Chapter 5:

Stereochemistry
Chiral Molecules

CHEM 201 – Organic Chemistry

Sesil Çınar
Bilgi University
Fall 2022-2023
We will consider:

❖ How to identify, categorize, and name the three-

dimensional arrangement of atoms and molecules

❖ How such arrangements can lead to unique

properties and behaviors
Chirality & Stereochemistry
❖ An object is achiral (not chiral) if the object and
its mirror image are identical

❖ A chiral object is one that

cannot be superposed on its
mirror image
The Biological Significance of Chirality
❖ Chiral molecules are molecules that cannot be superposed
onto their mirror images

O O
NH One enantiomer causes
N O birth defects, the other
cures morning sickness
O
Thalidomide

HO

NH
HO
One enantiomer is a bronchodilator, OMe
the other inhibits platelet aggregation
Tretoquinol
OMe
OMe
The Biological Significance of Chirality
❖ Only one amino acid in
a pair of enantiomers
can interact with a
hypothetical binding site
in an enzyme.
 Isomerism
Isomers
(different compounds with same
molecular formula)

Constitutional Isomers Stereoisomers

(isomers whose atoms (isomers that have the same
have a different connectivity but differ in spatial
connectivity) arrangement of their atoms)

Enantiomers Diastereomers
(stereoisomers that are (stereoisomers that are
nonsuperimposable mirror NOT mirror images of
images of each other) each other)
❖ Geometrical isomers (cis & trans isomers) are:
● Diastereomers

e.g.
Ph
Ph Ph and Ph
(cis) (trans)

Cl Cl Cl H
and
H H H Cl
(cis) (trans)
Identification and comparisons-1
Enantiomers and Chiral Molecules
❖ Enantiomers occur only with compounds
whose molecules are chiral

❖ A chiral molecule is one that is NOT

superposable on its mirror image

❖ A chiral molecule and its mirror image are

said to be enantiomers of each other
 OH
(2-Butanol)

(I) and (II) are

nonsuperposable
H OH HO H mirror images of
each other
(I) (II)
Molecules Having One Chirality Center Are Chiral
❖ A chirality center is a tetrahedral carbon
atom that is bonded to four different groups

Cl
❖ A molecule that contains one Me C* Et
chirality center is chiral and can H
exist as a pair of enantiomers

H Cl Cl H
Me Et Et Me
(III) (IV)
mirror
(III) and (IV) are nonsuperposable mirror images of each other
 Example: Predict the existence of
enantiomeric forms by drawing 3D formulas
• 2-Fluoropropane
• 2-Bromopentane

mirror
(V) and (VI) are superposable
⇒ not enantiomers ⇒ achiral

Identification and comparisons-2

How to Test for Chirality: Planes of Symmetry
Plane of symmetry
Cl

Me Me

H
❖ A molecule will not be achiral
chiral if it possesses a
plane of symmetry
Cl
No plane of
Me Et
symmetry
H
Identification and comparisons-3 chiral
Naming Enantiomers: The R,S -System

OH H OH HO H
Recall:
(I) (II)
2-Butanol
How to Assign (R) and (S) Configurations
HO H
❖ Example (2-Butanol)

①
O H④
Step 1: 1. Assign priorities from highest to
lowest based on atomic number
C C
② or ③ ② or ③

① ④
O H 2. When a priority cannot be
assigned, then the next
Step 2: ③ C ② CH set of atoms in the
3 unassigned groups is
H3C C examined.
H2
(H, H, H) (C, H, H)
 3. Visualize the molecule so that the
① lowest priority group is directed OH
OH away from you, then trace a path
④ from highest to lowest priority.
H
③ ②
Me Et Et
Me
(R)-2-Butanol OH
OH H
HO
= H
Me Et
Me Et Et
Arrows are clockwise Me

❖ If the path is a clockwise motion, then the configuration at the

asymmetric carbon is (R).
❖ If the path is a counter-clockwise motion, then the configuration is (S)
❖ Other examples
①
Cl Cl Counter-
④ clockwise
③
H CH3 HO CH3 (S)
HO
②
Clockwise
②
OCH3 OCH3
④
③ (R)
H3C CH2CH3 Br CH2CH3
①
Br
❖ Other examples
● Rotate C–Cl bond such that H is pointed
to the back
②
Cl Cl
④
③
Br H H OH
HO ①Br

Cl Clockwise

Br OH (R)
❖ Other examples
● Rotate C–CH3 bond such that H is
pointed to the back
②
H OCH3
④
I H ①
OCH3 I
H3C H3C ③

Counter-clockwise
OCH3

H3C I (S)
Specific names-1-2
❖ Example ③
CH3
④ (S)
C O as C O
H ②
O C CH=CH2
HO ①
C C as C C 4. For groups containing double
C C or triple bonds, assign
C C priorities as if both atoms
C C as C C were duplicated or triplicated
C C
Compare CH3 & CH CH2 :
H H
CH CH2 equivalent to C C H
C C
Thus, CH3  (H, H, H)

CH CH2  (C, C, H)
Properties of Enantiomers: Optical Activity
❖ Enantiomers: Mirror images that are not superposable
H H
* *
Cl CH3 H3C Cl
H3CH2C CH2CH3
mirror
❖ Enantiomers have identical physical properties
Compound bp (oC) mp (oC)
(R)-2-Butanol 99.5
(S)-2-Butanol 99.5
(+)-(R,R)-Tartaric Acid 168 – 170
(–)-(S,S)-Tartaric Acid 168 – 170
(+/–)-Tartaric Acid 210 – 212
Properties of Enantiomers: Optical Activity
❖ Enantiomers: Mirror images that are not superposable
H H
* *
Cl CH3 H3C Cl
H3CH2C CH2CH3
mirror
❖ Enantiomers have identical physical properties
● Have the same chemical properties (except
reaction/interactions with chiral substances)
● Show different behavior only when they
interact with other chiral substances
● Rotate plane-polarized light in opposite
direction
❖ Enantiomers rotate plane-polarized light in
opposite direction Optical Activity

The Polarimeter: A device for measuring the

optical activity of a chiral compound

a = observed
The electric field of light is
oscillating in all possible planes
optical rotation

oscillates in only one plane

 ❖ Two enantiomers should have the same
value of specific rotation, but the signs are
opposite
CH3 CH3
* *
H CH2CH3 H3CH2C H
HO OH
temperature
25 o 25 o
[a] = + 13.5 [a] = − 13.5
D mirror D
clockwise
counter-clockwise
wavelength of light
(e.g. D-line of Na lamp, l=589.6 nm)
General definitions-1
Racemic Forms
❖ An equimolar mixture of two enantiomers is called
a racemic mixture (or racemate or racemic form)

equal & opposite

rotation by the
rotation enantiomer

CH3 H3C
H OH HO H
C2H5 C2H5
(R)-2-Butanol (S)-2-Butanol
(if present)

A racemic mixture causes no net rotation of plane-polarized light

Enantiomeric Excess
● Also known as the optical purity

● Can be calculated from optical rotations

% enantiomeric observed specific rotation

= x 100
excess * specific rotation of the
pure enantiomers
❖ Example
● A mixture of the 2-butanol enantiomers
showed a rotation of +6.76.
● An enantiomerically pure sample of (S)-(+)-2-
butanol shows a specific rotation of +13.52
25
[a]D = +13.52
% enantiomeric +6.76
= x 100 = 50%
excess * +13.52
100 moles mixture: 25 moles of (R)-enantiomer
75 moles of (S)-enantiomer

Optical Activity
Molecules with More than One
Chirality Center
❖ In compounds with n tetrahedral
stereocenters, the maximum number of
stereoisomers is 2n
How to Draw Stereoisomers with More than One
Chirality Center?
 ❖ To draw the enantiomer of the first stereoisomer, we
simply draw its mirror image

(R)(S) (R)(S)

(2S, 3R)-2,3-Dibromobutane (2R, 3S)-2,3-Dibromobutane

❖ Structures 1 and 2 are enantiomers; structures 3 and 4 are
also enantiomers
To draw another
❖❖ Structures 1 and 3 stereoisomer, we interchange
are stereoisomers two
and they are groups
not mirror
at anyof
images one of the
each chirality
other. centers
They are diastereomers.

(R)(R) (S)(S)

(2R, 3R)-2,3-Dibromobutane (2S, 3S)-2,3-Dibromobutane

 Br Br
(S)
C* H H C Cl
(I) Cl (R) (II)
HO C* H H C OH
CH3 (R) (S) CH
3

Br (R) Br
(S)
Cl C H H C Cl
(III) (IV)
CH3 C H H C CH3
HO (S) (R) OH

❖ (I) & (II) are enantiomers of each other

❖ (III) & (IV) are enantiomers of each other
❖ Diastereomers of each other:
● (I) & (III), (I) & (IV), (II) & (III), (II) & (IV)
 For n tetrahedral stereocenters, the
Meso Compounds maximum number of stereoisomers is 2n
(I) & (II) are enantiomers of
H H each other and chiral
*
C Br Br C CH
(I) CH3 3 (II)
CH3 C* Br Br C CH3
H H
What is the relationship between all of the possible
H stereoisomers? H
CH C Br Br C CH
(III) 3 3 (IV)
H C Br Br C H (III) & (IV) are identical
CH3 CH3 and achiral
Note: (III) contains a plane of symmetry, is a meso compound, and is
achiral ([a] = 0o).

❖ (I) & (III), (II) & (III) are diastereomers

❖ Only 3 stereoisomers:
● (I) & (II) {enantiomers}, (III) = (IV) {meso}
Stereoisomerism of Cyclic Compounds

a meso compound
achiral
Me Me

H H

Plane of
symmetry
Identifications and Comparisons
 Cyclohexane Derivatives
❖ 1,4-Dimethylcyclohexane
• Both cis- & trans-1,4-
Plane of
Me Me dimethylcyclo-
symmetry hexanes are achiral
and optically inactive

Me Me
• The cis & trans forms
Me H
are diastereomers
Me H Me Me

H H
cis-1,4-dimethyl trans-1,4-dimethyl
cyclohexane cyclohexane
❖ 1,3-Dimethylcyclohexane
NO plane of symmetry
Has two chirality centers but only three
stereoisomers Plane of
symmetry Me Me
* *
Me Me
* *
cis-1,3-dimethyl trans-1,3-dimethyl
cyclohexane cyclohexane
Me Me
Me
H H
Me H H
H Me Me
H
(meso) enantiomers
 ❖ 1,2-Dimethylcyclohexane
NO plane of symmetry
Plane of
symmetry*

cis-1,2-dimethyl trans-1,2-dimethyl
cyclohexane cyclohexane
H H
Me Me
Me Me
H H

*consider the boat conformation enantiomers

The Synthesis of Chiral Molecules
Racemic Forms
Ni
CH3CH2CCH 3 + H H (+
−)-CH3CH2CHCH 3
O OH

Butanone Hydrogen (+
− )-2-Butanol
(achiral (achiral (chiral
molecules) molecules) molecules; but
50:50 mixture
(R) & (S))
 Ni
CH3CH2CCH 3 + H H (+
−)-CH3CH2CHCH 3
O OH

Butanone Hydrogen (+
− )-2-Butanol
(achiral (achiral (chiral
molecules) molecules) molecules; but
50:50 mixture
(R) & (S))
 O +
O
H , H2O
OEt heat OH + EtOH
F F
racemate ( +
−) racemate ( +
−)

O O
H2O
OEt lipase OH
F F
racemate ( +
−) (−)
(> 69% ee)
O
+ OEt + EtOH
● Enantioselective rxn: F
a reaction that produces (+)
preferentially one enantiomer (> 99% ee)
 O +
O
H , H2O
OEt heat OH + EtOH
F F
racemate ( +
−) racemate ( +
−)

O O
H2O
OEt lipase OH
F F
racemate ( +
−) (−)
(> 69% ee)
O
+ OEt + EtOH
● Enantioselective rxn: F
a reaction that produces (+)
preferentially one enantiomer (> 99% ee)