Chapter 7 Stereochemistry Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. 1

The term “chirality” applies to these isomers and is introduced here. Stereochemistry The class of stereoisomers that is presented in Chapter 7 is different than the cis/trans (or E/G) geometric isomers. These isomers are a result of a mirror image relationship between two compounds. The term “chirality” applies to these isomers and is introduced here. 3

7.1 Molecular Chirality: Enantiomers 2

Chirality A molecule is chiral if its two mirror image forms are not superimposable upon one another. A molecule is achiral if its two mirror image forms are superimposable. An achiral molecule does not exhibit stereoisomerism. 3

Bromochlorofluoromethane is chiral Cl It is not superimposable point for point on its mirror image. Note the four different attachments on C. Br H F 4

Bromochlorofluoromethane is chiral Cl Cl Br Br H H F F To demonstrate nonsuperimposability, rotate this model 180° around a vertical axis. 4

Bromochlorofluoromethane is chiral Cl Br Br Cl H H F F The structure on the right has been rotated. 4

Another look 6

These two structures are enantiomers. Nonsuperimposable mirror images are called enantiomers, they occur in pairs. These two structures are enantiomers. 7

Classification of Isomers constitutional isomers stereoisomers diastereomers enantiomers (geometric) Includes E-Z isomers 8

Isomers with Chiral Centers diastereomers enantiomers meso compounds 8

Chlorodifluoromethane is achiral 9

Chlorodifluoromethane is achiral The two structures at the top are mirror images, but because they can be superimposed on each other they are identical and are not enantiomers. 9

7.2 The Chirality Center 11

This means that this carbon must be sp3 and can not be sp2 or sp. A Chiral Compound A compound containing a carbon atom with four different groups attached to it. This means that this carbon must be sp3 and can not be sp2 or sp. w x y z C The carbon is called a(n): chirality or chiral center asymmetric center stereocenter stereogenic center 12

Chirality and chirality centers A molecule with a single chirality center is chiral. Enantiomeric structures are possible. Bromochlorofluoromethane is an example. Cl F Br H C 13

Chirality and chirality centers 2-Butanol is another example. CH3 OH H C CH2CH3 Note that the CH2 and CH3's are not chiral. 13

Examples of molecules with 1 chirality center CH2CH3 CH2CH2CH2CH3 CH3CH2CH2 4-ethyl-4-methyloctane, a chiral alkane 13

Examples of molecules with 1 chirality center OH 3,7-dimethyl-1,6-octadien-3-ol,Linalool, a naturally occurring chiral alcohol 13

Examples of molecules with 1 chirality center CHCH3 1,2-Epoxypropane: one of the ring carbon atoms is a chirality center. attached to this chirality center are: —H —CH3 —OCH2 or just —O —CH2O or just —CH2 13

Examples of molecules with 1 chirality center Limonene also has a chirality center as part of the ring. CH3 H C CH2 attached to the chirality center are: —H —CH2CH2 —CH2CH= —C= 13

Examples of molecules with 1 chirality center D T H Chiral as a result of isotopic substitution 13

A molecule with a single chirality center must be chiral (enantiomeric structures are possible). But, a molecule with two or more chirality centers may have structures that are chiral and others that are not (Sections 7.11-7.14). Distinguish: enantiomers, diastereomers and meso compounds. 18

7.3 Symmetry in Achiral Structures 19

Symmetry tests for achiral structures Any molecule with a plane of symmetry or a center of symmetry must be achiral. 18

Plane of symmetry A plane of symmetry bisects a molecule into two mirror image halves. Chlorodifluoromethane has a plane of symmetry. 21

Plane of symmetry A plane of symmetry bisects a molecule into two mirror image halves. 1-Bromo-1-chloro-2-fluoroethene has a plane of symmetry. 21

Center of symmetry A point in the center of the molecule is a center of symmetry if a line drawn from it to any element, when extended an equal distance in the opposite direction, encounters an identical element. 21

7.4 Optical Activity Optical activity is a property of some compounds containing chiral centers (enantiomers and diastereomers). 19

Two enantiomers have equal and opposite specific rotation values. Optical Activity A substance is optically active if it rotates the plane of polarized light. In order for a substance to exhibit optical activity, it must contain a chiral carbon or carbons. Two enantiomers have equal and opposite specific rotation values. 2

Light Light has wave properties, i.e. shows a periodic increase and decrease in amplitude of the electromagnetic wave. 3

Light Optical activity is usually measured using light having a wavelength of 589 nm (monochromatic). This is the wavelength of the yellow light from a sodium lamp and is called the D line of sodium. 4

Polarized Light Ordinary (nonpolarized) light consists of many beams vibrating in different planes. Plane-polarized light consists of only those beams that vibrate in the same plane. 5

Polarization of light is accomplished using a Nicol prism or a polaroid lens. Light that passes through is in the plane of the crystals 6

Rotation of Plane-polarized Light by a chiral compound  7

Therefore, specific rotation [] is defined as: Observed rotation () depends on the number of molecules encountered and is proportional to: path length (l), and concentration (c). Therefore, specific rotation [] is defined as: 100  cl c = concentration = g/100 mL l = length in decimeters  = observed rotation [] = 8

A racemic mixture is optically inactive. ( = 0) A mixture containing equal amounts of a pair of enantiomers is called a racemic mixture. A racemic mixture is optically inactive. ( = 0) A compound that is optically inactive can be either an achiral substance, a racemic mixture or a meso compound. 9

Optical purity = []o / []p (observed/pure) An optically pure substance consists exclusively of a single enantiomer. The excess of one enantiomer over another in a mixture is given by: Enantiomeric excess = (R-S)/(R+S) by weight or % one enantiomer – % other enantiomer Optical purity = []o / []p (observed/pure) Optical purity = enantiomeric excess 10

7.5 Absolute and Relative Configuration 19

Absolute configuration is the precise arrangement of atoms in space. Relative configuration compares the arrangement of atoms in space of one compound with those of another. Until the 1950s, all configurations were relative. Absolute configuration is the precise arrangement of atoms in space. Note: Absolute configuration and Specific rotation are not readily predicted from one another. 15

Relative Configuration Pd CH3CHCH OH CH2 CH3CHCH2CH3 OH [] + 33.2° [] + 13.5° No bonds are made or broken at the chirality center in this experiment. In this case, when (+)-3-buten-2-ol and (+)-2-butanol have the same sign of rotation, the arrangement of atoms in space is analogous. The two have the same relative configuration. 16

Two Possibilities H HO H HO H2, Pd H OH H OH H2, Pd But in the absence of additional information, we can't tell which structure corresponds to (+)-3-buten-2-ol, and which one to (–)-3-buten-2-ol. 17

Two Possibilities H HO H HO H2, Pd H OH H OH H2, Pd Nor can we tell which structure corresponds to (+)-2-butanol, and which one to (–)-2-butanol. 17

enantiomers enantiomers Optical Rotations H HO H HO H2, Pd [] +33.2° [] +13.5° H OH H OH H2, Pd [] –13.5° [] –33.2° enantiomers enantiomers 17

Relative Configuration HBr CH3CH2CHCH2OH CH3 CH3CH2CHCH2Br CH3 [] -5.8° [] + 4.0° Relative configuration is independent of specific optical rotation. No bonds are made or broken at the chirality center in the reaction shown, so the relative positions of the atoms are the same, yet the sign of rotation changes. 16

7.6 The Cohn-Ingold-Prelog R-S Notational System Designating Absolute Configuration 19

Two Requirements for a System for Specifying Absolute Configuration 1. Rules for ranking substituents at a chirality center are needed. 2. A convention for orienting a molecule so that order of appearance of substituents can be compared with rank. The system used was devised by R. S. Cahn, Sir Christopher Ingold, and V. Prelog. This CIP ranking system is the same as was used for E-Z isomers. 2

Order of decreasing rank: 4 > 3 > 2 > 1 Example 4 3 2 1 4 3 2 1 Order of decreasing rank: 4 > 3 > 2 > 1 5

The Cahn-Ingold-Prelog Rules (Table 7.1) 1. Rank the substituents at the chirality center according to same rules used in E-Z notation. 2. Orient the molecule so that lowest-ranked substituent points away from you. 3. If the order of decreasing precedence traces a clockwise path, the absolute configuration is R. If the path is counterclockwise, the configuration is S. 6

Order of decreasing rank: 4 > 3 > 2 > 1 Example 4 3 2 1 4 3 2 1 Order of decreasing rank: 4 > 3 > 2 > 1 clockwise R counterclockwise S 5

Enantiomers of 2-butanol C OH H3C H CH3CH2 C HO CH3 H CH2CH3 (S)-2-Butanol (R)-2-Butanol 8

Very important! Two different compounds with the same sign of rotation need not have the same configuration. Verify this statement by doing Problem 7.9 on page 289. All four compounds have positive rotations. What are their configurations according to the Cahn-Ingold-Prelog rules? 10

Chirality Center in a Ring H3C R —CH2C=C > —CH2CH2 > —CH3 > —H 11

7.7 Fischer Projections Purpose of Fischer projections is to show configuration at chirality center without necessity of drawing wedges and dashes or using models. 19

Rules for Fischer Projections Br Cl F Arrange the molecule so that at the chirality center, horizontal bonds point toward you and vertical bonds point away from you. This is important because the Fisher Projection is planar. 13

Rules for Fischer Projections Br Cl Br Cl F F Projection of molecule on page is a cross. When represented this way it is understood that horizontal bonds project outward, vertical bonds are back. 13

7.8 Properties of Enantiomers 19

Physical Properties of Enantiomers Same: melting point, boiling point, density, index of refraction, etc (all physical properties). Different: properties that depend on shape of molecule (biological-physiological properties) can be different. 11

(–)-Carvone spearmint oil (+)-Carvone caraway seed oil Odor CH3 CH3 O O H3C CH2 H3C CH2 (–)-Carvone spearmint oil (+)-Carvone caraway seed oil 12

Chiral Drugs Ibuprofen is chiral, but normally sold as a racemic mixture. The S enantiomer is the one responsible for its analgesic and anti-inflammatory properties. CH2CH(CH3)2 H H3C C O HO 13

7.9 The Chirality Axis Compounds with no Chiral Center 19

The Chirality Axis Some molecules are chiral but do not contain a chirality center. Some of these contain a chirality axis, an axis about which groups are arranged so that the spatial arrangement is not superimposable on its mirror image. Examples include substituted biphenyls and allenes: 2

In the appropriately substituted biphenyls, rotation around the bond joining the rings is restricted and the enantiomers can be isolated: Conformational isomers that are stable, isolable compounds are called atropisomers.

Substituted 1,1’-binaphthyl derivatives exhibit atropisomerism due to hindered rotation about the single bond that connects the two naphthalene rings. An example is (S)-(-)-BINAP shown below and discussed further in Chapter 14.

7.10 Reactions that Create a Chirality Center 19

Many Reactions Convert Achiral Reactants to Chiral Products It is important to recognize, however, that if all of the components of the starting state (reactants, catalysts, solvents, etc.) are achiral, any chiral product will be formed as a racemic mixture. This generalization can be more simply stated as "Optically inactive starting materials can't give optically active products." (Remember: In order for a substance to be optically active, it must be chiral and one enantiomer must be present in greater amounts than the other.) 2

Example CH3COOH O H3C O CH2 C H CH3CH CH2 Achiral Chiral, but racemic

Epoxidation from this direction gives R epoxide. 50% R Epoxidation from this direction gives S epoxide. S 3

Example Br2, H2O CH3CH CH2 CH3CHCH2Br OH Achiral Chiral, but racemic 2

Example HBr CH3CH CHCH3 CH3CHCH2CH3 Br Achiral Chiral, but racemic 2

Many Reactions Convert Chiral Reactants to Chiral Products However, if the reactant is racemic, the product will also be racemic. Remember: "Optically inactive starting materials can't give optically active products." 2

Example HBr CH3CHCH2CH3 OH CH3CHCH2CH3 Br Chiral, but racemic

Many Biochemical Reactions Convert an Achiral Reactant to a Single Enantiomer of a Chiral Product Reactions in living systems may be catalyzed by enzymes, which are enantiomerically homogeneous. The enzyme (catalyst) is part of the reacting system, so such reactions don't violate the generalization that "Optically inactive starting materials can't give optically active products." 2

Example C OH H HO2C HO2CCH2 HO2C H H2O C fumarase H CO2H Fumaric acid (S)-(–)-Malic acid Achiral Single enantiomer 2

Chiral Molecules with Two 7.11 Chiral Molecules with Two Chirality Centers How many stereoisomers are possible when a molecule contains two chirality centers? 19

2,3-Dihydroxybutanoic Acid CH3CHCHCOH HO OH 3 2 What are all the possible R and S combinations of the two chirality centers in this molecule ? 4 Combinations = 4 Stereoisomers Carbon-2 R R S S Carbon-3 R S R S 6

2,3-Dihydroxybutanoic Acid CH3CHCHCOH HO OH 3 2 What is the relationship between these stereoisomers ? enantiomers: 2R,3R and 2S,3S 2R,3S and 2S,3R Carbon-2 R R S S Carbon-3 R S R S 6

R S R S R S HO CO2H CH3 H OH CO2H CH3 H HO OH [] = -9.5° [] = +9.5° [] = -17.8° [] = +17.8° enantiomers CO2H H CH3 HO R S CO2H CH3 H OH R S 12

2,3-Dihydroxybutanoic Acid CH3CHCHCOH HO OH 3 2 But not all relationships are enantiomeric. Stereoisomers that are not enantiomers are diastereomers. Carbon-2 R R S S Carbon-3 R S R S 6

R S R S R S HO CO2H CH3 H OH CO2H CH3 H HO OH [] = -9.5° [] = +9.5° [] = -17.8° [] = +17.8° enantiomers diastereomers CO2H H CH3 HO R S CO2H CH3 H OH R S 12

Fischer Projections For Fischer projection: horizontal bonds point toward you; vertical bonds point away. A staggered conformation does not have the correct orientation of bonds for Fischer projection. CO2H CH3 13

Fischer Projections Transform molecule to eclipsed conformation in order to construct Fischer projection. CO2H CH3 OH H 13

Easiest to apply using Fischer projections Erythro and Threo Stereochemical prefixes used to specify relative configuration in molecules with two chirality centers Easiest to apply using Fischer projections Orientation: vertical carbon chain 6

Erythro When the carbon chain is vertical and the same (or analogous) substituents are on the same side of the Fischer projection, this is the erythro form. CO2H CH3 OH H CO2H HO H HO H –9.5° CH3 +9.5° 14

Threo When the carbon chain is vertical and the same (or analogous) substituents are on opposite sides of the Fischer projection, this is the threo form. CO2H CH3 OH H HO OH CO2H CH3 H HO +17.8° –17.8° 14

Two Chirality Centers in a Ring trans-1-Bromo-1-chlorocyclopropane nonsuperimposable mirror images; enantiomers 16

Two Chirality Centers in a Ring cis-1-Bromo-1-chlorocyclopropane nonsuperimposable mirror images; enantiomers 16

Two Chirality Centers in a Ring cis-1-Bromo-1-chloro- cyclopropane trans-1-Bromo-1-chloro- cyclopropane Stereoisomers that are not enantiomers are diastereomers (these are not mirror images). 16

Achiral Molecules with Two 7.12 Achiral Molecules with Two Chirality Centers It is possible for a molecule to have chirality centers yet be achiral. 19

2,3-Butanediol CH3CHCHCH3 HO OH Consider a molecule with two equivalently substituted chirality centers such as 2,3-butanediol. 6

Three Stereoisomers of 2,3-Butanediol 2R,3R 2S,3S 2R,3S chiral chiral achiral 6

Three Stereoisomers of 2,3-Butanediol OH CH3 HO CH3 OH H HO H CH3 OH 2R,3R 2S,3S 2R,3S chiral chiral achiral 6

Three Stereoisomers of 2,3-Butanediol These two are enantiomers. 2R,3R 2S,3S chiral chiral 6

Three Stereoisomers of 2,3-Butanediol OH CH3 HO CH3 OH H HO These two are enantiomers. 2R,3R 2S,3S chiral chiral 6

Three Stereoisomers of 2,3-Butanediol The third structure is superposable on its mirror image. Therefore, this structure and its mirror image are the same. It is called a meso form. A meso form is an achiral molecule that has chirality centers. 2R,3S achiral 6

Three Stereoisomers of 2,3-Butanediol Fischer projections of the meso form. H HO CH3 H CH3 OH 2R,3S achiral 6

Three Stereoisomers of 2,3-Butanediol Meso forms have a plane of symmetry and/or a center of symmetry. Plane of symmetry is most common case. Top half of molecule is mirror image of bottom half. 2R,3S achiral 6

Three Stereoisomers of 2,3-Butanediol HO CH3 H CH3 OH A line drawn the center of the Fischer projection of a meso form bisects it into two mirror- image halves. 2R,3S achiral 6

S R R Cyclic Compounds chiral meso There are three stereoisomers of 1,2-dichloro- cyclopropane; the achiral (meso) cis isomer and two enantiomers of the trans isomer. 22

Molecules with Multiple 7.13 Molecules with Multiple Chirality Centers 19

How Many Stereoisomers? Maximum number of stereoisomers = 2n. Where n = number of structural units capable of stereochemical variation. Structural units include chirality centers and cis and/or trans double bonds. Number is reduced to less than 2n if meso forms are possible. 24

Example O HOCH2CH—CH—CH—CHCH OH 4 chirality centers 16 stereoisomers 6

One is "natural" cholic acid. Cholic Acid (Figure 7.11) HO OH H H3C CH2CH2CO2H CH3 11 chirality centers 211 = 2048 stereoisomers One is "natural" cholic acid. A second is the enantiomer of natural cholic acid. 2046 are diastereomers of cholic acid. 26

How Many Stereoisomers? 3-Penten-2-ol R E E S HO H H OH Z R Z S HO H H OH 27

Reactions that Produce Diastereomers 7.14 Reactions that Produce Diastereomers 19

Stereochemistry of Addition to Alkenes + E—Y E Y In order to know understand stereochemistry of product, you need to know two things: (1) Stereochemistry of alkene (cis or trans; Z or E) (2) Stereochemistry of mechanism (syn or anti) 2

Bromine Addition to trans-2-Butene Fig. 7.12 Anti addition to trans-2-butene gives meso diastereomer. 4

Bromine Addition to cis-2-Butene Fig. 7.12 Anti addition to cis-2-butene gives racemic mixture of chiral diastereomer. 4

Epoxidation of trans-2-Butene Problem 7.26 RCO3H + R S 50% 50% Syn addition to trans-2-butene gives racemic mixture of chiral diastereomer. 4

Epoxidation of cis-2-Butene Problem 7.26 RCO3H S R meso syn addition to cis-2-butene gives meso diastereomer 4

Stereospecific Reaction Of two stereoisomers of a particular starting material, each one gives different stereoisomeric forms of the product. Related to mechanism: terms such as syn addition and anti addition refer to stereospecificity. 8

Stereospecific reactions Compound Reaction Attack Product(s) trans-2-butene cis-2-butene bromination anti 2R,3R + 2S,3S epoxidation syn meso . Stereospecific reactions 7

Stereoselective reaction A single starting material can give two or more stereoisomeric products, but gives one of them in greater amounts than any other. CH3 CH2 H CH3 H H H2 Pt CH3 + H CH3 68% 32% 9

Resolution of Enantiomers 7.15 Resolution of Enantiomers separation of a racemic mixture into its two enantiomeric forms 19

P(+) C(+) C(-) C(+) C(-) 2P(+) C(+)P(+) C(-)P(+) C(+)P(+) C(-)P(+) Strategy P(+) C(+) C(-) pure Enantiomers, racemic C(+) C(-) Add pure enantiomer 2P(+) C(+)P(+) C(-)P(+) C(+)P(+) C(-)P(+) Separate diastereomers pure 11

Stereoregular Polymers 7.16 Stereoregular Polymers atactic isotactic syndiotactic 19

Atactic Polypropylene Random stereochemistry of sidechains (methyl groups here) attached to main chain = stereorandom polymer (atactic). Properties not very useful for fibers etc. Formed by free-radical polymerization. 13

Isotactic Polypropylene All sidechains (methyl groups here) on same side of main chain = stereoregular polymer (isotactic). Useful properties. Prepared by coordination polymerization under Ziegler-Natta conditions. 13

Syndiotactic Polypropylene Sidechains (methyl groups here) alternate from one side to the other on main chain = stereoregular polymer (syndiotactic). Useful properties. Prepared by coordination polymerization under Ziegler-Natta conditions. 13

Chirality Centers Other than Carbon 7.17 Chirality Centers Other than Carbon 19

Silicon b b a a Si d d Si c c Silicon, like carbon, forms four bonds in its stable compounds and many chiral silicon compounds have been resolved. 6

Nitrogen in Amines b b a very fast a N : : N c c Pyramidal geometry at nitrogen can produce a chiral structure, but enantiomers equilibrate too rapidly to be resolved. 6

Phosphorus in Phosphines b b a slow a P : : P c c Pyramidal geometry at phosphorus can produce a chiral structure; pyramidal inversion slower than for amines and compounds of the type shown have been resolved. 6

Sulfur in Sulfoxides b b a slow a + S : : S + O_ O_ Pyramidal geometry at sulfur can produce a chiral structure; pyramidal inversion is slow and compounds of the type shown have been resolved. 6

End of Chapter 7 Stereochemistry 19