1. Organic Chemistry By Dr. Mehnaz Kamal Assistant Professor, Pharmaceutical Chemistry Prince Sattam Bin Abdulaziz University

2. 1-What is Optical Isomerism 2-What is Polarimeter ? 3- Chirality 4- Enantiomers and diastereomers

3. Isomers Structural isomerism (Constitutional isomers) Position of function groups Skeleton or chain of carbon Functional group Stereoisomerism Optical isomers (Diastereomers (Enantiomers Geometrical Cis & trans ConformationalConfigurational Type of Isomerism

5. Optical isomerism An isomerism resulting from ability of certain molecules to rotate plane of polarized light -- -- the light is rotated plane-polarized light to either to the right or left right ( clockwise ) + d ( dexter ) dextro left ( anticlockwise ) - l ( laevous ) levo

6.  Any material that rotates the plane of polarized light.  Optically active compound is non- superimposable on its mirror image. Types of Optical isomerism 1-Optically active.  If a molecule is super-imposable on its mirror image, the compound does not rotate the plane polarized light. Example: Alanine (amino acid) 2-Optically inactive

7. Enantiomers Have Equal And Opposite Rotations W C X Z Y W C X Y Z (+) dextrorotatory(-) levorotatory Enantiomers All Other Physical Properties Are The Same Enantiomers (from Greek enantio, “opposite” and merso, “part”) have opposite configuration Optically active. Enantiomers: isomers that are nonsuperimposable mirror images of each other Types of Optical isomerism  If one stereoisomer is “right-handed,” its enantiomer is “left-handed.”

8. Optical Isomerism Optically active Non Super Imposable (Enantiomers) Optically inactive Non-Superimposable (Diastereomers)

9. Chirality And Chiral Compounds

10. If a molecule is not superimposable on its mirror image, it is chiral. If it is superimposable on its mirror image, it is achiral. What is chirality? hand Chirality (cheir, Greek for hand). chirality. The property of nonsuperimposability of an object on its mirror image is called chirality. Things that are chiral have non superimposable mirror images

11. What is Chiral carbon? Chiral carbon: It is an sp 3 -hybridized carbon atom with four different groups attached to it. enantiomers. Chiral compound exists in a pair of enantiomers. Chiral carbons have no symmetry they are asymmetric Chiral center is indicated by an *.  If one stereoisomer is “right-handed,” its enantiomer is “left- handed.”

12. Chiral Centers One of the ways a molecule can be chiral is to have a stereocenter. A point in a molecule where four different groups (or atoms) are attached to carbon is called a chiral center also called: asymmetric center stereocenter stereogenic center To locate a stereogenic center, examine each tetrahedral carbon atom in a molecule, and look at the four groups—not the four atoms—bonded to it. Always omit from consideration all C atoms that cannot be tetrahedral stereogenic centers. These include *CH 2 and CH 3 groups * Any sp or sp 2 hybridized C

13. Stereogenic Carbons stereocenter *

14. What is the relationship between chirality and enantiomers? A chiral molecule always has an enantiomer. An achiral molecule never has an enantiomer. Recall that enantiomers are non- superimposable mirror images.

15.  Enantiomers have identical physical and chemical properties except in two important respects : 1.They rotate the plane polarized light in opposite directions, however in equal amounts.  The isomer that rotates the plane to the left (anticlockwise) is called the levo isomer and is designated (-)  While the one that rotates the plane to the right (clockwise) is called the dextro isomer and designated (+). chiral 2. They react at different rates with other chiral compounds.  This is the reason that many compounds are biologically active while their enantiomers are not. achiral  They react at the same rates with achiral compounds.

16. Summary of the Basic Principles of Chirality: Everything has a mirror image. The fundamental question is whether the molecule and its mirror image are superimposable. If a molecule and its mirror image are not superimposable, the molecule and its mirror image are an enatiomers. The terms stereogenic center and chiral molecule are related but distinct. In general, a chiral molecule must have one or more stereogenic centers. The presence of a plane of symmetry makes a molecule achiral.  Any material which rotates the plane of the polarized light is termed "optically active.“  Compounds featuring chiral centers are optically active.  An isomer of optically active compound can rotate the plane of polarized light to the left (levorotatory), in which case it will be designated (l, or -), or to the right (dextrorotatory) in which case it will be termed (d, or +).

17. Label the stereogenic centers in each molecule and decide if it is chiral. a) CH 3 CH 2 CH(Cl)CH 2 CH 3 achiral b) CH 3 CH(OH)CH=CH 2 chiral c) (CH 3 ) 2 CHCH 2 CH 2 CH(CH 3 )CH 2 CH 3 chiral

18.  A molecule that has a plane of symmetry or a center of symmetry is superimposeabl ◦ Plane of symmetry plane bisect molecule so one half is the mirror of the other half.  Another test for chirality is to assess whether the object itself has a mirror plane of symmetry or center of symmetry (point of inversion). Symmetry plane of symmetry

19. Examples plane of symmetry :

20. R. S. Cahn, Sir Christopher Ingold, and V. Prelog (according to Cahn-Ingold-Prelog) Absolute Configuration ( AC )

21. The system that is used was devised by R. S. Cahn, Sir Christopher Ingold, and V. Prelog. Called “sequence rule” 1-Need rules for ranking substituents at stereogenic center in order of decreasing precedence 2-Need convention for orienting molecule so that order of appearance of substituents can be compared with rank Absolute Configuration ( AC )

22. 1. Rank the substituents at the stereogenic center according to same rules used in E-Z notation (Assign each group priority 1-4.) 2. Orient the molecule so that lowest- ranked substituent points away from you (lowest priority group (4) is in the back, look at remaining 3 groups in a plane. 3. If the order of decreasing precedence traces a clockwise path, the absolute configuration is R. If the path is anticlockwise, the configuration is S. Sequence Rules Rotate to the right-hide the hydrogen, and that will look like this--------> 1 (S)-Bromochlorofluoromethane (R)-Bromochlorofluoromethane 2 3 4

23. Absolute Configuration ( AC )

25. First, we assign priorities: we next make sure that the #4 priority group (the hydrogen) is pointed back away from ourselves, into the plane of the page (it is already).

26. Is the actual spatial arrangement of atoms or groups around a chiral carbon In 1891 German chemist [ Emil Fisher ] introduce formula showing the spatial arrangement of atoms Horizontal lines come out of the page Vertical lines go back into page Method to project a tetrahedral carbon onto a flat surface Tetrahedral carbon represented by two crossed lines to show configuration at stereogenic center without necessity of drawing wedges and dashes or using models. Absolute Configuration ( AC ) Fischer projections

27. Absolute Configuration ( AC ) Rules 1. Draw Fischer Projection formula 2. Rank the substitution according to the priority order(1-4) 3-Place the group of lowest priority, usually H, at the top of the Fischer projection by using one of the allowed motions The lowest-priority group is thus oriented back away from viewer 4. Draw an arrow from group with highest priority to second highest priority. if the arrow is …… a- clockwise, the configuration is R b- anti-clockwise, the configuration S

28. (±)- Ethanolamine CH 3 CH(OH)NH 2 has one chiral carbon, so 2- enantiomers H2NH2NH2NH2N CH 3 H OH H2NH2NH2NH2N OH H Mirror Fischer projection formula Fischer projections Absolute Configuration ( AC )

29. Groups are assigned a priority ranking using the same set of rules as are used in ( E ) and ( Z ) system CH 3 CH(OH)NH 2 1. Draw Fischer Projection formula H2NH2NH2NH2N CH 3 OH H Fischer projections Absolute Configuration ( AC )

30. 2. Rank the substitution according to the priority order H2NH2NH2NH2N CH 3 OH H OH > NH 2 > CH 3 > H 12 3 Fischer projections Absolute Configuration ( AC ) (R)-ethanolamine (+)- ethanolamine

31. 3. The group (atom) with lowest priority [H] should be away from the observer, if not do an even number of changes to get H away from the observer H2NH2NH2NH2N CH 3 OH H 1 OH OH H2NH2NH2NH2N H2NH2NH2NH2N H H 2 Absolute Configuration ( AC ) Fischer projections

32. 4. Draw an arrow from group with highest priority ( OH ) to second highest priority ( NH2 ). if the arrow is …… a- clockwise, the configuration is R b- anti-clockwise, the configuration S HO H NH 2 CH 3 (R)-ethanolamine (+)- ethanolamine Absolute Configuration ( AC ) Fischer projections

33. Draw the formulas for the two enantiomers of each of the following compunds then assign each as Ror S H.W

34.  A Fischer projection can have one group held steady while the other three rotate in either a clockwise or a counterclockwise direction ◦ Effect is to simply rotate around a single bond Absolute Configuration ( AC ) Fischer projections

35. Rules for manipulating Fischer projections:  A Fischer projection can be rotated on the page by 180°, but not by 90° or 270° ◦ Only a 180° rotation maintains the Fischer convention by keeping the same substituent groups going into and coming out of the plane Absolute Configuration ( AC ) Fischer projections

36.  A 90° rotation breaks the Fischer convention by exchanging the groups that go into and come out of the plane ◦ A 90° or a 270° rotation changes the representation to the enantiomer Absolute Configuration ( AC ) Fischer projections

37. Determination of Number of stereoisomers 2 n where n = number of chiral carbons n = zero no possible stereoisomers 1 2 stereoisomers are possible 2 4 ~ ~ ~ ~ ~ ~ ~ 3 8 ~ ~ ~ ~ ~ ~ 4 16 ~ ~ ~ ~ ~ ~ 5 32 ~ ~ ~ ~ ~ ~ Optical isomerism Diastereomers Diastereomers are stereoisomers that are not mirror images of one another and are non- superimposable on one another. Stereoisomers with two or more stereocenters can be diastereomers. It is sometimes difficult to determine whether or not two molecules are diastereomers :2-bromo-3-chlorobutane Example:2-bromo-3-chlorobutane

38. (±)- CH 3 CH(Cl)CH(Br)NH 2 n = 2 ….. So No. of stereoisomer 4 1,3 and 1,4 2,3 and 2,4 are diastereoisomers Optical isomerism Diastereomers

39. Determination of Absolute configuration(AC) in enatiomer 1 a. At C 1 : H NH 2 C2C2 C2C2 H Br 2 1 So, AC at C 1 is S Br > NH 2 > C 2 > H Diastereomers Optical isomerism

40. a. At C 2 : H C1C1 CH 3 ClCH 3 H Cl C1C1 2 1 AC at C 2 is S Cl > C 1 > CH 3 > H Determination of (AC) in enatiomer 1 Diastereomers Optical isomerism So for overall 1 ( 1S, 2S ) 2 ( 1R, 2R ) Similarly: 3 ( 1R, 2S ) ) 4 ( 1S, 2R )

41.  Louis Pasteur discovered that sodium ammonium salts of tartaric acid crystallize into right handed and left handed forms  The solutions contain mirror image isomers, called enantiomers and they crystallized in distinctly different shapes  A (50:50) racemic mixture of both crystal types dissolved together was not optically active  The optical rotations of equal concentrations of these forms have opposite optical rotations the effect of each molecule is cancelled out by its enantiomer Racemic mixture Optical isomerism

42. *It is optically inactive as it shows no rotation of PP light(because the rotation by each enantiomer is cancelled) *It is often designated as being (±) or (dl) or (RS). *A solution of either a racemic mixture or of achiral compound said to be optically inactive * Can be separated (resolved) into 2 optically active enantiomers. a sample that is optically inactive can be either an achiral substance or a racemic mixture Racemic mixture Thus Optical isomerism

43. Resolution of racemic mixture 1- Treat the mixture with microorganism ( R) RCOOH ( R) RCOO - (S) R’NH 3 + + ( R) R’NH 2 ( S) RCOOH ( R) RCOO - (R) R’NH 3 + Racemic mixture 2- Using chiral reagent Optical isomerism The pure compounds need to be separated or resolved from the mixture (called a racemate)

44. Using a Chiral amine changes the relationship of the products Now we can separate the Diastereomeric Salts * To separate components of a racemate (reversibly) we make a derivative of each with a chiral substance that is free of its enantiomer (resolving agent) *This gives Diastereomers that are separated by their differing solubility *The resolving agent is then removed

45. Optical isomerism Meso-compound A meso compound is an achiral compound that has chiral centers. It is superimposed on its mirror image and is optically inactive although it contains two or more stereocenters. A meso compound, should have : *two or more stereocenters, * an internal plane, *the stereochemistry should be R and S.R and S *They are diastereomers of the (R,R) and (S,S) isomer. *Only 3 stereoisomers

46. It is a general rule that any molecule with at least one stereocenter is chiral – but as with most rules, there is an exception. Some molecules have more than one stereocenter but are actually achiral – these are called meso compounds. Tartaric acid, a byproduct of the wine- making process, provides a good example With two stereocenters, there should, in theory, be four stereoisomers of tartaric acid. In fact, there are only three. First of all, there is a pair of enantiomers with (2R,3R) and (2S, 3S) stereochemistry Meso-compound Optical isomerism

47. Now, carefully consider a (2S, 3R) stereoisomer. You may notice that, when it is rotated into just the right conformation, this isomer has a plane of symmetry passing through the C 2 -C 3 bond That means that this molecule is not chiral, even though it has two stereocenters! It also means that (2R,3S) tartaric acid and (2S,3R) tartaric acid are not enantiomers, as we might have expected – they are in fact the very same molecule, meso-tartaric acid. This achiral molecule is, however, still a diastereomer of both R,R and S,S tartaric acid. Notice that the two ‘stereocenters’ of (meso)-tartaric acid have the same four substituents – this is a prerequisite for meso compounds; otherwise there would be no plane of symmetry

49. 49  Tartaric acid has 2 chiral centers, 2 enantiomeric forms and 1 meso form  Enantiomeric forms are chiral and meso form is achiral, but both have two chiral centers  The two structures on the right in the figure are identical so the compound (2R, 3S) is achiral  Identical substitution on both chiral centers. Optical isomerism Meso-compound

50. Applications of isomersem

51. In living organisms, virtually every molecule that contains a chiral center is found as a single enantiomer, not a racemic mixture. At the molecular level, our bodies are chiral and interact differently with the individual enantiomers of a particular compound. For example, the two enantiomers of carvone produces very different responses in humans: (−)-carvone is the substance responsible for the smell of spearmint oil, and (+)-carvone—the major flavor component of caraway seeds—is responsible for the characteristic aroma of rye bread. Chirality in Nature

52. The sedative thalidomide, was sold in Europe from 1956 to the early 1960s. It was prescribed to treat nausea during pregnancy, but unfortunately only the (+) enantiomer was safe for that purpose. The (−) enantiomer was discovered to be a relatively potent teratogen, which caused the children of many women who had taken thalidomide to be born with missing or undeveloped limbs. As a result, thalidomide was quickly banned for this use. It is currently used to treat leprosy, however, and it has also shown promise as a treatment for AIDS (acquired immunodeficiency syndrome). A racemic mixtur e

53. Ibuprofen, a common analgesic and anti- inflammatory agent that is the active ingredient in pain relievers The drug is sold as a racemic mixture that takes approximately 38 minutes to achieve its full effect in relieving pain and swelling in an adult human. Because only the (+) enantiomer is active in humans, however, the same mass of medication would relieve symptoms in only about 12 minutes if it consisted of only the (+) enantiomer. Unfortunately, isolating only the (+) enantiomer would substantially increase the cost of the drug. Conversion of the (−) to (+) enantiomer in the human body accounts for the delay in feeling the full effects of the drug A pharmaceutical example of a chiral compound

55. Extra examples

56. Step 1: Hold the molecule so that 1-The chiral center is on the plane of the paper, 2-Two bonds are coming out of the plane of the paper and are on a horizontal plane, 3-The two remaining bonds are going into the plane of the paper and are on a vertical plane To convert this stereoformula into a Fischer projection use the following proced Steps

57. Step 2: Push the two bonds coming out of the plane of the paper onto the plane of the paper Step 3: Pull the two bonds going into the plane of the paper onto the plane of the paper. Step 4: Omit the chiral atom symbol for convenience

58. To determine the absolute configuration of a chiral center in a Fisher projection, use the following two-step procedure. Step 1: Assign priority numbers to the four ligands on the chiral centeligands Step 2: If the lowest priority ligand is on a vertical bond, meaning that it is pointing away from the viewer, trace the three highest-priority ligands starting at the highest-priority ligand

59. If the lowest-priority ligand is on a horizontal bond, meaning that it is pointing toward the viewer, trace the three highest-priority ligands starting at the highest-priority ligand

60. A Fischer projection restricts a three- dimensional molecule into two dimensions. Consequently, there are limitations as to the operations that can be performed on a Fischer projection without changing the absolute configuration at chiral centers. The operations that do not change the absolute configuration at a chiral center in a Fischer projections can be summarized as two rules. Rule 1: Rotation of the Fischer projection by 180º in either direction without lifting it off the plane of the paper does not change the absolute configuration at the chiral center.

61. Rule 2: Rotation of three ligands on the chiral center in either direction, keeping the remaining ligand in place, does not change the absolute configuration at the chiral center.

62. The operations that do change the absolute configuration at a chiral center in a Fischer projection can be summarized as two rules. Rule 1: Rotation of the Fischer projection by 90º in either direction changes the absolute configuration at the chiral center.

63. Rule 2: Interchanging any two ligands on the chiral center changes the absolute configuration at the chiral center.

64. Assign R or S configuration to the following Fischer projection of alanine Strategy Follow the steps listed in the text 1.Assign priorities to the four substituents on the chiral carbon 2.Manipulate the Fischer projection to place the group of lowest priority at the top by carrying out one of the allowed motions 3.Determine the direction 1→2→3 of the remaining three group Configuration of alanine Absolute Configuration ( AC )

65. Solution  The priorities of the groups are (1) –NH 2, (2) –CO 2 H, (3) –CH 3, and (4) –H  To bring the lowest priority (–H ) to the top we might want to hold the –CH 3 group steady while rotating the other three groups counterclockwise Absolute Configuration ( AC ) Configuration of alanine

66. Exercises

67. Draw the formulas for the two enantiomers of each of the following compunds then assign each as Ror S

68. Examine the following structural formulas and select those that are chiral.

69. Label the stereogenic centers in each molecule and decide if it is chiral. a) CH 3 CH 2 CH(Cl)CH 2 CH 3 achiral b) CH 3 CH(OH)CH=CH 2 chiral c) (CH 3 ) 2 CHCH 2 CH 2 CH(CH 3 )CH 2 CH 3 chiral

70. How many stereogenic centers does each molecule have? a) b)

71. Q: Decide the chiral carbons in the following formulas? a. c. b. d.

72. Practice Exercise How many chiral carbon atoms are there in the open-chain form of fructose Answer: three

73. Solve: The carbon atoms numbered 2, 3, 4, and 5 each have four different groups attached to them, as indicated here: How many chiral carbon atoms are there in the open-chain form of glucose

74. * Identify the stereocenters (chiral carbon atoms) in the following molecule? *

76. http://chemwiki.ucdavis.edu/Organic_Chemistry/Chirality/Absolute_Config uration,_R-S_Sequence_Rules http://www2.chemistry.msu.edu/faculty/reusch/VirtTxtJml/sterism3.htm http://catalog.flatworldknowledge.com/bookhub/4309?e=averill_1.0- ch24_s02 http://colapret.cm.utexas.edu/courses/Nomenclature_files/Stereochemistry.htm