Chirality: The Handedness of Molecules

167

Tartaric acid is found in grapes and other fruits, both free and as

its salts (see Section 6.4B). Inset: A model of tartaric acid.

Chirality:

The Handedness

of Molecules

6.1 What Are Stereoisomers?

6.2 What Are Enantiomers?

6.3 How Do We Designate the Configuration of a

Stereocenter?

6.4 What Is the 2

Rule?

6.5 How Do We Describe the Chirality of

Cyclic Molecules with Two Stereocenters?

6.6 How Do We Describe the Chirality

of Molecules with Three or More

Stereocenters?

6.7 What Are the Properties of Stereoisomers?

6.8 How Is Chirality Detected in the

Laboratory?

6.9 What Is the Significance of Chirality in the

Biological World?

6.10 How Can Enantiomers Be Resolved?

HOW TO

6.1 How to Draw Enantiomers

6.2 How to Determine the R & S Configuration

without Rotating the Molecule

6.3 How to Determine Whether Two Compounds Are

the Same, Enantiomers, or Diastereomers without

the Need to Spatially Manipulate the Molecule

CHEMICAL CONNECTIONS

6A Chiral Drugs

KEY QUESTIONS

IN THIS CHAPTER,

we will explore the relationships between three-dimensional ob-

jects and their mirror images. When you look in a mirror, you see a reﬂection, or mirror

image, of yourself. Now, suppose your mirror image becomes a three-dimensional object.

Mirror image The reﬂection

of an object in a mirror.

CHAPTER 6 Chirality: The Handedness of Molecules168

We could then ask, “What is the relationship between you and your mirror image?” By

relationship, we mean “Can your reﬂection be superposed on the original ‘you’ in such

a way that every detail of the reﬂection corresponds exactly to the original?” The answer

is that you and your mirror image are not superposable. If you have a ring on the little

ﬁnger of your right hand, for example, your mirror image has the ring on the little ﬁnger

of its left hand. If you part your hair on your right side, the part will be on the left side in

your mirror image. Simply stated, you and your reﬂection are different objects. You cannot

superpose one on the other.

An understanding of relationships of this type is fundamental to an understanding

of organic chemistry and biochemistry. In fact, the ability to visualize molecules as three-

dimensional objects is a survival skill in organic chemistry and biochemistry. We suggest

that you purchase a set of molecular models. Alternatively you may have access to a com-

puter lab with a modeling program. We urge you to use molecular models frequently as an

aid to visualizing the spatial concepts in this and later chapters.

6.1 What Are Stereoisomers?

Stereoisomers have the same molecular formula and the same connectivity of atoms in

their molecules, but different three-dimensional orientations of their atoms in space. The

one example of stereoisomers we have seen thus far is that of cis–trans isomers in cycloal-

kanes (Section 3.7) and alkenes (Section 4.1C):

and

cis -1,2-Dimethyl-

cyclohexane

trans -1,2-Dimethyl-

cyclohexane

cis -2-Butene trans -2-Butene





C  C





and





C  C





In this chapter, we study enantiomers and diastereomers (Figure 6.1).

Stereoisomers Isomers

that have the same

molecular formula and

the same connectivity, but

different orientations of

their atoms in space.

The horns of this African

gazelle show chirality and are

mirror images of each other.

William H. Brown

Isomers

Different compounds with

the same molecular formula

Constitutional isomers

Isomers with a different

connectivity of

their atoms

Stereoisomers

Isomers with the same

connectivity of atoms,

but a different orientation

of their atoms in space

Enantiomers

Stereoisomers whose molecules

are nonsuperposable

mirror images

Diastereomers

Stereoisomers whose

molecules are not

mirror images

FIGURE 6.1

Relationships among isomers.

1696.2 What Are Enantiomers?

6.2 What Are Enantiomers?

Enantiomers are stereoisomers that are nonsuperposable mirror images. The signiﬁcance

of enantiomerism is that, except for inorganic and a few simple organic compounds, the

vast majority of molecules in the biological world show this type of isomerism, including

carbohydrates (Chapter 17), lipids (Chapter 19), amino acids and proteins (Chapter 18),

and nucleic acids (DNA and RNA, Chapter 20). Further, approximately one-half of the

medications used in human medicine also show this type of isomerism.

As an example of a molecule that exhibits enantiomerism, let us consider 2-butanol.

As we go through the discussion of this molecule, we focus on carbon 2, the carbon bearing

the

OH group. What makes this carbon of interest is that it has four different groups

bonded to it. The most common cause of enantiomerism among organic molecules is a

carbon bonded to four different groups.



CHCH

2-Butanol

The structural formula we have just drawn does not show the shape of 2-butanol or

the orientation of its atoms in space. To do this, we must consider the molecule as a three-

dimensional object. On the left are a ball-and-stick model of 2-butanol and a perspective

drawing of what we will call the “original” molecule. In this drawing, the

OH and

groups on carbon-2 are in the plane of the paper; the

H is behind the plane and the

group is in front of the plane.

Original





Mirror image





To the right in the preceding diagram is the mirror image of the original molecule.

Every molecule and, in fact, every object in the world around us, has a mirror image. The

question we now need to ask is “What is the relationship between the original of 2-butanol

and its mirror image?” To answer this question, you need to imagine that you can pick up

the mirror image and move it in space in any way you wish. If you can move the mirror im-

age in space and ﬁnd that it ﬁts over the original so that every bond, atom, and detail of

the mirror image exactly matches the bonds, atoms, and details of the original, then the

two are superposable. In this case, the mirror image and the original represent the same

molecule; they are only oriented differently in space. If, however, no matter how you turn

the mirror image in space, it will not ﬁt exactly on the original with every detail matching,

then the two are nonsuperposable; they are different molecules.

The key point here is that either an object is superposable on its mirror image or it isn’t. Now

let us look at 2-butanol and its mirror image and ask, “Are they or are they not superposable?”

The following drawings illustrate one way to see that the mirror image of 2-butanol is

not superposable on the original molecule:

rotate about the

C ¬ OH bond by 180°

The original

molecule

The mirror image

rotated by 180°

The mirror image of

the original molecule

180°

Enantiomers

Stereoisomers that are

nonsuperposable mirror

images; the term refers to a

relationship between pairs

of objects.

the four different

“groups” bonded to this

carbon are

OH,

, and

CHAPTER 6 Chirality: The Handedness of Molecules170

Imagine that you hold the mirror image by the C

OH bond and rotate the bottom

part of the molecule by 180° about this bond. The

OH group retains its position in

space, but the

group, which was to the right and in the plane of the paper, is still

in the plane of the paper, but now to the left. Similarly, the

group, which

was in front of the plane of the paper and to the left, is now behind the plane and to

the right.

Now move the rotated mirror image in space, and try to ﬁt it on the original so that

all bonds and atoms match:





The mirror image

rotated by 180









The original molecule



H pointing toward you

H pointing away

pointing toward you

pointing away

By rotating the mirror image as we did, its

OH and

groups now ﬁt exactly on

top of the

OH and

groups of the original. But the

H and

groups

of the two do not match: The

H is away from you in the original, but toward you in the

mirror image; the

group is toward you in the original, but away from you in

the mirror image. We conclude that the original of 2-butanol and its mirror image are non-

superposable and, therefore, are different compounds.

To summarize, we can rotate the mirror image of 2-butanol in space in any way

we want, but as long as no bonds are broken or rearranged, only two of the four groups

bonded to carbon-2 of the mirror image can be made to coincide with those on the origi-

nal. Because 2-butanol and its mirror image are not superposable, they are enantiomers.

Like gloves, enantiomers always occur in pairs.

Objects that are not superposable on their mirror images are said to be chiral (pro-

nounced



ral, rhymes with spiral; from the Greek: cheir, hand); that is, they show hand-

edness. Chirality is encountered in three-dimensional objects of all sorts. Your left hand

is chiral, and so is your right hand. A spiral binding on a notebook is chiral. A machine

screw with a right-handed twist is chiral. A ship’s propeller is chiral. As you examine the

objects in the world around you, you will undoubtedly conclude that the vast majority of

them are chiral.

As we said before we examined the original and the mirror image of 2-butanol,

the most common cause of enantiomerism in organic molecules is the presence of a

carbon with four different groups bonded to it. Let us examine this statement further by

considering a molecule such as 2-propanol, which has no such carbon. In this molecule,

carbon-2 is bonded to three different groups, but no carbon is bonded to four different

groups. The question we ask is, “Is the mirror image of 2-propanol superposable on the

original, or isn’t it?”

Charles D. Winters

Left- and right-handed sea

shells. If you cup a right-

handed shell in your right

hand with your thumb

pointing from the narrow

end to the wide end, the

opening will be on your right.

Chiral From the Greek

cheir, meaning hand; objects

that are not superposable on

their mirror images.

1716.2 What Are Enantiomers?

In the following diagram, on the left is a three-dimensional representation of 2-propanol,

and on the right is its mirror image:

Original





Mirror image





The question we now ask is “What is the relationship of the mirror image to the original?”

This time, let us rotate the mirror image by 120° about the

OH bond and then compare

it with the original. 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 structures we ﬁrst drew for the original

and its mirror image are, in fact, the same molecule viewed from different perspectives:

rotate about the

C ¬ OH bond by 120°

The original

The mirror image

rotated by 180°

The mirror image

180°

every single group on this atom matches up with the corresponding

groups in the mirror image (i.e., they are superposable)

If an object and its mirror image are superposable, then the object and its mirror im-

age are identical, and there is no possibility of enantiomerism. We say that such an object

is achiral (without chirality).

An achiral object has at least one plane of symmetry. A plane of symmetry (also called

a mirror plane) is an imaginary plane passing through an object and dividing it so that one-

half of the object is the reﬂection of the other half. The beaker shown in Figure 6.2 has a

single plane of symmetry, whereas a cube has several planes of symmetry. 2-Propanol also

has a single plane of symmetry.

To repeat, the most common cause of chirality in organic molecules is a tetrahedral

carbon atom with four different groups bonded to it. We call such a carbon atom a chiral

center. Chiral centers are one type of stereocenter, which describes an atom at which the

interchange of two atoms or groups of atoms bonded to it produces a different stereoisomer.

2-Butanol has one stereocenter; 2-propanol has none.

As another example of a molecule with a stereocenter, consider 2-hydroxypropanoic

acid, more commonly named lactic acid. Lactic acid is a product of anaerobic glycolysis

FIGURE 6.2

Planes of symmetry in (a) a beaker, (b) a cube, and (c) 2-propanol. The beaker and 2-propanol each

have one plane of symmetry; the cube has several planes of symmetry, only three of which are

shown in the figure.

Achiral An object that

lacks chirality; an object that

has no handedness and is

superposable on its mirror

image.

Plane of symmetry An

imaginary plane passing

through an object and

dividing it such that one half

is the mirror image of the

other half.

Chiral center An atom,

such as carbon, with four

different groups bonded

to it.

Stereocenter An atom

at which the interchange

of two atoms or groups

of atoms bonded to it

produces a different

stereoisomer.

(a)

(b) (c)

Plane of

symmetry

Planes of

symmetry

CHAPTER 6 Chirality: The Handedness of Molecules172

and is what gives sour cream its sour taste. Figure 6.3 shows three-dimensional representa-

tions of lactic acid and its mirror image. In these representations, all bond angles about

the central carbon atom are approximately 109.5°, and the four bonds projecting from it

are directed toward the corners of a regular tetrahedron. Lactic acid shows enantiomerism;

that is, it and its mirror image are not superposable, but rather are different molecules.















FIGURE 6.3

Three-dimensional

representations of lactic

acid and its mirror image.

HOW TO 6.1

Now that we know what enantiomers are, we can think about how to represent

their three-dimensional structures on a two-dimensional page. Let us take one

of the enantiomers of 2-butanol as an example. Following are four different

representations of this enantiomer:

(1)

(2)

OHH

(3)

HOH

(4)

In our initial discussions of 2-butanol, we used (1) to show the tetrahedral

geometry of the stereocenter; in it, two groups are in the plane of the paper, a

third is coming out of the plane toward us, and the fourth is behind the plane,

away from us. We can turn (1) slightly in space and tip it a bit to place the carbon

framework in the plane of the paper. Doing so gives us representation (2), in

which we still have two groups in the plane of the paper, one coming toward

us and one going away from us. For an even more abbreviated representation

of this enantiomer of 2-butanol, we can turn (2) into the line-angle formula (3).

Although we don’t normally show hydrogens in a line-angle formula, we do so

in (3) just to remind ourselves that the fourth group on this stereocenter is really

there and that it is H. Finally, we can carry the abbreviation a step further and

write 2-butanol as (4). Here, we omit the H on the stereocenter, but we know

that it must be there (carbon needs four bonds), and we know that it must be

behind the plane of the paper. Clearly, the abbreviated formulas (3) and (4) are

the easiest to draw, and we will rely on these representations throughout the

remainder of the text. When you have to draw three-dimensional representa-

tions of stereocenters, try to keep the carbon framework in the plane of the

paper and the other two atoms or groups of atoms on the stereocenter toward

and away from you, respectively. Using representation (4) as a model, we get

the following two different representations of its enantiomer:

Alternative representations

for its mirror image

One enantiomer

of 2-butanol

OH OH

Notice that in the first alternative, the carbon skeleton has been reversed.

Draw Enantiomers

1736.3 How Do We Designate the Conﬁguration of a Stereocenter?

EXAMPLE 6.1

Each of the following molecules has one stereocenter:

(a)

CHCH

(b)

Identify the stereocenter in each and draw stereorepresenta-

tions of the enantiomers of each.

STRATEGY

When locating stereocenters, it is often helpful to draw in

the hydrogens in line-angle drawings. Carbon atoms with

only one or two lines extending from them, as well as sp

and sp hybridized carbons, can be excluded from consider-

ation. Once the stereocenters are identified, use dashed and

solid wedges to show the bonds to substituents.

SOLUTION

You will find it helpful to study models of each pair of enan-

tiomers and to view them from different perspectives. As

you work with these models, notice that each enantiomer

has a carbon atom bonded to four different groups, which

makes the molecule chiral. Translate what you see in each

model by using perspective drawings. The hydrogen at the

stereocenter is shown in (a) but not in (b).

HCl Cl H

(a)

Cl Cl

(b)

See problems 6.15, 6.19–6.22

PROBLEM 6.1

Each of the following molecules has one stereocenter:

(a) (b) (c)

Identify the stereocenter in each and draw stereorepresentations of the enantiomers of each.

6.3 How Do We Designate the Configuration

of a Stereocenter?

Because enantiomers are different compounds, each must have a different name. The over-

the-counter drug ibuprofen, for example, shows enantiomerism and can exist as the pair

of enantiomers shown here:

The inactive enantiomer

of ibuprofen

The active enantiomer

COOH

HCH

HOOC

HCH

Only one enantiomer of ibuprofen is biologically active. This enantiomer reaches thera-

peutic concentrations in the human body in approximately 12 minutes. However, in this

case, the inactive enantiomer is not wasted. The body converts it to the active enantiomer,

but that takes time.

What we need is a way to name each enantiomer of ibuprofen (or any other pair of

enantiomers for that matter) so that we can refer to them in conversation or in writing.

To do so, chemists have developed the R,S system. The ﬁrst step in assigning an R or S

R,S system A set of

rules for specifying the

conﬁguration about a

stereocenter.

CHAPTER 6 Chirality: The Handedness of Molecules174

conﬁguration to a stereocenter is to arrange the groups bonded to it in order of priority.

For this, we use the same set of priority rules we used in Section 4.2C to assign an E,Z con-

ﬁguration to an alkene.

To assign an R or S conﬁguration to a stereocenter,

1. Locate the stereocenter, identify its four substituents, and assign a priority from 1 (high-

est) to 4 (lowest) to each substituent.

2. Orient the molecule in space so that the group of lowest priority (4) is directed away

from you, as would be, for instance, the steering column of a car. The three groups

of higher priority (1–3) then project toward you, as would the spokes of a steering

wheel.

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

lowest priority (3).

4. If reading the groups proceeds in a clockwise direction, the conﬁguration is desig-

nated R (Latin: rectus, straight, correct); if reading proceeds in a counterclockwise

direction, the conﬁguration is S (Latin: sinister, left). You can also visualize this situa-

tion as follows: Turning the steering wheel to the right equals R, and turning it to the

left equals S.

Group of

lowest

priority

points away

from you

R From the Latin rectus,

meaning right; used in the

R,S system to show that

the order of priority of

groups on a stereocenter

is clockwise.

S From the Latin sinister,

meaning left; used in the

R,S system to show that

the order of priority of

groups on a stereocenter

is counterclockwise.

EXAMPLE 6.2

Assign an R or S configuration to each stereocenter:

(a) (b)

Cl H

STRATEGY

First determine the priorities of the groups bonded to the stereocenter. If necessary reorient the molecule so that the group

of lowest priority is away from you. Then read the R/S configuration by going from highest to lowest priority.

SOLUTION

View each molecule through the stereocenter and along the bond from the stereocenter toward the group of lowest priority.

(a) The order of priority is

Cl 



H. The group of lowest priority, H, points away from you.

Reading the groups in the order 1, 2, 3 occurs in the counterclockwise direction, so the configuration is S.

the hydrogen is pointing away

from you and out of view

(b) The order of priority is

OH 

CH  CH 



H. With hydrogen, the group of lowest priority, point-

ing away from you, reading the groups in the order 1, 2, 3 occurs in the clockwise direction, so the configuration is R.

See problems 6.24–6.27, 6.29, 6.39

1756.3 How Do We Designate the Conﬁguration of a Stereocenter?

PROBLEM 6.2

Assign an R or S configuration to each stereocenter:

(a)

HOH

(b)

COH

(c)

COHH

CH “ O

Now let us return to our three-dimensional drawing of the enantiomers of ibuprofen and

assign each an R or S conﬁguration. In order of decreasing priority, the groups bonded to

the stereocenter are

COOH 



 H. In the enantiomer on the left,

reading the groups on the stereocenter in order of priority occurs clockwise. Therefore,

this enantiomer is (R)-ibuprofen, and its mirror image is (S)-ibuprofen:

(R )-Ibuprofen

(the inactive enantiomer)

(S )-Ibuprofen

(the active enantiomer)

COOH

HCH

HOOC

HOW TO 6.2

If you are having difficulty visualizing the spatial rotation of perspective drawings, the following techniques

may be of use.

SCENARIO 1: The lowest priority group is already directed away from you. If the perspective drawing con-

tains the lowest priority group on a dashed bond, it is a simple matter of reading the other

three groups from highest to lowest priority.

the R/S configuration is read without the need for any spatial manipulation

(R)-2-Fluoropentane

the lowest priority group is

already pointed away from you

SCENARIO 2: The lowest priority group is directed toward you. If the perspective drawing contains the low-

est priority group on a wedged bond, read the priority of the other three groups, but assign a

configuration that is opposite to what is actually read.

the lowest priority group is

pointed toward you

the R/S configuration is read, but then the opposite configuration is chosen.

In this example, the priority reading appears to be R, but we switch it to S

because the lowest priority group is pointed toward you

(S)-2-Fluoropentane

Determine the R & S Configuration without Rotating the Molecule

CHAPTER 6 Chirality: The Handedness of Molecules176

6.4 What Is the 2

Rule?

Now let us consider molecules with two stereocenters. To generalize, for a molecule with n

stereocenters, the maximum number of stereoisomers possible is

. We have already veriﬁed

that, for a molecule with one stereocenter,

 2 stereoisomers (one pair of enantiomers)

are possible. For a molecule with two stereocenters,

 4 stereoisomers are possible; for a

molecule with three stereocenters,

 8 stereoisomers are possible, and so forth.

A. Enantiomers and Diastereomers

We begin our study of molecules with two stereocenters by considering 2,3,4-trihydroxybu-

tanal. Its two stereocenters are marked with asterisks:

2,3,4-Trihydroxybutanal

HOCH

HCHO

The maximum number of stereoisomers possible for this molecule is 2

 4, each of which

is drawn in Figure 6.4.

Stereoisomers (a) and (b) are nonsuperposable mirror images and are, therefore, a

pair of enantiomers. Stereoisomers (c) and (d) are also nonsuperposable mirror images

and are a second pair of enantiomers. We describe the four stereoisomers of 2,3,4-trihy-

droxybutanal by saying that they consist of two pairs of enantiomers. Enantiomers (a) and

(b) are named erythrose, which is synthesized in erythrocytes (red blood cells)—hence the

name. Enantiomers (c) and (d) are named threose. Erythrose and threose belong to the

class of compounds called carbohydrates, which we discuss in Chapter 17.

SCENARIO 3: The lowest priority group is in the plane of the page. If the perspective drawing contains the

lowest priority group in the plane of the page, view down the bond connecting the group to the

stereocenter and draw a Newman projection (Section 3.6A).

view down the bond with the group pointing away from

you and draw a Newman projection of the molecule.

Read the R/S configuration in the Newman projection

the lowest priority

group is in the

plane of the page

(R)-2-Fluoropentane

the H is in the

back of the

Newman

projection

CHO

One pair of enantiomers

(erythrose)

(a)

OHH

CHO

(b)

CHO

A second pair of enantiomers

(threose)

(c)

CHO

HO H

(d)

FIGURE 6.4

The four stereoisomers of

2,3,4-trihydroxybutanal,

a compound with two

stereocenters. Configurations

(a) and (b) are (2R,3R)

and (2S,3S), respectively.

Configurations (c) and (d)

are (2R,3S) and (2S,3R),

respectively.

1776.4 What Is the 2

Rule?

We have speciﬁed the relationship between (a) and (b) and between (c) and (d).

What is the relationship between (a) and (c), between (a) and (d), between (b) and (c),

and between (b) and (d)? The answer is that they are diastereomers. Diastereomers are

stereoisomers that are not enantiomers; that is, they are stereoisomers that are not mirror

images of each other.

Diastereomers

Stereoisomers that are

not mirror images of each

other; the term refers

to relationships among

objects.

HOW TO 6.3

If you are having difficulty visualizing the spatial rota-

tion of perspective drawings, the following technique

may be of use.

STEP 1: Verify that the compounds are stereo-

isomers. Make sure that the two compounds

in question have the same molecular for-

mula and the same connectivity of atoms.

Chemical Formula for both: C

BrO

Both have a 6-carbon chain with Br at

the 5 position and OH at the 2 position

Determine Whether Two Compounds Are the Same, Enantiomers, or

Diastereomers without the Need to Spatially Manipulate the Molecule

STEP 2: Assign R/S configurations to each stereo-

center in both compounds. See How To 6.2

for instructions.

(R)

(S)

STEP 3: Compare the configuration at corresponding

stereocenters. If the configurations match,

the compounds are identical. If the configu-

rations are opposite at each corresponding

stereocenter, the compounds are enantio-

mers. Any other scenario indicates that the

compounds are diastereomers.

same configuration

different configuration

(R)

(S)



Possible Scenario Relationship

all configurations

the same

identical

compounds

all configurations

opposite

enantiomers

any other scenario diastereomers

EXAMPLE 6.3

Following are stereorepresentations of the four stereoisomers of 1,2,3-butanetriol:

(1)

CHOH

CHO H

(2)

CHOH

(3)

CHO H

(4)

CHO H

CHOH

Configurations are given for the stereocenters in (1) and (4).

(a) Which compounds are enantiomers? (b) Which compounds are diastereomers?

CHAPTER 6 Chirality: The Handedness of Molecules178

STRATEGY

Determine the R/S configuration of the stereocenters in each compound and compare corresponding stereocenters to deter-

mine their relationship (see How To 6.3).

SOLUTION

(a) Compounds (1) and (4) are one pair of enantiomers, and compounds (2) and (3) are a second pair of enantiomers. Note

that the configurations of the stereocenters in (1) are the opposite of those in (4), its enantiomer.

(b) Compounds (1) and (2), (1) and (3), (2) and (4), and (3) and (4) are diastereomers.

See problem 6.23

PROBLEM 6.3

Following are stereorepresentations of the four stereoisomers of 3-chloro-2-butanol:

(1)

CHOH

CCl H

(2)

CHOH

CHCl

(3)

CHO H

CHCl

(4)

CHO H

CCl H

(a) Which compounds are enantiomers? (b) Which compounds are diastereomers?

B. Meso Compounds

Certain molecules containing two or more stereocenters have special symmetry properties

that reduce the number of stereoisomers to fewer than the maximum number predicted by

the

rule. One such molecule is 2,3-dihydroxybutanedioic acid, more commonly named

tartaric acid:

2,3-Dihydroxybutanedioic acid

(tartaric acid)

‘

C ¬

H ¬

‘

COH

Tartaric acid is a colorless, crystalline compound occurring largely in the vegeta-

ble kingdom, especially in grapes. During the fermentation of grape juice, potassium

bitartrate (one

COOH group is present as a potassium salt,

COO





) deposits as

a crust on the sides of wine casks. Then, collected and puriﬁed, it is sold commercially

as cream of tartar.

Carbons 2 and 3 of tartaric acid are stereocenters, and, from the

rule, the

maximum number of stereoisomers possible is

 4. Figure 6.5 shows the two pairs

of mirror images of this compound. Structures (a) and (b) are nonsuperposable mir-

ror images and, therefore, are a pair of enantiomers. Structures (c) and (d) are also

mirror images, but they are superposable. To see this, imagine that you rotate (d)

by 180° in the plane of the paper, lift it out of the plane of the paper, and place it

on top of (c). If you do this mental manipulation correctly, you will find that (d) is

1796.4 What Is the 2

Rule?

COOH

A meso compound

(c)

COOH

OHH

(d)

COOH

A pair of enantiomers

(a)

COOH

HO H

(b)

HO H

COOH

FIGURE 6.5

Stereoisomers of tartaric acid. One pair of enantiomers and one meso compound. The presence of

an internal plane of symmetry indicates that the molecule is achiral.

Meso compound An

achiral compound

possessing two or more

stereocenters.

superposable on (c). Therefore, (c) and (d) are not different molecules; they are the

same molecule, just oriented differently. Because (c) and its mirror image are super-

posable, (c) is achiral.

Another way to verify that (c) is achiral is to see that it has a plane of symmetry that

bisects the molecule in such a way that the top half is the reﬂection of the bottom half.

Thus, even though (c) has two stereocenters, it is achiral. The stereoisomer of tartaric acid

represented by (c) or (d) is called a meso compound, deﬁned as an achiral compound that

contains two or more stereocenters.

We can now return to the original question: How many stereoisomers are there of

tartaric acid? The answer is three: one meso compound and one pair of enantiomers.

Note that the meso compound is a diastereomer of each of the other stereoisomers.

EXAMPLE 6.4

Following are stereorepresentations of the three stereoisomers of 2,3-butanediol:

(1)

CHOH

CHO H

(2)

CHOH

(3)

CHO H

CHOH

(a) Which are enantiomers? (b) Which is the meso compound?

STRATEGY

Enantiomers are nonsuperposable mirror images. A meso compound is an achiral compound with two or more stereocen-

ters, that is, a compound with two or more stereocenters that has a superposable mirror image.

SOLUTION

(a) Compounds (1) and (3) are enantiomers.

(b) Compound (2) has an internal plane of symmetry and, therefore, is a meso compound.

See problems 6.23, 6.36, 6.38

CHAPTER 6 Chirality: The Handedness of Molecules180

6.5 How Do We Describe the Chirality of Cyclic

Molecules with Two Stereocenters?

In this section, we concentrate on derivatives of cyclopentane and cyclohexane that contain

two stereocenters. We can analyze chirality in these cyclic compounds in the same way we

analyzed it in acyclic compounds.

A. Disubstituted Derivatives of Cyclopentane

Let us start with 2-methylcyclopentanol, a compound with two stereocenters. Using the 2

rule,

we predict a maximum of

 4 stereoisomers. Both the cis isomer and the trans isomer are chi-

ral. The cis isomer exists as one pair of enantiomers, and the trans isomer exists as a second pair:

cis-2-Methylcyclopentanol

(a pair of enantiomers)

trans-2-Methylcyclopentanol

(a pair of enantiomers)

1,2-Cyclopentanediol also has two stereocenters; therefore, the 2

rule predicts a max-

imum of

 4 stereoisomers. As seen in the following stereodrawings, only three stereo-

isomers exist for this compound:

cis -1,2-Cyclopentanediol

(a meso compound)

trans -1,2-Cyclopentanediol

(a pair of enantiomers)

plane of

symmetry

the mirror image is

superposable on the

original

The cis isomer is achiral (meso) because it and its mirror image are superposable. Alternatively,

the cis isomer is achiral because it possesses a plane of symmetry that bisects the molecule

into two mirror-image halves. The trans isomer is chiral and exists as a pair of enantiomers.

PROBLEM 6.4

Following are four Newman projection formulas for tartaric acid:

COOH

HOH

COOH

OHH

(1)

COOH

HO H

COOH

OHH

(2)

H COOH

COOH

OHH

(3)

H COOH

COOH

(4)

(a) Which represent the same compound? (b) Which represent enantiomers? (c) Which represent(s) meso tartaric acid?

1816.5 How Do We Describe the Chirality of Cyclic Molecules with Two or More Stereocenters?

EXAMPLE 6.5

How many stereoisomers are possible for 3-methylcyclo-

pentanol?

STRATEGY

First identify all possible stereocenters, draw all possible

pairs of stereoisomers, and determine which, if any, of the

possible pairs of stereoisomers are meso compounds.

SOLUTION

There are two stereocenters in this compound and, therefore,

four stereoisomers of 3-methylcyclopentanol. The cis isomer

exists as one pair of enantiomers and the trans isomer as a

second pair:

cis-3-Methylcyclopentanol

(a pair of enantiomers)

OHCH

HO CH

trans-3-Methylcyclopentanol

(a pair of enantiomers)

OHCH

HO CH

See problems 6.31, 6.33–6.35, 6.38, 6.39

PROBLEM 6.5

How many stereoisomers are possible for 1,3-cyclopentanediol?

B. Disubstituted Derivatives of Cyclohexane

As an example of a disubstituted cyclohexane, let us consider the methylcyclohexanols.

4-Methylcyclohexanol can exist as two stereoisomers—a pair of cis–trans isomers:

cis -4-Methylcyclohexanol trans -4-Methylcyclohexanol

plane of symmetry

Both the cis and the trans isomers are achiral. In each, a plane of symmetry runs through

the

and OH groups and the two attached carbons.

3-Methylcyclohexanol has two stereocenters and exists as

 4 stereoisomers, with the cis

isomer existing as one pair of enantiomers and the trans isomer as a second pair:

cis -3-Methylcyclohexanol

(a pair of enantiomers)

trans -3-Methylcyclohexanol

(a pair of enantiomers)

Similarly, 2-methylcyclohexanol has two stereocenters and exists as 2

 4 stereoisomers,

with the cis isomer existing as one pair of enantiomers and the trans isomer as a second pair:

cis -2-Methylcyclohexanol

(a pair of enantiomers)

trans -2-Methylcyclohexanol

(a pair of enantiomers)

CHAPTER 6 Chirality: The Handedness of Molecules182

6.6 How Do We Describe the Chirality of Molecules

with Three or More Stereocenters?

The 2

rule applies equally well to molecules with three or more stereocenters. Here is a

disubstituted cyclohexanol with three stereocenters, each marked with an asterisk:

2-Isopropyl-5-methyl-

cyclohexanol

Menthol

OH OH

There is a maximum of 2

 8 stereoisomers possible for this molecule. Menthol, one of

the eight, has the conﬁguration shown on the right. The conﬁguration at each stereocenter

is indicated. Menthol is present in peppermint and other mint oils.

EXAMPLE 6.6

How many stereoisomers exist for 1,3-cyclohexanediol?

STRATEGY

Locate all stereocenters and use the 2

rule to determine the maximum number of stereoisomers possible. Determine which,

if any, of the possible stereoisomers are meso compounds.

SOLUTION

1,3-Cyclohexanediol has two stereocenters, and, according to the 2

rule, a maximum of 2

 4 stereoisomers is possible.

The trans isomer of this compound exists as a pair of enantiomers. The cis isomer has a plane of symmetry and is a meso

compound. Therefore, although the

rule predicts a maximum of four stereoisomers for 1,3-cyclohexanediol, only three

exist—one pair of enantiomers and one meso compound:

cis-1,3-Cyclohexanediol

(a meso compound)

trans-1,3-Cyclohexanediol

(a pair of enantiomers)

OH HO

plane of symmetry

See problems 6.31, 6.33–6.35, 6.38, 6.39

PROBLEM 6.6

How many stereoisomers exist for 1,4-cyclohexanediol?

1836.7 What Are the Properties of Stereoisomers?

Cholesterol, a more complicated molecule, has eight stereocenters:

This is the stereoisomer found in

human metabolism

Cholesterol has 8 stereocenters;

256 stereoisomers are possible

To identify the stereocenters, remember to add an appropriate number of hydrogens to

complete the tetravalence of each carbon you think might be a stereocenter.

6.7 What Are the Properties of Stereoisomers?

Enantiomers have identical physical and chemical properties in achiral environments.

The enantiomers of tartaric acid (Table 6.1), for example, have the same melting point,

the same boiling point, the same solubilities in water and other common solvents, and

the same values of

(the acid ionization constant), and they all undergo the same

acid–base reactions. The enantiomers of tartaric acid do, however, differ in optical activ-

ity (the ability to rotate the plane of polarized light), a property that is discussed in the

next section.

Diastereomers have different physical and chemical properties, even in achiral

environments. Meso-tartaric acid has different physical properties from those of the

enantiomers.

TABLE 6.1 Some Physical Properties of the Stereoisomers of Tartaric Acid

(R,R)-Tartaric acid

CHOH

CHO H

COOH

(S,S)-Tartaric acid

CHO H

CHOH

COOH

Meso-tartaric acid

CHOH

COOH

Specific rotation* 12.7 12.7 0

Melting point (°C) 171

174 171174 146148

Density at 20 °C

(g/cm

)

1.7 598 1.7598 1.660

Solubility in water at

20 °C

(g100 mL)

139 139 125

(25 °C)

2.98 2.98 3.23

(25 °C)

4.34 4.34 4.82

*Specific rotation is discussed in the next section.

CHAPTER 6 Chirality: The Handedness of Molecules184

6.8 How Is Chirality Detected in the Laboratory?

As we have already established, enantiomers are different compounds, and we must ex-

pect, therefore, that they differ in some property or properties. One property that differs

between enantiomers is their effect on the plane of polarized light. Each member of a pair

of enantiomers rotates the plane of polarized light, and for this reason, enantiomers are

said to be optically active. To understand how optical activity is detected in the laboratory,

we must ﬁrst understand plane-polarized light and a polarimeter, the instrument used to

detect optical activity.

A. Plane-Polarized Light

Ordinary light consists of waves vibrating in all planes perpendicular to its direction of

propagation (Figure 6.6). Certain materials, such as calcite and Polaroid™ sheet (a plastic

ﬁlm containing properly oriented crystals of an organic substance embedded in it), selec-

tively transmit light waves vibrating in parallel planes. Electromagnetic radiation vibrating

in only parallel planes is said to be plane polarized.

B. A Polarimeter

A polarimeter consists of a light source, a polarizing ﬁlter and an analyzing ﬁlter (each

made of calcite or Polaroid™ ﬁlm), and a sample tube (Figure 6.6). If the sample tube is

empty, the intensity of light reaching the detector (in this case, your eye) is at its maximum

when the polarizing axes of the two ﬁlters are parallel. If the analyzing ﬁlter is turned either

clockwise or counterclockwise, less light is transmitted. When the axis of the analyzing ﬁlter

is at right angles to the axis of the polarizing ﬁlter, the ﬁeld of view is dark. This position of

the analyzing ﬁlter is taken to be 0° on the optical scale.

The ability of molecules to rotate the plane of polarized light can be observed with the

use of a polarimeter in the following way: First, a sample tube ﬁlled with solvent is placed

in the polarimeter, and the analyzing ﬁlter is adjusted so that no light passes through to

the observer; that is, the ﬁlter is set to 0°. Then we place a solution of an optically active

compound in the sample tube. When we do so, we ﬁnd that a certain amount of light now

passes through the analyzing ﬁlter. We also ﬁnd that the plane of polarized light from the

polarizing ﬁlter has been rotated so that it is no longer at an angle of 90° to the analyzing

ﬁlter. Consequently, we rotate the analyzing ﬁlter to restore darkness in the ﬁeld of view.

The number of degrees,

a, through which we must rotate the analyzing ﬁlter to restore

darkness to the ﬁeld of view is called the observed rotation. If we must turn the analyzing

Optically active Showing

that a compound rotates the

plane of polarized light.

FIGURE 6.6

Schematic diagram of a polarimeter with its sample tube containing a solution of an optically active

compound. The analyzing filter has been turned clockwise by a degrees to restore the dark field.

Plane-polarized light Light

vibrating only in parallel

planes.

Polarimeter An instrument

for measuring the ability of

a compound to rotate the

plane of polarized light.

Observed rotation The

number of degrees through

which a compound rotates

the plane of polarized light.

Filled

sample tube

Plane of

polarized

light

Polarizing

filter

180o

Light

source

180o



Analyzing filter

needs to be rotated

until darkness is

again achieved

A polarimeter is used to

measure the rotation of

plane-polarized light as it

passes through a sample.

Richard Megna, 1992/

Fundamental Photographs

1856.9 What Is the Signiﬁcance of Chirality in the Biological World?

ﬁlter to the right (clockwise) to restore the dark ﬁeld, we say that the compound is dextro-

rotatory (Latin: dexter, on the right side); if we must turn it to the left (counterclockwise),

we say that the compound is levorotatory (Latin: laevus, on the left side).

The magnitude of the observed rotation for a particular compound depends on its

concentration, the length of the sample tube, the temperature, the solvent, and the wave-

length of the light used. The speciﬁc rotation,

[a], is deﬁned as the observed rotation at a

speciﬁc cell length and sample concentration expressed in grams per milliliter.

Specific rotation  [a]



Observed rotation (degrees)

Length (dm)  Concentration

The standard cell length is 1 decimeter

(1 dm  0.1 m). For a pure liquid sample, the con-

centration is expressed in grams per milliliter (

gmL; density). The temperature (T, in de-

grees centigrade) and wavelength (

l, in nanometers) of light are designated, respectively,

as superscripts and subscripts. The light source most commonly used in polarimetry is the

sodium D line

(l  589 nm), the same line responsible for the yellow color of sodium-

vapor lamps.

In reporting either observed or speciﬁc rotation, it is common to indicate a dextro-

rotatory compound with a plus sign in parentheses,

(



)

, and a levorotatory compound

with a minus sign in parentheses,

(



)

. For any pair of enantiomers, one enantiomer is

dextrorotatory and the other is levorotatory. For each member, the value of the speciﬁc

rotation is exactly the same, but the sign is opposite. Following are the speciﬁc rotations of

the enantiomers of 2-butanol at 25 °C, observed with the D line of sodium:

HOH

(S)-(+)-2-Butanol

[]

+ 13.52

HO H

(R )-(–)-2-Butanol

[]

–13.52

C. Racemic Mixtures

An equimolar mixture of two enantiomers is called a racemic mixture, a term derived from

the name “racemic acid” (Latin: racemus, a cluster of grapes), originally given to an equi-

molar mixture of the enantiomers of tartaric acid (Table 6.1). Because a racemic mixture

contains equal numbers of the dextrorotatory and the levorotatory molecules, its speciﬁc

rotation is zero. Alternatively, we say that a racemic mixture is optically inactive. A racemic

mixture is indicated by adding the preﬁx

({ ) to the name of the compound.

6.9 What Is the Significance of Chirality

in the Biological World?

Except for inorganic salts and a relatively 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. Of course, instances do occur in which more than one stereoisomer is found, but

these rarely exist together in the same biological system.

A. Chirality in Biomolecules

Perhaps the most conspicuous examples of chirality among biological molecules are the en-

zymes, all of which have many stereocenters. An example is chymotrypsin, an enzyme found

in the intestines of animals. This enzyme catalyzes the digestion of proteins (Section 19.5).

Chymotrypsin has 251 stereocenters. The maximum number of stereoisomers possible is

Dextrorotatory Rotating

the plane of polarized light

in a polarimeter to the right.

Levorotatory Rotating the

plane of polarized light in a

polarimeter to the left.

Specific rotation Observed

rotation of the plane of

polarized light when a

sample is placed in a

tube 1.0 dm long at a

concentration of 1.0 g/mL.

Racemic mixture A

mixture of equal amounts of

two enantiomers.

Optically inactive Showing

that a compound or mixture

of compounds does not

rotate the plane of polarized

light.

CHAPTER 6 Chirality: The Handedness of Molecules186

thus 2

251

, a staggeringly large number, almost beyond comprehension. Fortunately, nature

does not squander its precious energy and resources unnecessarily: Only one of these stereo-

isomers is produced and used by any given organism.

Because enzymes are chiral substances, most either produce or react with only sub-

stances that match their stereochemical requirements.

B. How an Enzyme Distinguishes between a Molecule

and Its Enantiomer

An enzyme catalyzes a biological reaction of a molecule by ﬁrst positioning it at a binding site

on the enzyme’s surface. An enzyme with binding sites speciﬁc for three of the four groups

on a stereocenter can distinguish between a molecule and its enantiomer or one of its dia-

stereomers. Assume, for example, that an enzyme involved in catalyzing a reaction of glycer-

aldehyde has on its surface a binding site speciﬁc for

H, a second speciﬁc for

OH, and

a third speciﬁc for

CHO. Assume further that the three sites are arranged on the enzyme

surface as shown in Figure 6.7. The enzyme can distinguish

(R) () glyceraldehyde (the

natural, or biologically active, form) from its enantiomer because the natural enantiomer

can be absorbed, with three groups interacting with their appropriate binding sites; for the

S enantiomer, at best only two groups can interact with these binding sites.

Because interactions between molecules in living systems take place in a chiral envi-

ronment, it should come as no surprise that a molecule and its enantiomer or one of its dia-

stereomers elicit different physiological responses. As we have already seen, (S)-ibuprofen

is active as a pain and fever reliever, whereas its R enantiomer is inactive. The S enantiomer

of the closely related analgesic naproxen is also the active pain reliever of this compound,

but its R enantiomer is a liver toxin!

HOOC

OCH

(S )-Ibuprofen (S )-Naproxen

6.10 How Can Enantiomers Be Resolved?

Resolution is the separation of a racemic mixture into its enantiomers. Because two en-

antiomers have the same physical properties, separating them, in general, is difﬁcult, but

scientists have developed a number of ways to do it. In this section, we illustrate just two of

the several laboratory methods for resolution: the use of enzymes as chiral catalysts and the

use of solid chiral materials to differentiate between enantiomers made to come in contact

with these materials.

This enantiomer of glyceraldehyde fits the three

specific binding sites on the enzyme surface

This enantiomer of glyceraldehyde

does not fit the same binding sites

enzyme surface

(R)-(+)-glyceraldehyde

)-(–)-glyceraldehyde

CHO

FIGURE 6.7

A schematic diagram

of an enzyme surface

capable of interacting with

(R) ( ) glyceraldehyde at

three binding sites, but with

(S) ( ) glyceraldehyde at

only two of these sites.

Resolution Separation of

a racemic mixture into its

enantiomers.

1876.10 How Can Enantiomers Be Resolved?

Chemical

Connections

CHIRAL DRUGS

(S)-(–)-3,4-Dihydroxyphenylalanine

(L-DOPA)

[

–13.1°

Dopamine

+CO

COOH

enzyme-catalyzed

decarboxylation

R¬ CO

R¬ H + CO

decarboxylation

Dopamine decarboxylase is speciﬁc for the S enan-

tiomer, which is commonly known as L-DOPA. It is es-

sential, therefore, to administer the enantiomerically

pure prodrug. Were the prodrug to be administered in

a racemic form, there could be a dangerous buildup

of the R enantiomer, which cannot be metabolized by

the enzymes present in the brain.

Question

Following are structural formulas for three other

angiotensin-converting enzyme (ACE) inhibitors, all

members of the “pril” family. Which are chiral? For

each that is chiral, determine the number of stereoiso-

mers possible for it. List the similarities in structure

among each of these four drugs.

COOH

Ramipril (Vasotec)

COOH

Quinapril (Accupril)

Enalapril (Altace)

COOH

Che

ical

Ch i l

ect

Co ect o s

Some of the common drugs used in human medi-

cine (for example, aspirin, Section 14.4B) are achiral.

Others are chiral and are sold as single enantio-

mers. The penicillin and erythromycin classes of an-

tibiotics and the drug Captopril are all chiral drugs.

Captopril, which is highly effective for the treatment

of high blood pressure and congestive heart failure,

was developed in a research program designed

to discover effective inhibitors of angiotensin-

converting enzyme (ACE). Captopril is manufac-

tured and sold as the (S,S)-stereoisomer. A large

number of chiral drugs, however, are sold as race-

mic mixtures. The popular analgesic ibuprofen (the

active ingredient in Motrin

, Advil

, and many other

nonaspirin analgesics) is an example. Only the S

enantiomer of the pain reliever ibuprofen is biologi-

cally active.

COOH

(CH

)

CHCH

COOH

Captopril

(S)-Ibuprofen

For racemic drugs, most often only one en-

antiomer exerts the beneﬁcial effect, whereas the

other enantiomer either has no effect or may exert

a detrimental effect. Thus, enantiomerically pure

drugs should, more often than not, be more effec-

tive than their racemic counterparts. A case in point

is 3,4-dihydroxyphenylalanine, which is used in the

treatment of Parkinson’s disease. The active drug is

dopamine. Unfortunately, this compound does not

cross the blood–brain barrier to the required site of

action in the brain. Consequently, what is adminis-

tered instead is the prodrug, a compound that is not

active by itself, but is converted in the body to an

active drug. 3,4-Dihydroxyphenylalanine is such a

prodrug; it crosses the blood–brain barrier and then

undergoes decarboxylation, catalyzed by the en-

zyme dopamine decarboxylase, to give dopamine.

Decarboxylation is the loss of carbon dioxide from

a carboxyl group (R

H).

CHAPTER 6 Chirality: The Handedness of Molecules188

A. Enzymes as Resolving Agents

One class of enzymes that has received particular attention in this regard is the esterases,

which catalyze the hydrolysis of esters (Section 14.1C) to give an alcohol and a carbox-

ylic acid. We illustrate this method by describing the resolution of (R,S)-naproxen. The

ethyl esters of both (R)- and (S)-naproxen are solids with very low solubilities in water.

Chemists then use an esterase in alkaline solution to selectively hydrolyze the (S)-ester,

which goes into the aqueous solution as the sodium salt of the (S)-carboxylic acid. The

(R)-ester is unaffected by these conditions. Filtering the alkaline solution recovers the

crystals of the (R)-ester. After the crystals are removed, the alkaline solution is acidiﬁed

to precipitate pure (S)-naproxen. The recovered (R)-ester can be racemized (converted

to an R,S-mixture) and again treated with the esterase. Thus, by recycling the (R)-ester,

all the racemic ester is converted to (S)-naproxen.

(S)-Naproxen

Ethyl ester of (R )-naproxen

(not affected by the esterase)

Ethyl ester of (S )-naproxen

1) esterase

NaOH, H

HCl, H

OCH

HCH

OCH

HCH

The sodium salt of (S)-naproxen is the active ingredient in Aleve

and a score of other over-

the-counter nonsteroidal anti-inﬂammatory preparations.

B. Resolution by Means of Chromatography

on a Chiral Substrate

Chromatography is a term used to describe the purification of substances in which

a sample to be purified interacts with a solid material, and different components of

the sample separate based on differences in their interactions with the solid material.

The solid material is packed into a column, and a solution of the substance dissolved

in a suitable solvent is passed down the column. The more weakly bound components

of the mixture pass through the column more quickly than the more tightly bound

components.

A common method for resolving enantiomers today is chromatography using a chi-

ral packing material in the column. Each enantiomer in principle interacts differently

with the chiral packing material, and the elution time will be different for each enan-

tiomer. A wide variety of chiral column packing materials have been developed for this

purpose.

Recently, the U.S. Food and Drug Administration established new guidelines for the

testing and marketing of chiral drugs. After reviewing these guidelines, many drug compa-

nies have decided to develop only single enantiomers of new chiral drugs. In addition to

regulatory pressure, there are patent considerations: If a company has patents on a racemic

drug, a new patent can often be taken out on one of its enantiomers.

189Summary of Key Questions

SUMMARY OF KEY QUESTIONS

s Stereoisomers have the same connectivity of their atoms,

but a different three-dimensional orientation of their

atoms in space.

s A mirror image is the reflection of an object in a mirror.

6.1 What Are Stereoisomers?

s A stereocenter is an atom at which the interchange of two

atoms or groups of atoms bonded to it produces a differ-

ent stereoisomer.

s The most common type of stereocenter among organic

compounds is a chiral center, a tetrahedral carbon atom

with four different groups bonded to it.

s Enantiomers are a pair of stereoisomers that are non-

superposable mirror images. A molecule that is not super-

posable on its mirror image is said to be chiral.

s Chirality is a property of an object as a whole, not of a

particular atom.

s An achiral object possesses a plane of symmetry—an

imaginary plane passing through the object and dividing

it such that one half is the reflection of the other half.

6.2 What Are Enantiomers?

priority is directed away from the observer, and (3) the

remaining three groups are read in order, from highest

priority to lowest priority.

s If the reading of groups is clockwise, the configuration is

R (Latin: rectus, right). If the reading is counterclockwise,

the configuration is S (Latin: sinister, left).

s The configuration at a stereocenter can be specified by the

R,S convention.

s To apply this convention, (1) each atom or group of atoms

bonded to the stereocenter is assigned a priority and

numbered from highest priority to lowest priority, (2) the

molecule is oriented in space so that the group of lowest

6.3 How Do We Designate the Configuration of a Stereocenter?

s For a molecule with n stereocenters, the maximum num-

ber of stereoisomers possible is 2

6.6 How Do We Describe the Chirality of Molecules with Three or More Stereocenters?

s A meso compound contains two or more stereocenters

assembled in such a way that its molecules are achiral.

s Enantiomers have identical physical and chemical proper-

ties in achiral environments.

s Diastereomers have different physical and chemical

properties.

s For a molecule with n stereocenters, the maximum num-

ber of stereoisomers possible is 2

s Diastereomers are stereoisomers that are not mirror images.

s Certain molecules have special symmetry properties that

reduce the number of stereoisomers to fewer than that

predicted by the 2

rule.

6.4 What Is the 2

Rule?

s When evaluating the symmetry of cyclic structures, such

as derivatives of cyclohexane and cyclopentane, it is help-

ful to evaluate planar representations.

6.5 How Do We Describe the Chirality of Cyclic Molecules with Two Stereocenters?

s Diastereomers have different physical and chemical

properties.

s Enantiomers have identical physical and chemical proper-

ties in achiral environments.

6.7 What Are the Properties of Stereoisomers?

s A polarimeter is an instrument used to detect and measure

the magnitude of optical activity. Observed rotation is the

number of degrees the plane of polarized light is rotated.

s Light that vibrates in only parallel planes is said to be

plane polarized.

6.8 How Is Chirality Detected in the Laboratory?

CHAPTER 6 Chirality: The Handedness of Molecules190

s A common method for resolving enantiomers is chroma-

tography using a chiral packing material in the column.

Each enantiomer in principle interacts differently with the

chiral packing material and the elution time will be differ-

ent for each enantiomer.

s Resolution is the experimental process of separating a

mixture of enantiomers into two pure enantiomers.

s One means of resolution is to treat the racemic mixture

with an enzyme that catalyzes a specific reaction of one

enantiomer, but not the other.

6.10 How Can Enantiomers Be Resolved?

four groups on a stereocenter can distinguish between a

molecule and its enantiomer or its diastereomers.

s An enzyme catalyzes the biological reactions of molecules

by first positioning them at a binding site on its surface.

An enzyme with a binding site specific for three of the

6.9 What Is the Significance of Chirality in the Biological World?

1. Enantiomers are always chiral. (6.2)

2. An unmarked cube is chiral. (6.1)

3. Stereocenters can be designated using E and Z. (6.3)

4. A chiral molecule will always have a diastereomer. (6.2)

5. Every object in nature has a mirror image. (6.1)

6. A molecule that possesses an internal plane of symme-

try can never be chiral. (6.2)

7. Pairs of enantiomers have the same connectivity. (6.1)

8. Enantiomers, like gloves, occur in pairs. (6.2)

9. A cyclic molecule with two stereocenters will always

have only three stereoisomers. (6.5)

10. An achiral molecule will always have a diastereomer. (6.2)

11. The cis and trans isomers of 2-butene are chiral. (6.1)

12. A human foot is chiral. (6.1)

13. A compound with n stereocenters will always have 2

stereoisomers. (6.4)

14. A molecule with three or more stereocenters cannot be

meso. (6.6)

15. A molecule with three or more stereocenters must be

chiral. (6.6)

16. Each member of a pair of enantiomers will have the

same boiling point. (6.7)

17. If a molecule is not superposable on its mirror image, it

is chiral. (6.1)

18. For a molecule with two tetrahedral stereocenters, four

stereoisomers are possible. (6.2)

19. Constitutional isomers have the same connectivity. (6.1)

20. Enantiomers can be separated by interacting them with

the same chiral environment or chemical agent. (6.10)

21. Enzymes are achiral molecules that can differentiate

chiral molecules. (6.9)

22. Cis and trans stereoisomers of a cyclic compound can

be classified as diastereomers. (6.5)

23. 3-Pentanol is the mirror image of 2-pentanol. (6.2)

24. Diastereomers do not have a mirror image. (6.2)

25. The most common cause of chirality in organic mol-

ecules is the presence of a tetrahedral carbon atom with

four different groups bonded to it. (6.1)

26. Each member of a pair of enantiomers will have the

same density. (6.7)

27. The carbonyl carbon of an aldehyde or a ketone cannot

be a stereocenter. (6.1)

28. For a molecule with three stereocenters, 3

 9 stereo-

isomers are possible. (6.2)

29. Diastereomers can be resolved using traditional meth-

ods such as distillation. (6.10)

30. A racemic mixture is optically inactive. (6.8)

31. 2-Pentanol and 3-pentanol are chiral and show enantio-

merism. (6.2)

32. A diastereomer of a chiral molecule must also be chiral.

(6.2)

33. In order to designate the configuration of a stereocen-

ter, the priority of groups must be read in a clockwise or

QUICK QUIZ

Answer true or false to the following questions to assess your general knowledge of the concepts in this chapter. If

you have difficulty with any of them, you should review the appropriate section in the chapter (shown in parenthe-

ses) before attempting the more challenging end-of-chapter problems.

s Specific rotation is the observed rotation measured with

a cell 1 dm long and a solution with a concentration of

1.00 g/mL.

s If the analyzing filter must be turned clockwise to restore

the zero point, the compound is dextrorotatory. If the

analyzing filter must be turned counterclockwise to

restore the zero point, the compound is levorotatory.

s A compound is said to be optically active if it rotates the

plane of polarized light. Each member of a pair of enantio-

mers rotates the plane of polarized light an equal number

of degrees, but opposite in direction.

s A racemic mixture is a mixture of equal amounts of two

enantiomers and has a specific rotation of zero.

s A meso compound is optically inactive.

191Problems

counterclockwise fashion after the lowest priority group

is placed facing toward the viewer. (6.3)

34. A compound with n stereocenters will always be one of

the 2

stereoisomers of that compound. (6.4)

35. Each member of a pair of enantiomers could react dif-

ferently in a chiral environment. (6.7)

36. A chiral molecule will always have an enantiomer. (6.2)

37. Each member of a pair of diastereomers will have the

same melting point. (6.7)

38. If a chiral compound is dextrorotatory, its enantiomer is

levorotatory by the same number of degrees. (6.8)

39. All stereoisomers are optically active. (6.8)

40. There are usually equal amounts of each enantiomer of

a chiral biological molecule in a living organism. (6.9)

Detailed explanations for many of these answers can be found in the

accompanying Solutions Manual.

Answers: (1) T (2) F (3) F (4) F (5) T (6) T (7) T (8) T (9) F (10) F

(11) F (12) T (13) F (14) F (15) F (16) T (17) T (18) T (19) F (20) T

(21) F (22) T (23) F (24) F (25) T (26) T (27) T (28) F (29) T (30) T

(31) F (32) F (33) F (34) T (35) T (36) T (37) F (38) T (39) F (40) F

PROBLEMS

A problem marked with an asterisk indicates an applied “real-world” problem. Answers to problems whose

numbers are printed in blue are given in Appendix D.

6.7 Define the term stereoisomer. Name four types of

stereoisomers.

6.8 In what way are constitutional isomers different from

stereoisomers? In what way are they the same?

6.9 Compare and contrast the meaning of the terms

conformation and configuration.

*6.10 Which of these objects are chiral (assume that there

is no label or other identifying mark)?

(a) A pair of scissors (b) A tennis ball

(e) The swirl created in water as it drains out of a

sink or bathtub

*6.11 Think about the helical coil of a telephone cord or

the spiral binding on a notebook, and suppose that

you view the spiral from one end and find that it has

a left-handed twist. If you view the same spiral from

the other end, does it have a right-handed twist or a

left-handed twist from that end as well?

*6.12 Next time you have the opportunity to view a collec-

tion of augers or other seashells that have a helical

twist, study the chirality of their twists. Do you find

an equal number of left-handed and right-handed

augers, or, for example, do they all have the same

handedness? What about the handedness of augers

compared with that of other spiral shells?

Section 6.1 Chirality

Kaz Chiba/Getty Images, Inc.

Median cross section

through the shell of a

chambered nautilus found

in the deep waters of the

Pacific Ocean. The shell

shows handedness; this

cross section is a right-

handed spiral.

*6.13 Next time you have an opportunity to examine any of

the seemingly endless varieties of spiral pasta (rotini,

fusilli, radiatori, tortiglioni), examine their twist. Do

the twists of any one kind all have a right-handed

twist, do they all have a left-handed twist, or are they

a racemic mixture?

6.14 One reason we can be sure that

-hybridized

carbon atoms are tetrahedral is the number of

stereoisomers that can exist for different organic

compounds.

(a) How many stereoisomers are possible for

CHCl

, CH

, and CHBrClF if the four bonds to

carbon have a tetrahedral geometry?

(b) How many stereoisomers are possible for each

of the compounds if the four bonds to the

carbon have a square planar geometry?

6.15 Which compounds contain stereocenters? (See

Example 6.1)

(a) 2-Chloropentane

(b) 3-Chloropentane

(d) 1,2-Dichloropropane

6.16 Using only C, H, and O, write a structural formula for

the lowest-molecular-weight chiral molecule of each

of the following compounds:

(a) Alkane (b) Alcohol

(e) Carboxylic acid

Section 6.2 Enantiomers

CHAPTER 6 Chirality: The Handedness of Molecules192

6.17 Which alcohols with the molecular formula C

are chiral?

6.18 Which carboxylic acids with the molecular formula

are chiral?

6.19 Draw the enantiomer for each molecule: (See

Example 6.1)

COOHCH

(a)

CHOH

CHO

(b)

COOH

(c)

(d)

(e)

(f)

COOH

(g)

HOH

OHH

(h)

Br OH

(i)

(j)

(k)

(l)

6.20 Mark each stereocenter in these molecules with an

asterisk (note that not all contain stereocenters): (See

Example 6.1)

(a)

(b)

(c)

–

(d)

6.21 Mark each stereocenter in these molecules with an

asterisk (note that not all contain stereocenters): (See

Example 6.1)

(a)

HO OH

(b) HO

(c)

(d)

6.22 Mark each stereocenter in these molecules with an

asterisk (note that not all contain stereocenters):

(See Example 6.1)

(a)

CCH “ CH

(b)

COOH

HCOH

(c)

CHCHCOOH

(d)

‘

CCH

(e)

HCOH

(f)

CHCH “CH

(g)

COOH

HOCCOOH

COOH

(h)

(CH

)

CCH

CH(OH)CH

6.23 Following are eight stereorepresentations of lactic

acid: (See Examples 6.3, 6.4)

COOH

OHH

(a)

HHO

HOOC

(b)

(c)

COOH

(d)

COOHH

CHOH

COOH

(e)

CHOH

COOH

(f)

193Problems

CCH

COOH

(g)

CH COOH

(h)

Take (a) as a reference structure. Which stereorepre-

sentations are identical with (a) and which are mirror

images of (a)?

6.24 Assign priorities to the groups in each set: (See

Example 6.2)

Section 6.3 Designation of Conﬁguration: The R,S Convention

Each enantiomer has a distinctive odor characteristic

of the source from which it can be isolated. Assign an

R or S configuration to the stereocenter in each. How

can they have such different properties when they

are so similar in structure?

6.27 Following is a staggered conformation of one of the

stereoisomers of 2-butanol: (See Example 6.2)

(a) Is this (R)-2-butanol or (S)-2-butanol?

(b) Draw a Newman projection for this staggered

conformation, viewed along the bond between

carbons 2 and 3.

gered conformations of this molecule. Which of

your conformations is the more stable? Assume

that

OH and

are comparable in size.

(a)

(b)

CH  CH

COOH

(c)

COO





(d)



COO



(e)

(

)

CH  CH

(

)

C  CH

6.25 Which molecules have R configurations? (See

Example 6.2)

(a)

Br H

(b)

HOCH

(c)

(d)

HCH

*6.26 Following are structural formulas for the enantio-

mers of carvone: (See Example 6.2)

(–)-Carvone

(Spearmint

oil)

(

±)-Carvone

(Caraway and

dillseed oil)

6.28

Write the structural formula of an alcohol with molec-

ular formula

that contains two stereocenters.

*6.29 For centuries, Chinese herbal medicine has used

extracts of Ephedra sinica to treat asthma. Investigation

of this plant resulted in the isolation of ephedrine, a

potent dilator of the air passages of the lungs. The

naturally occurring stereoisomer is levorotatory and

has the following structure: (See Example 6.2)

Ephedrine

Assign an R or S configuration to each stereocenter.

Sections 6.5 and 6.6 Molecules with Two or More Stereocenters

Ephedra sinica,

a source of

ephedrine, a potent

bronchodilator.

*6.30 The specific rotation of naturally occurring ephed-

rine, shown in Problem 6.29, is

41°. What is the

specific rotation of its enantiomer?

CHAPTER 6 Chirality: The Handedness of Molecules194

6.31 Label each stereocenter in these molecules with an

asterisk and tell how many stereoisomers exist for

each. (See Examples 6.5, 6.6)

(a)

CHCHCOOH

OHHO

(b)

COOH

CH COOH

CHHO COOH

(c)

(d) (e)

(f)

O COOH

(g)

(h)

How many stereoisomers are possible for each

molecule?

*6.32 Label the four stereocenters in amoxicillin, which

belongs to the family of semisynthetic penicillins:

COOH

Amoxicillin

*6.33

Label all stereocenters in loratadine (Claritin

) and

fexofenadine (Allegra

), now the top-selling antihista-

mines in the United States. Tell how many stereoiso-

mers are possible for each. (See Examples 6.5, 6.6)

Loratadine

(Claritin)

(a)

COOH

Fexofenadine

(Allegra)

(b)

How many stereoisomers are possible for each

compound?

*6.34 Following are structural formulas for three of the

most widely prescribed drugs used to treat depres-

sion. Label all stereocenters in each compound and

tell how many stereoisomers are possible for each

compound. (See Examples 6.5, 6.6)

Fluoxetine

(Prozac

)

(a)

HCH

Sertraline

(Zoloft

)

(b)

Paroxetine

(Paxil

)

(c)

195Chemical Transformations

*6.35 Triamcinolone acetonide, the active ingredient in

Azmacort

Inhalation Aerosol, is a steroid used to

treat bronchial asthma: (See Examples 6.5, 6.6)

Triamcinolone acetonide

(a) Label the eight stereocenters in this molecule.

(b) How many stereoisomers are possible for the

molecule? (Of this number, only one is the

active ingredient in Azmacort.)

6.36 Which of these structural formulas represent meso

compounds? (See Example 6.4)

(a) (b)

(c)

(d)

(e) (f)

6.37 Draw a Newman projection, viewed along the bond

between carbons 2 and 3, for both the most stable and

the least stable conformations of meso-tartaric acid:

ƒƒ

OHOH

CHCH COOHHOOC

6.38 How many stereoisomers are possible for 1,3-dimeth-

ylcyclopentane? Which are pairs of enantiomers?

Which are meso compounds? (See Examples 6.4–6.6)

6.39 In Problem 3.59, you were asked to draw the more

stable chair conformation of glucose, a molecule in

which all groups on the six-membered ring are equa-

torial: (See Examples 6.2, 6.5, 6.6)

(a) Identify all stereocenters in this molecule.

(b) How many stereoisomers are possible?

(d) What is the configuration (R or S) at carbons 1

and 5 in the stereoisomer shown?

6.40 What is a racemic mixture? Is a racemic mixture optically

active? That is, will it rotate the plane of polarized light?

6.41 Test your cumulative knowledge of the reactions

learned so far by completing the following chemical

transformations. Pay particular attention to the stereo-

chemistry in the product. Where more than one stereo-

isomer is possible, show each stereoisomer. Note that

some transformations will require more than one step.

(c)

(a)

(b)

(d)

(e)

(f)

(h)

(g)

(i)

(j)

CHEMICAL TRANSFORMATIONS

CHAPTER 6 Chirality: The Handedness of Molecules196

PUTTING IT TOGETHER

The following problems bring together concepts and material from Chapters 4–6. Although the focus may be on

these chapters, the problems will also build on concepts discussed thus far.

Choose the best answer for each of the following questions.

1. Which of the following will not rotate the plane of polar-

ized light?

(a) A 50:50 ratio of (R)-2-butanol and cis-2-butene.

(b) A 70:20 ratio of (R)-2-butanol and S-2-butanol.

trans-2-butene.

(d) A 20:70 ratio of trans-2-butene and cis-2-butene.

(e) None of the above (i.e., all of them will rotate

plane-polarized light)

6.42 Predict the product(s) of the following reactions (in

cases where more than one stereoisomer is possible,

show each stereoisomer):

(a)

(b)

6.43 What alkene, when treated with H

/Pd, will ensure a

100% yield of the stereoisomer shown?

(a)

(b)

6.44 Which of the following reactions will yield a racemic

mixture of products?

(a)

(c)

(d)

HCl

(b)

HBr

(e)

(f)

HBr

6.45 Draw all the stereoisomers that can be formed in the

following reaction:

HCl

Comment on the utility of this particular reaction as

a synthetic method.

6.46 Explain why the product of the following reaction

does not rotate the plane of polarized light:

(b)

(a)

LOOKING AHEAD

*6.47 Identify objects in your surroundings and take turns

deciding if each object is chiral or achiral.

6.48 Take turns identifying the planes of symmetry in

cubane (note: the hydrogen atoms are not shown).

Cubane

6.49

Discuss whether the following pairs of objects are

true enantiomers of each other. For those that are not

true enantiomers, decide what it would take for them

to be true enantiomers.

(a) your right hand and left hand

(b) your right eye and left eye

with a right, front flat tire

6.50 Compound A (C

) is not optically active and cannot

be resolved. It reacts with Br

in CCl

to give com-

pound B (C

). When compound A is treated with

/Pt, it is converted to compound C (C

). When

treated with HBr, compound A is converted to com-

pound D (C

Br). Given this information, propose

structural formulas for A, B, C, and D. There are at

least three possibilities for compound A and, in turn,

three possibilities for compounds B, C, and D. As a

group, try to come up with all the possibilities.

GROUP LEARNING ACTIVITIES

197Putting It Together

2. Which of the following cis isomers of dimethylcyclohex-

ane is not meso?

(a) cis-1,4-dimethylcyclohexane

(b) cis-1,3-dimethylcyclohexane

(d) All of the above (i.e., none of them is meso)

(e) None of the above (i.e., all of them are meso)

3. How many products are possible in the following Lewis

acid–base reaction?





(a) One (b) Two (c) Three (d) Four

(e) None (no reaction will take place)

4. What is the relationship between the following two

molecules?

(a) They are identical.

(b) They are enantiomers.

(d) They are constitutional isomers.

(e) They are nonisomers.

5. Which stereoisomer of 2,4-hexadiene is the least stable?

(a) Z,Z-2,4-hexadiene

(b) Z,E-2,4-hexadiene

(d) E,E-2,4-hexadiene

(e) All are equal in stability.

6. Select the shortest C

C single bond in the following

molecule.

(a) a (b) b (c) c (d) d (e) e

7. Which of the following statements is true of b-bisabolol?

-Bisabolol



(a) There are 6 stereoisomers of b-bisabolol.

(b) b-Bisabolol is soluble in water.

(d) b-Bisabolol has a meso stereoisomer.

(e) None of the above.

8. How many products are formed in the following

reaction?

(a) 1 (b) 2 (c) 3 (d) 4 (e) 5

9. Which of the following is true when two isomeric

alkenes are treated with

Pt?

(a) The alkene that releases more energy in the

reaction is the more stable alkene.

(b) The alkene with the lower melting point will

release less energy in the reaction.

(d) Both alkenes will release equal amounts of energy

in the reaction.

(e) None of these statements is true.

10. An unknown compound reacts with two equivalents of

catalyzed by Ni. The unknown also yields 5 CO

and

4 H

O upon combustion. Which of the following could

be the unknown compound?

(a) (b)

(e)

11. Provide structures for all possible compounds of for-

mula C

that would react quantitatively with NaNH

12. Answer the questions that follow regarding the following

compound, which has been found in herbal preparations

of Echinacea, the genus name for a variety of plants mar-

keted for their immunostimulant properties.

(a) How many stereoisomers exist for the compound

shown?

CHAPTER 6 Chirality: The Handedness of Molecules198

(b)

(c)

18. Predict whether solutions containing equal amounts

of each pair of the structures shown would rotate the

plane of polarized light.

(b)

(a)

(c)

19. Complete the following chemical transformations.

(a)

Any alkyne enantiomer

(b)

Any alkene

(c)

20. Provide a mechanism for the following series of

reactions. Show all charges and lone pairs of elec-

trons in your structures as well as the structures of

all intermediates.

(b) Would you expect the compound to be soluble in

water?

(d) What would be the product formed in the reaction

of this compound with an excess amount of

Pt?

13. Provide IUPAC names for the following compounds.

(a)

(c)

(b)

14. Compound A is an optically inactive compound with a

molecular formula of C

. Catalytic hydrogenation of

A gives an optically inactive compound, B (C

), as

the sole product. Furthermore, reaction of A with HBr

results in a single compound, C, with a molecular for-

mula of C

Br. Provide structures for A, B, and C.

15. An optically active compound, A, has a molecular for-

mula of C

. Hydroboration–oxidation of A yields an

optically active product, B, with a molecular formula of

O. Catalytic hydrogenation of A yields an optically

inactive product, C, with a molecular formula of C

Propose structures for A, B, and C.

16. Based on the following hydrogenation data, which is

more stable, the alkene (A) with the double bond out-

side of the ring or the alkene (B) with the double bond

inside the ring? Use a reaction energy diagram to illus-

trate your point.

B C

A C

20.69 kcal/mol

23.84 kcal/mol

17. Explain whether the following pairs of compounds

could be separated by resolution of enantiomers. If such

separation is not possible, indicate so and explain your

answer.

(a)

199Putting It Together

1) NaNH

2) Br(CH

)

3) NaNH

21. Predict the major product or products of each of the fol-

lowing reactions. Be sure to consider stereochemistry in

your answers.

(a)

1) BH



THF

2) HOOH

, NaOH , H

(b)

(c)

Lindlar’s Pd

(e)

(f)

(d)

22. Provide a mechanism for the following reaction.

Show all charges and lone pairs of electrons in

your structures as well as the structures of all

intermediates.