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4.15 SUMMARY
Stereochemistry is chemistry in three dimensions. At its most fundamental level, its concern is molecular
structure; at another level, it is chemical reactivity. Table 4.2 summarizes some of its basic definitions.
TABLE 4.2 Classification of Isomers
Definition
Example
Isomers are different compounds that have the same molecular
formula. They may be either constitutional isomers or stereoisomers.
1. Constitutional
Three constitutionally isomeric compounds
isomers are isomers
have the molecular formula C3H8O:
that differ in the order
in which their atoms
are connected.
2. Stereoisomers are
isomers that have the
same constitution but
differ in the
arrangement of their
atoms in space.
The two enantiomeric forms of 2chlorobutane are
The cis and trans isomers of 4(a) Enantiomers are methylcyclohexanol are stereoisomers, but
stereoisomers that they are not related as an object and its mirror
are related as an
image; they are diastereomers.
object and its
nonsuperimposable
mirror image.
(b) Diastereomers are
stereoisomers that
are not mirror
images.
Section A molecule is chiral if it cannot be superimposed on its mirror image. Nonsuperimposable mirror
4.1
images are enantiomers of one another. Molecules in which mirror images are superimposable are
achiral.
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Section
4.2
The most common kind of chiral molecule contains a carbon atom that bears four different atoms or
groups. Such an atom is called a chirality center. Table 4.2 shows the enantiomers of 2chlorobutane. C-2 is a chirality center in 2-chlorobutane.
Section A molecule that has a plane of symmetry or a center of symmetry is achiral. cis-44.3
Methylcyclohexanol (Table 4.2) has a plane of symmetry that bisects the molecule into two mirrorimage halves and is achiral. The same can be said for trans-4-methylcyclohexanol.
Section Optical activity, or the degree to which a substance rotates the plane of polarized light, is a physical
4.4
property used to characterize chiral substances. Enantiomers have equal and opposite optical
rotations. To be optically active a substance must be chiral, and one enantiomer must be present in
excess of the other. A racemic mixture is optically inactive and contains equal quantities of
enantiomers.
Section Relative configuration compares the arrangement of atoms in space to some reference. The prefix
4.5
cis in cis-4-methylcyclohexanol, for example, describes relative configuration by referencing the
orientation of the CH3 group to the OH. Absolute configuration is an exact description of the
arrangement of atoms in space.
Section Absolute configuration in chiral molecules is best specified using the prefixes R and S of the Cahn–
4.6
Ingold–Prelog notational system. Substituents at a chirality center are ranked in order of decreasing
precedence. If the three highest ranked substituents trace a clockwise path (highest → second
highest → third highest) when the lowest ranked substituent is held away from you, the
configuration is R. If the path is counterclockwise, the configuration is S. Table 4.2 shows the R and
S enantiomers of 2-chlorobutane.
Section A Fischer projection shows how a molecule would look if its bonds were projected onto a flat
4.7
surface. Horizontal lines represent bonds pointing toward you; vertical lines represent bonds
pointing away from you. The projection is normally drawn so that the carbon chain is vertical, with
the lowest numbered carbon at the top.
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Section
4.8
Both enantiomers of the same substance are identical in most of their physical properties. The most
prominent differences are biological ones, such as taste and odor, in which the substance interacts
with a chiral receptor site. Enantiomers also have important consequences in medicine, in which the
two enantiomeric forms of a drug can have much different effects on a patient.
Section Molecules without chirality centers can be chiral. Biphenyls that are substituted can exhibit an axis
4.9
of chirality. When A≠ B, and X ≠ Y, the two conformations are nonsuperimposable mirror images
of each other; that is, they are enantiomers. The bond connecting the two rings lies along a chirality
axis.
Section When a molecule has two chirality centers and these two chirality centers are not equivalent, four
4.10
stereoisomers are possible.
Stereoisomers that are not mirror images are classified as diastereomers. Each enantiomer of
erythro-3-bromo-2-butanol is a diastereomer of each enantiomer of threo-3-bromo-2-butanol.
Section Achiral molecules that contain chirality centers are called meso forms. Meso forms typically
4.11
contain (but are not limited to) two equivalently substituted chirality centers. They are optically
inactive.
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Section For a particular constitution, the maximum number of stereoisomers is 2 n, where n is the number of
4.12
chirality centers. The number of stereoisomers is reduced to less than 2 n when there are meso
forms.
Section Resolution is the separation of a racemic mixture into its enantiomers. It is normally carried out by
4.13
converting the mixture of enantiomers to a mixture of diastereomers, separating the diastereomers,
then regenerating the enantiomers.
Section Atoms other than carbon can be chirality centers. Examples include those based on tetracoordinate
4.14
silicon and tricoordinate sulfur or phosphorus as the chirality center. In principle, tricoordinate
nitrogen can be a chirality center in compounds of the type N(x, y, z), where x, y, and z are different,
but inversion of the nitrogen pyramid is so fast that racemization occurs virtually instantly at room
temperature.
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PROBLEMS
Molecular Chirality
4.26 Which of the isomeric alcohols having the molecular formula C6H14O are chiral? Which are achiral?
4.27 Including stereoisomers, write structural formulas for all of the compounds that are trichloro derivatives
of
(a) cyclobutane
(b) cyclopentane
Which are chiral? Which are achiral?
4.28 In each of the following pairs of compounds one is chiral and the other is achiral. Identify each
compound as chiral or achiral, as appropriate.
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(a)
(b)
(c)
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(d)
(e)
(f)
(g)
4.29 Compare 2,3-pentanediol and 2,4-pentanediol with respect to the number of stereoisomers possible for
each. Which ones are chiral? Which are achiral?
4.30 Of the isomers shown, which are chiral? Which ones are constitutional isomers of each other?
Stereoisomers? Enantiomers? Diastereomers?
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4.31
Diltiazem is prescribed to treat hypertension, and simvastatin is a cholesterol-lowering drug. Locate the
chirality centers in each.
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4.32 Among compounds (a)–(d), identify those that have a chirality axis.
A
B
X
Y
(a) (CH3)3C—
H—
H—
H—
(b) (CH3)3C—
(CH3)3C—
H—
H—
(c) (CH3)3C—
H—
(CH3)3C—
H—
(d) (CH3)3C—
(CH3)3C—
(CH3)3C—
(CH3)3C—
R,S-Configurational Notation
4.33 The absolute configuration of (−)-bromochlorofluoromethane is R. Which of the following is (are) (−)BrClFCH?
4.34 A subrule of the Cahn–Ingold–Prelog system specifies that higher mass number takes precedence over
lower when distinguishing between isotopes.
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(a) Determine the absolute configurations of the reactant and product in the biological oxidation of
isotopically labeled ethane described in Section 4.2.
(b) Because OH becomes bonded to carbon at the same side from which H is lost, the oxidation
proceeds with retention of configuration. Compare this fact with the R and S configurations you
determined in part (a) and reconcile any apparent conflicts.
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4.35
Specify the configuration of the chirality center as R or S in each of the following.
(a) (−)-2-Octanol
(b) Monosodium L-glutamate (only this stereoisomer is a flavor-enhancing agent)
4.36 The name cis-3-bromocyclohexanol correctly describes the constitution and relative stereochemistry of
the compound shown. The molecule, however, is chiral so if we wish to distinguish between it and its
enantiomer we need to specify its absolute configuration using R,S notation. Which of the four
possibilities is correct?
(1R,3R)-3-bromocyclohexanol
(1R,3S)-3-bromocyclohexanol
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(1S,3S)-bromocyclohexanol
(1S,3R)-3-bromocyclohexanol
4.37 The antiparkinson drug droxidopa has the structural formula shown with configurations at C-2 and C-3
of S and R, respectively. Add appropriate wedges and/or dashes to show the stereochemistry.
Structural Relationships
4.38 Identify the relationship in each of the following pairs. Do the drawings represent constitutional
isomers or stereoisomers, or are they just different ways of drawing the same compound? If they are
stereoisomers, are they enantiomers or diastereomers?
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(a)
(b)
(c)
(d)
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(e)
(f)
(g)
(h)
(i)
(j)
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4.39 Muscarine is a poisonous substance present in the mushroom Amanita muscaria. Its structure is
represented by the constitution shown here.
(a) Including muscarine, how many stereoisomers have this constitution?
(b) One of the substituents on the ring of muscarine is trans to the other two. How many of the
stereoisomers satisfy this requirement?
(c) Muscarine has the configuration 2S,3R,5S. Write a structural formula of muscarine showing its
correct stereochemistry.
4.40 (−)-Menthol is the most stable stereoisomer of 2-isopropyl-5-methylcyclohexanol and has the R
configuration at the hydroxyl-substituted carbon.
(a) Draw the preferred conformation of (−)-menthol.
(b) (+)-Isomenthol has the same constitution as (−)-menthol. The configurations at C-1 and C-2 of (+)isomenthol are the opposite of the corresponding chirality centers of (−)-menthol. Write the
preferred conformation of (+)-isomenthol.
Optical Activity
4.41 A certain natural product having [α]D + 40.3° was isolated. Two very different structures were
independently proposed for this compound. Which one do you think is more likely to be correct? Why?
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4.42
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One of the principal substances obtained from archaea (one of the oldest forms of life on Earth) is
derived from a 40-carbon diol. Given the fact that this diol is optically active, is it compound A or is it
compound B?
4.43 (a) An aqueous solution containing 10 g of optically pure fructose was diluted to 500 mL with water
and placed in a polarimeter tube 20 cm long. The measured rotation was −5.20°. Calculate the
specific rotation of fructose.
(b) If this solution were mixed with 500 mL of a solution containing 5 g of racemic fructose, what
would be the specific rotation of the resulting fructose mixture? What would be its optical purity?
Descriptive Passage and Interpretive Problems 4
Prochirality
Consider two chemical changes: one occurring at a tetrahedral sp3 carbon C(x,x,y,z), the other at a trigonal sp
2 carbon C(x,y,z), where x, y, and z are different atoms or groups attached to C. Each reactant is achiral; both
are converted to the chiral product C(w,x,y,z). In the first case w replaces one of the x atoms or groups, in the
other w adds to the trigonal carbon.
Both transformations convert C in each achiral reactant to a chirality center in the product. The two achiral
reactants are classified as prochiral. C is a prochirality center in C(x,x,y,z) and has two prochiral faces in
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C(x,y,z).
In achiral molecules with tetrahedral prochirality centers, substitution of one of the two x groups by w gives
the enantiomer of the product that results from substitution of the other. The two x groups occupy mirrorimage sites and are enantiotopic.
Enantiotopic groups are designated as pro-R or pro-S by a modification of Cahn–Ingold–Prelog notation. One
is assigned a higher priority than the other without disturbing the priorities of the remaining groups, and the
R,S configuration of the resulting chirality center is determined in the usual way. If it is R, the group assigned
the higher rank is pro-R. If S, this group is pro-S. Ethanol and citric acid illustrate the application of this
notation to two prochiral molecules.
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Citric acid played a major role in the development of the concept of prochirality. Its two CH2CO2H chains
groups behave differently in a key step of the Krebs cycle, so differently that some wondered whether citric
acid itself were really involved. Alexander Ogston (Oxford) provided the answer in 1948 when he pointed
out that the two CH2CO2H groups are differentiated when citric acid interacts with the chiral environment of
an enzyme.
The two prochiral faces of a trigonal atom C(x,y,z) are enantiotopic and designated Re and Si according to
whether x, y, and z trace a clockwise (Re) or counterclockwise (Si) path in order of decreasing Cahn–Ingold–
Prelog precedence. An acetaldehyde molecule that lies in the plane of the paper, for example, presents either
the Re or Si face according to how it is oriented.
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The stereochemical aspects of many enzyme-catalyzed reactions have been determined. The enzyme alcohol
dehydrogenase catalyzes the oxidation of ethanol to acetaldehyde by removing the pro-R hydrogen
(abbreviated as HR). When the same enzyme catalyzes the reduction of acetaldehyde to ethanol, hydrogen is
transferred to the Re face.
4.44 Which molecule is prochiral?
A. Ethane
B. Propane
C. Butane
D. Cyclopropane
4.45 How many of the carbons in 2-methylpentane [(CH3)2CHCH2CH2CH3] are prochirality centers?
A. One
B. Two
C. Three
D. Four
4.46 What are the pro-R and pro-S designations for the enantiotopic hydrogens in 1-propanol?
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4.47 The enzyme fumarase catalyzes the addition of water to the double bond of fumaric acid.
The —OH group and the pro-R hydrogen of the CH2 group of (S)-(−)malic acid come from water.
What stereochemical pathway describes the addition of water to the double bond?
A. syn Addition
B. anti Addition
4.48
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To which prochiral face of the double bond of fumaric acid does the —OH group add to in the
fumarase-catalyzed hydration of fumaric acid described in the preceding problem?
A. Re
B. Si
4.49 A method for the stereoselective synthesis of chiral epoxides gave the product shown in high
enantiomeric excess. To which faces of the doubly bonded carbons is oxygen transferred?
A. Re Re
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B. Re Si
C. Si Si
D. Si Re
4.50 When the achiral dione shown (below left) was incubated in water with baker’s yeast, reduction of one
of the C O groups occurred to give a single stereoisomer of the product. This product corresponded to
hydrogen transfer to the Re face of the pro-R carbonyl group. Which product is this?
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