STEREOCHEMISTRY

<SKO3013>
<BASIC ORGANIC CHEMISTRY>
DR YUHANIS MHD BAKRI
DEPARTMENT OF CHEMISTRY
FACULTY OF SCIENCE AND MATHEMATICS
UNIVERSITI PENDIDIKAN SULTAN IDRIS
Also adapted from: Organic
Chemistry, 9th Edition, Global
Edition. L. G. Wade, Jr.
 Isomerism
• Molecules that have the same molecular
formula but differ in the arrangement of their
atoms are called isomers.
• Constitutional (or structural) isomers differ in
their bonding sequence.
• Stereoisomers differ only in the arrangement
of the atoms in space.
 STEREOCHEMISTRY
The study of 3D structure of molecules

ISOMERS
Different compounds with same molecular formula

Constitutional
Isomer Geometrical
(or Structural Isomer
Stereoisomers
Isomer)
 CONSTITUTIONAL ISOMERS
(STRUCTURAL ISOMERS)
Isomers: SAME molecular formula,
DIFFERENT bonding sequence

• Constitutional isomers have the same chemical formula, but the

atoms are connected in a different order.
• Constitutional isomers have different properties.
• The number of isomers increases rapidly as the number of
carbon atoms increases.
 EXAMPLE 1: C2H6O

CH3-CH2-OH CH3-O-CH3

Ethanol Dimethyl
ether
 EXAMPLE 1: C5H10

1-pentene 2-pentene

Cyclopentane Methylcyclobutane
 Geometric Isomers:
Cis and Trans OR E and Z
• Stereoisomers are compounds
with the atoms bonded in the
same order, but their atoms have
different orientations in space.
• Cis and trans are examples of
geometric stereoisomers; they
occur when there is a double bond
in the compound.
• Since there is no free rotation
along the carbon–carbon double
bond, the groups on these carbons
can point to different places in
space.
Geometric Isomers
 Geometric Isomers:
Cis and Trans OR E and Z
• Stereoisomers are compounds
with the atoms bonded in the
same order, but their atoms have
different orientations in space.
• Cis and trans are examples of
geometric stereoisomers; they
occur when there is a double bond
in the compound.
• Since there is no free rotation
along the carbon–carbon double
bond, the groups on these carbons
can point to different places in
space.
 Conformations
-displayed through Sawhorse, Newman projection
-cyclohexane (Boat and Chair conformation)
 Conformations of Ethane

Pure conformers cannot be isolated in most cases,

because the molecules are constantly rotating through
all the possible conformations.
 Newman Projections

The Newman projection is the best way to judge the

stability of the different conformations of a molecule.
 Ethane Conformations

The torsional energy of ethane is lowest in the staggered conformation. The

eclipsed conformation is about 3.0 kcal/mol (12.6 kJ/mol) higher in energy. At
room temperature, this barrier is easily overcome, and the molecules rotate
constantly.
 Propane Conformations

Propane is shown here as a perspective drawing and as a Newman

projection looking down the C1—C2 bond.
 Propane Conformations

The staggered conformations of propane are lower in energy than the

eclipsed conformations. Since the methyl group occupies more space than a
hydrogen, the torsional strain will be 0.3 kcal/mol higher for propane than for
ethane.
 Butane Conformations

• Butane has two different staggered conformations: gauche (60° between the
methyl groups) and anti (180° between the methyl groups).
• The eclipsed conformation where the dihedral angle between the methyl
groups is 0° is referred to as totally eclipsed.
Conformational Analysis of Butane
 Steric Strain in Butane

• The totally eclipsed conformation is higher in energy because it forces

the two end methyl groups so close together that their electron clouds
experience a strong repulsion.
• This kind of interference between two bulky groups is called steric strain
or steric hindrance.
 Conformations of Higher Alkanes

• The higher alkanes resemble butane in their preference

for anti and gauche conformations about the carbon–carbon
bonds.
Chair Conformation of Cyclohexane
 Chair Conformation

• The chair is the most stable conformational

isomer of cyclohexane.
• The chair has no eclipsing interactions.
• Bond angles in the chair conformation are 109.5°.
Boat Conformation of Cyclohexane
 Boat and Twisted Boat
Conformation
• Eclipsing bonds result in torsional strain.
• The twisted boat conformation has fewer eclipsing
bond interactions and less interference between the
flagpole hydrogens.
Conformational Energy Diagram of
Cyclohexane
 Axial and Equatorial Positions

• Axial bonds (red) are directed

vertically parallel to the axis
of the ring.
• Equatorial bonds (green) are
directed outward toward the
equator of the molecule.
 Chair–Chair Interconversion

The most important result in chair conversion is that any

substituent that is axial in the original conformation becomes
equatorial in the new conformation.
Axial Methyl in Methylcyclohexane
Equatorial Methyl Group
 1,3-Diaxial Interaction

The axial substituent interferes with the axial hydrogens on C3 and C5.
This interference is called a 1,3-diaxial interaction.
 Energy Differences

Substituents are less crowded in the equatorial positions.

 Cis-1,3-dimethylcyclohexane

• Cis-1,3-dimethylcyclohexane can have both methyl groups in

axial positions or both in equatorial positions.
• The conformation with both methyl groups being equatorial is
more stable.
 Trans-1,3-dimethylcyclohexane

Both conformations have one axial and one equatorial methyl

group so they have the same energy.
 Cis-1,4-di-tert-butylcyclohexane

The most stable conformation of cis-1,4-di-tert-butylcyclohexane is the

twist boat. Both chair conformations require one of the bulky
t-butyl groups to occupy an axial position.
 STEREOISOMERS
SAME bonding sequence or bonded in the same
order,
DIFFERENT orientation of atoms
 Chirality

• “Handedness”: Right-hand glove does not fit the left hand.

• An object is chiral if its mirror image is different from the original
object.
 Achiral
• Mirror images that can be superposed are achiral (not
chiral).
 Stereoisomers
Enantiomers are compounds that are
nonsuperimposable mirror images. Any molecule
that is chiral must have an enantiomer.
 Chiral Carbon Atom
• Also called asymmetric carbon atom
• A carbon atom that is bonded to four different
groups is chiral.
• Its mirror image will be a different compound
(enantiomer).
 Stereocenters
• An asymmetric carbon atom is the most common
example of a chirality center.
• Chirality centers belong to an even broader group
called stereocenters. A stereocenter (or
stereogenic atom) is any atom at which the
interchange of two groups gives a stereoisomer.
• Asymmetric carbons and the double-bonded
carbon atoms in cis-trans isomers are the most
common types of stereocenters.
Examples of Chirality Centers

Asymmetric carbon atoms are examples of chirality

centers, which are examples of stereocenters.
 Achiral Compounds

Take this mirror image and try to

superimpose it on the one to the left
matching all the atoms. Everything will
match.

When the images can be superposed, the compound is achiral.

 Planes of Symmetry

• A molecule that has a plane of symmetry is achiral.

 Cis Cyclic Compounds

• Cis-1,2-dichlorocyclohexane is achiral because the molecule has

an internal plane of symmetry. Both structures above can be
superimposed.
 Trans Cyclic Compounds

• Trans-1,2-dichlorocyclohexane does not have a plane of

symmetry, so the images are nonsuperimposable and the
molecule will have two enantiomers.
 (R) and (S) Configuration

• Both enantiomers of alanine receive the same name in the IUPAC

system: 2-aminopropanoic acid.
• Only one enantiomer is biologically active. In alanine only the left
enantiomer can be metabolized by the enzyme.
• We need a way to distinguish between them.
 Cahn–Ingold–Prelog
Convention
• Enantiomers have different spatial arrangements of the
four groups attached to the asymmetric carbon.
• The two possible spatial arrangements will be called
configurations.
• Each asymmetric carbon atom is assigned a letter, (R) or
(S), based on its three-dimensional configuration.
• Cahn–Ingold–Prelog convention is the most widely
accepted system for naming the configurations of
chirality centers.
 (R) and (S) Configuration:
Step 1 Assign Priority

• Assign a relative “priority” to each group bonded to the

asymmetric carbon. Group 1 would have the highest
priority, group 2 second highest, etc.
• Atoms with higher atomic numbers receive higher
priorities.

I > Br > Cl > S > F > O > N > 13C > 12C > Li > 2H > 1H
 Assign Priorities

Atomic number: F > N > C > H

(R) and (S) Configuration: Breaking Ties

In case of ties, use the next atoms along the chain of each
group as tiebreakers.
(R) and (S) Configuration: Multiple Bonds

Treat double and triple

bonds as if each were a
bond to a separate atom.
 (R) and (S) Configuration:
Step 2
• Working in 3-D, rotate the
molecule so that the lowest
priority group is in back.
• Draw an arrow from the
highest to lowest priority
group.
• Clockwise = (R)
Counterclockwise = (S)
 Assign Priorities

Counterclockwise
(S)

Draw an arrow from Group 1 to Group 2 to Group 3 and

back to Group 1. Ignore Group 4.

Clockwise = (R) and Counterclockwise = (S)

 Example

Clockwise
(R)

When rotating to put the lowest priority group in the back,

keep one group in place and rotate the other three.
Example (Continued)
 Solved Problem 1
Draw the enantiomers of 1,3-dibromobutane and label them as (R)
and (S). (Making a model is particularly helpful for this type of
problem.)
 Solved Problem 1
Draw the enantiomers of 1,3-dibromobutane and label them as (R) and (S). (Making a model is
particularly helpful for this type of problem.)

Solution
The third carbon atom in 1,3-dibromobutane is asymmetric. The bromine atom receives first priority,
the (–CH2CH2Br) group second priority, the methyl group third, and the hydrogen fourth. The
following mirror images are drawn with the hydrogen atom back, ready to assign (R) or (S) as shown.
Configuration in Cyclic Compounds
 Properties of Enantiomers
• Same boiling point, melting point, and density
• Same refractive index
• Rotate the plane of polarized light in the same
magnitude, but in opposite directions.
• Different interaction with other chiral molecules
• Active site of enzymes is selective for a specific enantiomer.
• Taste buds and scent receptors are also chiral. Enantiomers
may have different smells.
 Polarized Light
Plane-polarized light is composed of waves that vibrate in
only one plane.
 Optical Activity

• Enantiomers rotate the plane of polarized light in opposite

directions, but in the same number of degrees.
 Polarimeter

Clockwise Counterclockwise
Dextrorotatory (+) Levorotatory (–)

Not related to (R) and (S)

 Specific Rotation
Observed rotation depends on the length of the cell and
concentration, as well as the strength of optical activity,
temperature, and wavelength of light.

where  (observed) is the rotation observed in the

polarimeter, c is concentration in g/mL, and l is length of
sample cell in decimeters.
 Solved Problem 2
When one of the enantiomers of 2-butanol is placed in a polarimeter, the observed rotation
is 4.05° counterclockwise. The solution was made by diluting 6 g of 2-butanol to a total of 40 mL, and
the solution was placed into a 200-mm polarimeter tube for the measurement. Determine the specific
rotation for this enantiomer of 2-butanol.

Solution
Since it is levorotatory, this must be (–)-2-butanol The concentration is 6 g per 40 mL = 0.15 g/mL, and
the path length is 200 mm = 2 dm. The specific rotation is
 Racemic Mixtures

• Equal quantities of d- and l-enantiomers

• Notation: (d,l) or ()
• No optical activity
• The mixture may have different boiling point (b. p.) and melting
point (m. p.) from the enantiomers!
 Racemic Products
If optically inactive reagents combine to form a chiral
molecule, a racemic mixture is formed.
 Optical Purity

• Optical purity (o. p.) is sometimes called enantiomeric

excess (e. e.).
• One enantiomer is present in greater amounts.

observed rotation
o. p. = × 100
rotation of pure enantiomer
 Calculate % Composition

The specific rotation of (S)-2-iodobutane is +15.90°.

Determine the % composition of a mixture of (R)- and
(S)-2-iodobutane if the specific rotation of the mixture is
–3.18°.
 Chirality of Conformers

• If equilibrium exists between two chiral conformers,

the molecule is not chiral.
• Judge chirality by looking at the most symmetrical
conformer.
• Cyclohexane can be considered to be planar, on
average.
 Chirality of Conformational Isomers

The two chair conformations of cis-1,2-dibromocyclohexane are

nonsuperimposable, but the interconversion is fast and the
molecules are in equilibrium. Any sample would be racemic and, as
such, optically inactive.
 Nonmobile Conformers

• The planar conformation of the biphenyl derivative is too

sterically crowded. The compound has no rotation around the
central C—C bond and, thus, it is conformationally locked.
• The staggered conformations are chiral; they are
nonsuperimposable mirror images.
 Allenes
• Some allenes are chiral even though they
do not have a chiral carbon.
• Central carbon is sp hybridized.
• To be chiral, the groups at the end
carbons must have different groups.
Penta-2,3-diene Is Chiral
 Fischer Projections
• Flat representation of a 3-D molecule
• A chiral carbon is at the intersection of horizontal and vertical lines.
• Horizontal lines are forward, out of plane.
• Vertical lines are behind the plane.
Fischer Projections (Continued)
 Fischer Rules
• Carbon chain is on the vertical line.
• Highest oxidized carbon is at the top.
• Rotation of 180° in plane doesn’t change the
molecule.
• Rotation of 90° is not allowed.
 180° Rotation

• A rotation of 180° is allowed because it will not change the

configuration.
 90° Rotation

• A 90° rotation will change the orientation of the horizontal and

vertical groups.
• Do not rotate a Fischer projection 90°.
 Glyceraldehyde
• The arrow from group 1 to group 2 to group 3 appears
counterclockwise in the Fischer projection. If the molecule is
turned over so the hydrogen is in back, the arrow is
clockwise, so this is the (R) enantiomer of glyceraldehyde.
 Fischer Mirror Images
• Fisher projections are easy to draw and make it easier to find
enantiomers and internal mirror planes when the molecule has
two or more chiral centers.

CH3
H Cl
Cl H
CH3
 Fischer (R) and (S)
• Lowest priority (usually H) comes forward, so assignment rules are
backward!
• Clockwise 1-2-3 is (S) and counterclockwise 1-2-3 is (R).
• Example:
Diastereomers: Cis-Trans Isomerism
on Double Bonds
• These stereoisomers are not mirror images of each other, so they
are not enantiomers. They are diastereomers.
 Diastereomers: Cis-Trans
Isomerism on Rings
• Cis-trans isomers are not mirror images, so these are
diastereomers.
 Diastereomers
• Molecules with two or more chiral carbons
• Stereoisomers that are not mirror images
 Two or More Chiral Carbons
• When compounds have two or more chiral centers they
have enantiomers, diastereomers, or meso isomers.
• Enantiomers have opposite configurations at each
corresponding chiral carbon.
• Diastereomers have some matching and some opposite
configurations.
• Meso compounds have internal mirror planes.
• Maximum number of isomers is 2n, where n = the
number of chiral carbons.
Comparing Structures
 Meso Compounds

• Meso compounds have a plane of symmetry.

• If one image is rotated 180°, then it can be superimposed on the
other image.
• Meso compounds are achiral even though they have chiral
centers.
 Absolute and Relative
Configurations
• The absolute configuration is the detailed picture of a
molecule, including how the atoms are arranged in
space.
• The relative configuration is the experimentally
determined relationship between the configurations of
two molecules, even though we may not know the
absolute configuration of either.
 Number of Stereoisomers

• The 2n rule will not apply to compounds that may have a

plane of symmetry. 2,3-dibromobutane has only three
stereoisomers: (±) diastereomer and the meso diastereomer.
 Properties of Diastereomers
• Diastereomers have different physical properties, so they
can be easily separated.
• Enantiomers differ only in reaction with other chiral
molecules and the direction in which polarized light is
rotated.
• Enantiomers are difficult to separate.
• Convert enantiomers into diastereomers to be able to
separate them.
Diastereomers and Their Physical
Properties