Chapter 5

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

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

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

NH
HO
OMe
Tretoquinol
OMe
OMe

● One enantiomer is a
bronchodilator, the other inhibits
platelet aggregation

Ch.
 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.
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.
 Examples
Molecular Constitutional
Formula Isomers

C4H10 and
Butane 2-Methylpropane

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

OH and CH3 O CH3

C2H6O
Ethanol Methoxymethane

O
OCH3
OH and
C4H8O2
O
Butanoic acid Methyl propanoate
Ch.
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
nonsuperimposable 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 Stereoisomers
Isomers (isomers that have the same
(isomers whose atoms connectivity but differ in
have a different spatial arrangement of their
connectivity) atoms)

Enantiomers
Diastereomers
(stereoisomers that are
(stereoisomers that are
nonsuperimposable
NOT mirror images of
mirror
each other)
images of 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 superimposable on its mirror
image
 The relationship between a chiral
molecule and its mirror image is
one that is enantiomeric. A chiral
Ch. 5
 OH
(2-Butanol)

(I) and (II) are

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

Ch. 5
4. Molecules Having One Chirali
Center Are Chiral
 A chirality center is a
tetrahedral carbon atom that is
bonded to four different groups

 A molecule that contains one

chirality center is chiral and can
exist as a pair of enantiomers

Ch. 5
 The presence of a single chirality
center in a molecule guarantees
that the molecule is chiral and
that enantiomeric forms are
possible

 An important property of
enantiomers with a single chirality
center is that interchanging any
two groups at the chirality center
converts one enantiomer into the
other Ch. 5
 Any atom at which an interchange
of groups produces a stereoisomer
is called a stereogenic center (if
the atom is a carbon atom it is
usually called a stereogenic
carbon)
 If all of the tetrahedral atoms in a
molecule have two or more
groups attached that are the
same, the molecule does not have
a chirality center. The molecule is
superimposable on its mirror Ch. 5
 Cl
Me C* Et
H

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

mirror
(III) and (IV) are
nonsuperimposable mirror
images of each other Ch. 5
 Cl
Me C Me
H

H Cl same Cl
H H
Cl Cl H
Me Me as Me Me Me Me
(V) (V) (VI)

mirror
(V) and (VI) are
superimposable
⇒ 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)
Tetrahedra
l (A) & (B)
mirror
stereogeni are
⇒ chiral
c center
enantiomer
Ch. 5
 Cis and trans alkene isomers
contain trigonal stereogenic
centers
Ph H H Ph

H Ph Ph H
Trigonal (C) (D)
stereogeni mirror
c center
⇒ achiral (C) & (D) are
identical
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
Ch. 5
Plane of symmetry
Cl

Me Me

H
achiral

Cl
No plane
Me Et
of
symmetry H
chiral
Ch. 5
7. Naming Enantiomers:
The 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)
© 2014 by John Wiley & Sons, Inc. All rights reserved. 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 configurationCh. 5
 Example HO H (2-Butanol)

① H④
O
Step 1:
C C
② or ③ ② or ③

① ④
O H
Step 2: ③ C ② CH
3
H3C 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)
H3C CH2CH3 Br CH2CH3
Br
①
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 ② C  (O, O, C)
② CH3
H
① Cl O (S) ③
C  (O, H, H)

Ch. 5
8. Properties of Enantiomers:
Optical Activity
 Enantiomers
● Mirror images that are not
superimposable
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.) o
Compound bp ( C) mp ( C)
o

(R)-2-Butanol 99.5
(S)-2-Butanol 99.5
(+)-(R,R)-Tartaric 168 –
Acid 170
(–)-(S,S)-Tartaric 168 –
Acid 170
(+/–)-Tartaric Acid 210 –
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
● Rotate plane-polarized light in
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
observe
temperature d
rotation
25 
[]D =
c x ℓ
wavelength
concentratio length of cell
of light
n of sample in dm
(e.g. D-line
solution (1 dm = 10
of Na lamp,
in g/mL cm)
=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
9A. Racemic Forms
 An equimolar mixture of two
enantiomers is called a racemic
mixture (or racemate or racemic
form)
 A racemic mixture causesequal
no &net
opposite
rotation of plane-polarized
rotation lightby 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 Enantiomer
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 molesof one molesof other
% enantiomeric enantiomer enantiomer
= x 100
excess totalmolesof 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 , H2O
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
12.Molecules with More than On
Chirality Center
 In compounds with n tetrahedral
stereocenters, the maximum
number of stereoisomers is 2n

Ch. 5
12A. How to Draw Stereoisomers fo
Molecules Having More than O
Chirality Center

Br
4 2
5 * * 1 2,3-Dibromopentane
3
Br

Ch. 5
 Start by drawing the portion of the
carbon skeleton that contains the
chirality centers in such a way
that as many of the chirality
centers are placed in the plane of
the paper as possible, and as
symmetrically as possible
3 2
C C

Ch. 5
 Next we add the remaining groups
that are bonded at the chirality
centers in such a way as to
maximize the symmetry between
the chirality centers
H H
Br Br

Ch. 5
 To draw the enantiomer of the
first stereoisomer, we simply draw
its mirror image

H H H H
Br Br Br Br

mirror

Ch. 5
 To draw another stereoisomer, we
interchange two groups at any
one of the chirality centers
• All of the possible stereoisomers for
a compound can be drawn by
successively interchanging two
groups at each chirality center
H Br Br H
Br H H Br

mirror
Ch. 5
 Next we examine the relationship
between all of the possible
pairings of formulas to determine
which are pairs of enantiomers,
which are diastereomers
H H H H H Br Br H
Br Br Br Br Br H H Br

1 2 3 4

Ch. 5
 H H H H H Br Br H
Br Br Br Br Br H H Br

1 2 3 4
 Structures 1 and 2 are enantiomers;
structures 3 and 4 are also enantiomers
 Structures 1 and 3 are stereoisomers
and they are not mirror images of each
other. They are diastereomers
• Diastereomers have different physical
properties - different melting points
and boiling points, different
solubilities, and so forth
Ch. 5
 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
 (I) & (II) are enantiomers of each
other
 (III) & (IV) are enantiomers of 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 of each other:
● (I) & (III), (I) & (IV), (II) & (III),
(II) & (IV)
Ch. 5
12B. 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-dibromobutane
has two stereocenters, but only
has 3 stereoisomers (not 4)
Ch. 5
 H H
(I ) CH3 C Br Br C CH
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
(I ) CH3 C Br Br C CH
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 of each
other and chiral
 (III) & (IV) are identical and achiral
Ch. 5
 H H
(I ) CH3 C Br Br C CH
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
12C. How to Name Compounds with
More than One Chirality Cente
a
 H Br
2,3-Dibromobutane Br b
H
2 3

1 4
● Look through C2–Ha bond
a④
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
Br b ① b
H
H Br
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

Cl H enantiomers H Cl

CH3 CH3
mirror
 (I) and (II) are both chiral and they
are enantiomers of 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 of
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- &

Me
symmetry Me trans-1,4-
dimethylcyclo-
hexanes are
Me Me
achiral and
Me H optically
Me H Me Me inactive

H H • The cis & trans

cis-1,4-dimethyl trans-1,4-dimethyl forms are
cyclohexane cyclohexane diastereomersCh. 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 mirror
quite complicated
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 Me mirror 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 2 1 (III)
Me
(III) become C1’ H
H
of (I) Ch. 5
 Me Me
2'
H H 2
1' Me Me 1

(I) H H (II)

Although (I) and

(II) are Me
2 1 (III)
enantiomers to Me
H
each other, they H
can interconvert
rapidly  (I) and
(II) are achiral 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