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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 Cis-trans isomers result from restricted rotation 6.2 A chiral object has a nonsuperimposable mirror image 6.3 An asymmetric center is the cause of chirality in a molecule 6.4 Isomers with one asymmetric center 6.5 How to draw enantiomers 6.6 Naming enantiomers by the R,S system 6.7 Chiral compounds are optically active 6.8 How specific rotation is measured 6.9 Isomers with more than one asymmetric center 6.10 Meso compounds have asymmetric centers but are optically inactive 6.11 How enantiomers can be separated 6.12 Receptors 6.13 The stereochemistry of reactions 6.14 The stereochemistry of enzyme-catalyzed reactions # Sections that will be skipped Recommended additional problems 30, 32, 34, 35, 36, 42, 49, 55

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6.1 Cis-trans isomers result from restricted rotation Alkenes and cycloalkanes

CH3

CH3

CH3

CH3

CH3

CH3

I II III

H

H3C H

CH3 H

H CH3

CH3

IV V 6.2 A chiral object has a nonsuperimposable mirror image

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6.3 An asymmetric center is the cause of chirality in a molecule 6.4 Isomers with one asymmetric center 6.5 How to draw enantiomers A. What Are Enantiomers?

Isomers

Constitutional Isomer Stereoisomer (Structural Isomer)

Enantiomer Diastereomer Enantiomers (a pair of enantiomers): mirror image but not superimposable

Br

CH3CH2 CH3

H

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Important Terminologies: achiral, chiral, plane of symmetry, mirror image and stereocenter B. Drawing Enantiomers: Criteria of being chiral: four different substituents (SP3 hybridization) and no plane of symmetry. Examples:

OH

Br

CH3CH2H

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6.6 Naming enantiomers by the R,S system (i) Locate the stereocenter and prioritize its four substitutents from 1 (highest) to 4 (lowest). (ii) Rotate in the order from 1 to 2 to 3. (iii) If the 4 (lowest) substituent is pointing away from you, clockwise rotation will be R and counterclockwise rotation will be S. (iv) If the 4 (lowest) substituent is pointing toward you, clockwise rotation will be S and counterclockwise rotation will be R. (v) Examples

Cl

OH

OH

C

Cl

O

H

CH3HO2CCl

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6.7 Chiral compounds are optically active 6.8 How specific rotation is measured 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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6.9 Isomers with more than one asymmetric center

Know the difference between enantiomers and diastereomers

C OH

OH

O

H

OH

A. Assign R and S for identification:

H

CHO

OH

OH

CH2OH

H

HO

CHO

H

H

CH2OH

HO

I II

H

CHO

OH

H

CH2OH

HO

HO

CHO

H

OH

CH2OH

H

III IV

Enantiomers: Diastereomers: B. Racemic Mixtures: a pair of enantiomers in 1/1 ratio Optical property is canceled intermolecularly.

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6.10 Meso compounds have asymmetric centers but are optically inactive Meso Compounds (the presence of plane of symmetry) Optical property is canceled intramolecularly.

CC

OH

HO

O

HO

OH

O

HO2CCO2H

HO

OH

A. Assign R and S for identification and check the presence of plane of symmetry:

H

CO2H

OH

OH

CO2H

H

HO

CO2H

H

H

CO2H

HO

I II

H

CO2H

OH

H

CO2H

HO

HO

CO2H

H

OH

CO2H

H

III IV

B. More examples: (i)

HO2CCH3

HO

OH

(ii)

HO2CCO2H

HO

Br

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(iii)

I II III IV

OH

CH3

OH

CH3

OH

CH3

OH

CH3

CH3

CH3

V

(iv)

CH3

OH

CH3

OH CH3

OH

H3COH

I II III IV

V

OH

CH3

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C. Molecules with three or ore stereocenters

OH

OH

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

HOHO

H

H H

H

6.11 How enantiomers can be separated A. 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.

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B. 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]

6.12 Receptors The Significance of Chirality in the Biological World

HO2C

H3C H

HO2C

H3C H

OCH3 (S)-Ibuprofen (S)-Naproxen

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6.13 The stereochemistry of reactions 6.14 The stereochemistry of enzyme-catalyzed reactions

C

C H

CO2-

CO2-

H

HHOC

C

-O2C

CO2-

+ H2O

H

H

fumurate

fumarase

malate