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Chapter 6. Isomers and Stereochemistry

Learning objectives:

1. Differentiate chiral and achiral molecules.

2. Recognize and draw structural isomers (constitutional isomers), stereoisomers

including enantiomers and diastereomers, racemic mixture, and meso compounds.

3. Identify the stereocenters in a molecule and assign the configuration as R or S.

4. Know the relationship between enantiomers and their specific rotations.

Sections to be covered (in the order of delivery):

6.1 Stereoisomers

6.2 Chiral Molecules

6.3 Enantiomers and Diastereomers

6.4 Properties of Chiral Molecules

6.1 Stereoisomers

Important Terminologies: achiral, chiral, plane of symmetry, mirror image and

superimposable

A. Classification of Isomers

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Examples:

B. Cis-trans (E/Z) Isomers are Diastereomers of Restricted C-C Bond Rotation

CH3

CH3

CH3

CH3

CH3

CH3

I II III

H

H3C H

CH3 H

H CH3

CH3

IV V

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C. A chiral object has a nonsuperimposable mirror image

D. Drawing Mirror Image (Enantiomers)

Examples:

OH

Br

CH3CH2

H

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E. Self-assessment Questions

Can you identify stereoisomer and same molecule using mirror image?

Can you draw the mirror image of a given compound?

Can you describe the definition of structural isomer, conformer (conformational

isomer), stereoisomer, enantiomer and diastereomer?

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6.2 Chiral Molecules

Chiral molecules: molecules without plane of symmetry!

Enantiomers: chiral molecules that are mirror image to each other

Diastereomers: chiral molecules that are not mirror image to each other

A. Criteria of Being Chiral Molecule

Know stereocenter (chiral center, chiral atom)

(i) Universal definition

Not superimposable with its mirror image.

or

No plane of symmetry.

(ii) Simplified criteria but may have exception

The presence of stereocenter (chiral center, chiral atom): four different

substituents for an sp3 hybridized atom.

Chiral molecules may have no stereocenter.

Having sterocenters may not be chiral.

(iii) Stereocenter and chiral center (chiral atom)

B. Find Plane of Symmetry

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C. Stereocenters (chiral atoms)

For molecules that are hard to find plane of symmetry, find stereocenter (atom).

sp3 hybridized C and N

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S and P

Examples:

D. Identify Chiral Molecules Using Stereocenter

(i) Molecules with odd number of stereocenters:

(ii) Molecules with even number of stereocenters:

Look for plane of symmetry or assign R and S

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E. Assign R and S for Stereocenters

Know racemic mixture and meso compounds

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(i) Useful for molecules that have multiple stereocenters

(ii) How to Assign R and S for Stereocenters?

1. Prioritize (atomic number) four substituents (groups) attached to a stereocenter.

2. Place the less prioritized one (4) away from you and then rotate from 1-2-3.

Examples:

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F. Self-assessment Questions

Can you identify stereoisomer(s)?

Can you explain the relationship among stereocenter, chiral molecule,

enantiomer and diastereomer?

Can you assign R and S of stereocenter (atom)?

Can you explain what are racemic mixture and meso compound?

6.3 Enantiomers and Diastereomers

Know the difference between enantiomers and diastereomers

Mirror image to each other: enantiomers

Not mirror image to each other: diastereomers (commonly have multiple

stereocenters)

Both enentiomers and diastereomers are stereoisomers

Example:

Threonine

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A. Assign R and S for identification:

Enantiomers:

Diastereomers:

B. Racemic Mixtures: a pair of enantiomers in 1/1 ratio

Optical property is canceled intermolecularly.

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C. Meso Compounds (the presence of plane of symmetry)

Meso compounds have asymmetric centers but are optically inactive

Optical property is canceled intramolecularly.

C

C

OH

HO

O

HO

OH

O

HO2C

CO2H

HO

OH

(i) Assign R and S for identification and check the presence of plane of symmetry:

D. More examples Racemic Mixture and Meso Compounds

(i)

HO2C

CH3

HO

OH

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(ii)

I II III IV

OH

CH3

OH

CH3

OH

CH3

OH

CH3

CH3

CH3

V

(iii)

CH3

OH

CH3

OH CH3

OH

H3COH

I II IIIIV

V

OH

CH3

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E. Molecules with Three or More Stereocenters

OH

OH

Menthol

Number of possible stereoisomers: 2n, n = number of stereocenters

HOHO

H

H H

H

F. Self-assessment Questions

Can you identify a pair of enantiomers and diastereomers?

Can you explain racemic mixture and meso compound?

Can you calculate the possible stereoisomers for molecules with three or more

stereocenters?

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6.4 Properties of Chiral Molecules

Important Terminologies: plane-polarized light, optically active, optical activity.

A. Plane-Polarized Light

B. A Polarimeter

Specific rotation: the observed rotation of an optically active substance at a

concentration of 1 g/100 mL in a sample tube 10 cm long;

for a pure liquid, concentration is in g/mL (density)

C. Chiral compounds with clockwise rotation is designated as (+).Chiral compounds

with counterclockwise rotation is designated as (-).

(+) and (-) have no correlation with R and S assignment.

Light source

Light filter with grid

Sample tube with chiral compound

Rotatable filter with grid

1

2

3

4

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D. Racemic Mixture and Meso Compounds Are Optically Inactive

E. Properties of stereoisomers

Enantiomers: same chemical properties (reactivity), same physical properties

(ex. boiling point, melting point, density and pKa) except for the

specific rotation (a pair of Enantiomers has the exact opposite

direction in rotation).

Diastereomers: different chemical and physical properties.

(i) Separation of Enantiomers: Resolution

[R]

[S]

[R]

[R]

[R][R]

[R][S]

[S][S]

[S]

[S]

Addition of optically pure

reagent

[R*]

[R,R*]

a racemic mixture

a pair of enantiomers ([R] and [S])

[R,R*]

[R,R*]

[R,R*]

[R,R*]

[S,R*]

[S,R*] [S,R*]

[S,R*]

[S,R*]

a mixture of diastereomers ([R,R*] and [S,R*])

separation of diastereomers

[R,R*]

[S,R*]

Removal of optically pure

reagent

Removal of optically pure

reagent

[R*]

[R*]

[S] [S]

[S]

[S] [S]

[R][R]

[R]

[R] [R]

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(ii) The Significance of Chirality in the Biological World

HO2C

H3C H

HO2C

H3C H

OCH3 (S)-Ibuprofen (S)-Naproxen

F. Stereoselectivity: Selection Between Stereoisomers

(i) reactions for alkenes

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(ii) The stereochemistry of enzyme-catalyzed reactions

C

C H

CO2-

CO2-

H

HHOC

C

-O2C

CO2-

+ H2O

H

H

fumurate

fumarase

malate

G. Self-assessment Questions

Do you know the relationship of chemical and physical properties between a pair

of enantiomers and diastereomers?

Can you explain why racemic mixture and meso compound are optically inactive?

Can you explain the process of separating a pair of enantiomers (resolution)?

Can you identify a stereoselective reaction?