William Brown Thomas Poon

www.wiley.com/college/brown

Chapter SixChirality: The Handedness of

Molecules

6-2

Isomers In this chapter, we concentrate on enantiomers

and diastereomers.

6-3

Enantiomers• Enantiomers: Nonsuperposable mirror images• As an example of a molecule that exists as a pair

of enantiomers, consider 2-butanol.

OHC

H3C CH2CH3H

HOC

CH3H

CH3CH2Original molecule Mirror image

6-4

Enantiomers• One way to see that the mirror image of 2-butanol

is not superposable on the original is to rotate the mirror image.

Original molecule

OHC

H3C CH2CH3H

OHC

CH3H

CH3CH2

OHC

H3C HCH2CH3

Mirror image The mirror imagerotated by 180°

180°rotate the

mirror imageby 180° about

the C-OH bond

6-5

Enantiomers• Now try to fit one molecule on top of the other so

that all groups and bonds match exactly.

• The original and mirror image are not superposable.• They are different molecules with different

properties.• They are enantiomers (nonsuperposable mirror

images).

OHC

H3C CH2CH3H

OHC

H3C HCH2CH3

The original molecule

The mirror imageturned by 180°

6-6

Enantiomers• Objects that are not superposable 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.

6-7

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

2-propanol.• Notice that this molecule has no stereocenter.

Original molecule Mirror image

OHC

H3C CH3H

OHC

CH3H

H3C

6-8

Enantiomers• To see the relationship between the original and

its mirror image, rotate the mirror image by 120°.

• When we do this rotation, 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.

Original molecule Mirror image

OHC

H3C CH3H

OHC

CH3H

H3C

OHC

H3C CH3

H

The mirror imagerotated by 120°

120° rotate by 120°about the

C-OH bond

6-9

Enantiomers• To summarize• An object that is nonsuperposable on its mirror

image is chiral (it shows 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.

• An object that is superposable on its mirror image is achiral (without chirality).

• Nonsuperposable mirror images are called enantiomers.

• Enantiomers, like gloves, always come in pairs.

6-10

Drawing Enantiomers• Following are four different representations for

one of the enantiomers of 2-butanol.

• Both (1) and (2) show all four groups bonded to the stereocenter and show the tetrahedral geometry.

• (3) is a more abbreviated line-angle formula; although we show the H here, we do not normally show them in line-angle formulas.

• (4) is the most abbreviated representation; you must remember that there is an H present on the stereocenter.

OHC

H3C CH2CH3H

OHC

H3C CH2CH3

HH OH OH

(1) (2) (3) (4)

6-11

Drawing Mirror Images• On the left is one enantiomer of 2-butanol.• On the right are two representations for its mirror

image (in this case, its enantiomer).OH OH OH

One enantiomerof 2-butanol

Alternative representationsfor its mirror image

6-12

Naming Enantiomers - R,S• Because enantiomers are different compounds,

each must have a different name.• Here are the enantiomers of the over-the-counter

drug ibuprofen.

• The R,S system is a way to distinguish between enantiomers without having to draw them and point to one or the other.

COOH

H CH3

HOOC

H3C H

The active enantiomerThe inactive enantiomerof ibuprofen

6-13

The R,S System• To assign an R or S configuration:• Assign a priority from 1 (highest) to 4 (lowest) to

each group on the stereocenter; for priority rules, see Section 4.3C.

• Orient the stereocenter so that the group of lowest priority is facing away from you.

• Read the three groups projecting toward you in order from (1) to (3).

• If reading the groups is clockwise, the configuration is R (Latin, rectus, straight, correct).

• If reading the groups is counterclockwise, the configuration is S (Latin: sinister, left).

6-14

The R,S System • Problem: Assign an R or S configuration to each

stereocenter.

(a)H Cl

OHH

(b)

NH3+O-

O(c)

6-15

The R,S System• ProblemProblem: Assign an R or S configuration to the

enantiomers of ibuprofen.• Remember to add the H at the

stereocenter.COOH

CH3

HOOC

CH3

The active enantiomerThe inactive enantiomerof ibuprofen

6-16

Enantiomers & Diastereomers

• For a molecule with 1 stereocenter, 21 = 2 stereoisomers are possible.

• For a molecule with 2 stereocenters, a maximum of 22 = 4 stereoisomers are possible.

• For a molecule with nn stereocenters, a maximum of 2n stereoisomers are possible.

6-17

Enantiomers & Diastereomers• 2,3,4-Trihydroxybutanal

• Two stereocenters; 22 = 4 stereoisomers are possible.

HOCH2-CH-CH-CHOHOH

O* *

C

C

H OHCHO

OH

CH2OH

H

C

C

HHOCHO

HO

CH2OH

H H

CH2OH

HO

C

C

H OHCHO

C

C

HHOCHO

H

CH2OH

OH

A pair of enantiomers(Erythrose)

A pair of enantiomers(Threose)

6-18

Meso Compounds• Meso compound: an achiral compound

possessing two or more stereocenters.• Tartaric acid contains two stereocenters.• Two stereocenters; 2n = 4, but only three

stereoisomers exist, one meso compound and one pair of enantiomers.

C

C

H OH

COOH

OH

COOH

H

C

C

HHO

COOH

HO

COOH

H

C

C

H OH

COOH

H

COOH

HO

C

C

HHO

COOH

H

COOH

OH

A pair of enantiomersA meso compound(plane of symmetry)

6-19

Cyclic Molecules• 2-Methylcyclopentanol• 2 stereocenters; according to the 2n rule, a

maximum of 4 stereoisomers are possible.• How many actually exist? Answer 4, two pairs of

enantiomers.

cis-2-Methylcyclopentanol trans-2-Methylcyclopentanol

H3C

HO

CH3

OH

H3C

HO

CH3

OH

6-20

Cyclic Molecules• 1,2-Cyclopentanediol• 2 stereocenters = a maximum of 4 stereoisomers.• How many exist? Answer: three, one meso

compound (the cis isomer) and one pair of enantiomers (the trans isomer).

HO

HO

OH

OH

HO

HO

OH

OHcis-1,2-Cyclopentanediol trans-1,2-Cyclopentanediol

6-21

Cyclic Molecules• 4-Methylcyclohexanol• How many stereoisomers are possible?• Answer: two. The cis isomer (achiral) and the

trans isomer (also achiral).

OHH3C OHH3C

cis-4-Methylcyclohexanol trans-4-Methylcyclohexanol

6-22

Cyclic Molecules• 3-Methylcyclohexanol• 2 stereocenters = a maximum of 4 stereoisomers• How many exist? Answer: four, two pairs of

enantiomers.

trans-3-Methylcyclohexanolcis-3-Methylcyclohexanol

OH

CH3

HO

H3C

OH

CH3

HO

H3C

6-23

Cyclic Molecules• 2-Methylcyclohexanol• 2 stereocenters = a maximum of 4 stereoisomers• how many exist? Answer: four, two pairs of

enantiomers.

trans-2-Methylcyclohexanolcis-2-Methylcyclohexanol

OH

CH3

HO

H3C

OH

CH3

HO

H3C

6-24

Cyclic Molecules• 1,3-Cyclohexanediol• 2 stereocenters = a maximum of 4 stereoisomers• How many exist? Answer: three, the cis isomer

(meso) and the trans isomer (a pair of enantiomers).

trans-1,3-Cyclohexanediolcis-1,3-Cyclohexanediol

OH

OH

OH

OH

HO

HO

HO

HO

6-25

Three Or More Stereocenters• How many stereocenters are present in the

molecule on the left?• How many stereoisomers are possible?• One of the possible stereoisomers is menthol.• Assign an R or S configuration to each

stereocenter in menthol.

2-Isopropyl-5-methyl-cyclohexanol

OH

Menthol

OH

6-26

Three Or More Stereocenters• Cholesterol• On the left is the carbon skeleton of cholesterol.• How many stereocenters are present?• How many stereoisomers are possible?

HO HOThis is the stereoisomer found in

human metabolism

H

H

H

The carbon skeleton ofcholesterol

H

6-27

Optical Activity• Ordinary light: Light waves vibrating in all

planes perpendicular to its direction of propagation.

• Plane-polarized light: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 rotates the plane of plane-polarized light.

6-28

Polarimeter• Figure 6.6 Schematic diagram of a polarimeter.

6-29

Optical Activity• Dextrorotatory: Clockwise rotation of the plane of

plane-polarized light.• Levorotatory: Counterclockwise rotation of the

plane of plane-polarized light.• Specific rotation: The observed rotation of an

optically active substance at a concentration of 1 g/100 mL in a sample tube 10 cm long; for a pure liquid, concentration is in g/mL (density).

DD

H3CC

OHH

COOH

CH3C

HOH

COOH

[]21 = -2.6°= +2.6°21[](R)-(-)-Lactatic acid(S)-(+)-Lactic acid

6-30

Chirality in the Biological World• 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.

• It’s a chiral world!

6-31

Chirality in Biomolecules• Enzymes (protein bio-catalysts) 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.

6-32

Chirality in the Biological World• Figure 6.7 Schematic diagram of the surface of

an enzyme capable of distinguishing between enantiomers.

6-33

Chirality in 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, whereas its R enantiomer is inactive.

• The S enantiomer of naproxen is the active pain reliever, whereas its R enantiomer is a liver toxin!HOOC

CH3

HOOC

CH3

OCH3(S)-Ibuprofen (S)-Naproxen

6-34

Resolution• Racemic mixture: An equimolar mixture of two

enantiomers.• Because a racemic mixture contains equal

numbers of dextrorotatory and levorotatory molecules, its specific activity is zero.

• Resolution: The separation of a racemic mixture into its enantiomers.

6-35

Resolution• Enzymes as resolving agents.

H3CO

OEtH CH3

CO OCH3

C

HH3C

O

EtO

NaOH, H2O2. HCl, H2O

H3CO

C

H CH3

OH

O

Ethyl ester of (S)-naproxen Ethyl ester of (R)-naproxen(not affected by the esterase)

+

1. esterase

(S)-Naproxen

6-36

Chirality and the Handedness of Molecules

End Chapter 6End Chapter 6