Organic Chemistry I Stereochemistry Unit 9

1. Organic Chemistry IStereochemistryUnit 9 Dr. Ralph C. Gatrone Department of Chemistry and Physics Virginia State University

2. Chapter Objectives • Enantiomers • Chirality • Optical Activity • Specifying Configuration • Diastereomers • Resolution • Prochirality • Chirality in Nature

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

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

5. Stereochemistry • Some objects are not the same as their mirror images • 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 sp3 hybridized carbon

6. Enantiomers – Mirror Images • 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 • Enantiomers • Arises when we have 4 different groups on an sp3 Carbon atom

7. Chirality and Enantiomers • Chirality arises • sp3 C atom has 4 different substituents • The C is referred to as • A chiral center • A stereogenic center • An asymmetric center • Chirality is a molecular property • Due to presence of a chiral center

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

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

10. Chirality Centers • 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 • If two groups are the same, then there is only one way • A chiral molecule usually has at least one chirality center

11. 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) • In cyclic molecules, we compare by following in each direction in a ring

12. Light • 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 • That single plane of light is known as “Plane Polarized Light”

13. Optical Activity • Biot in early 19th 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)

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

15. Measurement of Optical Rotation • 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 angle between the entrance and exit planes is the optical rotation.

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

17. Specific Rotation • Amount of rotation is dependent upon number of molecules encountered • Therefore define specific rotation, []D for an optically active compound • []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)

18. Discovery of Enantiomers • 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 solutions contain mirror image isomers, called enantiomers and they crystallized in distinctly different shapes – such an event is rare

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

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

21. Relative 3-Dimensionl Structure • 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

22. Sequence Rules for Specification of Configuration • 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 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

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

24. 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, CO2H is O while CH3 is H CO2H priority = 2 and CH3 priority is 3 Rewrite structure just using numbers – no atoms

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

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

27. Sequence Rules • 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. Sequence Rules

29. What if the structure is written differently?

30. Fischer Projections • Developed by Emil Fischer for carbohydrates • Demonstrating projections on flat surface

31. Fischer Projections • Useful for molecules with more than one chiral center

32. 2S,3S 2R,3R 2R,3S 2S,3R Two Chiral Centers • 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

33. Diastereomers • Cis and trans alkenes are diastereomers • Molecules have different chemical and physical properties

34. Tartaric Acid • 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 • 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

35. 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 • Diastereomers have a complete set of different common physical properties

36. Molecules with More Than Two Chirality Centers • Molecules can have very many chirality centers • 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 2n Cholesterol has eight chiral centers and 28 possible isomers

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

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

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

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

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

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

43. Biological Chemistry • Enzymes yield a single enantiomer • Enzymes are chiral and induce chirality

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

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

46. Prochirality • a molecule is prochiral if it can become chiral in a single chemical step • sp2 carbons are designated • Re (similar to R) or Si (similar to S) • Consider the following:

48. sp3 hybridized carbon atoms • Prochiral center • Becomes chiral by changing one attached group • Consider the following:

50. Designation • pro-R: replaced atom leads to R configuration • pro-S: replaced atom leads to S configuration