1. © 2006 Thomson Higher Education Chapter 9 Stereochemistry

2. Handedness Right and left hands are not identical Right and left hands are mirror images of each other Almost all the molecules in the human body are handed Handedness primarily arises from the tetrahedral stereochemistry of sp 3 -hybridized carbon atoms

3. 9.1 Enantiomers and the Tetrahedral Carbon Molecular handedness Molecules CH 3 X and CH 2 XY are identical to their mirror images Molecular images can superimpose on their mirror images Molecule CHXYZ is not identical to its mirror image Molecular image can not superimpose on its mirror image

4. Enantiomers and the Tetrahedral Carbon Enantiomers From the Greek enantio, meaning “opposite” Stereoisomers in which molecules are not identical to their mirror images Result whenever a tetrahedral carbon is bonded to four different substituents CHXYZ (one need not be H) Lactic acid (2-hydroxypropanoic acid) has four different groups (-H, -OH, -CH 3, -CO 2 H) bonded to the central carbon atoms and exists as a pair of enantiomers

5. Enantiomers and the Tetrahedral Carbon (+)-lactic acid Occurs in muscle tissue Found in sour milk (-)-lactic acid Found in sour milk

6. Enantiomers and the Tetrahedral Carbon A molecule of (+)-lactic acid can not superimpose on a molecule of (-)-lactic acid Regardless of how the molecules are oriented, they are not identical When the –H and –OH substituents match up, the –CO 2 H and the CH 3 substituents do not When –CO 2 H and the CH 3 match up, -H and –OH do not

7. 9.2 The Reason for Handedness in Molecules: Chirality Chiral From the Greek cheir meaning “hand” Molecules that are not identical to their mirror images, and thus exist in two enantiomeric forms A molecule is not chiral if it has a plane of symmetry Plane of symmetry A plane that cuts through the middle of an object (or molecule) so that one half of the object is a mirror image of the other half

8. The Reason for Handedness in Molecules: Chirality A laboratory flask has a plane of symmetry One half of the flask is a mirror image of the other half A hand does not have a plane of symmetry One half of the hand is not a mirror image of the other half

9. The Reason for Handedness in Molecules: Chirality Achiral A molecule that has a plane of symmetry in any of its possible conformations (must be identical to its mirror image) Propanoic acid, CH 3 CH 2 CO 2 H Has a plane of symmetry and so must be achiral

10. The Reason for Handedness in Molecules: Chirality Lactic Acid Has no plane of symmetry in any conformation and is chiral

11. The Reason for Handedness in Molecules: Chirality Chirality center A carbon atom bonded to four different groups in an organic molecule The central carbon atom in 5-bromodecane Most common cause of chirality Chirality is a property of the entire molecule

12. The Reason for Handedness in Molecules: Chirality Methylcyclohexane Achiral because there is no carbon atom in the molecule that is bonded to four different groups Has a plane of symmetry passing through the methyl group and through C1 and C4 of the ring

13. The Reason for Handedness in Molecules: Chirality 2-Methylcyclohexanone Chiral because C2 is bonded to four different groups: a –CH 3 group, an –H atom, a –COCH 2 – ring bond (C1) and a –CH 2 CH 2 – ring bond (C3) Has no plane of symmetry

14. The Reason for Handedness in Molecules: Chirality Note: Carbons in –CH 2 -, –CH 3, C=O, C=C, and C≡C groups cannot be chirality centers

15. Worked Example 9.1 Drawing the Three Dimensional Structure of a Chiral Molecule Draw the structure of a chiral alcohol.

16. Worked Example 9.1 Drawing the Three Dimensional Structure of a Chiral Molecule Strategy An alcohol is a compound that contains the –OH functional group To make an alcohol chiral, we need to have four different groups bonded to a single carbon atom, say –H, –OH, –CH 3, and –CH 2 CH 3

17. Worked Example 9.1 Drawing the Three Dimensional Structure of a Chiral Molecule Solution

18. 9.3 Optical Activity Stereochemistry Study originated in the early 19 th century during the investigations by the French physicist Jean-Baptiste Biot into the nature of plane-polarized light A beam of ordinary light consists of electromagnetic waves that oscillate in an infinite number of planes at right angles to the direction of light travel Optically active organic substances Biot observed that when a beam of plane-polarized light passes through a solution of certain organic molecules, the plane of polarization is rotated

19. Optical Activity Polarimeter Measures the amount of rotation A solution of optically active organic molecules is placed in a sample tube Plane-polarized light is passed through the tube Rotation of the polarization plane occurs Light goes through a second polarizer called the analyzer The new plane of polarization and degree of rotation can be found by rotating the analyzer until the light passes through it Amount of rotation is denoted  and is expressed in degrees

20. Optical Activity Assigning direction of rotation Levorotatory molecules Optically active molecules that rotate polarized light to the left (counterclockwise) Given the symbol (-) (-)-Morphine Dextrorotatory molecules Optically active a molecules that rotate polarized light to the right (clockwise) Given the symbol (+) (+)-sucrose

21. Optical Activity Rotation The amount of rotation observed in a polarimetry experiment depends on the number of optically active molecules Number of optically active molecules depends on sample concentration and sample pathlength The specific rotation, [  ] D Optical rotation expression under standard conditions The observed rotation when light of 589.6 nanometer (nm; 1 nm = 10 -9 m) wavelength is used with a sample pathlength l of 1 decimeter (dm; 1 dm = 10cm) and a sample concentration C of 1 g /mL Light of 589.6 nm, sodium D line, is the yellow light emitted from common sodium lamps

22. Optical Activity When optical rotation data are expressed in the standard way the specific rotation, [  ] D, is a physical constant characteristic of a given optically active compound (+)-lactic acid has [  ] D = +3.82 (-)-lactic acid has [  ] D = -3.82 Two enantiomers rotate the plane-polarized light to exactly the same extent but in opposite directions

23. Worked Example 9.2 Calculating an Optical Rotation A 1.20 g sample of cocaine, [  ] D = -16, was dissolved in 7.50 mL of chloroform and placed in a sample tube having a pathlength of 5.00 cm. What was the observed rotation?

24. Worked Example 9.2 Calculating an Optical Rotation Strategy Observed rotation, , is equal to specific rotation [  ] D, times sample concentration, C, times pathlength l :  = [  ] D x C x l where [  ] D = -16 l = 5.00 cm = 0.500 dm and C = 1.20 g /7.50 mL = 0.160 g /mL

25. Worked Example 9.2 Calculating an Optical Rotation Solution  = -16 x 0.500 x 0.160 = -1.3º

26. 9.4 Pasteur’s Discovery of Enantiomers Louis Pasteur discovered enantiomers in 1848 when he began his study of crystalline tartaric acid salts derived from wine He observed that two distinct kinds of crystals precipitated from a concentrated solution of ammonium tartrate The two kinds of crystals were mirror images Pasteur separated the crystals into piles of “left- handed” crystals and “right- handed” crystals

27. Pasteur’s Discovery of Enantiomers Solution of ammonium tartrate The original mixture, a 50 : 50 mixture of right and left, was optically inactive Solutions of crystals from each of the sorted piles were optically active Their specific rotations were equal in amount but opposite in sign Enantiomers, also called optical isomers Have identical physical properties, such as melting and boiling point Differ in the direction in which their solutions rotate plane-polarized light

28. 9.5 Sequence Rules for Specifying Configuration Configuration The three-dimensional arrangement of substituents at a chirality center Sequence rules for configuration of a chirality center: 1. Look at the four atoms directly attached to the chirality center and assign priorities in order of decreasing atomic number The atom with the highest atomic number is ranked first; the atom with the lowest atomic number (usually hydrogen) is ranked fourth

29. Sequence Rules for Specifying Configuration 2. If a decision cannot be reached by ranking the first atoms in the substituents, look at the second, third, or fourth atoms outward until a difference is found 3. Multiple-bonded atoms are equivalent to the same number of single-bonded atoms

30. Sequence Rules for Specifying Configuration Stereochemical configuration around the carbon Once priorities have been assigned to the four groups attached to the chiral carbon, orient the molecule so that the group of lowest priority (4) points directly back Look at the three remaining substituents R configuration If a curved arrow drawn (1 2 3) through substituents is clockwise S configuration If a curved arrow drawn (1 2 3) through substituents is counterclockwise

31. Sequence Rules for Specifying Configuration (-)-Lactic acid Rule 1 -OH has priority 1 -H has priority 4 Rule 2 -CO 2 H is higher in priority than –CH 3 O (the highest second atom in –CO 2 H) outranks H (the highest second atom in –CH 3 Has R configuration Curved arrow from 1 (-OH) to 2 (-CO 2 H) to 3 (-CH 3 ) is clockwise

32. Sequence Rules for Specifying Configuration (-)-Glyceraldehyde S configuration (+)-Alanine S configuration Both have the S configuration, although one is levorotatory and the other is dextrorotatory The sign of optical rotation, (+) or (-) is not related to the R,S designation

33. Sequence Rules for Specifying Configuration Absolute configuration The exact three-dimensional structure of a chiral molecule They are specified verbally by the Cahn- Ingold-Prelog R,S convention In 1951, an X-ray spectroscopic method for determining the absolute spatial arrangement of atoms in a molecule was found Based on these results, it can be said with a certainty that the R,S conventions are correct

34. Worked Example 9.3 Assigning Configuration to Chirality Centers Orient each of the following drawings so that the lowest- priority group is toward the rear, and then assign R or S configuration:

35. Worked Example 9.3 Assigning Configuration to Chirality Centers Strategy Start by indicating where the observer must be located–180º opposite the lowest-priority group Then imagine yourself in the position of the observer, and redraw what you see

36. Worked Example 9.3 Assigning Configuration to Chirality Centers Solution In (a) you would be located in front of the page toward the top right of the molecule, and you would see group 2 to your left, group 3 to your right, and group 1 below you. This corresponds to an R configuration

37. Worked Example 9.3 Assigning Configuration to Chirality Centers In (b), you would be located behind the page toward the top left of the molecule from your point of view, and you would see group 3 to your left, group 1 to your right, and group 2 below you. This corresponds to an R configuration

38. Worked Example 9.4 Drawing the Three-Dimensional Structure of an Enantiomer Draw the tetrahedral representation of (R)-2-chlorobutane.

39. Worked Example 9.4 Drawing the Three-Dimensional Structure of an Enantiomer Strategy Begin assigning priorities to the four substituents bonded to the chirality center: (1) –Cl, (2) –CH 2 CH 3, (3) –CH 3, (4) –H To draw a tetrahedral representation of the molecule, orient the lowest-priority –H group away from you and imagine that the other three groups are coming out of the page toward you Place the remaining three substituents such that the direction of travel 1 2 3 is clockwise (right turn), and tilt the molecule toward you to bring the rear hydrogen into view

40. Worked Example 9.4 Drawing the Three-Dimensional Structure of an Enantiomer Solution

41. 9.6Diastereomers Molecules with more than one chirality center A molecule with n chirality centers can have up to 2 n stereoisomers (although it may have fewer) Amino acid threonine (2-amino-3-hydroxybutanoic acid) Has two chirality centers (C2 and C3) Four possible stereoisomers

42. Diastereomers The four stereoisomers of 2-amino-3-hydroxybutanoic acid

43. Diastereomers The four stereoisomers of 2-amino-3-hydroxybutanoic acid can be grouped into two pairs of enantiomers The 2R, 3R stereoisomer is the mirror image of 2S, 3S The 2R, 3S stereoisomer is the mirror image of 2S, 3R Diastereomers They are stereoisomers that are not mirror images 2R, 3R stereoisomer and 2R, 3S stereoisomer They are stereoisomers but not enantiomers Enantiomers have opposite configurations at all chirality centers Diastereomers have opposite configurations at one or more of the chirality centers but the same configuration at others

44. Diastereomers Of the four stereoisomers of threonine, only the 2S, 3R isomer [  ] D = -28.3 occurs naturally in plants and animals and is an essential human nutrient Most biological molecules are chiral, and usually only one stereoisomer is found in nature

45. Diastereomers Epimers Two diastereomers that differ at only one chirality center but are the same at all the others Cholestanol and coprostanol are both found in human feces and both have nine chirality centers Eight of the nine chirality centers are identical, but the one at C5 is different Cholestanol and coprostanol are epimeric at C5

46. 9.7 Meso Compounds Tartaric acid A compound with more than one chirality center

47. Meso Compounds 2R, 3R and 2S, 3S structures represent a pair of enantiomers because they are not identical 2R, 3S and 2S, 3R structures are identical The molecule has a plane of symmetry Achiral

48. Meso Compounds Meso compounds Molecule that are achiral, yet contain chirality centers Tartaric acid exists as only three stereoisomers: two enantiomers and one meso form

49. Meso Compounds The (+)- and (-)-tartaric acids Have identical melting points, solubilities, and densities Differ in sign of their rotation of plane-polarized light The meso isomer is diastereomeric with the (+) and (-) forms It has no mirror-image relationship to (+)- and (-)-tartaric acids Is a different compound Has different physical properties

50. Worked Example 9.5 Distinguishing Chiral Compounds from Meso Compounds Does cis-1,2-dimethylcyclobutane have any chirality centers? Is it chiral?

51. Worked Example 9.5 Distinguishing Chiral Compounds from Meso Compounds Strategy To find a chiral center, look for a carbon atom bonded to four different groups To see whether the molecule is chiral, look for the presence or absence of a symmetry plane Not all molecules with chirality centers are chiral overall – meso compounds are an exception

52. Worked Example 9.5 Distinguishing Chiral Compounds from Meso Compounds Solution A look at the structure of cis-1,2-dimethylcyclobutane show that both methyl-bearing ring carbons (C1 and C2) are chirality centers Overall the compound is achiral because there is a symmetry plane bisecting the ring between C1 and C2 Cis-1,2-dimethylcyclobutane is a meso compound

53. 9.8 Racemates and the Resolution of Enantiomers Racemate or racemic mixture Denoted by either the symbol (±) or the prefix d,l to indicate an equal mixture of dextrorotatory and levorotatory forms Show no optical rotation because the (+) rotation form one enantiomer exactly cancels the (-) rotation from the other Pasteur started with a 50 : 50 mixture of the two chiral tartaric acid enantiomers He was able to resolve, or separate, the racemic tartaric acid into its (+) and (-) enantiomers

54. Racemates and the Resolution of Enantiomers The most common method of resolution uses an acid-base reaction between the racemate of a chiral carboxylic acid (RCO 2 H) and an amine base (RNH 2 ) to yield an ammonium salt Reaction of the racemate of a chiral acid, lactic acid, and an achiral amine base, methylamine, CH 3 NH 2 The product is a 50 : 50 mixture of methylammonium (+)-lactate and methylammonium (-)-lactate

55. Racemates and the Resolution of Enantiomers Reaction of the racemate of lactic acid and a single enantiomer of a chiral amine base (R)-1-phenylethylamine (+)- and (-)-lactic acids react with (R)-1-phenylethylamine to give an R,R ammonium salt and an S,R ammonium salt Ammonium salts are two different diastereomers with different chemical and physical properties

56. Worked Example 9.6 Predicting the Chirality of a Product We’ll see in Section 16.3 that carboxylic acids (RCO 2 H) react with alcohols (R’OH) to form esters (RCO 2 R’). Suppose that (±)-lactic acid reacts with CH 3 OH to form the ester, methyl lactate. What stereochemistry would you expect the product(s) to have? What is the relationship of the products?

57. Worked Example 9.6 Predicting the Chirality of a Product Solution Reaction of a racemic acid with an achiral alcohol such as methanol yields a racemic mixture of mirror- image (enantiomeric) products:

58. 9.9 A Brief Review of Isomerism Isomers are compounds that have the same chemical formula but different structures

59. A Brief Review of Isomerism Two fundamental types of isomers: 1. Constitutional isomers Compounds whose atoms are connected differently Kinds of constitutional isomers Skeletal isomers Functional isomers Positional isomers

60. A Brief Review of Isomerism 2. Stereoisomers Compounds whose atoms are connected in the same order but with a different geometry Enantiomers

61. A Brief Review of Isomerism Diastereomers Cis-trans isomers are non-mirror-image stereoisomers

62. 9.10 Stereochemistry of Reactions: Addition of H 2 O to an Achiral Alkene Most of the biochemical reactions that take place in the body, as well as many organic reactions in the laboratory, yield products with chirality Addition of H 2 O to but-1-ene in the laboratory yields butan-2-ol, a chiral alcohol A 50 : 50 mixture of R and S enantiomers are produced

63. Stereochemistry of Reactions: Addition of H 2 O to an Achiral Alkene But-1-ene is first protonated to yield an intermediate secondary (2º) carbocation The trivalent carbon is sp 2 -hybridized and planar The cation has no chirality centers, has a plane of symmetry, and is achiral The cation can react with H 2 O equally well from either the top or the bottom Reaction from the top leads to (S)-butan-2-ol through the transition state 1 (TS 1) Reaction from the bottom leads to (R)-butan-2-ol through the transition state 2 (TS 2)

64. Stereochemistry of Reactions: Addition of H 2 O to an Achiral Alkene The two transition states TS 1 and TS 2 Are mirror images Have identical energies Form at identical rates Are equally likely to occur

65. Stereochemistry of Reactions: Addition of H 2 O to an Achiral Alkene A reaction between two optically inactive (achiral) reactants always leads to an optically inactive product Optically active products can result only from an optically active reactant Enzyme-catalyzed reactions give a single enantiomer of a chiral product, even when the substrate is achiral One step in the citric acid cycle is the aconitase-catalyzed addition of water to cis-asconitate Only the (2R, 3S) enantiomer of the product is formed

66. 9.11 Stereochemistry of Reactions: Addition of H 2 O to a Chiral Alkene Reactions of single enantiomer of a chiral reactant Addition of H 2 O to the chiral alkene (R)-4-methylhex- 1-ene The product is 4-methylhexan-2-ol which has two chirality centers and so has four possible stereoisomers

67. Stereochemistry of Reactions: Addition of H 2 O to a Chiral Alkene C4 has the R configuration in the starting material and this chirality center is unaffected by the reaction The configuration at C4 in the product remains R (assuming that the relative priorities of the four attached groups are not changed by the reaction) C2 is the newly formed chiral center in the product The stereochemistry at C2 is established by reaction of H 2 O with a carbocation intermediate This carbocation does not have a plane of symmetry and so does not react equally well from top and bottom faces Two diastereomeric products (2R, 4R)-4-methylhexan- 2-ol and (2S, 4R)-4-methylhexan-2-ol are formed in unequal amounts The mixture is optically active

68. Stereochemistry of Reactions: Addition of H 2 O to a Chiral Alkene The reaction of a chiral reactant with an achiral reactant always leads to unequal amounts of diastereomeric products If the chiral reactant is optically active because only one enantiomer is reacted, then the products are also optically active

69. 9.12 Chirality at Nitrogen, Phosphorus, and Sulfur The most common cause for chirality is the presence of four different substituents bonded to a tetrahedral atom The atom does not necessarily have to be a carbon A nonbonding pair can be a substituent Nitrogen, phosphorus and sulfur can all be chiral centers Trivalent nitrogen compounds Undergo a rapid umbrella-like inversion that interconverts enantiomers Except for in special cases, individual enantiomers cannot be isolated

70. Chirality at Nitrogen, Phosphorus, and Sulfur Trivalent phosphorus compounds or phosphines The inversion at phosphorus is substantially slower than inversion at nitrogen Stable chiral phosphines can be isolated (R)- and (S)-methylpropylphenylphosphine are configurationally stable at 100 ºC

71. Chirality at Nitrogen, Phosphorus, and Sulfur Trivalent sulfur compounds called sulfonium salts (R 3 S + ) can be chiral Undergo relatively slow inversions Chiral sulfonium salts are configurationally stable and can be isolated Coenzyme S-adenosylmethionine is involved in many metabolic pathways as a source of CH 3 groups The “S” in S-adenosylmethionine stands for sulfur and means that the adenosyl group is attached to the sulfur atom of methionine The molecule has (S) stereochemistry at sulfur, its (R) enantiomer is also known, but has no biological activity

72. 9.13 Prochirality Prochiral molecule A molecule that can be converted from achiral to chiral in a single chemical step An unsymmetrical ketone, butan-2-one, is prochiral because it can be converted to the chiral alcohol butan-2-ol by addition of hydrogen

73. Prochirality The enantiomer formed depends on which face of the planar carbonyl group undergoes reaction The stereochemical descriptors Re and Si are used to distinguish possibilities 1. Assign priorities to the three groups attached to the trigonal, sp 2 -hybridized carbon 2. Imagine curved arrow from the highest to second-highest to third-highest priority substituent

74. Prochirality Re designator is used on the face where the arrows curve clockwise Addition of hydrogen from the Re faces gives (S)-butan-2-ol Si designator is used to the face where the arrows curve counterclockwise Addition of hydrogen from the Si faces gives (R)-butan-2-ol

75. Prochirality Compounds with tetrahedral, sp 3 -hybridized atoms can be prochiral Prochirality center An atom in a compound that can be converted into a chirality center by changing one of its attached substituents An sp 3 -hybridized atom is a prochirality center if changing one of its attached groups makes it a chirality center -CH 2 OH carbon atom of ethanol Changing one of its attached –H atoms converts it into a chirality center

76. Prochirality Distinguishing between two identical atoms (or groups) on a prochirality center Imagine raising the priority of one atom over the other without affecting its priority with respect to other attached groups On the –CH 2 OH carbon of ethanol, imagine replacing one of the 1 H atoms (protium) by 2 H (deuterium) The atom whose replacement leads to an R chirality center is said to be pro-R The atom whose replacement leads to an S chirality center is said to be pro-S

77. Prochirality Many biological reactants involve prochiral compounds One of the steps in the citric cycle is the addition of H 2 O to fumarate to give malate Addition of –OH occurs on the Si face of fumarate and gives (S)-malate as product

78. Prochirality Alcohol dehydrogenase occurs during the reaction of ethanol with coenzyme NAD + catalyzed by yeast Occurs with exclusive removal of the pro-R hydrogen from ethanol and with addition only to the Re face of NAD +

79. 9.14 Chirality in Nature Enantiomers of a chiral molecule Have same physical properties Usually have different biological properties (+) enantiomer of limonene has the odor of oranges (–) enantiomer of limonene has the odor of lemons

80. Chirality in Nature Dramatic examples of how a change in chirality can affect the biological properties of a molecule are seen in many drugs Fluoxetine, a heavily prescribed medication sold under the trade name Prozac Racemic fluoxetine is an effective antidepressant but has no activity against migraine The pure S enantiomer works well in preventing migraine

81. Chirality in Nature To have a biological effect, a substance typically must fit into an appropriate receptor that has an exactly complementary shape Biological receptors (such as enzymes) are chiral Only one enantiomer of a chiral substrate can fit into the receptor The mirror-image enantiomer will be a misfit

82. Chirality in Nature The reaction of ethanol with NAD + catalyzed by yeast alcohol dehydrogenase The reaction occurs with exclusive removal of the pro- R hydrogen from ethanol and with addition only to the Re face of NAD + Imagine that the enzyme site has three binding sites: One for the coenzyme One for the –OH group One for the CH 3 group Only the pro-R hydrogen of the substrate is exposed to the coenzyme when it sits in the active site