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9. Stereochemistry Based on McMurry’s Organic Chemistry, 6 th edition.

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1 9. Stereochemistry Based on McMurry’s Organic Chemistry, 6 th edition

2 2 Stereochemistry Some objects are not the same as their mirror images (technically, they have no plane of symmetry) A right-hand glove is different than a left-hand glove (See Figure 9.1) The property is commonly called “handedness” Organic molecules (including many drugs) have handedness that results from substitution patterns on sp 3 hybridized carbon

3 3 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 These are stereoisomers called enantiomers Called chiral molecules Lack a plane of symmetry

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6 6 Plane of Symmetry The plane has the same thing on both sides for the flask There is no mirror plane for a hand

7 7 Examples of Enantiomers Molecules that have one carbon with 4 different substituents have a nonsuperimposable mirror image – chiral molecule - pair of enantiomers But there are chiral molecules that lack this feature

8 8 Mirror-image Forms of Lactic Acid When H and OH substituents match up, COOH and CH 3 don’t when COOH and CH 3 coincide, H and OH don’t

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10 10 9.2 The Reason for Handedness: Chirality Molecules that are not superimposable with their mirror images are chiral (have handedness) A plane of symmetry divides an entire molecule into two pieces that are exact mirror images A molecule with a plane of symmetry is the same as its mirror image and is said to be achiral (See Figure 9.4 for examples)

11 11 Chirality If an object has a plane of symmetry it is necessarily the same as its mirror image The lack of a plane of symmetry is called “handedness”, chirality Hands, gloves are prime examples of chiral object They have a “left” and a “right” version

12 12 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

13 13 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

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16 16 Interchanging any two substituents on a chirality center converts it to its mirror image. Only sp 3 hybridized C atoms can be chirality centers.

17 17 A pair of enantiomers have identical physical properties except for the direction in which they rotate the plane of polarized light. A single enantiomer is said to be optically active.

18 18 9.3 Optical Activity Light restricted to pass through a plane is plane- polarized 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 Phenomenon discovered by Biot in the early 19 th century

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21 21 A Simple Polarimeter Measures extent of rotation of plane polarized light Operator lines up polarizing analyzer and measures angle between incoming and outgoing light

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23 23 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 Anti-clockwise is levorotatory

24 24 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.

25 25 Specific Rotation To have a basis for comparison, 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) See Table 9.1 for examples

26 26 Specific Rotation and Molecules Characteristic property of a compound that is optically active – the compound must be chiral The specific rotation of the enantiomer is equal in magnitude but opposite in sign

27 27 9.4 Pasteur’s Discovery of Enantiomers (1849) Louis Pasteur 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

28 28 Relative 3-Dimensionl Structure The original method was 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 This does not apply in general

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30 30 9.5 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 chirality 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

31 31 Sequence Rules (IUPAC) Assign each group priority according to the Cahn- Ingold-Prelog scheme With the lowest priority group pointing away, look at remaining 3 groups in a plane Clockwise is designated R (from Latin for “right”) Counterclockwise is designated S (from Latin word for “left”)

32 32 R-Configuration at Chirality Center Lowest priority group is pointed away and direction of higher 3 is clockwise, or right turn

33 33 Examples of Applying Sequence Rules If lowest priority is back, clockwise is R and counterclockwise is S R = Rectus S = Sinister

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35 35 9.6 Diastereomers 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 See Figure 9-10 2R,3S2S,3R 2R,3R 2S,3S

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38 38 9.7 Meso Compounds Tartaric acid has two chirality centers and two diastereomeric forms One form is chiral and the other is achiral, but both have two chirality 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

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40 40 9.8 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 2 n Cholesterol has eight chirality centers Morphine has five (9.17)

41 41 9.9 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 Daistereomers have a complete set of different common physical properties

42 42 9.10 Racemic Mixtures and Their Resolution A 50:50 mixture of two chiral compounds that are mirror images does not rotate light – called a racemic mixture (named for “racemic acid” that was the double salt of (+) and (-) tartaric acid The pure compounds need to be separated ot resolved from the mixture (called a racemate) 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

43 43 9.11 A Brief Review of Isomerism

44 44 Constitutional Isomers Different order of connections gives different carbon backbone and/or different functional groups

45 45 Stereoisomers Same connections, different spatial arrangement of atoms Enantiomers (nonsuperimposable mirror images) Diastereomers (all other stereoisomers) Includes cis, trans and configurational

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47 47 9.12 Stereochemistry of Reactions: Addition of HBr to Alkenes Many reactions can produce new chirality centers in compounds. ( 0  1, 1  2, etc.) What is the stereochemistry of the chiral product? What relative amounts of stereoisomers form? Example addition of HBr to 1-butene

48 48 Achiral Intermediate Gives Racemic Product Addition via carbocation Top and bottom are equally accessible

49 49 9.13 Stereochemistry of Reactions: Addition of Br 2 to Alkenes Stereospecific Forms racemic mixture Bromonium ion leads to trans addition

50 50 Addition of Bromine to Trans 2- Butene Gives meso product (both are the same)

51 51 Reaction between two optically inactive (achiral) partners that produces a product with a center of chirality, always leads to an optically inactive product – either racemic or meso. If you start out with optically inactive reactants, you will end up with optically inactive products.

52 52 Problems 9.20 and 9.21 Draw detailed mechanism and consider stereochemistry of addition of Br 2 to cis and trans 2-hexene

53 53 9.14 Stereochemistry of Reactions: Addition of HBr to a Chiral Alkene Gives diastereomers in unequal amounts. Facial approaches are different in energy Product is optically active

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55 55 As a general rule, reaction of a chiral reactant with an achiral reactant which introduces a new center of chirality, leads to unequal amounts of the distereometric products. If the chiral reactant is optically active the product will also be optically active.

56 56 Problem 9.22 HBr + racemic (+) 4-methyl-1-hexene Problem 9.23 What products are formed from reaction of HBr with 4-methylcyclopentene

57 57 Chapter 9 Homework 27-30, 32-34, 36-43, 45, 46, 48-50, 52, 53, 57, 59, 65-67, 73 Owl for Chapt 9 Nov 18 Test on Chapter 9 Nov 20

58 58 9.15 Chirality at Atoms Other Than Carbon Trivalent nitrogen is tetrahedral Does not form a chirality center since it rapidly flips Also applies to phosphorus but it flips more slowly

59 59 9.16 Chirality in Nature Stereoisomers are readily distinguished by chiral receptors in nature Properties of drugs depend on stereochemistry Think of biological recognition as equivalent to 3- point interaction See Figure 9-19

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63 63 9.17 Prochirality A molecule that is achiral but that can become chiral by a single alteration is a prochiral molecule

64 64 Prochiral distinctions: faces Planar faces that can become tetrahedral are different from the top or bottom A center at the planar face at a carbon atom is designated re if the three groups in priority sequence are clockwise, and si if they are counterclockwise

65 65 Prochiral distinctions, paired atoms or groups An sp 3 carbon with two groups that are the same is a prochirality center The two identical groups are distinguished by considering either and seeing if it was increased in priority in comparison with the other If the center becomes R the group is pro-R and pro- S if the center becomes S

66 66 Prochiral Distinctions in Nature Biological reactions often involve making distinctions between prochiral faces or or groups Chiral entities (such as enzymes) can always make such a distinction Examples: addition of water to fumarate and oxidation of ethanol

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