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Frederick A. Bettelheim William H. Brown Mary K. Campbell Shawn O. Farrell www.cengage.com/chemistry/bettelheim Chapter 15 Chirality: The Handedness of Molecules William H. Brown • Beloit College Isomers Types of isomers • In this chapter we study enantiomers and diastereomers. Is omers same different connectivity connectivity Stereoisomers Constitutional Isomers without with stereocenters stereocenters Achiral Cis-Trans Is omers Chiral Enantiomers Diastereomers 15-2 Enantiomers Enantiomers: Nonsuperposable mirror images. • As an example of a molecule that exists as a pair of enantiomers, consider 2-butanol. OH C H H3 C CH 2 CH 3 Origin al molecu le HO H C CH 3 CH3 CH2 Mirror image 15-3 Enantiomers One way to see that the mirror image of 2-butanol is not superposable on the original is to rotate the mirror image. OH C H H3 C CH2 CH3 Original molecule 180° OH H C CH 3 CH3 CH2 Mirror image rotate by 180° about the C-OH b on d OH C CH CH 2 3 H3 C H The mirror image rotated b y 180° 15-4 Enantiomers • Now try to fit one molecule on top of the other so that all groups and bonds match exactly. OH The mirror image turn ed by 180° C CH CH 2 3 H3 C H OH The original molecule C H H3 C CH2 CH3 • The original and mirror image are nonsuperposable. • They are different molecules. • Nonsuperposable mirror images are enantiomers. 15-5 Enantiomers Objects that are nonsuperposable on their mirror images are chiral (from the Greek: cheir, hand). • They show handedness. The most common cause of enantiomerism in organic molecules is the presence of a carbon with four different groups bonded to it. • A carbon with four different groups bonded to it is called a stereocenter. 15-6 Enantiomers • If an object and its mirror image are superposable, they are identical and there is no possibility of enantiomerism. • We say that such an object is achiral (without chirality). • As an example of an achiral molecule, consider 2propanol. • notice that it has no stereocenter. OH C H H3 C CH3 Origin al molecu le OH H C CH 3 H3 C Mirror image 15-7 Enantiomers • To see the relationship between the original and its mirror image, rotate the mirror image by 120°. OH C H H3 C CH3 Origin al molecu le 120° OH H C CH 3 H3 C Mirror image rotate by 120° about th e C-OH bond OH C H H3 C CH3 The mirror image rotated b y 120° • When we do this rotation, we see that all atoms and bonds of the mirror image fit exactly on the original. • This means that the original and its mirror image are the same molecule. • They are just viewed from different perspectives. 15-8 Enantiomers • To summarize; • Objects that are nonsuperposable on their mirror images are chiral (they show handedness). • The most common cause of chirality among organic molecules is the presence of a carbon with four different groups bonded to it. • We call a carbon with four different groups bonded to it a stereocenter. • Objects that are superposable on their mirror images are achiral (without chirality). • Nonsuperposable mirror images are called enantiomers. • Enantiomers always come in pairs. 15-9 The R,S System Because enantiomers are different compounds, each must have a different name. • Here are the enantiomers of the over-the-counter drug ibuprofen. H CH3 COOH The inactive enan tiom er H3 C H HOOC Th e activ e enantio mer • The R,S system is a way to distinguish between enantiomers without having to draw them and point to one or the other. HW:1- What is a racemic mixture?; 2- Why is ibuprophen sold as a racemic mixture?; 3- What would be the effect if it weren’t? *expect a test question on this! 15-10 The R,S System The first step in assigning an R or S configuration to a stereocenter is to arrange the groups on the stereocenter in order of priority. • Priority is based on atomic number. • The higher the atomic number, the higher the priority. • *Note: a double bond is treated as 2 single bonds to the element. EX: C=O would be C-O-O when assigning priority 15-11 R,S Priority of Some Groups Atom or Grou p -I -Br -Cl -SH -OH -N H 2 O -COH O -CN H 2 O -CH -CH 2OH -CH 2N H 2 -CH 2CH 3 -CH 2H -H Reason for Priority: First Point of D ifferen ce (Atomic numbers) iodine (53) bromin e (35) ch lorine (17) su lfu r (16) oxygen (8) nitrogen (7) carbon to oxygen, oxygen, th en oxygen (6 —> 8, 8, 8) carbon to oxygen, oxygen, th en nitrogen (6 —> 8, 8, 7) carbon to oxygen, oxygen, th en hydrogen (6 —> 8, 8, 1) carbon to oxygen (6 —> 8) carbon to nitrogen (6 —> 7) carbon to carbon (6 —> 6) carbon to hydrogen (6 —> 1) hydrogen (1) 15-12 The R,S System Example: Assign priorities to the groups in each set. (a) -CH2 OH and -CH2 CH2 OH (b) -CH2 CH2 OH and -CH2 NH2 O (c) -CH2 OH and -CH2 CH2 COH (d ) -CH2 NH2 O and -CH2 COH 15-13 The R,S System Example: Assign priorities to the groups in each set. Solution: (a) -CH2 OH and -CH2 CH2 OH -CH2 OH -CH2 CH2 OH Higher priority Lower priority O (c) -CH2 OH and -CH2 CH2 COH O -CH2 OH -CH2 CH2 COH Higher priority Low er priority (b) -CH2 CH2 OH and -CH2 NH2 -CH2 CH2 OH -CH2 NH2 Lower priority Higher priority O (d) -CH2 NH2 and -CH2 COH O -CH2 NH2 -CH2 COH Higher priority Low er priority 15-14 The R,S System • To assign an R or S configuration: 1. Assign a priority from 1 (highest) to 4 (lowest) to each group bonded to the stereocenter. 2. Orient the molecule in space so that the group of lowest priority (4) is directed away from you. The three groups of higher priority (1-3) then project toward you. 3. Read the three groups projecting toward you in order from highest (1) to lowest (3) priority. 4. If reading the groups 1-2-3 is clockwise, the configuration is R. If reading them is counterclockwise, the configuration is S. 15-15 The R,S System *Get a kit and construct the following 2 molecules • Example: Assign an R or S configuration to each stereocenter. OH (a) C H CH2 CH3 2-Bu tanol H3 C H2 N H (b) C H3 C COOH Alanin e 15-16 The R,S System • Example: Assign an R or S configuration to each stereocenter. 1 (a) OH 4 C 3 H3 C 2 R R H CH2 CH3 (R)-2-Butan ol 1 4 H2 N H (b) 3 H3 C C R R 2 COOH (R)-Alanine 15-17 The R,S System • Returning to our original three-dimensional drawings of the enantiomers of ibuprofen. 4 3 3 H CH3 1 2 COOH R (R )-Ibuprofen (the in acti ve en antiomer) H3 C H4 1 2 HOOC S (S)-Ibuprofen (the acti ve enenti omer) 15-18 Two or More Stereocenters For a molecule with n stereocenters, the maximum number of possible stereoisomers is 2n. • We have already verified that, for a molecule with one stereocenter, 21 = 2 stereoisomers (one pair of enantiomers) are possible. • For a molecule with two stereocenters, a maximum of 22 = 4 stereoisomers (two pair of enantiomers) are possible. • For a molecule with three stereocenters, a maximum of 23 = 8 stereoisomers (four pairs of enantiomers) are possible, and so forth. 15-19 Two Stereocenters 2,3,4-Trihydroxybutanal • Two stereocenters; 22 = 4 stereoisomers exist (two pairs of enantiomers). CHO CHO CHO CHO H C OH HO C H H C OH HO C H H C OH HO C H HO C H C OH CH2 OH CH2 OH (a) (b) A p air of enantiomers (Erythreose) H CH2 OH CH2 OH (c) (d) A pair of en antiomers (Threos e) • Diastereomers: Stereoisomers that are not mirror images. • (a)-(c) and (b)-(c), for example, are diastereomers. 15-20 Stereoisomers Example: Mark all stereocenters in each molecule and tell how many stereoisomers are possible for each. OH (a) CH2 =CHCHCH2 CH3 HO (d) HO (b) CH3 CH3 (e) OH (c) NH2 OH COOH NH2 OH O OH OH (f) NH2 15-21 Stereoisomers Example: Mark all stereocenters in each molecule and tell how many stereoisomers are possible for each. Solution: OH (a) CH2 =CHCHCH2 CH3 * (b) 21 = 2 HO NH2 HO 21 = 2 CH3 CH3 * (c) 21 = 2 * COOH (d) OH O OH * (e) * 22 = 4 OH * * OH NH2 22 = 4 * OH (f) * NH2 22 = 4 15-22 Stereoisomers • The 2n rule applies equally well to molecules with three or more stereocenters. H H3 C H3 C * HO * * * * * * * Cholesterol h as 8 stereocenters; 256 s tereoisomers are poss ible H3 C H H HO H H H Th is is th e stereoisomer found in human metabolism 15-23 Optical Activity • Ordinary light: Light waves vibrating in all planes • • • • perpendicular to its direction of propagation. Plane-polarized light: Light waves vibrating only in parallel planes. Polarimeter: An instrument for measuring the ability of a compound to rotate the plane of plane-polarized light. Optically active: Showing that a compound is capable rotating the plane of plane-polarized light. *NOTE: D,L will not be on this test (slides 24-26). The designation is primarily used with carbs and amino acids, so we will wait until that unit to cover it. 15-24 Polarimeter Figure 15.6 Schematic diagram of a polarimeter with its sample tube containing a solution of an optically active compound. 15-25 Optical Activity • Dextrorotatory: Clockwise rotation of the plane of plane-polarized light. Indicated by (+). • Levorotatory: Counterclockwise rotation of the plane of plane-polarized light. Indicated by (-). • Specific rotation: The observed rotation of an optically active substance at a concentration of 1 g/mL in a sample tube 10 cm long. COOH C H H3 C OH (S)-(+)-Lactic acid 21 [] D = +2.6° COOH H C CH3 HO (R)-(-)-Lactatic acid 21 [] D = -2.6° 15-26 Chirality of Biomolecules Except for inorganic salts and a few low-molecular-weight organic substances, the molecules in living systems, both plant and animal, are chiral. • Although these molecules can exist as a number of stereoisomers, almost invariably only one stereoisomer is found in nature. • Instances do occur in which more than one stereoisomer is found, but these rarely exist together in the same biological system. 15-27 Chirality of Biomolecules How an enzyme distinguishes between a molecule and its enantiomer. Figure 15.7 A schematic diagram of an enzyme surface that can interact with (R)-glyceraldehyde at three binding sites but with (S)-glyceraldehyde at only two of the three sites. 15-28 Chirality of Biomolecules Enzymes (protein biocatalysts) all have many stereocenters. • An example is chymotrypsin, an enzyme in the intestines of animals that catalyzes the digestion of proteins. • Chymotrypsin has 251 stereocenters. • The maximum number of stereoisomers possible is 2251! • Only one of these stereoisomers is produced and used by any given organism. • Because enzymes are chiral substances, most either produce or react with only substances that match their stereochemical requirements. 15-29 Chirality of Biomolecules • Because interactions between molecules in living systems take place in a chiral environment, a molecule and its enantiomer or one of its diastereomers elicit different physiological responses. • As we have seen, (S)-ibuprofen is active as a pain and fever reliever, while its R enantiomer is inactive (although the body can convert R to S, but it takes time). • The S enantiomer of naproxen is the active pain reliever, but its R enantiomer is a liver toxin! H3 C H HOOC (S)-Ib uprofen H3 C H HOOC (S)-N aproxen OCH3 15-30