UNIT 3

STEREOCHEMISTRY

Stereochemistry refers to chemistry in three dimensions.

Stereoisomers have the same order of attachment of atoms, but different arrangement of the
atoms in space.

Geometrical isomerism
(cis-trans)

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 Enantiomers

Superposable (superimposable): the ability of every identical atom lies on one another in two
different molecules.

Left and right hand are mirror image of each other but not superposable

A molecule is chiral if its two mirror-image forms are not superimposable in three dimensions.
Achiral molecule: has superimposable mirror image.

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Chiral Achiral
2-butanol

I and II are mirror images of each other (figures a and b)

I and II are not superposable and so are enantiomers (figure c)
2-butanol is a chiral molecule

2-propanol

2-propanol is not chiral

Enantiomers : Chiral molecule and its mirror molecule

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Chirality Center (*)
(chiral center, stereogenic center, stereocenter, asymmetric center, asymmetric carbon)

• A tetrahedral carbon atom that bears four different atoms or groups called a chiral center

• a chiral center cannot be sp- or sp2-hybridized carbon (must be sp3).

Test for chirality

1. a molecule with one chiral center is chiral
a molecule that has no chiral center is achiral
a molecule with more than one chiral center may or may not be chiral. In this case we use
the second test for chirality

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2. All molecules with planes of symmetry are achiral
(A plane of symmetry divides an entire molecule into two pieces that one half of the
molecule is the mirror image of the other half)

2-chloropropane vs. 2-chlorobutane

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Nomenclature of Chiral Compounds (R-S Notation System)
(Cahn-Ingold-Prelog system)
 The four groups attached to the stereogenic carbon are assigned priorities from highest (1) to lowest (4)
 Atoms directly attached to the stereogenic center are compared. Priorities are assigned as follows
• Atoms with higher atomic number are given higher priority (1)
• Align the lowest priority group (4) behind the chiral carbon.
• The molecule is rotated to put the lowest priority group back
• if the direction of 123 is clockwise, the enantiomer is R
• if 123 is counterclockwise, the enantiomer is S
• If priority cannot be assigned based on directly attached atoms, the next layer of atoms is
examined

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Groups with double or triple bonds are assigned priorities as if their atoms were duplicated
or triplicated.

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 Properties of Enantiomers

• Enantiomers have almost all identical physical properties (melting point, boiling point, density)

• Enantiomers rotate the plane of plane-polarized light in equal but opposite directions (Optical Activity)

Optical activity is the ability of a chiral substance to rotate the plane of plane-polarized light and is
measured using an instrument called a polarimeter.

• Chiral compounds rotate the plane of plane-polarized light. Rotation measured in degrees
clockwise (dextrorotatory) = +
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counterclockwise (levorotatory) = -
 Specific Rotation []: standard amount of optical rotation by 1 g/mL of compound in a
standard 1dm cell.

• There is no straightforward correlation between the R, S designation of an enantiomer and the direction
[(+) or (-)] in which it rotates plane polarized light

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 Fischer Projections
It is a 2-dimensional representation of chiral molecules.
 Vertical lines represent bonds that project behind the plane of the paper
 Horizontal lines represent bonds that project out of the plane of the paper

R/S in Fischer
 When the lowest priority is on the top or bottom, we can assign R/S directly as the usual R/S rule.
 When the lowest priority is on horizontal line, we can assign R/S by taking the opposite direction of
R/S rule.

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 H
CH3 H CH3 C O
Br OH HO CH2CH3 H OH H OH
H CH3 Br CH2OH
(S)- (R)- (R)- ?

Assigning R/S for molecules with more than one chiral center.

1 1 1 1
CH3 (3) CH3 CH3 CH3
2 2 2 2
H OH H OH H OH H OH
(2)
3 (2) 3
H Cl H 3 Cl H 3 Cl H Cl
(1) (1)
4CH3 4CH3 4CH3 4CH3
(3)
has two chiral centers The configuration of The configuration of (2S, 3R)
at C2 and C3 Carbon-2 is 2S Carbon-3 is 3R

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Multiple Stereogenic Centers: Diastereomers
 Molecules with More than One Stereogenic Center

Four stereoisomers possible.

 Stereoisomers I and II are enantiomers.

 Stereoisomers III and IV are enantiomers

What is the relation between I and III?

Diastereomers are stereoisomers which are not mirror image of each other.
 I and III are diastereomers.
 I and IV are diastereomers.

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The maximum number of stereoisomers available will not exceed 2n, where n is equal
to the number of stereogenic centers.

n=2
22 = 4 stereoisomers

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Meso Compounds
 are compounds with chiral centers but which are not chiral.
 Not optically active
 Superposable on its mirror image
 Has a plane of symmetry

(2R,3S)-2,3-dibromobutane (same as its mirror image)

Meso compound

Sometimes molecules with 2 or more stereogenic centers will have less than the
maximum amount of stereoisomers
Only three, not four, stereoisomeric 2,3-butanediols are
possible.

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Which of the following structure represent a meso compound?

Which of the following has a meso form?

a) 2,3-dibromobutane c) 2,4-dibromopentane
b) 2,3-dibromopentane

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 The D,L-system

 Sugars commonly follow the D, L system of nomenclature.

 Based on the configuration of Glyceraldehyde.

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Racemic mixture
 an equimolar mixture of two enantiomers
(±)-2-butanol

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The Biological importance of Chirality

• Most of the molecules that make up plants and animals are chiral.
Amino acids and natural sugars are chiral
• Chiral molecules affect the human body in different way.
The binding specificity of a chiral receptor site for a chiral molecule is usually only
favorable in one way

D-Glucose
Only D-glucose found in nature and
digestible.

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Chiral drugs

Generally the (±)-ibuprofene racemate is

used, but only (S)-enantiomer has the anti-
inflammatory action
Ibuprofen

an anti-inflammatory drug

(S)-Naproxen

The racemic mixture was used as antinausea drug for

pregnant women in Europe (1959-1962).
(R)-thalidomide has antinausea effect.
(S)-thalidomide has different biological activity and was
shown to be responsible for over 2000 cases of birth defect
in children born to women who took it while pregnancy.19
Thalidomide
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 Conformational Isomerism
• Conformations: the temporary molecular shapes that result from rotations of groups
about single bonds; structures related by bond rotations.
• Conformational analysis: the analysis of the energy changes that a molecule undergoes as
groups rotate about single bonds.

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 Conformation of Ethane
 Staggered and eclipsed.

Staggered conformation Eclipsed conformation

All the 6 C-H bonds are as far away as possible All the 6 C-H bonds are as close as
possible to each other.
 most stable conformation
Repulsions between bonds on adjacent
atoms destabilize the eclipsed
conformation
Conformations in which the torsion angles between adjacent bonds are other than 60 are said to
have torsional strain

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Conformations of Propane

Conformations of Butane

Anti conformation is the most stable conformation of butane. 23

 Conformations and Stabilities of Cycloalkanes
Angle Strain: the strain in a molecule due to its bond angles deviate from 109.5

Ring Strain – total strain (sum of torsional, steric and angle strain) in a cycloalkane compared to
an open, noncyclic reference compound.
Cyclopropane

• Large ring strain due to angle compression

• Very reactive, weak bonds

Angle strain – the strain due to expansion or compression of bond angles

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Three kinds of strain contribute to the overall energy of a cycloalkane.

• Angle strain – the strain due to expansion or compression of bond angles .

• Torsional strain – the strain due to eclipsing of bonds on neighbouring atoms.
• Steric strain – the strain due to repulsive interaction when atoms approach each
other too closely.

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 Cyclobutane

Angle strain due to compression

Torsional strain partially relieved by ring-puckering
Unstable molecule

Cyclopentane

Angle strain is relatively small because the 108 angles of a regular pentagon are not
much different from the normal 109.5 bond angles of sp3-hybridized carbon.

• Small angle strain.

• Stable molecule 26
 Cyclohexane
 The bond angles is 109.5 and all hydrogens are staggered.
 No angle strain and no torsional strain.
 Two conformations: Chair and boat Regular hexagon

Chair Conformer Boat Conformer

• C—C bond angles are all 109.5° • free of angle strain.
• free of angle strain. • C—C bond angles are all 109.5°
• free of torsional strain • has torsional strain and flagpole
interaction
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Chair conformer is the most stable form of cyclohexane
 Axial hydrogens - have their bonds parallel to a vertical axis that passes through the ring's center.
Directed up and down on adjacent carbons.
 Equatorial hydrogens-located approximately along the equator of the molecule.

The axial and equatorial hydrogens are exchangeable by a process called “ring flipping”.

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Monosubstituted Cyclohexanes
CH3

Methyl group prefer axial or equatorial position?

At room temperature approximately 95% of the molecules are in the chair conformation that has
an equatorial methyl group

1,3-diaxial repulsions

An axial substituent is crowded because of 1,3-diaxial repulsions 29

Disubstituted Cyclohexanes

The cis stereoisomer has two chair conformations of equal energy, each containing one
axial and one equatorial methyl group.

Both methyl groups are equatorial in the most stable conformation of trans-1,2-
dimethylcyclohexane.
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A summery of the various axial and equatorial relationship among substituted
groups in the different possible cis and trans substitution patterns for disubstituted
cycloalkanes.

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Cis-1,3-Disubstituted cyclohexane with two different alkyl groups, the conformation of
lower energy is the one having the larger group in the equatorial position

Name?
H3C CH3 CH3
H3C
CH3
CH3

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