAON
  31. 31. Terms used to describe Optical Isomerism Achiral molecule: It is identical to its mirror image means carries plane of symmetry and do not rotate the Plane polarized light. Chiral center: For a molecule to be chiral, it must have at least one chiral center- a carbon with four nonequivalent groups. Any molecule that contain a chiral center will be chiral unless the molecule has a plane of symmetry, in which case the molecule is achiral (meso) Chiral molecule: A chiral molecule is one that can not be superimposed on its mirror image and possess chiral centre . It rotate the PPL Diastereomers: Diastereomers are stereoisomers that are not mirror images of each other. For a molecule to have a diastereomer, it must contain more than on chiral center. Enantiomers: Mirror images of each other are enantiomers R.C.P.KASEGAON
  32. 32. Meso compounds: Compoundsthat contain a chiral center but is achiral because of plane of symmetry Optically active: Compounds having the ability to rotate thePPL Racemic mixture: A racemic mixture is a 50:50 mixture of two enantiomers. Racemic mixture do not rotate PPL R.C.P.KASEGAON
  33. 33. PROPERTIES OF ENANTIOMERS Optical isomers that are apposite mirror images are called enantiomers. These always exist as discrete pairs. For example, there are two optical isomers of lactic acid. (A) Is the mirror image of (B) and are a pair of enantiomers R.C.P.KASEGAON
  34. 34. Enantiomers are stable, isolable compounds that differ from one another in 3-Dimentional spatial arrangements. Enantiomers cannot be interconverted under ordinary conditions Enantiomers have identical properties in all respect except in their interaction with plane polarized light. They have same melting point, density, solubility, color, and reactivity towards acids and bases. They differ, however, in the direction in which they rotate the PPL. Both rotate the PPL to exactly the same extent (same angle) but one rotates the plane to the right and other to the left. A mixture of equal amounts of two enantiomers is a racemic mixture. Such a mixture is optically inactive because the two components rotate the PPL equally in opposite directions and cancel one other. R.C.P.KASEGAON
  35. 35. PROPERTIES OF DIASTEREOMERS Diastereomers are stereoisomers that are not mirror images of each other. For a molecule to have a diastereomer, it must typically contain a chiral center. In general, each chiral carbon atom in a molecule doubles the number of theoretically possible isomers. Hence, molecules with n number of chiral carbon atoms have 2n stereoisomers. Figure shows the 4 isomers of 3-bromo-2-butanol, which has two chiral carbon atoms R.C.P.KASEGAON
  36. 36. Notice that (A) is the mirror image of (B), (C) is the mirror image of (D). Thus the four isomers are two pairs of enantiomers. Now compare (A) with (C). They are neither superimposable nor are they mirror images. They are called diastereomers. (A) and (D) are also diastereomers, as are (B) and (C), and (B) and (D). Diastereomers have different properties. Two diastereomers will have different melting points, boiling points, and solubilities. They will also have different reactivities toward most reagents R.C.P.KASEGAON
  37. 37. Diastereomers images. Since are stereoisomers that are not apposite mirror we used the right-hand/left-hand analogy to describe the relationship between two enantiomers, we might extend the analogy by saying that the relationship between diastereomers is like that of hands from hand look similar, but different people. Your hand and your friend’s they aren’t identical and they aren’t mirror images. The same is true of diastereomers: they’re similar, but they aren’t identical and they aren’t mirror images. R.C.P.KASEGAON
  38. 38. Meso Compounds A meso compound is a molecule that contains a chiral center, but is achiral as a result of having a plane of symmetry in the molecule. A compound with two or more chiral carbon atoms but also having a plane of symmetry is called meso compound. The molecules having plane of symmetry dividing them midway between the two chiral carbons in each. R.C.P.KASEGAON
  39. 39. Notice that one half of the molecule is the mirror image of the other. Both molecules are optically inactive, even though each has two chiral centers. Neither will rotate the PPL R.C.P.KASEGAON
  40. 40. OPTICAL ACTIVITY WITHOUT ASYMMETRICCARBON Compounds containing a chiral carbon are optically active. However, there exist some compounds which do not possess a chiral atom but are optically active provided that the molecule is dissymmetric. ALLENE DERIVATIVES Some derivatives of allenes (CH2=C=CH2) exhibit optical isomerism. Example is I,3-diphenylpropadiene. In allenes, the central carbon forms two sp-sp2 sigma bonds. The central carbon has also two p- orbitals which are mutually perpendicular. These form pi-bonds with the p-orbitals on the other carbon atoms. As a result, the substituents at one end of the molecule are in plane which is perpendicular to that of the substituents at the other end, so that the compound exists in two forms which are non-superimposable mirror images and are optically active. R.C.P.KASEGAON
  41. 41. R.C.P.KASEGAON
  42. 42. BIPHENYL DERIVATIVES Substituted biphenyls show optical isomerism when substituents in the 2-positions are large enough to prevent rotation about the bond joining the two benzene rings. For example, biphenyl-2,2’-disulphonic acid exist in two forms. R.C.P.KASEGAON
  43. 43. These two forms are non-superimposable mirror images. They do not interconvert at room temperature because the energy required to twist one ring through 180 angle relative to the other is too high. This in turn is because, during the twisting process, the two –SO3H groups must come into very close proximity when the two benzene rings become coplanar and strong repulsive forces are introduced. R.C.P.KASEGAON
  44. 44. FISCHER PROJECTION When we attempt to depict configurations, we face the problem of representing three dimensional structures on a two dimensional surface. To overcome this difficulty we use the so- called Fischer projection. It is the most convenient way of viewing molecules with more than one chiral centers. Fischer projection is a convenient 2-D drawing that represents a 3-D molecule. To make a Fischer projection, you view a chiral center so that two substituents are coming out of the plane at you (to hug you), and the two substituents are going back into the plane. Then the chiral center becomes a cross on the fischer projection. Every cross in Fischer Projection is a chiral center. R.C.P.KASEGAON
  45. 45. This is the structure of an asymmetric carbon atom drawn in a prescribed orientation and then projected into a planar surface. Thus planar formulas of the asymmetric carbon are obtained by placing it so that the two substituents are horizontal and project out towards the viewer (shown by thick wedge-like bonds), while the two other substituents are vertical and project away from the viewer (shown by dotted bonds). Remember in Fischer projection molecule is oriented so that the vertical bonds at chirality center are directed away from you and horizontal are directed towards you R.C.P.KASEGAON
  46. 46. Planar representation of two forms of lactic acid may be given as In these formulas the horizontal bonds i.e., C—OH and C—H project towards us out of the plane of the paper whereas the vertical bonds i.e., C—COOH and C— CH3 project away from us. Inspection of the models shows that one interchange of a pair of substituents inverts the configuration (changes one enantiomer into) its minor image), whereas an even number of such interchanges does not. Thus interchanging of —H for —OH in I gives the enantiomer II while the interchange of CH3 for —COOH and —H for —OH leaves the configuration unchanged. R.C.P.KASEGAON
  47. 47. R.C.P.KASEGAON
  48. 48. Assigning Configuration to chiral carbon atom 1. Absolute Configuration 2. Relative Configuration R.C.P.KASEGAON
  49. 49. D & L-System-Relative Configuration The D & L convention, not to be confused with the d (dextro) and l (levo) descriptors used to designate the direction of specific rotation of chiral compounds, is a convention used to distinguish between enantiomers of chiral monosaccharide's and chiral alpha-amino acids, based on the molecule drawn as a Fischer projection in a specific orientation. The L and D forms of the sugar depends on the orientation of the -H and -OH groups around the carbon atom adjacent to the terminal primary alcohol carbon (carbon 5 in glucose) determines whether the sugar belongs to the D or L series. R.C.P.KASEGAON
  50. 50. D & L-System-Relative Configuration The D- and L- notation is based on glyceraldehyde When the -OH group on this carbon is on the right, then sugar is the D- isomer; when it is on the left, then it is the L-isomer C O H HO C H CH2OH L-Glycerose (L- Glyceraldehyde) C O H H C OH CH2OH D-Glycerose (D-Glyceraldehyde) C O H C H HO C C O H C OH H C OH H C H HO C H HO CH OH H HO 2 L-Glucose OH H H OH CH2OH D-Glucose R.C.P.KASEGAON
  51. 51. D & L-System-Relative Configuration Most of the monosaccharide occurring in mammals is D sugars, and the enzymes responsible for their metabolism are specific for this configuration. In solution, glucose is dextrorotatory-hence the alternative name dextrose. The presence of asymmetric carbon atoms also confers optical activity on the compound. When a beam of plane- polarized light is passed through a solution of an optical isomer, it will be rotated either to the right, dextrorotatory (+); or to the left, levorotatory (-). The direction of rotation is independent of the stereochemistry of the sugar, so it may be designated D (-), D (+), L (-), or L (+). For example, the naturally occurring form of fructose is the D (-) isomer. R.C.P.KASEGAON
  52. 52. Application of D,L convention to monosaccharide: One enantiomer of a chiral monosaccharide is labeled D and the other L. To determine whether a given enantiomer of a chiral monosaccharide is D or L Steps in determination of D & L isomerism in monosaccharide 1. Make sure the acyclic form of the molecule is drawn as a Fischer projection. If the monosaccharide is an aldose, the aldehyde group must be on top; if it is a ketoses, the carbonyl carbon must be the second carbon from the top. 2. Number the carbon atoms starting at the top. 3.Locate the carbon atom that bears the second highest number, which is known as the penultimate carbon. If the hydroxy group on the penultimate carbon is on the right of the carbon chain, assign the label D to the compound; if it is on the left of the carbon chain, assign the label L. Penultimate carbon: Penultimate means next to last. The penultimate (second to last carbon) carbon is the last chiral carbon of the chain. R.C.P.KASEGAON
  53. 53. H2C OH C O H C OH HO C H HO C H CH2OH C H H C OH HO C H OH H OH H CH2OH Step-I O O OH 1 H2C 2 C 1 C H H C OH HO C H HO C H HO C H H 2C OH OH H O 3 4 H 5 OH 6 CH2OH 3 4 5 6CH2OH Step-II O 1 C H H C OH H C OH HO C H HO C H OH H H 2 2 3 4 5 OH 6 CH OH 1 H2C OH 2 C O 3 4 5 6 CH2OH L-Fructose HO C H Penultimate Carbon Step-III D-Glucose Determination of Relative configuration in Monosaccharide R.C.P.KASEGAON
  54. 54. Application of D,L convention to alpha-amino acids: One enantiomer of a chiral alpha-amino acid is labeled D and the other L. To determine whether a given enantiomer of a chiral alpha-amino acid is D or L, use the following procedure. 1. Make sure that the molecule is drawn as the Fischer projection in which the carboxylic acid group is on top and the side chain on bottom. 2.If the amine group is on the right of the carbon chain, assign the label D to the compound; if it is on the left of the carbon chain, assign the label L. R.C.P.KASEGAON
  55. 55. C H CH2OH H2N Step-I COOH H COOH C NH2 CH2OH 2 H N 2 CH OH Step-II COOH C H H COOH C NH2 CH2OH D-serine L-Serine R.C.P.KASEGAON
  56. 56. ASSIGNING CONFIGURATIONS TO CHIRAL MOLECULES Absolute Configuration The actual 3-D arrangement of groups in a chiral is called absolute configuration. While molecule discussing between optical isomerism, we must distinguish relative (arrangement of and absolute configuration atoms or groups) about the asymmetric carbon atom. Let us consider a pair of enantiomers, say (+)- and (-)- lactic acids. R.C.P.KASEGAON
  57. 57. R-S System The actual 3-dimentional arrangement of groups in a chiral molecule is called absolute configuration. We can specify the configuration by using the R-S system. This is a newer and more systematic method of specifying absolute configuration to optically active compounds. Since it has been proposed by R.S. Cahn, C.K. Ingold and V . Prelog, therefore known as Cahn-Ingold Prelog system. This system of designating configuration has been used increasingly since the early 1960 and may eventually replace the DL-system. R.C.P.KASEGAON
  58. 58. In this system, four groups attached to the chiral carbon are arranged in decreasing order of priority (1,2,3,4) by applying priority rules. We then view the chiral carbon with the lowest priority group (4) on the side opposite the observer. In the above example, Ahas the highest priority followed by B and C, while D has the lowest priority (4). R.C.P.KASEGAON
  59. 59. (i) If the eye while moving from 1-2-3, travels in a clockwise or right- hand direction, the configuration is designated R (Latin, Rectus— right). (ii) If the eye while moving from 1-2-3 travels in counterclockwise or left- hand direction, the configuration is designated S (Latin, Sinister= left). R.C.P.KASEGAON
  60. 60. RULE 1: Look at the four atoms directly attached to the chirality center, and rank them according to atomic number. The atom with the highest atomic number has the highest ranking (first), and the atom with the lowest atomic number (usually hydrogen) has the lowest ranking (fourth). R.C.P.KASEGAON
  61. 61. RULE 2: For isotopes, the higher the atomic mass the higher the priority. For example, deuterium (Hydrogen-2) has higher priority than protium (Hydrogen-1) R.C.P.KASEGAON
  62. 62. RULE 3: If a decision can’t be reached by ranking the first atoms in the substituent, look at the second, third, or fourth atoms away from the chirality center until the first difference is found. RULE 4: Multiple-bonded atoms are equivalent to the same number of single bonded atoms. R.C.P.KASEGAON
  63. 63. Rule 5. Trace out of Lowest priority atom at backward position or bottom, If hydrogen already at backward site, then no need to change position of atom Rule 6. Assigning the configuration by viewing the molecule from 1-2-3-4 direction. If eye moves to clockwise direction, Hence it is termed as R configuration If eye moves to anticlockwise direction, Hence it is termed as S Configuration R.C.P.KASEGAON
  64. 64. Priority sequence of common groups and atoms R.C.P.KASEGAON
  65. 65. Consider the following example and specify configuration by R or S notation = 1,1- chlorobromoethane C Cl Br H3C H 1-bromo-1-chloroethane R.C.P.KASEGAON
  66. 66. Step-1:Determine the priority of groups attachedto the chiral carbon atom Hence the priority order is Step-2: Position the lowest priority group down away from This is groups bonded done by to the observer . interchanging the asymmetric carbon. R.C.P.KASEGAON
  67. 67. Numbering of substituents on the basis of atomic number C Br 3H3C H 2 Cl 1-bromo-1-chloroethane 1 4 R.C.P.KASEGAON
  68. 68. Specify the direction of decreasing priority of the three groups (1-3 If the groups (1,2,and 3) are arranged in clockwise fashion, the configuration is R. If the groups occurs in anticlockwise fashion, the configuration is S. 2 C Cl Br * 3 H3C 1 H 4 S- 1-bromo-1-chloroethane In the above example, configuration is S because groups(1,2 and 3) are arranged in anticlockwise fashion. R.C.P.KASEGAON
  69. 69. Configuration of compounds with more than 1 chiral center The configuration of compounds with more than one chiral center can also be specified by the R-S system. The configuration of each chiral carbon is determined individually, using the same rules as for compounds with one chiral center. C OH COOH H HO C H CH3 2,3-dihydroxybutanoic acid R.C.P.KASEGAON
  70. 70. 1. Step-I--Assign number to the chiral carbon chain C C OH HO COO H H H 1 2 3 4CH3 II C C OH HO I COOH H H 1 2 3 4 CH3 III I- At C2 - OH II.- COOH III. CH(OH)CH3 IV. H Assign the priority to substituents according to atomic number At C3 - I.- OH II. CH(OH)COOH III. CH3 IV. H 2. I IV IV R.C.P.KASEGAON
  71. 71. C II COOH C CH3 H H C C CH3 H H II COOH I OH OH III 2R 3. Assigning configuration at C2 by Moving hydrogen at backword C(R) OH C (S) HO H H 1 2 II COOH 3 I IV III I OH OH III IV CH3 4. Assigning configuration at C3 by Moving hydrogen atbackword IV C III CH3 C HO HOOC H OH I C H III CH3 C HO HOOC H OH I 3S C OH COOH H H HO I C II CH3 III IV II H IV II IV R.C.P.KASEGAON
  72. 72. C (R) C (S) OH HO 1 COOH H H 2 3 4 CH3 2R,3S, 2,3-dihydroxybutanoic acid 5. Assign the combined configuration R.C.P.KASEGAON
  73. 73. C CH3 H CH2CH3 NH2 butan-2-amine C H IV II CH2CH3 NH2 I III CH3 C CH3 H CH2CH3 NH2 Step-I- Prioritisation Step-II- Hydrogen to backward C CH2CH3 2 H N CH3 H 1 2 3 4 III. Rotation R, butan-2-amine R& S Nomenclature for organic Compounds R.C.P.KASEGAON
  74. 74. C CH2COOH CH2NH2 HSH2C CH2OH -4-amino-3-(hydroxymethyl)-3-(mercaptomethyl)butanoic acid Assign the R & S configuration of following compound R.C.P.KASEGAON
  75. 75. C CH2NH2 HSH2C 1 4 CH2COOH CH2OH 2 Step-i Assigning priority 3 C CH2NH2 HSH2C 1 2 CH2OH CH2COOH 4 Step-II- Lowest priority group to back or bottom 3 C CH2NH2 HSH2C 1 2 CH2OH CH2COOH Step-III- Eye movement from 1-2-3-4 by anti-clockwise- S configuration 3 C HO CH2OH 2 2 CH CH OH CH2CH2NH2 C CH2CH2OH 1 HO CH2OH 2 3 CH2CH2NH2 4 S-configuration R.C.P.KASEGAON
  76. 76. R & S Nomenclature of lactic acid C COOH CH3 HO H H HOOC CH3 OH Fischer Projection OH H3C 2 COOH H 4 R-Lactic acid C COOH CH3 H HO Absolute configuration OH HOOC CH3 H Fischer Projection OH CH3 HOOC H S- lactic acid 1 3 R.C.P.KASEGAON
  77. 77. R.C.P.KASEGAON
  78. 78. Look at (-)-lactic acid for an example of how to assign configuration. Sequence rule 1 says that OH is ranked 1 and H is ranked 4, but it doesn’t allow us to distinguish between CH3 and CO2H because both groups have carbon as their first atom. Sequence rule 2, however, says that CO2H ranks higher than CH3 because O (the highest second atom in CO2H) out ranks H (the highest second atom in CH3). Now, turn the molecule so that the fourth-ranked group (H) is oriented toward the rear, away from the observer. Since a curved arrow from 1 (OH) to 2 ( CO2H) to 3 (CH3) is clockwise (right turn of the steering wheel), (-)-lactic acid has the R configuration. Applying the same procedure to (+)-lactic acid leads to the opposite assignment. R.C.P.KASEGAON
  79. 79. OPTICAL ISOMERISM IN NATURE The (+)-limonene has the odor of oranges while (-)-limonene has the odor of lemons R.C.P.KASEGAON
  80. 80. Racemic fluoxetine is an effective antidepressant but it has no activity against migraine. The pure S enantiomer, however, works remarkably well in preventing migraine R.C.P.KASEGAON
  81. 81. Why do different stereoisomers have different biological activity??? To exert its biological action, a chiral molecule must fit into a chiral receptor at a target site, much as a hand fits into a glove. But just as a right hand can fit only into a right-hand glove, so a particular stereoisomer can fit only into a receptor having the proper complementary shape. Any other stereoisomer will be a misfit like a right hand in a left-handed glove. R.C.P.KASEGAON
  82. 82. R.C.P.KASEGAON
  83. 83. RESOLUTION OF RACEMICMIXTURES Synthesis of an optically active compound produces a mixture of + and –ve isomers in equal amounts. Recall that these isomers are non-superimposable mirror images and are called enantiomers. Such a mixture is called racemic mixture or a racemate. The separation of a racemic mixture into its two optically active compounds (+ and – isomers) is known as Resolution. If the enantiomers are separated, the mixture is said to have been resolved. R.C.P.KASEGAON
  84. 84. Resolution of racemic mixture 1. Mechanical separation 2. Chemical separation 3. Biochemical separation 4. Kinetic separation 5. Chiral chromatography/selection adsorption R.C.P.KASEGAON
  85. 85. MECHANICALSEPARATION This method is developed by L. Pasteur in 1848. It is applicable to only solid substances which form well defined crystals. Since crystals of the two forms differ in their shapes, these can be separated mechanically with the help of a magnifying glass and tweezers (forceps). This method is too tedious for practical purposes and is now of historical interest only because it was the first method which Pasteur employed for the separation of the tartaric acids. R.C.P.KASEGAON
  86. 86. R.C.P.KASEGAON
  87. 87. CHEMICALRESOLUTION This method is developed by L. Pasteur in 1858. It involves the use of an optically active compound which could react easily and selectively with either of the two enantiomers to produce a mixture of two diasteriomeric compounds. The two compounds so formed have different physical properties and therefore can be separated by conventional method of separation e.g., crystallization. The crystals of diastereoisomers so obtained can be broken down chemically to obtain the two enantiomers separately. R.C.P.KASEGAON
  88. 88. Separation of racemates into their component enantiomers is a process called resolution. Since enantiomers have identical physical properties, such as solubility and melting point, therefore, resolution is extremely difficult. Diastereomers, on the other hand, have different physical properties, and this fact is used to achieve resolution of racemates. Reaction of a racemate with an enantiomerically pure chiral reagent gives a mixture of diastereomers, which can be separated. R.C.P.KASEGAON
  89. 89. For example, a solution of racemic lactic acid may be treated with an optically active base such as the alkaloid (Brucine). The resulting product will consist of two salts (i) (+)- Acid. (—)- Base; and (ii) (—)- Acid( —)-Base Suppose the two enantiomorphic forms of lactic acid are represented by the symbols R.C.P.KASEGAON
  90. 90. And suppose the two enantiomorphic forms of brucine are represented by the symbols Inspection of the configurations of the two salts shows that they are not enantiomorphic. Therefore, they have different solubility in separated water and can be by fractional crystallisation. The isolated salts are then treated with dilute sulphuric acid when the optically active acids are regenerated. R.C.P.KASEGAON
  91. 91. R & S Nomenclature of lactic acid and 1-phenyl ethylamine C COOH CH3 HO H H OH 2 COOH H3C H 4 R-Lactic acid HOOC CH3 OH Fischer Projection C COOH CH3 H HO Absolute configuration OH HOOC CH3 H Fischer Projection OH CH3 HOOC H S- lactic acid 1 3 C H NH2 C6H5 H3C C6H5 2 3 CH3 1 NH2 H 4 S-Configuration R.C.P.KASEGAON
  92. 92. Example: (S)-1-Phenylethylamine combines with a racemic mixture of lactic acid to form diastereomeric salts. The diastereomers are separated by fractional crystallization. R.C.P.KASEGAON
  93. 93. 2. After the separation process, each of the diastereomers is subsequently treated with a strong acid suchas hydrochloric acid to regenerate the corresponding enantiomer of lacticacid 3. Note that the lactic acid would be soluble in the organic layer, while the ammonium salt would be in the water layer. Since enantiomerically pure compounds are very expensive, it is usually necessary to recover and reusethe chiral amine. This is achieved by treating the (S)-1-phenylethyl ammonium chloride salt with a base such as sodium hydroxide to regenerate and recover the chiralamine. R.C.P.KASEGAON
  94. 94. BIOCHEMICALRESOLUTION This method is developed by L. Pasteur in 1858. In this method, one of the enantiomers is destroyed biochemically, using a suitable microorganism such as yeast, mold or bacterium. The microorganism utilizes one of the enantiomers for its growth and leaves the other in the solution. The enantiomer left in the solution can be isolated by fractional crystallization. For example: Penicilium glaucum removes Dextro form from the racemic mixture of ammonium tartrate leaving a levo ammonium tartrate R.C.P.KASEGAON
  95. 95. Disadvantages of biochemical resolution Half of the material is lost. This method can not be used if the mixture is toxic to the microorganisms. R.C.P.KASEGAON
  96. 96. Kinetic Method The fact that enantiomers react with an optically active substance at different rates, is used for the separation of racemic mixtures. The procedure takes advantage of differences in reaction rates of enantiomers with chiral reagents. One enantiomer may react more rapidly, thereby leaving an excess of the other enantiomer behind. A disadvantage of resolutions of this type is that the more reactive enantiomer usually is not recoverable from the reaction mixture. R.C.P.KASEGAON
  97. 97. Selective Adsorption/Chiral chromatography Sometimes 'resolution' may be achieved by passing a solution of the racemate over a column of a finely powdered, adsorbent such as starch, sugar or quartz. The optically active surface of the adsorbent, adsorbs selectively one enantiomer and thus the solution emerging at the bottom is richer in the other enantiomer. Chromatographic methods, whereby the stationary phase is a chiral reagent that adsorbs one enantiomer more strongly than the other, have been used to resolve racemic compounds. R.C.P.KASEGAON
  98. 98. Importance of Resolution Majority of the drugs have many chiral centers. For example vitamin E has three chiral centers, therefore, 8 forms are possible. Among these 8 forms only one occurs naturally and is 100% potent. Other 7 forms have different potencies less than naturally occurring form. All forms of vitamin E has a positive impact but there are some cases where the other forms have a negative impact on the body are harmful. i.e., one enantiomer is biologically active while the other is either inactive or very harmful. R.C.P.KASEGAON
  99. 99. The Thalidomide Story Thalidomide was launched on October 1, 1957 as an anti-emetic drug that had an inhibitory effect on morning sickness, that’s why given to pregnant womens’ to relieve morning sickness. It was later realized that while the (+)- form of the molecule was a safe and effective anti- emetic, the (−)-form was an active teratogen. The drug caused numerous birth abnormalities when taken in the early stages of pregnancy because it contained a mixture of the two forms. Majority of the born kids were having no legs, arms, fingers. This happens because the R.C.P.KASEGAON
  100. 100. Pharmaceutical company was unable to resolve the + thalidomide R.C.P.KASEGAON
  101. 101. Reaction of Chiral Compounds. 1. Retention 2. Inversion 3. Racemisation R.C.P.KASEGAON
  102. 102. 1. Retention Bond at chiral carbon do not break : Configuration of substrate and product remains same. SN1 Reaction follows the retention configuration. Example: substitution of s-3-chloro, 3-methyl hexane with bromine to form s-3-bromo, 3-methyl hexane C Cl C3H7 C2H5 CH3 (S)-3-chloro-3-methylhexane * Br- C Br C3H7 C2H5 CH3 (S)-3-bromo-3-methylhexane * + Cl- R.C.P.KASEGAON
  103. 103. When an atom or group directly linked to chiral carbon atom is replaced, the reaction may proceed with inversion of configuration. This phenomenon was first of all observed by Walden (1895) and hence the name Walden inversion. Walden inversion may also be defined as the conversion of the (+)-form to (—)-form or vice versa. Thus (+)-malic acid may be converted to (— ).malic acid as follows. Walden inversion is the inversion of a chiral center in a molecule in a chemical reaction. Since a molecule can form two enantiomers around a chiral center, the Walden inversion converts the configuration of the molecule from one enantiomeric form to the other. R.C.P.KASEGAON
  104. 104. Thus (+)-malic acid may be converted to (—)-malic acid as follows. Since SN2 reactions always proceed with inversion of configuration, Walden inversion is a type of SN2 reaction C COOH H OH 2 CH COOH PCl5 -POCl3, HCl C COOH H Cl CH2COOH Chlorosuccinic acid (+) Malic acid AgOH C COOH HO H CH2COOH (-) Malic acid R.C.P.KASEGAON
  105. 105. R.C.P.KASEGAON
  106. 106. 3.Racemizati on The conversion of an optically active compound (+)- or (-)- into racemic mixture (±) is known as Racemization. Racemization can be accomplished by the means of heat, light or by the conversion of an optically active isomers into an optically inactive intermediate which then reverts to the racemic mixture. The conversion of either of the optically active lactic acids into a racemic mixture by heating its aqueous solution may proceed through an enol intermediate. R.C.P.KASEGAON
  107. 107. Since the enol is a planar molecule, so the possibility of frontal and rear attachment of H-atom to a carbon atom (in the enol form) is equally probable. Consequently equal number of molecules of (+)- and (-) form would result and racemic mixture would be produced. These changes are reversible and in actual practice we get an equilibrium mixture. The equilibrium mixture thus obtained contains one molecule of (+)- Acid and one molecule of (-)-Acid i.e., the racemic mixture of the acid. C CH3 H OH C 165°C 2 Molecules of (+) Lactic acid OH O C CH3 OH C OH Enol HO 2 C CH3 H OH C OH O C CH3 HO H C OH O (+) lactic acid (-) Lactic acid 165°C + Racemic Mixture of Lactic acid R.C.P.KASEGAON
  108. 108. the racemic mixture and meso acid. This is due to the fact that tartaric acid having two asymmetric carbon atoms may undergo inversion of H and OH only about one carbon or both, yielding meso or racemic form, C respectively. COOH H HO H OH COOH (+) Tartaric acid 165°C C COOH OH H HO H COOH (-) Tartaric acid 165°C C COOH OH H H OH COOH Meso- Tartaric acid R.C.P.KASEGAON
  109. 109. Optically active substances which cannot enolize because they have no hydrogen atom at a carbon to a carbonyl group, do not in general racemize except under conditions which bring about other chemical changes as well. R.C.P.KASEGAON
  110. 110. Racemization of Optically ActiveHalides The racemization of optically active halides may take place either by an SN1 or SN2 mechanism depending upon the experimental conditions. In polar solvents, S-butyl chloride racemizes by SN1 mechanism. Dissociation of the compound produces planar carbonium ion which can recombine with the anion i.e., Cl yielding both S and R forms of the compound. R.C.P.KASEGAON
  111. 111. Optically active halides also can be racemized by an SN2 mechanism. A solution of active 2-chlorobutane in acetone containing dissolved lithium chloride becomes racemic. Displacement of chloride ion of the halide by chloride ion (from LiCl) inverts configuration at the carbon atom undergoing substitution. A second such substitution regenerates the original enantiomer. Eventually, this back and forth process produces equal number of R and S forms; the substance is then racemic. R.C.P.KASEGAON
  112. 112. Asymmetric Synthesis The process in which an asymmetric compound is synthesized from a symmetric compound to yield the (+)- or (-)- isomer directly, is termed Asymmetric Synthesis. OR The process in which a chiral compound is synthesized from an achiral compound to yield the (+)- or (-)- isomer directly. R.C.P.KASEGAON
  113. 113. We have already seen that when a compound containing an asymmetric carbon atom is synthesized by ordinary laboratory methods from a symmetric compound, the product is a racemic mixture. If, however, such a synthesis is carried under the 'Asymmetric influence of a suitable optically active reagent, one of the optically active isomers, (+)-or(—)-, is produced in preference and in excess. R.C.P.KASEGAON
  114. 114. R.C.P.KASEGAON
  115. 115. pyruvic acid is first combined with an optically active alcohol, ROH, such as (+)- menthol* to form an ester which is then reduced, the product upon hydrolysis yields (+). lactic acid in excess. CH3 C O COOH Pyruvic acid + ROH Alcohol CH3 C O COOR -H2O 2 H /Ni CH3 C OH COOR H H2O ROH CH3 C OH COOH H (+)Lactic acid R.C.P.KASEGAON
  116. 116. In nature, numerous optically active substances such as terpenes, alkaloids and proteins are produced by asymmetric synthesis, under the influence of optically active enzymes. These enzymes unite with the substance available in plants and when the synthesis is complete, they separate from the product and are thus again free to combine with more of the parent inactive substance and the endless process continues. R.C.P.KASEGAON
  117. 117. A. PARTIAL ASYMMETRIC SYNTHESIS: Synthesis of a new chiral centre from an achiral centre by using optically active reagents Different methods of partial asymmetric synthesis: Use of chiral substrate (first generation method) Use of chiral auxiliary (second generation method) Use of chiral reagents (third generation methods) Use of chiral catalyst B.ABSOLUTE ASYMMETRIC SYNTHESIS: It is the synthesis of optically active products from achiral substrate without the use of optically active reagents . R.C.P.KASEGAON
  118. 118. 1. Use of chiral substrate (first generation method)-Chiral Pool It uses natures ready-made chiral centres as starting materials . More economical way of making compounds in enantiomeric pure form. This conversiondoesn’taffecttheexisting stereocenter Example: Conversion of L-tyrosine into L- DOPA. In this conversion starting material L-tyrosine is a naturally occurring chiral molecule . NH2 H COOH OH L-Tyrosine Tyrosinase O2 NH2 H COOH OH L-DOPA (Dopamine prodrug) OH 2 2 R.C.P.KASEGAON
  119. 119. 2) Use of chiral auxiliary (second generation method)  In this approach a prochiral substrate attach with a chiral auxiliary to give a chiral intermediate. During which auxiliary dictates the preferred stereochemistry. Finally we can remove the auxiliary from product to use it again . Example: asymmetric alkylation of cyclohexanone using SAMP . O + N H OCH3 NH2 N H OCH3 N i) LDA ii) (CH3)2SO4 iii) O3 O CH3 H Cyclohexanone 2-methyl cyclohexanone SAMP R.C.P.KASEGAON
  120. 120. 3)Use of chiral reagents (third generation methods)  In this method an inactive substrate converted selectively into one of the enantiomer(enantiospecific) .  In this type of synthesis chiral reagent turns achiral by transforming an achiral substrate to chiral . Thus the reagent is “self- immolative” CH3 C C O 2-oxopropanoic acid O OH + N 3 H C H 2 OH Mg2+ Ph CH3 C C O + OH2 OH s-(+)-mandelic acid H N OH Ph CH3 (S)-(1-benzyl-4-methyl-1,4-dihydropyridin-3-yl)methanol R.C.P.KASEGAON
  121. 121. 4)Use of chiral catalyst Effective optically pure catalysts are much more promising , because reagents are required in stoichiometric amounts ,while catalysts are required only in very small amounts. Eg: Sharpless asymmetric epoxidation- It is an enantio-selective reaction that oxidises alkenes to epoxides. R.C.P.KASEGAON
  122. 122. 4)Use of chiral catalyst R2 R3 R1 OH O R1 R1 R1 R3 R1 O OH R-isomer R3 OH + Ti O O C O CH O H CH3 CH3 C H H C CH3 CH3 H3C 3 H C CH3 CH3 S-Isomer H HO COOC2H5 C OH C H COOC2H5 (R)-DET(Diethyl tartarate) + Chiral Catalyst 2 Chiral Catalyst Ti O O O CH O C H CH3 CH3 C H H C CH3 CH3 H3C 3 H C COOC2H5 C H HO H C OH COOC2H5 (S)-DET + CH3 CH3 (Titanium isopropoxide) [O] [O] Titanium Isopropoxide R.C.P.KASEGAON
  123. 123. B) ABSOLUTE ASYMMETRICSYNTHESIS  It is the synthesis of optically active products from achiral substrate without th e use of optically active reagents .  In this type of synthesis a physical presence of chirality is necessary .  Eg: addition of bromine to 2,4,6-trinitrostilbene give a dextrorotatory product.  Here we are using circularly polarized light for the induction of chirality. NO2 O2N NO2 2,4,6 Trinitrostilbene C H C H Br2 NO2 NO2 O2N H C H C Br Br (+)1-(1,2-dibromo-2-(2,4,6-trinitrophenyl)ethyl)benzene R.C.P.KASEGAON

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