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Stereochemistry
 Some objects are not the same
as their mirror images
(technically, they have no plane
of symmetry)
Ex: When you hold a left hand
up a miror, the image you see
looks like a right hand.
The property is commonly
called “handedness”
 Organic molecules have
handedness that results from
substitution patterns on sp3
hybridized carbon
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Why this Chapter?
 Handedness is important in organic and biochemistry
# Many drugs and almost all the molecules in our bodies
are handed:
Molecular handedness makes possible the specific
interactions between enzymes and their substrates, that
are so crucial to enzyme function.
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5.1 Enantiomers and the Tetrahedral Carbon
Figure 5.1 Tetrahedral carbon atoms and their miror iamges.
 Molecules that have one carbon with 4 different substituents
(CHXYZ) have nonsuperimposable mirror images – enantiomers
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5.1 Enantiomers and the Tetrahedral Carbon
 When you cannot superimpose a model of a compound
(CHXYZ) on a model of its mirror image for the same
reason that you cannot superimpose a left hand on a
right hand,
the compound is not identical to its mirror image: they are
not the same!!!
Molecules that are not identical to their mirror images are
kinds of stereoisomers called enantiomers.
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Enantiomers are related to each other as a right hand is related
to a left hand and result whenever a tetrahedral carbon is
bonded to four different substituents.
Ex: lactic acid
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Figure 5.2 Attempts at superimposing the mirrorimage forms of lactic acid
(a) When the –H and –OH substituents match up, the –CO2H and –
CH3 substituents don’t.
(b) When –CO2H and –CH3 match up, -H and –OH don’t.
# Regardless of how the molecules are oriented, they aren’t
identical.
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5.2 The reason for Handedness in
Molecules: Chirality
 A molecule that is not identical to its mirror image is said to be
chiral (means “having handedness”)
 How can you predict whether a given molecule is or is not chiral?
⇒ A molecule is not chiral if it has a plane of symmetry.
A plane of symmetry is a plane
that cuts through the middle of a
molecule (or any object) in such
a way that one half of the
molecule (or object) is a mirror
image of the other half.
# A molecule with a plane of
symmetry is the same as its
mirror image and is said to be
achiral
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How can you predict whether a given
molecule is or is not chiral?
# If an object has a plane of symmetry, it is necessarily the
same as its mirror image. The lack of a plane of symmetry
is called “handedness”, chirality
Ex: Hands, gloves
They have a “left” and a “right” version
# A plane of symmetry divides an entire molecule into two
pieces that are exact mirror images.
⇒ A molecule with a plane of symmetry is the same as its
mirror image and is said to be achiral.
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Figure 5.4 The achiral propanoic acid molecule
versus the chiral lactic acid molecule
Propanoic acid has a plane of symmetry that makes one side
of the molecule a mirror image of the other side.
However, lactic acid has no such symmetry plane.
Chirality Centers
 A point in a molecule where four different groups (or atoms)
are attached to carbon is called a chirality center
(marked with an asterisk)
 There are two nonsuperimposable ways that 4 different
groups (or atoms) can be attached to one carbon atom
(R,S configuration, discussed later)
 A chiral molecule usually has at least one chirality
center
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Chirality Centers in Chiral Molecules
# C2 is bonded to four different groups
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More examples of chiral molecules:
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Problems 5.1-5.3
 Problem 5.1 Which of the following objects are chiral?
(a) Soda can
(b) Screw
(c) Beanstalk
(d) Shoe
Problem 5.2 Identify the chirality centers in the following molecules.
(a)
N
H
Problem 5.3 Alanine is chiral. Draw the two enantiomers of alanine
using the standard convention of solid, wedged, and dashed lines.
COOH
H
H3C
NH2
COOH
H2N
H
CH3
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5.3 Optical Activity
 A beam of ordinary light consists of electromagnetic waves that
oscillate in an infinite number of planes at right angles to the direction
of light travel.
 When a beam of ordinary light is passed through a device called a
polarizer, only the light waves oscillating in a single plane can pass
through and the light is said to be plane-polarized. Light waves in all
other planes are blocked out.
 A polarimeter measures the rotation of plane-polarized light that
has passed through a solution.
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Measurements
The plane polarized light is passed through the tube, and rotation of the
polarization plane occurs.
By rotating the second polarizer (analyzer) until the light passes through it,
we can find the new plane of polarization and can tell to what extent rotation
has occurred.
→The angle between the entrance and exit planes is the optical rotation.
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Optical Activity -continued.
 When a beam of plane-polarized light passes through a solution of
certain organic molecules, the plane of polarization is rotated.
 Not all organic compounds exhibit this property, but those
that do are said to be optically active (In other words, solutions
of chiral compounds rotate plane-polarized light and the
molecules are said to be optically active)
 Some optically active molecules rotate polarized light to the left
(counterclockwise) and are said to be levorotatory (-), whereas
others rotate polarized light to the right (clockwise) and said to be
dextrorotatory (+).
Ex: (-)-Morphine is levorotatory, and (+)-sucrose is dextrorotatory
Specific Rotation
 Specific rotation, []D for an optically active compound:
[]D = observed rotation/(pathlength x concentration)
= /(l x C) = degrees/(dm x g/mL)
 Specific rotation is that observed for 1 g/mL in solution in
a cell with a 10 cm path using light from sodium metal
vapor (589 nm)
→ Characteristic property of a compound that is optically
active – the compound must be chiral
# The specific rotation of the enantiomer is equal in
magnitude but opposite in sign
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Continued.
Problem 5.6 A 1.50g sample of coniine was dissolved in 10.0 mL of
ethanol and placed in a sample cell with a 5.00 cm path length. The
observed rotation at the sodium D line was +1.21o. Calculate []D for
coniine.
[]D = /(l x C) = degrees/(dm x g/mL) = + 1.21o /(0.500 dm x 0.150 g/mL)
= +16.1o
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5.4 Pasteur’s Discovery of Enantiomers
 Louis Pasteur discovered that sodium ammonium salts of tartaric
acid crystallize into right handed and left handed forms below 28℃.
 Although a 50:50 mixture of right and left was optically inactive,
solutions of the crystals from each of the sorted piles were optically
active, and their specific rotations were equal in amount but opposite
in sign.
 → He was the first chemist who discovered enantiomers.
Enantiomers, also called optical isomers, have identical physical
proiperties, such as m.p. and b.p., but differ in the direction in which
their solutions rotate plane-polarized light
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5.5 Sequence Rules for Specifying
Configuration
Drawings provide a visual representation of
stereochemistry, but a verbal method for indicating the 3dimensional arrangement (configuration) of substituents
at a chirality center is also needed.
 The method employs a set of sequence rules (CahnIngold-Prelog rules) to rank the four groups attached to
the chirality center and then looks at the handedness with
which those groups are attached.
,
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Sequence Rules (IUPAC)
Rule 1:
• Look at the four atoms directly attached to the chirality center, and
rank them according to atomic number.
# The atoms with the highest atomic number has the highest ranking
(first), and the atom with the lowest atomic number (usually H) has the
lowest ranking (fourth).
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Figure 5.7 Assigning configuration to a chirality center. When the
molecule is oriented so that the lowest-ranked group(4) is toward the
rear, the remaining three groups raidiate toward the viewer like the
spokes of the steering wheel.
• If the direction of travel 1→2 → 3 is clockwise (right turn), the center has
the R configuration
• If the direction of travel 1 → 2 → 3 is counterclockwise (left turn), the center
is S configuration
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 Rule 2:
If a decision can’t be reached by ranking the first atoms in the
substituents, look at the second, third, or fourth atoms until a
difference is found
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Rule 3:
 Multiple-bonded atoms are equivalent to the same number of
single-bonded atoms
Ex:
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Figure 5.8 Assigning configuration to (a) (-)-lactic
acid and (b) (+)-lactic acid
# The sign of optical rotation, (+) or (-), is not related to the R,S designation !!
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Figure 5.9 Assigning configuration to (a) (-)-glyceraldehyde and
(+)-alanine. Both happen to have the S configuration, although
one is levorotatory and the other is dextrorotatory.
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Continued.
Problem 5.9 Orient each of the following drawings so that the lowestpriority group is toward the rear, and then assign R or S configuration.
(a)
(b)
1
4
3
3
2
2
3
4
4
1
1
2
3
109o
S
R
Problem 5.10 Assign R or S configuration to the chirality center in each of the
following molecules.
(a)
(b)
CH3
OH
OH
o
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H
HS
CO2H
H3C
CO2H
H
S
H
HO2C
CH3
S
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Problem 5.11 Draw a tetrahedral representation of
(S)-2-pentanol (2-hydroxypentane).
OH
OH
C
H
CH3
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5.6 Diastereomers
 Molecules with more than one chirality center have
mirror image stereoisomers that are enantiomers
 In addition they can have stereoisomeric forms that are
not mirror images, called diastereomers
 As a general rule, a molecule with n chirality centers can
have up to 2n stereomers although it may have fewer.
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Figure 5.10
The four stereoisomers of threonine (2-amino-3-hydroxybutanoic acid)
# There are two pairs of enantiomers: 2R,3R/2S,3S and 2R,3S/2S,3R.
# What is the relationship between the 2R,3R isomer and the 2R,3S isomer?
They are stereoisomers, yet they aren’t enantiomers: diastereomers
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# In the special case where two diastereomers differ at only one
chirality center but are the same at all others, the compounds
are said to be epimers.
Ex:
# Eight of the nine chirality centers are identical, but the one at C5 is different.
Thus cholestanol and coprostanol are epimeric at C5.
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5.7 Meso Compounds
 Tartaric acid has two chirality centers.
(1) The 2R,3R and 2S,3S structures : a pair of enetiomers.
(2) The 2R,3S and 2S,3R structures : superimposable, and thus identical.
Because of the plane of symmetry, the molecule is achiral, despite the fact it
has two chirality centers.
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# A close look at the 2R,3S and 2S,3R structures shows that
they are superimposable, and thus identical, as can be seen by
rotating one structure 180o
An achiral compound with chirality centers is called a meso compound
– it has a plane of symmetry
⇒ Tartaric acid exists in three stereoisomeric forms: two enantiomers and
one meso form
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Tartaric acid - Continued
The (+)- and (-)-tartaric acids have identical melting points, solubilities, and
Densities, but they differ in the sign of their rotation of plane-polarized light.
The meso isomer is diastereomeric with the (+) and (-) forms. It is a different
compound altogether, and has different physical properties.
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Problem 5.16 Which of the following structures
represent meso compounds?
H3C
(a)
(b)
OH
H
H
OH
(d)
(c)
H
OH
H
H
Br
OH
H
CH3
Br
H
CH3
109o
S
S
H3C
Br
H
Br
H
CH3
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Problem 5.17 Which of the following have a meso form?
( Recall that the –ol suffix refers to an alcohol, ROH)
(b) 2,3-Petandiol
(c) 2,4-Pentanediol
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5.8 Racemic Mixtures and the
Resolution of Enantiomers
 A 50:50 mixture of two chiral compounds that are mirror images does
not rotate light – called a racemic mixture (also called a racemate)
 Through luck, Pasteur was able to separate, or resolve, racemic tataric
acid into its (+) and (-) enantiomers. Unfortunately, the crystallization
technique he used doesn’t work for most racemates, so other methods
are needed.
 Each pure compound can be separated or resolved from the mixture
by following the steps:
1. Make a derivative of each with a chiral substance that is free of its
enantiomer (a resolving agent) to obtain diastereomers.
2. Separate the resulting diastereomers (different solubility).
3. Remove the resolving agent.
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Figure 5.12 Reaction of racemic lactic acid with achiral
methylamine leads to a racemic mixture of ammonium salts.
# The situation is analogous to what happens when left and right hands (chiral)
pick up a ball (achiral). Both left and right hands pick up the ball equally well, and
the products - ball in right hand versus ball in left hand - are mirror images.
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Figure 5.13 Reaction of racemic tartaric acid with
(R)-1-phenylethylamine yields a mixture of two diastereomeric
ammonium salts, which have different properties and can be separated.
# The situation is analogous to what happens when left and right hands (chiral) put on
A right-handed glove (chiral). Left and right hands don’t put on the right-handed glove
in the same way, so the products - right hand in right-handed glove versus left hand
in right-handed glove – are not mirror images; they are similar but different.
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Problem 5.19 Suppose that acetic acid reacts with (S)-2-butanol to
form an ester. What stereochemistry would you expect the
product(s) to have? What is the relationship of the products?
O
O
OH
+
OH
C*
Acid
catalyst
O
+ H2O
S *
H
S
H
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5.9 A Review of Isomerism
 The flowchart summarizes the types of isomers we
have seen
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Constitutional Isomers
 Different order of connections gives different carbon
backbone and/or different functional groups
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Stereoisomers
 Atoms are connected in the same order but with a
different spatial arrangement of atoms.
1. Enantiomers (nonsuperimposable mirror images)
2. Diastereomers (all other stereoisomers)
# Cis-trans isomers are just a subclass of
diastereomers because they are non-mirrorimages.
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Problem 5.21 What kinds of isomers are the
following pars?
(a) (S)-5-Chloro-2-hexene and chlorocyclohexane
CH3
Cl
C
H
Cl
CH2CH=CHCH3
versus
C6H11Cl
(b) (2R,3R)-Dibromopentane and (2S,3R)-dibromopentane
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5.10 Chirality at Nitrogen, Phosphorus,
and Sulfur
 N, P, S are all commonly found in organic compounds, and all can be
chirality centers
 Trivalent nitrogen is tetrahedral, with its lone pair of electrons acting
as the fourth substituent.
 Is trivalent nitrogen chiral? Yes in principle, but no in practice!!
Most trivalent nitrogen compounds undergo a rapid umbrellar-like
inversion that interconverts enantiomers, so we can’t isolate individual
enantiomers except in special cases.
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 A similar situation occurs in trivalent phosphorus compounds.
However, the inversion at P is substantially slower than inversion at
N, so stable chiral phosphines can be isolated.
Ex:
 Divalent S compounds are achiral, but trivalent S compounds
( Sulfonium salts, R3S+ ) can be chiral due to their slow inversion.
Ex:
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5.11 Prochirality
 A molecule that is achiral but that can become chiral
by a single alteration is a prochiral molecule
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Prochiral Distinctions
(1) Faces:
 To distinguish between the possibilities, we use the stereochemical
descriptors Re and Se.
 Rank the three groups attached to the sp2 carbon, and imagine
curved arrows from the highest to second-highest to third-highest
ranked substituents.
 The face on which the arrows curve clockwise is designated Re
(similar to R), and the face on which the arrows curve
counterclockwise is designated Si (similar to S).
→ “Addition of hydrogen atom from the Re face gives (S)-butan-2-ol.”
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Continued
(2) Paired atoms or groups at a sp3-hybridized atom:
 An sp3 carbon with two groups that are the same is a prochirality
center
 If the center becomes R the group is pro-R, and pro-S if the center
becomes S
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Prochiral Distinctions in Nature
 Biological reactions often involve making distinctions between
prochiral faces or groups
 Chiral entities (such as enzymes) can always make such a distinction
 Example: addition of water to fumarate
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Another example: the reaction of ethanol with the coenzyme nicotinamide
adenosine dinucleotide (NAD+) catalyzed by yeast alcohol dehydrogenase
occurs with exclusive removal of the pro-R hydrogen from ethanol and
with addition only to the Re face of NAD+.
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# The conversion of citrate to (cis)-aconitate in the citric acid cycle has
been shown to occur with loss of a pro-R hydrogen, implying that the OH
and H groups leave from opposite sides of the molecule.
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5.12 Chirality in Nature and Chiral
Environments
 Stereoisomers are readily distinguished by chiral
receptors in nature
 Properties of drugs depend on stereochemistry
Ex:
The (+)-enantiomer of limonene has the odor of oranges and lemons,
but the (-) enantiomer has the odor of pine trees:
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Racemic fluoxetine is an extrordinarily effective antidepressant but has no
activity against migraine. The pure S enantiomer, however, works remarkably
well in preventing migrane.
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Continued
Figure 9.17 Imagine that a left hand interacts with a chiral object, much
as a biological receptor interacts with a chiral molecule. (a) One
enantiomer fits into the hand perfectly: green thumb, red palm, and
gray pinkie finger, with the blue substituent exposed. (b) The other
enantiomer can’t fit into the hand. When the green thumb and gray
pinkie finger interact appropriately, the palm holds a blue substituent
rather than a red one, with the red substituent exposed.
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How can a prochiral substrate
undergo a selective reaction?
 In the absence of a chiral environment, the two red substituents are
chemically identical, but in the presence of the chiral environment,
they are chemically distintive.
 Let’s imagine that a chiral enzyme receptor has three binding sites.
 When green and gray substituents of the prochiral substrate are held
appropriately, however, only one of the two red substituents -say, the
pro-S one - is also held while the other, pro-R, substutuent is exposed
for reaction.
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