1. The document discusses the history and concepts of optical isomerism, including the discovery of enantiomers by Pasteur and the proposal of the tetrahedral carbon model by van't Hoff. 2. It defines key terms like enantiomers, diastereomers, and meso compounds. Enantiomers are non-superimposable mirror images while diastereomers are stereoisomers that are not mirror images. Meso compounds have an internal plane of symmetry and are optically inactive. 3. Methods for separating enantiomers like crystallization and forming diastereomeric salts are described. The importance of enantiomers in biology is highlighted, as most biomolecules and

1. 1Optical Isomerism

2. ContentHistoryEnantiomersReasons for molecular handednessOptical activity of enantiomersNaming ConventionsDiastereomersMeso CompoundsResolution of EnantiomersImportance of Enantiomers2

3. Isomers3

4. History4

5. Discovery of Optical ActivityIn 1850, French Physicist Jean-BaptiseBiot observed that solutions of some organic compounds like sugar and camphor have the ability to rotate plane polarized lightUp till then the basis of this phenomenon was not yet known5

6. Separation of EnantiomersIn 1848 French Chemist Louis Pasteur separated a solution of optically inactive tartaric acid into two optically active components. He observed that:Each of these components had identical physical properties like density, melting point, solubility, etcButOne of the components rotated plane polarized light clockwise while the other component rotated the polarized light by the same amount counter clockwise. 6

7. Pasteur made a proposal that since the crystals of tartaric acid were mirror images of each other, their molecules were also mirror images of each other7

8. Additional research done by Pasteur revealed that one component of tartaric acid could be utilized for nutrition by micro-organisms but the other could not.Thus Pasteur concluded that biological properties of chemical substances depend not only on the nature of the atoms comprising the molecules but also on the manner in which these atoms are arranged in space. 8

9. The tetrahedral CarbonIn 1874 as a student at University of Utrecht, Jacobusvan't Hoff proposed the tetrahedral carbon. His proposal was based upon evidence of isomer number:Conversion of CH4 into CH3R(1 isomer)Conversion of CH3R into CH2RR1(1 isomer)van't Hoff realized that the four hydrogens in CH4 had to be equivalent and a geometrical square was ruled out because it would form 2 isomers for CH2RR1. Thus he proposed the tetrahedral carbon centre.9

10. Explanation of Optical Isomerism The tetrahedral carbon not only collaborated the absence of isomers in CH2YZ, but also predicted the existence of mirror image isomers. When carbon makes four single bonds with four different groups such as CHFClBr, non-super-imposable mirror-image molecules exist10

11. Enantiomers11

12. DefinitionAn enantiomer is one of two stereoisomers that are mirror images of each other and are non-superimposable.12

13. As seen here, the two molecules of lactic acid are mirror images of each other, but cannot superimpose.13(S)-Lactic acidor (+)-Lactic acid(R)-Lactic acidor (-)-Lactic acid

14. The Tetrahedral CarbonEnantiomers result when two compounds that are mirror-images of each other cannot superimposeEg. when a tetrahedral carbon is bonded to four different substituents(CR1R2R3R4)For example, in lactic acid, there are four different groups: -H, -OH, -CH3, -COOHCan you name other examples of enantiomers formed this way?Alanine, Tartaric Acid, Glyceraldehyde14

15. Reasons for molecular handedness(Chirality)15

16. ChiralityA molecule that is not superimposable to its mirror image is said to be chiralThe most common cause of chirality in organic molecules is the presence of a carbon atom bonded with 4 different groups(eg in lactic acid), this is also known as point chirality.These carbon atoms are called chirality centers or chirality centres.Can you think of other causes of Chirality? (be creative)16

17. Identifying Chiral MoleculesThe obvious way: find any carbon with 4 different substituents. If there are any, then the molecule is chiral. Isotopic differences are also considered different substituents.Thus, -CH2-, -CH3(methyl), >C=O(carbonyl), >C=C<(alkene) and -C@C-(alkyne) groups cannot be chirality centers as they all have less than 4 substituents.Easier way: look for the presence of a plane of symmetry, since a symmetrical molecule is identical to its mirror image and is thus achiral17

18. Drawing of EnantiomersFischer Projection (do not confuse with Lewis Structure)Natta Projection (we all know this)For cyclic moleculesHaworth ProjectionChair conformation18

19. 191. Fischer Projection 2. Haworth Projection3. Chair Conformation4. Natta Projections

20. Optical activity of enantiomers20

21. As seen from Biot’s experiment, enantiomers can rotate plane polarised light, since they are optically activeWhen a beam of plane polarised light passes through a solution of a non-racemic (scalemic) mixture (ie has enantiomeric excess of one of the enantiomers), rotation of the polarisation plane occurs.21

22. Polarimeter22

23. Optical ActivityObserved rotationThe number of degrees, , through which a compound rotates the plane of polarized light.Dextrorotatory (+)Acompound that rotates the plane of polarized light to the right.Levorotatory (-)Refers to a compound that rotates the plane of polarized light to the left.23

24. Specific Rotation Specific rotation refers to the observed rotation for a sample in a tube 1.0 dm in length and at a concentration of 1.0 g/mL.The degree of rotation also depends on the wavelength of the light (the yellow sodium D2 line near 589 nm is commonly used for measurements)24

25. Calculating Specific Rotation (liquids)The specific rotation of a compound is given by:Where:[a] is the specific rotationT is the temperaturel is the wavelength of light usedl is the path length of sample (in decimetres)d is the density of the sample (in g/cm3 for pure liquids)The sign of the rotation (+ or -) is always given25

26. Calculating Specific Rotation (liquids)The specific rotation of a compound is given by:Where:[a] is the specific rotationT is the temperaturel is the wavelength of light usedl is the path length of sample (in decimetres)c is the concentration of the sample (in g/cm3)The sign of the rotation (+ or -) is always given26

27. Optical PurityOptical purity: A way of describing the composition of a mixture of enantiomers.Enantiomeric excess: The difference between the percentage of two enantiomers in a mixture.optical purity is numerically equal to enantiomeric excess, but is experimentally determined.27

28. Naming Conventions28

29. Types of namingR,S designation+, - designation (explained just now)d,l Nomenclature29

30. R-, S- Naming ConventionThis convention labels each chiralcenterR or S according to a system by which its substituents are each assigned a priority based on atomic number.The priority of substituents are assigned based on Cahn–Ingold–Prelog priority rules30

31. Cahn–Ingold–Prelog priority rulesAssignment of PriorityCompare the atomic number of the atoms directly attached to the chirality center. The group with the atom of higher atomic number receives higher priority. (eg –Cl > –OH > –NH2 > –CH3)If different isotopes of the same element is attached to the chiral center, the group with the higher mass number recieves higher priority (2H > 1H)31

32. If double or triple bonded groups are encountered as substituents, they are treated as an equivalent set of single-bonded atoms.For example, C2H5– < CH2=CH– < HC≡C– 32

33. If there is a tie, consider the atoms at distance 2 from the chiralitycenter—as a list is made for each group of the atoms bonded to the one directly attached to the chiralitycenter. Each list is arranged in order of decreasing atomic number. Then the lists are compared atom by atom; at the earliest difference, the group containing the atom of higher atomic number receives higher priority. (eg. –COOH > –CH3)33

34. If there is still a tie, each atom in each of the two lists is replaced with a sub-list of the other atoms bonded to it (at distance 3 from the chiralitycenter), the sub-lists are arranged in decreasing order of atomic number, and the entire structure is again compared atom by atom. This process is repeated, each time with atoms one bond farther from the chiralitycenter, until the tie is broken.34

35. Identifying the ConfigurationAfter having ranked the four groups attached to the stereo-center, orientate the molecule such that the lowest ranking group points directly backLook at the 3 substituents left facing you: If the priority of the remaining three substituents decreases in clockwise direction, it is labeledR (for Rectus, Latin for right), if it decreases in counterclockwise direction, it is S (for Sinister, Latin for left).35

36. d,l NomenclatureThe d/l system names isomers after the spatial configuration of its atoms, by relating the molecule to glyceraldehyde. Glyceraldehyde is chiral itself, and its two isomers are labeled d and lThis nomenclature is still used in certain organic compounds like saccharides and amino acids36

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38. Identifying the ConfigurationFor Monosaccharides:The absolute configuration of all monosaccharides is denoted by the configuration at the chiralitycenter furthest from the anomeric centre (the carbonyl carbon in the open chain representation) If, in the Fischer projection, that centre has the hydroxyl group on the right, it is a d-sugar; if on the left, it is an l-sugar. By convention, the "D" and "L" symbols are written in small capitals.38

39. Non amino-acids such as Lactic, Ascorbic, Tartaric Acid also follow the same rules as Saccharides.39

40. Identifying the ConfigurationsFor Amino AcidsCORN Rule:The groups: COOH, R, NH2 and H (where R is a variant carbon chain)are arranged around the chiralcenter carbon atom. Starting with the hydrogen atom away from the viewer, if these groups are arranged clockwise around the carbon atom, then it is the d-form. If counter-clockwise, it is the l-form.40

41. Relation to other naming conventionsThe d/l labeling is unrelated to (+)/(−); it does not indicate which enantiomer is dextrorotatory and which is levorotatory. Rather, it says that the compound's stereochemistry is related to that of the dextrorotatory or levorotatory enantiomer of glyceraldehyde—the dextrorotatory isomer of glyceraldehyde is, in fact, the d- isomer. 41

42. Diastereomers42

43. 2n RuleAs a general rule the maximum number of isomers for a compound is 2n, with n being the number of chirality centers.*As seen in the next slide43

44. 44

45. DefinitionDiastereomers refer to enantiomers that are not mirror images of each otherThey can be chiral or achiralEg D-glucose and D-galactose45

46. Stereochemistry in SugarsAldoseAn aldose is a monosaccharide that contains only one aldehyde group per molecule. The chemical formula takes the form Cn(H2O)n.The maximum number of chirality centers for any aldose is 2n-2Since the “head”(-CH=O) and “tail”(-CH2OH) carbons cannot be chiral centers46

47. Examples (Aldotetrose)Aldotetroses are Aldoses with 4 carbonsAs such, the maximum number of enantiomers of aldotetroses is 4 (24-2)The 4 possible enantiomers of Aldotetroses47

48. Other examples of diastereomers48

49. ReasonsAs we can see, although Erythrose and Threose are stereoisomers, they are not enantiomers, since their molecules are not mirror-images of each other. They are thus called diastereomers49ErythroseThreoseThey are not mirror images of each other

50. This is because stereoisomers are only enantiomers because all their chirality centers have opposite configurations, but if not all chiralitycentres have opposite configurations, then they are diastereomers.50Example of d(+)-Glucose and D(+)-Galactose

51. Meso Compounds51

52. DefinitionA meso-compound is a non-optically active member of a set of stereoisomers.It does not give a (+) or (-) reading on a polarimeterIt is non-optically active as it is achiralIt is achiral since it has a plane of symmetry52

53. ExamplesTartaric acid has 3 stereoisomersd-(2S,3S)-(−)-tartaric acidl-(2R,3R)-(+)-tartaric acid(2R,3S)-mesotartaric acid53d-(2S,3S)-(−)-tartaric acidl-(2R,3R)-(+)-tartaric acid(2R,3S)-mesotartaric acid

54. Mesotartaric AcidLet’s assume the mirror image of mesotartaric acid:Flip the molecule:And you find that you get the same molecule54Flip this molecule 180 degrees

55. Meso CompoundsThus, we can say that mesotartaric acid is not an enantiomer, as it is superimposible with its mirror image.This is due to the fact that there is a plane of symmetry in the molecule55There is a plane of symmetryRotate this bond 180 degrees

56. Resolution of Enantiomers56

57. Resolution of EnantiomersIn the lab, if we make chiral compounds from achiral starting materials, we are bound to get a racemic mixture.The way we separate the mixture is known as resolutionResolution is important as most of the time enantiomerically pure compounds are required57

58. CrystallisationOne way of resolution would be crystallisation (like what Pasteur did), it’s use is limited to solid compounds (eg Sodium Ammonium Tartrate)It does not work for liquid compounds that do not crystallise under ordinary conditions58

59. The most common way of resolution would be to use an acid-base reaction between a racemic mixture of chiral carboxylic acid and an amine base to yield an ammonium salt, which can be crystallised.59+

60. Resolution of enantiomersAnother way would be using a chemical reaction to produce a diastereomer.This can be done in various ways, by esterification or by forming diastereomeric salt (Adduct).60

61. Resolution of enantiomers (Esterification)One way of resolution of enantiomers would be using an ester61TsOHor H2SO4++Chiral but enantiomerically pureDiastereomersChiral but Racemic

62. Diastereomers have different physical properties (solubility, boiling point etc), and should be quite easy to separate by distillation/crystallisation/chromatographyWhen a pure enantiomer (diastereomer) is separated, the original intended products can be obtained62Enantiomerically pure productNaOH, H2O+

63. Resolution of enantiomers (Forming a diastereomeric salt)When a racemic mixture of a carboxylic acid reacts with a single enantiomer of a chiral base, diastereomers are obtained.Diastereomers can then be separated just like previously63

64. Acidification of the two diastereomeric salts resolved the original racemic mixture.64Racemic MixtureEnantiomerically pure compound

65. Importance of Enantiomers65

66. Chirality in the Biological WorldEnzymes are like hands in a handshakeThe substrate fits into a binding site on the enzyme surfaceA left-handed molecule, like hands in gloves, will only fit into a left-handed binding site anda right-handed molecule will only fit into a right-handed binding site.Because of the differences in their interactions with other chiral molecules in living systems, enantiomers have different physiological properties. 66

67. Some Examplesd-Glucose can be used for metabolism for all organisms but not l-glucoseAlmost all of the amino acids in proteins are (S) at the α carbon.In most pharmaceutical drugs, only one of the enantiomers are biologically active.Eg. (S)Ibuprofen is an active analgestic agent but the (R) enantiomer is biologically inactive67a carbon

68. Chirality in the Biological WorldA schematic diagram of an enzyme active site capable of binding with (R)-glyceraldehyde but not with (S)-glyceraldehyde.68

69. CreditsMost of these information are taken from online sources[citation needed]However due to the fact that the layout was copied from the book, we apologise for the fact that this may be a little boring (for some)Done by: Jeff Xu, Luther Mok, Joshua Lay, Wen SongDesign by Jonathan Yong69

70. 70Thank You