Chapter 5

Stereochemistry
Chiral Molecules
1. Chirality & Stereochemistry
 An object is achiral (not chiral) if the
object and its mirror image are
identical

Ch. 5
 A chiral object is one that cannot be
superposed on its mirror image

Ch. 5
1A. The Biological Significance of
Chirality
 Chiral molecules are molecules that
cannot be superimposable with their
mirror images
O O ● One enantiomer
NH causes birth defects,
N O the other cures
morning sickness
O
Thalidomide
Ch. 5
 HO

NH
HO
OMe
Tretoquinol
OMe
OMe

● One enantiomer is a bronchodilator, the

other inhibits platelet aggregation

Ch. 5
 66% of all drugs in development are
chiral, 51% are being studied as a single
enantiomer

 Of the $475 billion in world-wide sales of

formulated pharmaceutical products in
2008, $205 billion was attributable to
single enantiomer drugs

Ch. 5
2. Isomerisom: Constitutional
Isomers & Stereoisomers
2A. Constitutional Isomers
 Isomers: different compounds that
have the same molecular formula
● Constitutional isomers: isomers
that have the same molecular
formula but different connectivity –
their atoms are connected in a
different order
Ch. 5
 Examples
Molecular Constitutional
Formula Isomers

C4H10 and
Butane 2-Methylpropane

Cl
C3H7Cl Cl
and
1-Chloropropane 2-Chloropropane
Ch. 5
 Examples
Molecular Constitutional
Formula Isomers

OH and CH3 O CH3

C2H6O
Ethanol Methoxymethane

O
OCH3
OH and
C4H8O2
O
Butanoic acid Methyl propanoate
Ch. 5
2B. Stereoisomers
 Stereoisomers are NOT constitutional
isomers

 Stereoisomers have their atoms

connected in the same sequence but
they differ in the arrangement of their
atoms in space. The consideration of
such spatial aspects of molecular
structure is called stereochemistry
Ch. 5 -
2C. Enantiomers & Diastereomers
 Stereoisomers can be subdivided into
two general categories:
enantiomers & diasteromers
● Enantiomers – stereoisomers
whose molecules are
nonsuperposable mirror images of
each other
● Diastereomers – stereoisomers
whose molecules are not mirror
images of each other Ch. 5 -
 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)
Ch. 5 -
Subdivision of Isomers
Isomers
(different compounds with same
molecular formula)

Constitutional Isomers Stereoisomers

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

Enantiomers Diastereomers
(stereoisomers that are (stereoisomers that are
nonsuperposable mirror NOT mirror images of
images of each other) each other)

Ch. 5 -
3. 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
 The relationship between a chiral
molecule and its mirror image is one
that is enantiomeric. A chiral
molecule and its mirror image are said
to be enantiomers of each other
Ch. 5 -
 OH
(2-Butanol)

(I) and (II) are

nonsuperposable
H OH HO H mirror images of
each other
(I) (II)

Ch. 5 -
4. A Single Chirality Center
Causes a Molecule to Be Chiral
 The most common type of chiral
compounds that we encounter are
molecules that contain a carbon atom
bonded to four different groups. Such
a carbon atom is called an asymmetric
carbon or a chiral center and is
usually designated with an asterisk (*)

Ch. 5 -
 Cl
Me C* Et
H

H Cl Cl H
Me Et Et Me
(III) (IV)

mirror

(III) and (IV) are nonsuperposable

mirror images of each other
Ch. 5 -
 Cl
Me C Me
H

H Cl Cl H
Me Me Me Me
(V) (VI)

mirror

(V) and (VI) are superposable

⇒ not enantiomers ⇒ achiral Ch. 5 -
4A. Tetrahedral vs. Trigonal
Stereogenic Centers
 Chirality centers are tetrahedral
stereogenic centers

H OH HO H
Me * Et Et * Me
(A) (B)
Tetrahedral
stereogenic mirror (A) & (B) are
center enantiomers
⇒ chiral
Ch. 5 -
 Cis and trans alkene isomers contain
trigonal stereogenic centers

Ph H H Ph

H Ph Ph H
Trigonal (C) (D)
stereogenic mirror
center
⇒ achiral (C) & (D) are identical

Ch. 5 -
4A. Tetrahedral vs. Trigonal
Stereogenic Centers
 Chirality centers are tetrahedral
stereogenic centers

 Cis and trans alkene isomers contain

trigonal stereogenic centers

Ch. 5 -
5. More about the Biological
Importance of Chirality

(+)-Limonene (-)-Limonene
(limonene enantiomer (limonene enantiomer
found in oranges) found in lemons)

Ch. 5 -
Thalidomide
 The activity of drugs containing
chirality centers can vary between
enantiomers, sometimes with serious
or even tragic consequences

 For several years before 1963

thalidomide was used to alleviate the
symptoms of morning sickness in
pregnant women
Ch. 5 -
 In 1963 it was discovered that thalidomide
(sold as a mixture of both enantiomers) was
the cause of horrible birth defects in many
children born subsequent to the use of the
drug
O O O O
NH NH
N O N O

O O
Thalidomide enantiomer of
(cures morning sickness) Thalidomide
(causes birth defects)
Ch. 5 -
6. How to Test for Chirality:
Planes of Symmetry
 A molecule will not be chiral if it
possesses a plane of symmetry
 A plane of symmetry (mirror plane) is an
imaginary plane that bisects a molecule
such that the two halves of the molecule
are mirror images of each other
 All molecules with a plane of symmetry
in their most symmetric conformation
are achiral Ch. 5 -
Plane of symmetry
Cl

Me Me

H
achiral

Cl

Me Et

H
No plane of symmetry chiral Ch. 5 -
7. Naming Enantiomers: R,S-System

OH H OH HO H
Recall:
(I) (II)

 Using only the IUPAC naming that we have

learned so far, these two enantiomers will
have the same name:
● 2-Butanol
 This is undesirable because each compound
must have its own distinct name
Ch. 5 -
7A. How to Assign (R) and (S)
Configurations
 Rule 1
● Assign priorities to the four
different groups on the stereocenter
from highest to lowest (priority
bases on atomic number, the higher
the atomic number, the higher the
priority)

Ch. 5 -
 Rule 2
● When a priority cannot be assigned
on the basis of the atomic number
of the atoms that are directly
attached to the chirality center,
then the next set of atoms in the
unassigned groups is examined.
This process is continued until a
decision can be made.

Ch. 5 -
 Rule 3
● Visualize the molecule so that the
lowest priority group is directed
away from you, then trace a path
from highest to lowest priority. 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)
Ch. 5 -
 HO H
 Example (2-Butanol)

① H④
O
Step 1:
C C
② or ③ ② or ③

①
O H④
Step 2: ③ C ② CH
3
H3 C C
H2
(H, H, H) (C, H, H)
Ch. 5 -
 ① OH
OH
④
H
③ ②
Me Et Et
Me
OH
OH H
HO
= H
Me Et
Me Et Et
Arrows are clockwise Me

(R)-2-Butanol
Ch. 5 -
 Other examples
①
Cl Cl Counter-
④ clockwise
③
H CH3 HO CH3 (S)
HO
②
Clockwise
②
OCH3 OCH3
④
③ (R)
H 3C CH2CH3 Br CH2CH3
①
Br
Ch. 5 -
 Other examples
● Rotate C–Cl bond such that H is pointed
to the back
②
Cl Cl
④
③
Br H H OH
HO ① Br

Cl Clockwise

Br OH (R)
Ch. 5 -
 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)
Ch. 5 -
 Rule 4
● For groups containing double or
triple bonds, assign priorities as if
both atoms were duplicated or
triplicated
e.g. C O as C O
O C

C C as C C
C C
C C
C C as C C
C C Ch. 5 -
 Example ③
CH3
④ (S)
H ②
CH=CH2
HO ①
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)
Ch. 5 -
 Other examples
② (R)
OH
④ ③ CH3
H
Cl ① O

③ OH
H2C
④ CH3 ② C  (O, O, C)
②
H
① Cl O (S) ③
C  (O, H, H)
Ch. 5 -
8. Properties of Enantiomers:
Optical Activity
 Enantiomers
● Mirror images that are not
superposable
H H
* *
Cl CH3 H3C Cl
H3CH2C CH2CH3

mirror
Ch. 5 -
 Enantiomers have identical physical
properties (e.g. melting point, boiling
point, refractive index, solubility etc.)
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
Ch. 5 -
 Enantiomers
● Have the same chemical properties
(except reaction/interactions with
chiral substances)
● Show different behavior only when
they interact with other chiral
substances
● Turn plane-polarized light on
opposite direction

Ch. 5 -
 Optical activity
● The property possessed by chiral
substances of rotating the plane of
polarization of plane-polarized light

Ch. 5 -
8A. Plane-Polarized Light
 The electric field (like the magnetic
field) of light is oscillating in all
possible planes
 When this light passes through a
polarizer (Polaroid lens), we get plane-
polarized light (oscillating in only one
plane)
Polaroid
lens
Ch. 5 -
8B. The Polarimeter
 A device for measuring the optical
activity of a chiral compound

 =observed
optical rotation

Ch. 5 -
8C. Specific Rotation
observed
temperature rotation
25 
[]D =
c x ℓ
wavelength
concentration length of cell
of light
of sample in dm
(e.g. D-line
solution (1 dm = 10 cm)
of Na lamp,
in g/mL
=589.6 nm)

Ch. 5 -
 The value of  depends on the
particular experiment (since there are
different concentrations with each run)
● But specific rotation [] should be
the same regardless of the
concentration

Ch. 5 -
 Two enantiomers should have the
same value of specific rotation, but the
signs are opposite
CH3 CH3
* *
H CH2CH3 H3CH2C H
HO OH

25 o 25 o
[] = + 13.5 [] =  13.5
D mirror D

Ch. 5 -
9. The Origin of Optical Activity

Ch. 5 -
Ch. 5 -
9A. Racemic Forms
 An equimolar mixture of two
enantiomers is called a racemic mixture
(or racemate or racemic form)
 A racemic mixture causes no net
rotation of plane-polarized light
equal & opposite
rotation by the
rotation enantiomer

CH3 H3C
H OH HO H
C2H5 C2H5
(R)-2-Butanol (S)-2-Butanol
(if present) Ch. 5 -
9B. Racemic Forms and Enantiomeric
Excess
 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%

Ch. 5 -
 An enantiomerically pure sample of (S)-(+)-
2-butanol shows a specific rotation of
+13.52
25
[]D = +13.52

 A sample of (S)-(+)-2-butanol that contains

less than an equimolar amount of (R)-(–)-2-
butanol will show a specific rotation that is
less than 13.52 but greater than zero
 Such a sample is said to have an
enantiomeric excess less than 100%
Ch. 5 -
 Enantiomeric excess (ee)
● Also known as the optical purity
mole of one moles of other
% enantiomeric enantiomer enantiomer
= x 100
excess total moles of both enantiomers

● Can be calculated from optical

rotations
% enantiomeric observed specific rotation
= x 100
excess * specific rotation of the
pure enantiomers
Ch. 5 -
 Example
● A mixture of the 2-butanol
enantiomers showed a specific
rotation of +6.76. The
enantiomeric excess of the (S)-(+)-
2-butanol is 50%

% enantiomeric +6.76
= x 100 = 50%
excess * +13.52

Ch. 5 -
10. The Synthesis of Chiral Molecules
10A. Racemic Forms
Ni
CH3CH2CCH3 + H H (
)-CH3CH2CHCH3
O OH

Butanone Hydrogen (
 )-2-Butanol
(achiral (achiral (chiral
molecules) molecules) molecules; but
50:50 mixture
(R) & (S))
Ch. 5 -
Ch. 5 -
10B. Stereoselective Syntheses
 Stereoselective reactions are reactions
that lead to a preferential formation of one
stereoisomer over other stereoisomers that
could possibly be formed
● enantioselective – if a reaction
produces preferentially one enantiomer
over its mirror image
● diastereoselective – if a reaction
leads preferentially to one diastereomer
over others that are possible

Ch. 5 -
 O +
O
H , H 2O
OEt heat OH + EtOH
F F
racemate ( 
) racemate ( 
)

O O
H2O
OEt lipase OH
F F
racemate ( 
) ()
(> 69% ee)
O
+ OEt + EtOH
F
(+)
(> 99% ee)
Ch. 5 -
11. Chiral Drugs
 Of the $475 billion in world-wide sales of
formulated pharmaceutical products in
2008, $205 billion was attributable to single
enantiomer drugs
NC HO
NH3
O
NMe2 CO2
HO H
Escitalpram L-DOPA
(anti-depressant ) (treatment for Parkinson's)
F

Ch. 5 -
 Naproxen
(anti-inflammatory drug) CO2H

CH3

MeO

NaO2C
CH3
HO
S CH3

Cl N

Singulair
(asthma and allergy treatment)
Ch. 5 -
12. Molecules with More than One
Chirality Center
 Diastereomers
● Stereoisomers that are not
enantiomers

● Unlike enantiomers, diastereomers

usually have substantially different
chemical and physical properties

Ch. 5 -
 Br Br
(I) Cl C H H C Cl
(II)
HO C H H C OH
CH3 CH3

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

Note: In compounds with n tetrahedral

stereocenters, the maximum number of
stereoisomers is 2n.
Ch. 5 -
 Br Br
(I) Cl C H H C Cl
(II)
HO C H H C OH
CH3 CH3

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

 (I) & (II) are enantiomers to each other

 (III) & (IV) are enantiomers to each
other
Ch. 5 -
 Br Br
(I) Cl C H H C Cl
(II)
HO C H H C OH
CH3 CH3

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

 Diastereomers to each other:

● (I) & (III), (I) & (IV), (II) & (III),
(II) & (IV)
Ch. 5 -
12A. Meso Compounds
 Compounds with two stereocenters do
not always have four stereoisomers
(22 = 4) since some molecules are
achiral (not chiral), even though they
contain stereocenters
 For example, 2,3-dichlorobutane has
two stereocenters, but only has 3
stereoisomers (not 4)

Ch. 5 -
 H H
CH3 C Br Br C CH
(I) 3 (II)
CH3 C Br Br C CH3
H H

H H
CH C Br Br C CH
(III) 3 3 (IV)
H C Br Br C H
CH3 CH3

Note: (III) contains a plane of

symmetry, is a meso compound, and is
achiral ([] = 0o).
Ch. 5 -
 H H
CH3 C Br Br C CH
(I) 3 (II)
CH3 C Br Br C CH3
H H

H H
CH C Br Br C CH
(III) 3 3 (IV)
H C Br Br C H
CH3 CH3

 (I) & (II) are enantiomers to each

other and chiral
 (III) & (IV) are identical and achiral
Ch. 5 -
 H H
CH3 C Br Br C CH
(I) 3 (II)
CH3 C Br Br C CH3
H H

H H
CH C Br Br C CH
(III) 3 3 (IV)
H C Br Br C H
CH3 CH3

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

 Only 3 stereoisomers:
● (I) & (II) {enantiomers}, (III)
Ch. 5 -
12B. How to Name Compounds with
More than One Chirality Center
a
H Br
 2,3-Dibromobutane Br b
H
2 3

1 4
● Look through C2–Ha bond
a ④
① Br H
③ 2 ②
C2: (R) configuration C1 C3

(H, H, H) (Br, C, H)
Ch. 5 -
● Look through C3–Hb bond
④
① b
Br H b
Br H
a
H
3 4 ③ 3 ②
2 CH3 C4 C2
Br
1
CH3 (H, H, H) (Br, C, H)
C3: (R) configuration

● Full name:
 (2R, 3R)-2,3-Dibromobutane

Ch. 5 -
13. Fischer Projection Formulas
13A. How To Draw and Use Fischer
Projections
Fischer
Projection
COOH COOH
Et Br
HO Ph Br Ph Br Ph
Et OH Et OH
H3C COOH
CH3 CH3

Ch. 5 -
 H Me
COOH Me OH
H H
Ph
H
OH Ph COOH

COOH COOH

HO H HO H
Fischer
Me H Me H
Projection
Ph Ph Ch. 5 -
 Cl H H Cl
H Cl Cl H

H3C CH3 H3C CH3

(I) (II)
(2S, 3S)-Dichlorobutane (2R, 3R)-Dichlorobutane

CH3 CH3

H Cl Cl H
enantiomers H Cl
Cl H

CH3 CH3
mirror
 (I) and (II) are both chiral and they are
enantiomers with each other Ch. 5 -
 CH3
H H
Cl Cl H Cl

H Cl
H3C CH3
(III) CH3
(2S, 3R)-Dichlorobutane Plane of
symmetry
 (III) is achiral (a meso compound)
 (III) and (I) are diastereomers to each
other
Ch. 5 -
14. Stereoisomerism of Cyclic
Compounds
a meso compound
mirror achiral

H Me H Me Me Me

Me H Me H H H

enantiomers Plane of
symmetry
Ch. 5 -
 14A. Cyclohexane Derivatives
 1,4-Dimethylcyclohexane

Plane of • Both cis- & trans-

Me
symmetry Me 1,4-dimethylcyclo-
hexanes are
achiral and
Me Me
optically inactive
Me H • The cis & trans
Me H Me Me forms are
diastereomers
H H
cis-1,4-dimethyl trans-1,4-dimethyl
cyclohexane cyclohexane
Ch. 5 -
 1,3-Dimethylcyclohexane
Plane of
symmetry

Me Me Me
* *
cis-1,3-dimethyl Me
H
cyclohexane H
(meso)

● cis-1,3-Dimethylcyclohexane has a
plane of symmetry and is a meso
compound Ch. 5 -
 1,3-Dimethylcyclohexane

NO plane of symmetry

Me Me Me Me
* * H H
H H
Me Me
trans-1,3-dimethyl
cyclohexane enantiomers

● trans-1,3-Dimethylcyclohexane
exists as a pair of enantiomers
Ch. 5 -
 1,3-Dimethylcyclohexane
● Has two chirality centers but only
three stereoisomers

cis-1,3-dimethyl trans-1,3-dimethyl
cyclohexane cyclohexane

Me Me Me
Me H H
H H H
H Me Me

(meso) enantiomers
Ch. 5 -
 1,2-Dimethylcyclohexane
mirror
H H
Me Me
Me Me
H H

enantiomers

● trans-1,2-Dimethylcyclohexane
exists as a pair of enantiomers
Ch. 5 -
 1,2-Dimethylcyclohexane
● With cis-1,2-dimethylcyclohexane
the situation is quite complicated
mirror
Me Me
H H
Me Me
(I) H H (II)

● (I) and (II) are enantiomers to each

other
Ch. 5 -
● However, (II) can rapidly be
interconverted to (III) by a ring flip
mirror
Me Me
2'
H H 2
1' Me Me 1

(I) H H (II)

Me
Me 2
1
H
H (III)
Ch. 5 -
 ● Rotation of (III) along the vertical
axis gives (I)
Me Me
2'
H H 2
1' Me Me 1

(I) H H (II)

C1 of (II) and (III)

become C2’ of (I) & Me
C2 of (II) and (III) 2 1 (III)
Me
become C1’ of (I) H
H
Ch. 5 -
 Me Me
2'
H H 2
1' Me Me 1

(I) H H (II)

Although (I) and (II) Me

are enantiomers to 2 1 (III)
Me
each other, they can H
H
interconvert rapidly
 (I) and (II) are
achiral
Ch. 5 -
15. Relating Configurations through
Reactions in Which No Bonds to
the Chirality Center Are Broken
 If a reaction takes place in a way
so that no bonds to the chirality
center are broken, the product will
of necessity have the same general
configuration of groups around the
chirality center as the reactant

Ch. 5 -
 Same configuration
O OH
NaBH4 H
H MeOH H
Me H Me H

Me H NaCN Me H
Ph Br DMSO Ph CN

Same configuration Ch. 5 -

15A. Relative and Absolute Configurations
 Chirality centers in different molecules have
the same relative configuration if they
share three groups in common and if these
groups with the central carbon can be
superposed in a pyramidal arrangement
Y The chirality centers
C in I and II have the
X A
B same relative
A C I configuration. Their
B common groups and
II central carbon can
be superposed. Ch. 5 -
 The absolute configuration of a chirality
center is its (R) or (S) designation, which
can only be specified by knowledge of the
actual arrangement of groups in space at
the chirality center

(R)-2-Butanol (S)-2-Butanol

HO H H OH

enantiomers
Ch. 5 -
 16. Separation of Enantiomers:
Resolution
 Resolution – separation of two enantiomers
O O
OH OMe OMe
e.g. O O
CF3 + CF3
R * R' O Ph Ph
(racemic) R R' R R'
OMe
Cl (1 : 1)
Ph CF3
(Mosher acid diastereomers
chloride) usually separable
either by flash column
chromatography or
recrystallization etc.
Ch. 5 -
 Kinetic Resolution
OH OH OH
R1 R1 R1
R * R * + R *
R2 R2 O R2
(racemic)

● One enantiomer reacts “fast” and

another enantiomer reacts “slow”

Ch. 5 -
 e.g.
Me3Si t i Me3Si Me3Si
BuOOH, Ti(O Pr)4
O
OH (-)-DET OH + OH
*
C5H11 HO COOEt
C5H11 C5H11
(racemic) (-)-DET:
HO COOEt
42% 43%
(D)-(-)-Diethyl Tartrate (99%ee) (99%ee)
 
Me3Si Me3Si

R' S OH H R OH

H R'

* stop reaction at  50%

* maximum yield = 50% Ch. 5 -
17. Compounds with Chirality
Centers Other than Carbon

R4 R3 H R3
Si Ge
R1 R2 R1 R2

R4 R3 R2 R1
N X S
R1 R2 O

Ch. 5 -
18. Chiral Molecules That Do Not
Possess a Chirality Center

P(Ph)2 (Ph)2P
P(Ph)2 (Ph)2P

(S)-BINAP (R)-BINAP

enantiomers Ch. 5 -
 mirror

H H
H H
C C C C C C
Cl Cl
Cl Cl

enantiomers

Ch. 5 -
 END OF CHAPTER 5 

Ch. 5 -