2- Introduction to Stereochemistry (1-86)

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Organic ChemistryOrganic ChemistryOrganic ChemistryOrganic ChemistryMagdi Awadalla Mohamed (PhD)

Assistant ProfessorDepartment of Pharmaceutical Chemistry

Faculty of PharmacySudan International University

March, 2013

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Dr. Magdi A. Mohamed, Faculty of

Pharmacy, Sudan International University,

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Stereochemistry

• Is the chemistry of molecules in three

dimensions.

• Related to actions of bioactive molecules:

� Proteins.

� Carbohydrates.

� Nucleic acids.

� Drug molecules.

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Isomerism

• Isomers are compounds with the same

molecular formula but different structures.

Isomers

Constitutional isomers Stereoisomers

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Constitutional Isomerism

• Same molecular formula.

• Different nature or sequence of bonding.

• Different structures.

• Different physical properties.

• Different chemical properties.

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Stereoisomerism

• Same molecular formula.

• Same nature or sequence of bonding.

• Different geometries.

• Different three-dimensional arrangements of

groups or atoms in the space.

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• Different spatial orientation of bonds.

Stereoisomers

Conformational

isomers

Configurational

isomers

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Conformational Isomers

• Conformations are different spatial

arrangements of a molecule that are

generated by rotation about single bonds.



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• Eclipsed conformation.

Ethane

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Ethane

• Eclipsed conformation.

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Ethane

• Staggered conformation.

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Ethane

• Staggered conformation.

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Projection Formulas of the Staggered

Conformation of Ethane

Newman Sawhorse

H

H

H H

H H

H

H H

H

H

H

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H

H

H H

H H

H

H H

H

H

H180°

Anti Relationships

•Two bonds are anti when the angle between

them is 180°.16



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H

H

H H

H H

H

H H

H

H

H

60°

Gauche Relationships

•Two bonds are gauche when the angle

between them is 60°.17



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•The terms anti and gauche apply only

to bonds (or groups) on adjacent

carbons, and only to staggered

conformations.

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• Torsional strain

Strain that results from eclipsed bonds.

• Van der Waals strain (steric strain)

Strain that results from atoms being too

close together (repulsive interaction).

• Angle strain

Strain that results from distortion of bond

angles from normal values (Baeyer strain).

Types of Strain

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0° 60° 120° 180° 240° 300° 360°

12 kJ/mol

Torsional strain destabilizes the eclipsed conformer.20


Pharmacy, Al-neelain University, 2012

Configurational isomers

• Configurational isomers are stereoisomers

that do not readily interconvert at room

temperature and can (in principle at least) be

separated. In practice it may not be a simple

task.



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Configurational isomers

• Optical isomers:

� Enantiomers.

� Diastereomers.

• Geometric isomers (rigid isomers):

� Double-bond.

� Ring structure.



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Molecular Chirality

• A molecule is chiral if its two mirror image

forms are not superposable upon one another

(e.g. bromochlorofluoromethane).

• A molecule is achiral if its two mirror image

forms are superposable (e.g.

chlorodifluoromethane).



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Molecular Chirality

• Is bromochlorofluoromethane chiral?



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Br

Cl

H

F

Molecular Chirality

• Is bromochlorofluoromethane superposable

on its mirror image?



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Cl

H

F

Br

Cl

H

F

Br

Molecular Chirality

• No! to show nonsuperposability rotate one

model 180°C around a vertical axis.



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Cl

H

F

Br

Cl

H

F

Br

Molecular Chirality

• Nonsuperposable mirror images are

called enantiomers.



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Cl

H

F

Br

BrCl

H

F

Enantiomers

• These are enantiomers with respect to each

other.



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Cl

H

F

Br

Cl

H

F

Br

Molecular Chirality

• Is chlorodifluoromethane chiral?



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F

Cl

H

F F F

Cl

H

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Molecular Chirality

• No, the two structures are mirror images, but

are not enantiomers, because they can be

superposed on each other.Dr. Magdi A. Mohamed, Faculty of


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F

Cl

H

F F F

Cl

H

The Chiral Center

• An atom, e.g. carbon, with four different

groups attached to it.

• Also called:

� stereogenic center.

� asymmetric center.

� stereocenter.



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The Chiral Center

• A molecule with a single stereogenic center

must be chiral.



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Symmetry in Achiral Structures

• Symmetry tests for achiral structures:

Any molecule with a plane of symmetry

or a center of symmetry must be achiral.



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Plane of Symmetry

• A plane of symmetry bisects a molecule into

two mirror image halves.



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Center of Symmetry

• A point in the center of

the molecule is a center

of symmetry if a line

drawn from it to some

element, when

extended an equal

distance in the opposite

direction, encounters an

identical element.



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Center of Symmetry

• A point in the center of

the molecule is a center

of symmetry if a line

drawn from it to some

element, when

extended an equal

distance in the opposite

direction, encounters an

identical element.



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Optical Activity

• A substance is optically active if it rotates

the plane of polarized light.

• In order for a substance to exhibit optical

activity, it must be chiral and one enantiomer

must be present in excess of the other.



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Polarized Light

• Ordinary (nonpolarized) light

consists of many beams

vibrating in different planes.



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• Plane-polarized light consists of

only those beams that vibrate in

the same plane.

Rotation of Plane-Polarized Light



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αααα• If the polarized-light is rotated in a clockwise

direction, the rotation, α (measured in

degrees), is said to be positive (+).

• If the rotation is counterclockwise, the

rotation is said to be negative (−).

• Separate enantiomers rotate the plane of

plane-polarized light equal amounts but in

opposite directions.



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• A substance that rotates plane-polarized light

in the clockwise direction is said to be

dextrorotatory (d).

• And one that rotates plane-polarized light in a

counterclockwise direction is said to be

levorotatory (l).



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• Observed rotation (α) depends on the number

of molecules encountered and is proportional

to:

� path length (l).

� concentration (c).

• The rotation (α) also depends on the

temperature and the wavelength of light that

is used.

• The magnitude of rotation is dependent on

the solvent when solutions are measured.Dr. Magdi A. Mohamed, Faculty of


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Specific Rotation

• [α] = specific rotation

• α = observed rotation.

• concentration (c) = g/100 mL.

• length (l) in decimeters.



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Specific Rotation: an Example

• This means that the D line of a sodium lamp (λ

= 589.6 nm) was used for the light, that a

temperature of 25°C was maintained, and that

a sample containing 100 g/100 mL of the

optically active substance, in a 1-dm tube,

produced a rotation of 3.12° in a clockwise

direction.Dr. Magdi A. Mohamed, Faculty of


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Racemic Mixture

• A mixture containing equal quantities

of enantiomers is called a racemic mixture.

• A racemic mixture is optically inactive (α = 0),

because complete cancellation occur.

• A sample that is optically inactive can be

either an achiral substance or a racemic

mixture.Dr. Magdi A. Mohamed, Faculty of


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Optical Purity

• A sample of an optically active substance that

consists of a single enantiomer is said to be

enantiomerically pure or to have an

enantiomeric excess of 100%.



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Optical Purity

• An optically pure substance consists

exclusively of a single enantiomer (100% ee).

• % Enantiomeric excess (ee%) =

moles of one enantiomer – moles of other enantiomer

total moles of both enantiomers

• % Optical purity = % Enantiomeric excess.



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Optical Purity

• The enantiomeric excess also can be

calculated from optical rotations:

• % Enantiomeric excess (ee%) =

observed specific rotation x 100

specific rotation of the pure enantiomer



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Absolute and Relative Configuration

• Relative configuration compares the

arrangement of atoms in space of one

compound with those of another.

• Absolute configuration is the precise

arrangement of atoms in space.



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Nomenclature of Enantiomers: The R,S-

System• The Cahn-Ingold-Prelog system.

• Steps:

� Rank the substituents at the stereogenic

center.

� Orient the molecule so that lowest-ranked

substituent points away from you.



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Example

Order of decreasing rank:

4 > 3 > 2 > 1



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2

1

4 3

2

1

Nomenclature of Enantiomers: The R,S-

System• The Cahn-Ingold-Prelog system.

• Steps:

� Rank the substituents at the stereogenic

center.

� Orient the molecule so that lowest-ranked

substituent points away from you.

� If the order of decreasing precedence traces

a clockwise path, the absolute configuration

is R. If the path is anticlockwise, the

configuration is S.Dr. Magdi A. Mohamed, Faculty of


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Example

Order of decreasing rank:

4 ∅ 3 ∅ 2



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2

1

4 3

2

1

clockwise anticlockwise

R S

How Are Substituents Ranked?

1. The substituents at the stereogenic

center are ranked according to the atomic

number of the atom that is directly attached

to the chirality center.

2. Higher atomic number outranks lower atomic

number.

3. When two atoms are identical, compare the

atoms attached to them on the basis of their

atomic numbers. Precedence is established

at the first point of difference (–Et > –Me).Dr. Magdi A. Mohamed, Faculty of


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How Are Substituents Ranked?

4. Work outward from the point of attachment,

comparing all the atoms attached to a

particular atom before proceeding further

along the chain (–CH(CH3)2 > –CH2CH2OH).

5. Evaluate substituents one by one.

Don't add atomic numbers within groups

(–CH2OH > –C(CH3)3).

6. An atom that is multiply bonded to another

atom is considered to be replicated as a

substituent on that atom (–CH=O > –CH2OH).Dr. Magdi A. Mohamed, Faculty of


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Fischer Projections



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• Purpose of Fischer projections is to show

configuration at stereogenic center without

necessity of drawing wedges and dashes or

using models.

Rules for Fischer Projections



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• Arrange the molecule so that horizontal bonds

at stereogenic center point toward you and

vertical bonds point away from you.

Br Cl

F

H

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Rules for Fischer Projections



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• Projection of molecule on page is a cross.

When represented this way it is understood

that horizontal bonds project outward, vertical

bonds are back.

H

F

ClBr

Physical & Chemical Properties of

Enantiomers



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• Identical physical properties (e.g. melting

point, boiling point, solubilities, density, etc).

• They cannot be separated by ordinary

methods (e.g. fractional crystallization or

fractional distillation).

• They differ in the sign of specific rotation.

• Identical chemical properties except when

they react with an optically active susbstance.

Molecules with More than one Chirality

Center



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• In compounds whose stereoisomerism is due

to chirality centers, the total number of

stereoisomers will not exceed 2n, where n is

equal the number of chirality centers.

• Example 2,3-dibromopentane.

Molecules with More than one Chirality

Center



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• Two chiral centers.

• 2n = 22 = 4 stereoisomers.

Br

2,3-dibromopentane

Br

* *



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H Br

HBr

3

Br H

BrH

4



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• Not superposable mirror images.

• 1 and 2 are enantiomers.

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• Not superposable mirror images.

• 3 and 4 are enantiomers.Dr. Magdi A. Mohamed, Faculty of


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• What is isomeric relation between the

compounds represented by 1 and 3?

H Br

HBr

3



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• They are stereoisomers and they are not

mirror images of each other.

• They are diastereomers.

H Br

HBr

3

Diastereomers



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• Stereoisomers that are not mirror images of

each other.

• They have different physical properties

(different melting points and boiling points,

different solubilities, and so forth).

Assignment



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• Consider the 4 stereoisomers for 2,3-

dibromopentane:

� if 3 and 4 are enantiomers, what are 1 and 4?

� what are 2 and 3, and 2 and 4?

� would you expect 1 and 3 to have the same

melting point?

Meso Compounds



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• A structure with two chirality centers does not

always have four possible stereoisomers.

• Sometimes there are only three.

• This happens because some molecules are

achiral even though they contain chirality

centers.

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Meso Compounds



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• How man stereoisomers does 2,3-

Dibromobutane have?

Meso Compounds



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• A and B are enantiomers.

• C and D are not enantiomers (superposable).

• C and D represent two different orientations

of the same compound.

Meso Compounds



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• The molecules represented by structure C (or

D) is not chiral even though it contains two

chirality centers (it has a plane of symmetry).

Meso Compounds



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• The plane of symmetry divides the molecule

into halves that are mirror images of each

other. Such molecules are called meso

compounds.

• Meso compounds are optically inactive.

Assignment



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• Which of the following would be optically

active?

� a pure sample of A.

� a pure sample of D.

� an equimolar mixture of A and B.

Naming Compounds with More than One

Chirality Center



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• If a compound has more than one chirality

center, we analyze each center separately and

decide whether it is (R) or (S).

• Then, using numbers, we tell which

designation refers to which carbon atom.

• Example: (2R,3R)-2,3-dibromobutane.

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How Are Pure Enantiomers Obtained?



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• Nature.

• Asymmetric synthesis.

• Separation of racemic mixtures:

� Pasteur’s methods (1848).

� Resolution of enantiomers by converting

them to diastereomers.

� Kinetic resolution (e.g. by enzymes).

� Resolution by chiral chromatography.



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• Enantiomers have identical solubilities in

ordinary solvents, and they have identical

boiling points.

• Consequently, the conventional methods for

separating organic compounds, such as

crystallization and distillation, fail when

applied to a racemic form.

Resolution of Enantiomers by Converting

them to Diastereomers



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• It is based on allowing a racemic form to react

with a single enantiomer of some other

compound.

• This changes a racemic form into a mixture of

diastereomers.

• Diastereomers, because they have different

melting points, different boiling points, and

different solubilities, can be separated by

conventional methods.

• Individual enantiomers are then regenerated.



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Stereogenic Centers Other than Carbon



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Chiral Molecules That Do Not Possess a

Chirality Center

• BINAP is an example of chiral atropisomers

(conformational isomers that are stable,

isolable compounds).



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Chiral Molecules That Do Not Possess a

Chirality Center

• The origin of chirality is the restricted rotation

about the bond between the two nearly

perpendicular naphthalene rings.



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Documents

2- Introduction to Stereochemistry (1-86)