STEREOCHEMISTRY

1
 Chapter Contents
Types of isomerism
Stereoisomers
Chirality and biological significance
R/S configuration
Optical Activity
Synthesis of Chiral molecules
Multiple chiral centers
Fischer projections
Configurations and reactions
Enantiomeric Resolution
Chiral centers other than carbon
E/Z-configuration for olefins
2
Isomerism: Constitutional Isomers and Stereoisomers

3
 Constitutional Isomers
Constitutional isomers are isomers which have the same
molecular formula but differ in the way their atoms are connected
CH3

CH
H3C CH3

2-methylpropane
Chemical Formula: C4H10

Stereoisomers
Stereoisomers are isomers with the same molecular formula and
same connectivity of atoms but different arrangement of atoms in
space
H OH HO H

(I) (II) 4
 Stereoisomers

Chiral molecules (possess molecular asymmetry)

Enantiomers
• Can exist as a pair of enantiomers with identical chemical
and physical properties
• The pair possesses a non-superimposable mirror image
relationship
• Ability to rotate plane polarized light in opposite
directions by each member of the pair

Achiral molecules (possess molecular symmetry)

Superposable on its mirror image

5
 Chirality
Chiral molecules - generally molecules containing an
asymmetric or chiral center
Asymmetric (chiral) center - tetrahedral atom bonded to
four different groups - indicated with an asterisk (*)

6
Chiral vs Achiral

7
 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
identical
 All molecules with a plane of symmetry possess identical
halves on either side of the plane and thus are achiral

Ch. 5 - 8
Plane of symmetry
Cl

Me Me

H
achiral

Cl

Me Et

H
chiral
No plane of symmetry Ch. 5 - 9
 Chirality and Biological Significance

Chiral objects are objects with left-handed and right-handed forms

Achiral objects - objects that have superimposable mirror images
Nonsuperimposable mirror images - a mirror image that is not the same as the
image itself - chiral objects have nonsuperimposable mirror images
10
Examples from real life

Ajino moto =
MSG

Thalidomide

11
 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
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

Ch. 5 - 12
 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 - 13
 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 - 14
 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)
 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.
 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 - 15
 Example HO H
(2-Butanol)

① ④
O H
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 - 16
 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 - 17
 Other examples
①
Cl Cl Counter-
clockwise
④
③
H CH3
(S)
HO CH3
HO
②
Clockwise
②
OCH3 OCH3
(R)
④
③
H3C CH2CH3 Br CH2CH3
① Br
Ch. 5 - 18
 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

(R)
Br OH
Ch. 5 - 19
 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

(S)
H3C I
Ch. 5 - 20
 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 - 21
 Example
③
CH3
(S)
④ ②
H 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 - 22
 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
(S)
O ③
C  (O, H, H)
Ch. 5 - 23
 Properties of Enantiomers

 Enantiomers
● Mirror images that are not superposable

H H
* *
Cl CH3 H3C Cl
H3CH2C CH2CH3

mirror

Ch. 5 - 24
 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 - 25
 Optical activity

 The property possessed by chiral substances of rotating the

plane of polarization of plane-polarized light is optical activity

 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)

Ch. 5 - 26
Plane-Polarized Light

Polaroid
lens

Ch. 5 - 27
 The Origin of Optical Activity

Two circularly- Two circularly-polarized

polarized beams beams counter-rotating
counter-rotating at at different velocities,
the same velocity (in such as after interaction
phase), and their with a chiral molecule,
vector sum and their vector sum
Ch. 5 - 28
The Origin of Optical Activity

Ch. 5 - 29
The Origin of Optical Activity

Ch. 5 - 30
 The Polarimeter
 A device for measuring the optical activity of a chiral compound

α= observed
optical rotation

Ch. 5 - 31
 Specific Rotation
observed
temperature rotation

25 α
[α]D =
c x ℓ
wavelength of
concentration length of cell
light
of sample in dm
(e.g. D-line of
solution (1 dm = 10 cm)
Na lamp,
in g/mL
λ=589.6 nm)

Ch. 5 - 32
• The value of α depends on the particular experiment (since

there are different concentrations with each run)

• But specific rotation [α] should be the same regardless of

the concentration

Ch. 5 - 33
 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
[α] = + 13.5 [α] = − 13.5
D mirror D

Ch. 5 - 34
 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 - 35
 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%

 An enantiomerically pure sample of (S)-(+)-2-butanol shows

a specific rotation of +13.52
25
[α]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 - 36
 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 - 37
 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 - 38
 The Synthesis of Chiral Molecules
Racemic Forms

Prochiral/Prostereogenic
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 - 39
Ch. 5 - 40
 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 - 41
 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 - 42
 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 - 43
 Naproxen
(anti-inflammatory drug) CO2H

CH3

MeO

NaO2C
CH3
HO
S CH3

Cl N

Singulair
(asthma and allergy treatment)
Ch. 5 - 44
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 - 45
 Br Br
Cl C H H C Cl
(I) (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 - 46
 Br Br
Cl C H H C Cl
(I) (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 - 47
 Br Br
Cl C H H C Cl
(I) (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 - 48
 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 - 49
 H H
CH3 C Br Br C CH
(I) 3 (II)
CH3 C Br Br C CH3
H H

H H
C Br Br C CH
(III) CH3 3 (IV)
H C Br Br C H
CH3 CH3
Note: (III) contains a plane of symmetry, is a meso compound,
and is achiral ([α] = 0o).

Ch. 5 - 50
 H H
CH3 C Br Br C CH
(I) 3 (II)
CH3 C Br Br C CH3
H H

H H
C Br Br C CH
(III) CH3 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 - 51
 H H
CH3 C Br Br C CH
(I) 3 (II)
CH3 C Br Br C CH3
H H

H H
C Br Br C CH
(III) CH3 3 (IV)
H C Br Br C H
CH3 CH3
 (I) & (III), (II) & (III) are diastereomers
 Only 3 stereoisomers:
● (I) & (II) {enantiomers}, (III) {meso}

Ch. 5 - 52
 How to Name Compounds with More than One
Chirality Center
a
 2,3-Dibromobutane H Br
b
Br H
● Look through C2–Ha bond 2 3

1 4

a④
①Br H
③ 2 ②
C2: (R) configuration C1 C3

(H, H, H) (Br, C, H)
Ch. 5 - 53
● Look through C3–Hb bond
④
Br b ① H b
H Br
a
H ③ ②
3 4 3
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 - 54
Fischer Projection Formulas: a 2D visual representation
of a 3D structure
How To Draw and Use Fischer Projections
Fischer
Projection

COOH COOH
Et Br
HO Ph Br Ph Br Ph
Et OH Et OH
H 3C COOH
CH3 CH3

Ch. 5 - 55
 H Me
COOH Me OH
H H
Ph
H
OH Ph COOH

COOH COOH

HO H HO H
Fischer
Projection
Me H Me H

Ph Ph Ch. 5 - 56
 Cl H H Cl
H Cl Cl H

H 3C CH3 H 3C CH3
(I) (II)
(2S, 3S)-Dichlorobutane (2R, 3R)-Dichlorobutane

CH3 CH3

H Cl Cl H
enantiomers

Cl H H Cl

CH3 CH3
mirror
 (I) and (II) are both chiral and they are enantiomers with
each other
Ch. 5 - 57
 CH3
H H
Cl Cl H Cl

H Cl
H3C CH3
(III) CH3
Plane of
(2S, 3R)-Dichlorobutane symmetry

 (III) is achiral (a meso compound)

 (III) and (I) are diastereomers to each other

Ch. 5 - 58
 Fischer to Sawhorse & Newman Projection
Formulae H OH
CH3 H OH
Cl H CH2CH3
H OH
Cl H
CH2CH3
CH3
H Cl CH3
CH2CH3

View Fischer projection Sawhorse projection Sawhorse projection

(eclipsed) Staggered
CH2CH3
Cl H
OH H OH
H

CH2CH3 H Cl
CH3 CH3
Newman projection Newman
projection
(eclipsed) (Staggered) 59
 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 - 60
The (E) - (Z) System for Alkene Diastereomers

 Cis-Trans System
● Useful for 1,2-disubstituted alkenes
● Examples:
H Br
(1) Cl vs Cl
Br H
H H
trans -1-Bromo- cis -1-Bromo-
2-chloroethene 2-chloroethene

Ch. 7 - 61
 ● Difficulties encountered for trisubstituted and
tetrasubstituted alkenes

CH3
e.g. Cl cis or trans?
Br
H
Cl is cis to CH3
and trans to Br

Ch. 7 - 62
 ● Examples
CH3
Cl
Br
H
 (E )-2-Bromo-1-chloropropene

Br
Cl
CH3
H
 (Z )-2-Bromo-1-chloropropene
Ch. 7 - 63
 ● Other examples

H (E )-1,2-Dichloroethene
(1) Cl [or trans-1,2-Dichloroethene]
1 Cl
2
H C1: Cl > H
C2: Cl > H

2 (Z )-1-Bromo-1,2-dichloroethene
Cl
(2) 1 Cl
Br C1: Br > Cl
C2: Cl > H
Ch. 7 - 64
 ● Other examples

Br
3 1
4
(3) 2
5
7
8 6
(Z )-3-Bromo-4-tert-butyl-3-octene

C3: Br > C
t n
C4: Bu > Bu

Ch. 7 - 65