1. 1 Fall, 2009 Organic Chemistry I Stereochemistry Unit 9 Organic Chemistry I Stereochemistry Unit 9 Dr. Ralph C. Gatrone Department of Chemistry and Physics Virginia State University

2. Fall, 20092 Chapter Objectives Enantiomers Enantiomers Chirality Chirality Optical Activity Optical Activity Specifying Configuration Specifying Configuration Diastereomers Diastereomers Resolution Resolution Prochirality Prochirality Chirality in Nature Chirality in Nature

3. Fall, 20093 Stereochemistry Consider your hands Consider your hands –Right Hand mirror image of Left Hand –Non-superimposable Consider molecules shown on left Consider molecules shown on left –First and Second sets are superimposable –Third set is non-superimposable with mirror image

4. Fall, 20094 Plane of Symmetry The plane has the same thing on both sides for the flask The plane has the same thing on both sides for the flask There is no mirror plane for a hand There is no mirror plane for a hand

5. Fall, 20095 Stereochemistry Some objects are not the same as their mirror images Some objects are not the same as their mirror images no plane of symmetry no plane of symmetry –A right-hand glove is different than a left-hand glove –The property is commonly called “handedness” Organic molecules (including many drugs) have handedness that results from substitution patterns on sp 3 hybridized carbon Organic molecules (including many drugs) have handedness that results from substitution patterns on sp 3 hybridized carbon

6. Fall, 20096 Enantiomers – Mirror Images Molecules exist as three-dimensional objects Molecules exist as three-dimensional objects –Some molecules are the same as their mirror image –Some molecules are different than their mirror image Stereoisomers that are non-superimposable with their mirror images are Stereoisomers that are non-superimposable with their mirror images are –Enantiomers –Arises when we have 4 different groups on an sp 3 Carbon atom

7. Fall, 20097 Chirality and Enantiomers Chirality arises Chirality arises –sp 3 C atom has 4 different substituents The C is referred to as The C is referred to as –A chiral center –A stereogenic center –An asymmetric center Chirality is a molecular property Chirality is a molecular property –Due to presence of a chiral center

8. Fall, 20098 Enantiomers and the Tetrahedral Carbon Enantiomers are molecules that are not superimposable with their mirror image Enantiomers are molecules that are not superimposable with their mirror image Illustrated by enantiomers of lactic acid Illustrated by enantiomers of lactic acid

9. Fall, 20099 Examples of Enantiomers Molecules that have one carbon with 4 different substituents have a nonsuperimposable mirror image – enantiomer Molecules that have one carbon with 4 different substituents have a nonsuperimposable mirror image – enantiomer

10. Fall, 200910 Chirality Centers A point in a molecule where four different groups (or atoms) are attached to carbon is called a chirality center A point in a molecule where four different groups (or atoms) are attached to carbon is called a chirality center There are two nonsuperimposable ways that 4 different different groups (or atoms) can be attached to one carbon atom There are two nonsuperimposable ways that 4 different different groups (or atoms) can be attached to one carbon atom –If two groups are the same, then there is only one way A chiral molecule usually has at least one chirality center A chiral molecule usually has at least one chirality center

11. Fall, 200911 Chirality Centers in Chiral Molecules Groups are considered “different” if there is any structural variation (if the groups could not be superimposed if detached, they are different) Groups are considered “different” if there is any structural variation (if the groups could not be superimposed if detached, they are different) In cyclic molecules, we compare by following in each direction in a ring In cyclic molecules, we compare by following in each direction in a ring

12. Fall, 200912 Light As light travels it oscillates at right angles to the forward direction As light travels it oscillates at right angles to the forward direction If it passes through a thin slit, all light except one plane (the slit) is topped If it passes through a thin slit, all light except one plane (the slit) is topped That single plane of light is known as “Plane Polarized Light” That single plane of light is known as “Plane Polarized Light”

13. Fall, 200913 Optical Activity Biot in early 19 th Century discovered Biot in early 19 th Century discovered –Plane-polarized light that passes through solutions of achiral compounds remains in that plane –Solutions of chiral compounds rotate plane-polarized light and the molecules are said to be optically active Some molecules caused plane polarized light to rotate to the right (dextrorotatory), others to the left (levorotatory) Some molecules caused plane polarized light to rotate to the right (dextrorotatory), others to the left (levorotatory)

14. Fall, 200914 Optical Activity Optical Activity Light passes through a plane polarizer Light passes through a plane polarizer Plane polarized light is rotated in solutions of optically active compounds Plane polarized light is rotated in solutions of optically active compounds Measured with polarimeter Measured with polarimeter Rotation, in degrees, is [  ] Rotation, in degrees, is [  ] Clockwise rotation is called dextrorotatory Clockwise rotation is called dextrorotatory Counterclockwise is levorotatory Counterclockwise is levorotatory

15. Fall, 200915 Measurement of Optical Rotation A polarimeter measures the rotation of plane- polarized that has passed through a solution A polarimeter measures the rotation of plane- polarized that has passed through a solution The source passes through a polarizer and then is detected at a second polarizer The source passes through a polarizer and then is detected at a second polarizer The angle between the entrance and exit planes is the optical rotation. The angle between the entrance and exit planes is the optical rotation.

16. Fall, 200916 A Simple Polarimeter Measures extent of rotation of plane polarized light Measures extent of rotation of plane polarized light Operator lines up polarizing analyzer and measures angle between incoming and outgoing light Operator lines up polarizing analyzer and measures angle between incoming and outgoing light

17. Fall, 200917 Specific Rotation Amount of rotation is dependent upon number of molecules encountered Amount of rotation is dependent upon number of molecules encountered Therefore define specific rotation, [  ] D for an optically active compound Therefore define specific rotation, [  ] D for an optically active compound [  ] D = observed rotation/(pathlength x concentration) =  /(l x C) = degrees/(dm x g/mL) [  ] D = observed rotation/(pathlength x concentration) =  /(l x C) = degrees/(dm x g/mL) Specific rotation is that observed for 1 g/mL in solution in cell with a 10 cm path using light from sodium metal vapor (589 nanometers) Specific rotation is that observed for 1 g/mL in solution in cell with a 10 cm path using light from sodium metal vapor (589 nanometers)

18. Fall, 200918 Discovery of Enantiomers Louis Pasteur (1849) discovered that sodium ammonium salts of tartaric acid crystallize into right handed and left handed forms Louis Pasteur (1849) discovered that sodium ammonium salts of tartaric acid crystallize into right handed and left handed forms The optical rotations of equal concentrations of these forms have opposite optical rotations The optical rotations of equal concentrations of these forms have opposite optical rotations The solutions contain mirror image isomers, called enantiomers and they crystallized in distinctly different shapes – such an event is rare The solutions contain mirror image isomers, called enantiomers and they crystallized in distinctly different shapes – such an event is rare

19. Fall, 200919 Enantiomers (+)-tartaric acid and (-) tartaric acid (+)-tartaric acid and (-) tartaric acid –Identical in every respect Chemical properties are identical Chemical properties are identical Spectroscopic properties are identical Spectroscopic properties are identical Physical properties are identical Physical properties are identical –Except Direction plane polarized light rotates Direction plane polarized light rotates Biological properties Biological properties

20. Fall, 200920 Enantiomers - Description How do we describe enantiomers? How do we describe enantiomers? Need a method to specify the arrangement of the groups on a chiral center. Need a method to specify the arrangement of the groups on a chiral center. Comparative Method Comparative Method

21. Fall, 200921 Relative 3-Dimensionl Structure a correlation system classifying related molecules into “families” focused on carbohydrates a correlation system classifying related molecules into “families” focused on carbohydrates –Correlate to D- and L- glyceraldehyde –D-erythrose is the mirror image of L-erythrose Does not apply in general Does not apply in general

22. Fall, 200922 Sequence Rules for Specification of Configuration A general method applies to the configuration at each chirality center (instead of to the the whole molecule) A general method applies to the configuration at each chirality center (instead of to the the whole molecule) The configuration is specified by the relative positions of all the groups with respect to each other at the chiral center The configuration is specified by the relative positions of all the groups with respect to each other at the chiral center The groups are ranked in an established priority sequence and compared The groups are ranked in an established priority sequence and compared The relationship of the groups in priority order in space determines the label applied to the configuration, according to a rule The relationship of the groups in priority order in space determines the label applied to the configuration, according to a rule

23. Fall, 200923 Sequence Rules Assign priorities to each group on chiral carbon using Cahn- Ingold-Prelog Rules

24. Fall, 200924 Sequence Rules Priorities are based on atomic number O: AN = 8 priority = 1 H: AN = 1, priority = 4 C = C = 6, tie, use next atom, CO 2 H is O while CH 3 is H CO 2 H priority = 2 and CH 3 priority is 3 Rewrite structure just using numbers – no atoms

25. Fall, 200925 Sequence Rules Must have the priority 4 group on upper dashed line Ignore the group

26. Fall, 200926 Sequence Rules If rotation is clockwise the configuration of the C is R If the rotation is counterclockwise the configuration is S

27. Fall, 200927 Sequence Rules What if 4 isn’t in upper dashed position? What if 4 isn’t in upper dashed position? Switch the 4 with the number that is in the upper dashed position. If you do this switch, you MUST switch the other positions also.

28. Fall, 200928 Sequence Rules

29. Fall, 200929 What if the structure is written differently?

30. Fall, 200930 Fischer Projections Developed by Emil Fischer for carbohydrates Developed by Emil Fischer for carbohydrates Demonstrating projections on flat surface Demonstrating projections on flat surface

31. Fall, 200931 Fischer Projections Useful for molecules with more than one chiral center Useful for molecules with more than one chiral center

32. Fall, 200932 Two Chiral Centers Molecules with more than one chirality center have mirror image stereoisomers that are enantiomers Molecules with more than one chirality center have mirror image stereoisomers that are enantiomers In addition they can have stereoisomeric forms that are not mirror images, called diastereomers In addition they can have stereoisomeric forms that are not mirror images, called diastereomers 2R,3S2S,3R 2R,3R 2S,3S

33. Fall, 200933 Diastereomers Cis and trans alkenes are diastereomers Cis and trans alkenes are diastereomers Molecules have different chemical and physical properties Molecules have different chemical and physical properties

34. Fall, 200934 Tartaric Acid Tartaric acid has two chiral centers and two diastereomeric forms Tartaric acid has two chiral centers and two diastereomeric forms One form is chiral and the other is achiral, but both have two chiral centers One form is chiral and the other is achiral, but both have two chiral centers An achiral compound with chirality centers is called a meso compound – it has a plane of symmetry An achiral compound with chirality centers is called a meso compound – it has a plane of symmetry The two structures on the right in the figure are identical so the compound (2R, 3S) is achiral The two structures on the right in the figure are identical so the compound (2R, 3S) is achiral

35. Fall, 200935 Physical Properties of Stereoisomers Enantiomeric molecules differ in the direction in which they rotate plane polarized but their other common physical properties are the same Enantiomeric molecules differ in the direction in which they rotate plane polarized but their other common physical properties are the same Diastereomers have a complete set of different common physical properties Diastereomers have a complete set of different common physical properties

36. Fall, 200936 Molecules with More Than Two Chirality Centers Molecules can have very many chirality centers Molecules can have very many chirality centers Each point has two possible permanent arrangements (R or S), generating two possible stereoisomers Each point has two possible permanent arrangements (R or S), generating two possible stereoisomers So the number of possible stereoisomers with n chirality centers is 2 n So the number of possible stereoisomers with n chirality centers is 2 n Cholesterol has eight chiral centers and 2 8 possible isomers

37. Fall, 200937 Racemic Mixtures A 50:50 mixture of a pair of enantiomers does not rotate light A 50:50 mixture of a pair of enantiomers does not rotate light called a racemic mixture called a racemic mixture Separation of a racemic mixture into individual enantiomers is resolution Separation of a racemic mixture into individual enantiomers is resolution Important Important –Albuterol – enantiomeric pair One causes bronchial passages to expand One causes bronchial passages to expand Other causes bronchial passages to contract Other causes bronchial passages to contract –Ibuprofen R analgesic R analgesic S no biological activity S no biological activity

38. Fall, 200938 A Brief Review of Isomerism The flowchart summarizes the types of isomers we have seen The flowchart summarizes the types of isomers we have seen

39. Fall, 200939 Constitutional Isomers Different order of connections gives different carbon backbone and/or different functional groups Different order of connections gives different carbon backbone and/or different functional groups

40. Fall, 200940 Stereoisomers Same connections, different spatial arrangement of atoms Same connections, different spatial arrangement of atoms –Enantiomers (nonsuperimposable mirror images) –Diastereomers (all other stereoisomers) Includes cis, trans and configurational Includes cis, trans and configurational

41. Fall, 200941 Stereochemistry and Reactions Most reactions generate a chiral center Most reactions generate a chiral center Alcohol is prepared as a racemic mixture Alcohol is prepared as a racemic mixture Why? Why?

42. Fall, 200942 Racemic Mixture Forms Addition of Hg(II) gives rise to two cations Addition of Hg(II) gives rise to two cations Addition of water gives rise to both enantiomers Addition of water gives rise to both enantiomers

43. Fall, 200943 Biological Chemistry Enzymes yield a single enantiomer Enzymes yield a single enantiomer Enzymes are chiral and induce chirality Enzymes are chiral and induce chirality

44. Fall, 200944 Reactions with Chiral Substrates Reaction goes through chiral carbocation Reaction goes through chiral carbocation Provides some stereochemical preference Provides some stereochemical preference Do not observe a 50:50 mixture Do not observe a 50:50 mixture Products are diastereomeric Products are diastereomeric

45. Fall, 200945 General Rule Reactions of chiral substrates with: Reactions of chiral substrates with: An achiral reactant gives unequal amounts of diastereomers An achiral reactant gives unequal amounts of diastereomers A chiral reactant gives a chiral product A chiral reactant gives a chiral product Reactions of achiral substrates with Reactions of achiral substrates with An achiral reactant gives an achiral product An achiral reactant gives an achiral product

46. Fall, 200946 Prochirality a molecule is prochiral if it can become chiral in a single chemical step a molecule is prochiral if it can become chiral in a single chemical step sp 2 carbons are designated sp 2 carbons are designated Re (similar to R) or Si (similar to S) Re (similar to R) or Si (similar to S) Consider the following: Consider the following:

47. Fall, 200947

48. Fall, 200948 sp 3 hybridized carbon atoms Prochiral center Prochiral center Becomes chiral by changing one attached group Becomes chiral by changing one attached group Consider the following: Consider the following:

49. Fall, 200949

50. Fall, 200950 Designation pro-R: replaced atom leads to R configuration pro-R: replaced atom leads to R configuration pro-S: replaced atom leads to S configuration pro-S: replaced atom leads to S configuration

51. Fall, 200951 Biological Chemistry Many biological reactions involve prochiral centers Many biological reactions involve prochiral centers Chiral centers are extremely important in biological processes and drug development Chiral centers are extremely important in biological processes and drug development

52. Fall, 200952 Chiral Drugs