Chapter 9
Introduction
• Isomers are compounds with the same chemical
formula but different structures
Constitutional isomers
• Constitutional isomers are isomers with different
order of connections: skeletal, functional and
positional
Stereoisomers
• Stereoisomers are isomers with same connections,
but different spatial arrangement of atoms
– Enantiomers – are nonsuperimposable mirror images
– Diastereomers – are all other stereoisomers
– include cis, trans and configurational
Introduction to Chirality
• Some objects are not the same as their mirror
images (technically, they have no plane of
symmetry)
– A right-hand glove is different than a left-hand glove
– The property is commonly called “handedness”
• Organic molecules (including many drugs)
have handedness that results from
substitution patterns on sp3 hybridized carbon
• Molecules exist as three-dimensional objects
– Some molecules are the same as their
mirror image
– Some molecules are different than their
mirror image
 These are stereoisomers called enantiomers
A.
The Tetrahedral Carbon
• Enantiomers - are molecules that are not the
same as their mirror image
– They are the “same” if the positions of the atoms can
coincide on a one-to-one basis
• We test if they are superimposable, which is imaginary
• This is illustrated by enantiomers of lactic acid
Mirror-image forms of Lactic Acid
• When H and OH
substituents match
up, COOH and CH3
don’t
• When COOH and CH3
coincide, H and OH
don’t
• Molecules that have one carbon with 4 different
substituents have a nonsuperimposable mirror
image – enantiomer
• Build molecular models to see this
B.
Chirality
• Chiral molecules - are not superimposable
with their mirror images
 They have handedness
 They lack a plane of symmetry
A molecule is not chiral if it has a plane of symmetry
• A plane of symmetry divides an entire molecule
into two pieces that are exact mirror images
– If an object has a plane of symmetry it is necessarily
the same as its mirror image
– An achiral molecule is a molecule with a plane of
symmetry and is the same as its mirror image
• The plane has the
same thing on both
sides for the flask
• There is no mirror
plane for a hand
Chirality
• Chirality - is the lack of a plane of symmetry
- is also called “handedness”
- Hands, gloves are prime examples
of chiral objects
They have a “left” and a “right” version
Chirality Centers
• Chirality center - is a point in a molecule where
four different groups (or atoms)
are attached to carbon
- is also called “asymmetric
center”, “stereogenic center”, or
“stereocenter”
• There are two nonsuperimposable ways that 4 different
groups (or atoms) can be attached to one carbon atom
– If two groups are the same, then there is only one way
Chirality Centers in Chiral Molecules
• A chiral molecule usually has at least one chirality
center
• Groups are considered “different” if there is any
structural variation
• In cyclic molecules, we compare by following in
each direction in a ring
Practice Problem: Identify the chirality centers in the following
molecules.
Practice Problem: Alanine, an amino acid found in proteins, is
chiral. Draw the two enantiomers of alanine
using the standard convention of solid,
wedged, and dashed lines.
Practice Problem: Identify the chirality centers in the following
molecules (red = O, yellow-green = Cl, pale
yellow = F)
C.
Optical Activity
• Optical Activity -
is the ability of a molecule
to rotate the plane of a
polarized light
 Light restricted to pass through a plane is planepolarized
Phenomenon discovered by Biot in the
early 19th century
• In the 19th century, Biot observed that:
– Achiral compounds do not change the plane of the
plane-polarized light and they are said to be optically
inactive
– Chiral compounds rotate the plane of the planepolarized light and they are said to be optically active
Optical Activity
• It is measured with a polarimeter
– Light passes through a plane polarizer
– Plane polarized light is rotated in solutions of
optically active compounds
• Rotation, in degrees, is []
– Clockwise rotation is called dextrorotatory (+)
– Counterclockwise rotation is levorotatory (-)
Measurement of Optical Rotation
• A polarimeter measures the rotation of planepolarized light that has passed through a solution
– The source passes through a polarizer and then is detected at a
second polarizer (analyzer)
– The angle between the entrance and exit planes is the optical
rotation.
A Simple Polarimeter
• It measures extent of
rotation of plane
polarized light
• Operator lines up
polarizing analyzer
and measures angle
between incoming and
outgoing light
Specific Rotation
• To have a basis for comparison, we use
specific rotation, []D for an optically active
compound:
Observed rotation,  (degrees)
[]D = ______________________________
Pathlength, l (dm) x Concentration, C (g/ml)
 ( o)
____________
[]D =
l (dm) x C (g/ml)
Specific Rotation
• Specific rotation, []D for an optically active
compound is that observed for:
– C = 1 g/mL in solution in cell
– l = 10 cm path
 l = 589 nm (yellow light emitted from sodium
metal vapor)
Specific Rotation
• For a compound to be optically active, the
compound must be chiral
Specific Rotation
• The specific rotation of the enantiomer is equal
in magnitude but opposite in sign
[]D = +3.82o
[]D = -3.82o
Practice Problem: A 1.50 g sample of coniine, the toxic extract
of poison hemlock, was dissolved in 10.0 mL
of ethanol and placed in a sample cell with
5.00 cm pathlength. The observed rotation at
the sodium D line was +1.21o. Calculate []D
for coniine.
D.
Pasteur’s Discovery of Enantiomers
• 1849: Louis Pasteur discovered that sodium
ammonium salts of tartaric acid crystallize into right
handed and left handed forms
– The optical rotations of equal concentrations of
these forms are opposite
• The solutions contain mirror image isomers, called
enantiomers and they crystallized in distinctly
different shapes
• Enantiomers are physically identical in all respects
except for their effect on plane-polarized light.
– They have the same melting point, the same boiling
point, the same solubilities, and the same
spectroscopic properties.
• A 50:50 mixture of two enantiomers is optically
inactive
Relative 3-Dimensional Structure
• The original method was
a correlation system,
classifying related
molecules into “families”
focused on carbohydrates
– Correlate to D- and Lglyceraldehyde
– D-erythrose is the mirror
image of L-erythrose
• This does not apply in
general
E.
Sequence Rules for Specification of
Configuration
• When naming a molecule, the three-dimensional
arrangement of atoms or configuration at a
chirality center is also needed.
– Cahn-Ingold-Prelog sequence rule is used for
the specification
Steps in determining a configuration at a chiral atom1
• Rule 1: Look at the four atoms directly attached
to the chirality center, and assign priorities in
order of decreasing atomic number (or mass
number).
Steps in determining a configuration at a chiral atom2
• Rule 2: If a decision about priority cannot be
reached by applying rule 1, compare atomic
numbers of the 2nd atoms in each substituent,
continuing on as necessary until the 1st point of
difference.
Steps in determining a configuration at a chiral atom3
• Rule 3: Multiple-bonded atoms are equivalent to
the same number of single-bonded atoms.
Sequence Rules (IUPAC)
• Assign each group priority according to the CahnIngold-Prelog scheme with the lowest priority group
pointing away, look at remaining 3 groups in a plane
• Clockwise is designated R
(from Latin for “right”)
• Counterclockwise is
designated S (from Latin
word for “left”)
The sign of optical rotation, (+) or (-), is not related to the
R, S designation
Practice Problem: Assign priorities to the following sets of
substituents:
a. -H, -Br, -CH2CH3, -CH2CH2OH
b. -CO2H, -CO2CH3, -CH2OH, -OH
c. -CN, -CH2NH2, -CH2NHCH3, -NH2
d. -Br, -CH2Br, -Cl, -CH2Cl
Practice Problem: Orient each of the following drawings so that
the lowest-priority group is toward the rear,
and then assign R or S configuration:
Practice Problem: Assign R or S configuration to the chirality
center in each of the following molecules:
Practice Problem: Draw a tetrahedral representation of (S)-2pentanol (2-hydroxypentane).
Practice Problem: Assign R or S configuration to the chirality
center in the following molecular model of the
amino acid methionine (red = O, blue = N,
yellow = S):
F.
Diastereomers
• Diastereomers are stereoisomers that are not mirror
images of each other
Can you identify the diastereomers?
• Molecules with more
than one chirality
center have mirror
image stereoisomers
that are enantiomers
2R,3R
• In addition they can
have stereoisomeric
forms that are not
mirror images, called
diastereomers
2R,3S
2S,3S
2S,3R
Practice Problem: Assign R,S configurations to each chirality
center in the following molecules. Which are
enantiomers, and which are diastereomers?
Practice Problem: Chloramphenicol, a powerful antibiotic
isolated in 1949 from the Streptomyces
venezuelae bacterium, is active against a
broad spectrum of bacterial infections and is
particularly valuable against typhoid fever.
Assign R,S configurations to the chirality
centers in chloramphenicol.
Practice Problem: Assign R,S configuration to each chirality
center in the following molecular model of the
amino acid isoleucine (red = O, blue = N)
G.
Meso Compounds
• Meso compounds are compounds that are achiral,
yet contain chirality centers
– They have a plane of symmetry
2n - 1
• Tartaric acid has two chirality centers and two
diastereomeric forms
Chiral
Achiral
• The two structures on the right in the figure are
identical so the compound (2R, 3S) is achiral
Practice Problem: Which of the following structures represent
meso compounds?
Practice Problem: Which of the following have a meso form?
a. 2,3-Dibromobutane
b. 2,3-Dibromopentane
c. 2,4-Dibromopentane
Practice Problem: Does the following structure represent a meso
compound? If so, indicate the symmetry plane
(red = O)
H.
Molecules with More than Two
Chirality Centers
• A molecule with n chirality centers has a
maximum of:
– 2n stereoisomers, or
– 2n-1 pairs of enantiomers
• Cholesterol has 28 = 256 stereoisomers
– Only one is naturally important
• Molecules can have very many chirality centers
• Each point has two possible permanent
arrangements (R or S), generating two
possible stereoisomers
Practice Problem: How many chirality centers does morphine
have? How many stereoisomers of morphine
are possible in principle?
I.
Physical Properties of Stereoisomers
• Enantiomers differ in the direction in which they rotate
plane polarized light but their other common physical
properties are the same (+ and -)
• Diastereomers have a complete set of different
common physical properties (+ and meso/ - and meso)
J.
Racemic Mixtures and their Resolution
• A racemic mixture is a 50:50 mixture of two chiral
compounds that are mirror images
– It does not rotate light (+)
– It is named for “racemic acid” that was the double salt of (+)
and (-) tartaric acid
• Resolution is the process by which a racemic mixture
is separated into its two pure enantiomers
To separate components of a racemate (reversibly)
1. We make a derivative of each with a chiral
substance that is free of its enantiomer (resolving
agent)
2. This gives diastereomers and these are separated
by their differing chemical and physical properties.
3. The resolving agent is then removed
Acid + Base (Achiral) 
Salt (Enantiomers)
Acid + Base (Chiral)

Salt (Diastereomers)
Practice Problem: What stereoisomers would result from
reaction of (+)-lactic acid with (S)-1-phenyl
ethylamine, and what is the relationship
between them?
Practice Problem: What kinds of isomers are the following pairs?
a. (S)-5-Chloro-2-hexene and chlorocyclohexane
b. (2R,3R)-Dibromopentane and (2S,3R)-dibromopentane
K.
Stereochemistry of Reactions
• Many reactions can produce new chirality
centers from compounds without them
– What is the stereochemistry of the chiral product?
– What relative amounts of stereoisomers form?
Addition of HBr to Alkenes
Achiral Intermediate Gives Racemic Product
• Addition is via carbocation (sp2-hybridized and planar)
• Top and bottom are equally accessible
The two transition states are mirror images
• Transition states are mirror images and product
is racemic
Addition of Br2 to Alkenes
• Bromine adds to alkenes to give 1,2-dihalides
– via three-membered ring bromonium ion intermediate
– anti stereochemistry
cis-2-Butene: Bromonium Intermediate Gives a
Racemic Mixture
• Stereospecific
• Bromonium ion leads to trans addition
trans-2-Butene: Bromonium Intermediate Gives a
Meso product
• Gives meso product (both are the same)
(achiral)
• Optically inactive reactants give optically inactive
products:
– Racemic mixture
– Meso product
What is the relationship between the products?
Practice Problem: Addition of Br2 to an unsymmetrical alkene
such as cis-2-hexene leads to racemic 2,3dibromohexane, even though reaction of Brion with the unsymmetrical bromonium ion
intermediate is not equally likely at both ends.
Make drawings of the intermediate and the
products, and explain the observed
stereochemical result.
Practice Problem: Predict the stereochemical outcome of the
reaction of Br2 with trans-2-hexene, and
explain your reasoning.
Addition of HBr to a Chiral Alkene
• Reaction of a chiral reactant with an achiral reactant
leads to unequal amounts of diastereomeric products
(optically active mixture)
Reaction of a chiral reactant with an achiral reactant
leads to unequal amounts of diastereomeric products.
• Facial approaches
are different in
energy
– One has more
steric strain
Practice Problem: What products are formed from the reaction
of HBr with racemic (+)-4-methyl-1-hexene?
What can you say about the relative amounts
of the products? Is the product mixture
optically active?
Practice Problem: What products are formed from reaction of
HBr with 4-methylcyclopentene? What can
you say about the relative amounts of the
products?
L.
Chirality at Atoms: Other Than Carbons
• Trivalent nitrogen
– It is tetrahedral
– It does not form a chirality center since it rapidly flips
• Trivalent Phosphorus
– It also applies to phosphorus but it flips more slowly
M.
Chirality in Nature
• Enantiomers have similar physical properties
but different biological properties.
• Properties of drugs depend on stereochemistry
Trade name: Prozac
• Stereoisomers are readily distinguished by
chiral receptors in nature
N.
Prochirality
• A prochiral molecule - is a molecule that is achiral
but that can become chiral
by a single alteration
Prochiral distinctions: faces
• Planar faces that can become tetrahedral are different
from the top or bottom
• A center at the planar face at a carbon atom is designated
re if the three groups in priority sequence are clockwise,
si if they are counterclockwise
Prochiral distinctions, paired atoms or groups
• A prochirality center - is an sp3 carbon with
two groups that are the
same
• To distinguish between the identical groups on a
prochirality center, imagine an increase in priority
in comparison with the other
– If the center becomes R, the group is pro-R
– If the center becomes S, the group is pro-S
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 H2O to fumarate gives malate
(OH on the si face)
• Example: Oxidation of ethanol to acetaldehyde
(removal of pro-R H)
Practice Problem: Identify the indicated hydrogens in the
following molecules as pro-R or pro-S:
Practice Problem: Identify the indicated faces in the following
molecules as re or si:
Practice Problem: Lactic acid buildup in tired muscles results
from reduction of pyruvate. If the reaction
occurs from the re face, what is the
stereochemistry of the product?
Chapter 9