Stereochemistry

Static Stereo Chemistry Stereo chemistry of Molecules

Representation in 3D,
Number of isomers, structure, energy,
physical and chemical properties

Dynamic Stereo Chemistry Stereochemistry of Reactions

Stereo chemical requirements and outcome of chemical reactions

1
 Compounds with no stereogenic centres
The presence of chiral atom is neither a necessary nor a sufficient
condition to be optically active

H3C H
Me H H Me C C C
C
C
H H H
Me Me achiral
H

These mirror images are not superimposable - enantiomers

rotation around the single
bond is restricted
O O
H H
N N
PPh2
PPh2 N N
H H
O O
nonsuperimposable enantiomers
2
3
Substituted allenes

4
5
6
7
biphenyls

has been resolved

half-life for racemization
is 78 min at 118oC

8
Biphenyl atropisomerism

9
 Optically active di- and mono-substituted biphenyls

When a substituent is present at the meta position with respect to

the σ bond joining the two rings, activation energy for racemisation of
chiral biphenyls is enhanced. This is called buttressing effect.

10
Configurational nomenclature of alkylidenecycloalkanes, oximes and spiranes

11
 Helical and propellor Molecules

Left handed and Right Handed Hexahelicene

Cl

Cl Cl Rotation restricted

Cl Cl
Cl Cl
N
Cl Cl
Cl Cl
Cl Cl
Cl Cl
Propellor 12
perchlorotriphenylamine
13
Static Stereochemistry

Stereo chemistry of Molecules

Representation in 3D,
Number of isomers, structure, energy,
physical and chemical properties

14
 Drawing Molecules

H HH H H H H HH HH HH H
H3 C OH

H HH H H HH H
HH H H HH
O
linoleic acid
or CH3CH2CH2CH2CH2CH=CHCH2CH=CHCH2CH2CH2CH2CH2CH2CH2CO2H
linoleic acid
or
H H H H H H H H H H H H H
H C C C C C C C C C C C C C C C C C CO2H

H H H H H H H H H H H H H H H H H
linoleic acid

X-ray picture of linoleic acid

OH

O
linoleic acid 15
 How do you identify isomers
Yes Do the compounds have the No
Isomers Not Isomers
Same molecular formulae?

Yes Do the compounds have the Constitutional

Stereoisomers No
Same Connectivity? O
OH

Can the compounds be interconverted by rotation about single bonds

H 3C H Yes
H No
H
H CH3 Conformational Configurational
H H
H H

H 3C CH3 Optical Is the isomerism at a double bond? Geometric

No Yes

Are the compounds have non-superimposable mirror images?

Yes No
Cl H
H 3C H H3C Cl
Enantiomers Diastereomer
Cl Cl H 3C H H3C H
Br Br

H3CH2C H H
CH3 H3C CH2CH3 16
 Chiral An object that has a non-superimposable mirror image is said to be
"chiral" (Greek = "handedness") and one that has a superimposable mirror
image is "achiral".

CHIRALITY is a property of an object which is non-

superimposable with its mirror image. Most objects in the
environment are chiral. In chemistry this term applies to molecules,
specific conformations of molecules, as well as to macroscopic objects
such as crystals.

Chirality is removed if an object /molecule acquires a plane of

symmetry, or a center of symmetry. 17
Enantiomers A pair of molecules that are non-superimposable mirror images
of each other.

The most common type of "chirality" is observed when a carbon atom has four
different groups attached to it (so it must be sp3 hybridised). This carbon atom
is then described as a chiral center or center of chirality.

Older terms are chiral, asymmetric or stereogenic center (stereocenter).

Cl Cl

H3CH2C H H CH2CH3
CH3 H3C

Cl=D? Small differences also matters

18
 Enantiomers and Chirality
O -
CN HO CN
R R
H H

How many products are formed ?

O
O HO CN
NC OH
R R
R R
H H
H H

A B
CN
CN
Approach from back face of the carbonyl
Approach from front face of the carbonyl

What is the relation between A & B?

HO
NC OH CN

A&B are non superimposable mirror images R R

H H

A B
A&B are chiral and Enontiomers (Mirror images)

19
 Elements of symmetry

O HO
HCN HO CN CN
Plane of symmetry (σ) through
Me Central C-atom, OH & CN
H3 C CH3 Me Me Me

Acetone Cyanohydrine

Cl H Cl H

F H F H

Center of symmetry (i) Or inversion center

H F H F
H Cl H Cl

Any structure that has no plane of symmetry or inversion center can exist as
two non super-imposable mirror-images (enantiomers)
20
Problem: Which of the following are chiral and why?

Me
Me

Me Me Me Me Me Me

Me Cl Me
Me Cl Me
Cl Cl

Cl Me Cl
Me Me Cl Me

21
 Stereogenic centres

If a molecule contains one carbon atom carrying four different groups, generally do not possess
a plane of symmetry or inversion center and must therefore be chiral.

A carbon atom carrying four different groups is a stereogenic or chiral centre

Constitutional and Stereo Isomers

OH R *
OH HO CN HO CN
R * R R
CN CN
H H
Enontiomers
Constitutional Isomers
Going from one enontiomer to the
other requires bond breaking
NC
R HO CN NC H H OH
R R
CN R R
H OH CN

Trans-cis isomers Three conformations of same enontiomer:

Going from one to the other requires
-bond should be broken rotation about C-C bond
Stereo isomers 22
 Racemic mixture
A racemic mixture is a mixture of two enantiomers in equal proportion

MeMgCl
:
CHO H OH
OH HO H
50 : 50

OH HO H HO H
CHO

O :
O O
OH

50 : 50

Q. The following compound racemises in base, why?

O
O
O O HO
B -
O O
O
R S
HO
H 23
H
H
Problem: Feist's acid (C6H6O4) is a cyclopropane based natural product and having two
stereocenter. The compound is chiral. Based on this information predict its correct structure?

CO2H CO2H
Hint:

CO2H HO2C CO2H CO2H

X X

HO2C CO2H HO2C CO2H

right structure

24
 GRAPHICAL REPRESENTATION OF NONPLANAR MOLECULES

Representation of the 3D-structures of molecules as their 2D-projections:

1. Fisher projection
Perspective formula
2. Wedge projection
COOH HOOC HOOC

H3C NH2
H3C NH2 H2 N CH3

H H

Fisher projection: H
The tetrahedral atom is viewed
perpendicularly to an edge formed 2 2
by connecting two of its ligands. COOH COOH
The convention is that the two 1 1 3
3
vertical bonds in the projection are H3C NH2 H2N CH3
pointing behind the plane of
projection (plane of paper sheet),
H H
and the two horizontal bonds are
pointing towards the viewer.
S R

D-H-A-R
25
Determination of absolute configuration from Fischer presentation

Cl Cl
Et nPr nPr Et
H H

(R)-3-chlorohexane (S)-3-chlorrohexane

* lowest priority group is in vertical

26
* lowest priority group is not vertical

Me Me
H OH HO H
Et Et
(S) (R)

Very true if LP is on vertical bond

Horribly wrong if LP is on horizontal bond
27
 In the case of large linear molecule the molecule backbone has to be laid on the
plane of the paper such that the substituents pointed towards and/or away from
the viewer

HOCH2CH(OH)CH(OH)CH(OH)CHO RRR RRS RSR RSS

SSS SSR SRS SRR
Ribose, carbohydrate
C5(H2O)5

OH OH OH
OH
CHO CHO CHO
CHO
HO HO HO
HO

OH OH OH OH OH OH OH OH

OH OH OH OH
CHO CHO
HO CHO CHO
HO HO HO
OH OH OH OH OH OH OH OH

28
 Sawhorse projection

The C-C bond is viewed at an angle.

View

This projection is difficult to use with acyclic molecules but is most popular for
representation of cyclic molecules e.g. saturated six-membered rings.

29
 Newman projection:

The molecule with two tetrahedral centers is viewed along the C-C axis.
The atom in front is represented as a three-way branch, the atom in the back as
a circle with three outgoing bonds.

DH2C-CH2D

This projection is most useful to understand steric relations between ligands

linked to adjacent tetrahedral centers and is most popular
30
 CH3 CH3
Cahn-Ingold-Prelog (CIP) rules:
HO H H OH

CH2 CH2

Absolute configuration : CH3 CH3

The R & S notation Both are "2-butanol''

1. Assign priority sequence to the four groups attached to a stereogenic

carbon following sequence rule
2. Observe the stereogenic centre from a direction opposite to the group
of lowest priority
3. Trace the path from 1 to 2 to 3.
If clockwise R (rectus, right)
If anti clockwise S (sinister, left)

31
 Sequence rules:
1. Priority is first assigned on the basis of the atomic number of the atom
that is directly attached to the stereo centre. CH 3 ?
(1) HO H (4)

CH2 ?
CH3
2. When a priority cannot be assigned on the basis of atomic number,
then the next set of atoms/groups are examined. (3) CH3 H, H, H

(1) HO H (4)

CH2 H, H
(2)
CH3 C
3. Rotate the structure so that (4) is directed away from us.
3
CH3 CH3
4 OH 1
HO H H
CH2
CH2CH3 32
R
CH3 2
4. Groups containing double or triple bonds are assigned as if both
atoms were duplicated and triplicated.

C Y C Y

(Y) (C)

(Y) (C)

C Y C Y

(Y) (C)
CH CH2 CH2CH3

Vinyl or ethyl which one gets higher priority?

H H
H H
C C H
C C H
H H
(C) (C)
H, C, C H, H, C

Vinyl>Ethyl 33
 Stereochemistry
Labeling Stereogenic Centers with R or S
• To assign a priority to an atom that is part of a multiple bond,
treat a multiply bonded atom as an equivalent number of
singly bonded atoms. For example, the C of a C=O is
considered to be bonded to two O atoms.

• Other common multiple bonds are drawn below:

34
 Stereochemistry

Labeling Stereogenic Centers with R or S

• If two isotopes are bonded to the stereogenic center,

assign priorities in order of decreasing mass number.
Thus, in comparing the three isotopes of hydrogen, the
order of priorities is:

35
 Assign a configuration, R or S to each of these compounds

Br
Cl

Cl
OH HO
Br

R OH

NH2
HS CHO
CO2H

R = Me; CF3

MeO CF3

COOH R or S ?
36
 Cl

Br Br
OH
(R)-3-chlorohexane
(R,E )-hept-4-en-3-ol Cl
(R)-3-(bromomethyl)-2,3- HO
dimethylpentane
(S)-3-(bromomethyl)-1-chloropentan-3-ol

OH
F3C OH

NH2
HS
CO2 H
(S)-1-(anthracen-9-yl)ethanol (R)-2-amino-3-mercaptopropanoic acid
(R)-1-(anthracen-9-yl)-2,2,2-trifluoroethanol

OH
NH 2
CHO

(R)-3,7-dimethyloct-6-enal
(1R,2S)-2-amino-1,2,3,4-tetrahydronaphthalen-1-ol

HN
O
OH MeO CF3
S COOH R
37
(S)-furan-2-yl(1H -pyrrol-2-yl)(thiophen-2-yl)methanol
 (S)-(4,4-dimethylpent-1-yn-3-yl)benzene

CIP rule: Ph>acetylene>tbu>H

38
 Z/E Geometry of Double Bonds

CIP rules used to geometrical isomers of olefinic compounds

Precedence of ligands at both X & Y of the double bonds is determined pairwise.
If both higher precedence ligands are
on the same side of the double bond the configuration is Z,
if on the opposite sides the configuration is E.

Z (zusammen, together) E (entgegen, opposite)

H H Br 1 F

1 1
H3C CH3 1
H Cl
(Z)-2-butene
Or cis-2-butene (E)-2-bromo-1-chloro-1-fluoroethene 39
 H CH3
Br CH2CH3
H3C

CH3
Cl H
H CH3

(Z)-1-bromo-1-chloro-1-butene (Z,4S)-3,4-dimethyl-2-hexene

Et CH2CH2CH3

H3C CH2CH2CH2CH3

(E)-3-methyl-4-propyl-3-octene
(2E),(4E)-2-chloro-2,4-hexadiene

40
 Nitrogen chirality center

The inversion barrier is only 6 kcal/mol for R= alkyl

Ammonia: inverts 2X1011 times per second
41
Inversion is very fast and difficult to separate
 Inversion becomes slow when
•N is in three-membered ring

❖ N cannot achieve a 1200 bond

angle in a 3-membered ring
❖ The two enantiomers can be
separated

•N-atom is connected to atom which has unshared lone pair of electrons

CH3
Cl Me Me Cl N

N N N

H3C
Tröger’s base
Me Me

Two enantiomers has been separated Nitrogen at bridgehead position, 42

Pyramidal inversion prevented, chiral
Phosphorus chirality center

P
C(CH3)3
CH3 CH3
P C(CH3)3

inversion barrier 32.7 kcal/mol

P
H3C
H2C=HCH2C

[]D = 16.80
S-enantiomer
43
 Nitrogen, Phosphorus, Sulfur attached to four different groups

CH3
CH3
Br
Br H N
N H
CH2CH2CH3
H3CH2CH2C CH2CH3 H3CH2C

a pair of enantiomers
O O

H P
P H
H3CH2CO OCH2CH3
OCH3 H3CH2CO

16 O
a pair of enantiomers
O18

a pair of enantiomers
H3C
44
Problem: Compound I has two stereoisomers, but compound
II and III exist as single compounds. Explain?

+ +
Me N H Me N H Me N
Et Cl Me Cl H

I II III

Problem: The following compound has only one chirality center,

why then dose it have four stereoisomers

Br

45
Diastereomers
•Diastereomers are stereoisomers that are not mirror images.
•Two diastereomers are different compounds and have different
relative stereochemistry.
Diastereomers may be chiral (have no plane of symmetry):
Ar CO2Me Ar CO2Me

O O

Diastereomers may be achiral

OH OH

plane of symmetry 46
Relative Configurations in Compounds with Multiple Chiral Centers.

•The use of CIP nomenclature requires assignment of R,S descriptors

for every center. The quicker way (older and a more ambiguous one) is
by using threo/erythro nomenclature.
•Threo/erythro It requires vertical projection of main chain.
•threo-compounds are defined as those that have two groups of higher
precedence on each carbon atom on the opposite sides of the chain.
•erythro on the same side.
CH3 CH3
CH3 CH3
* * H OH HO H
H3C CH CH CH3 HO H
H OH
H Cl Cl H
Cl OH Cl H H Cl
CH3 CH3 CH3
CH3
3-Chloro-2-butanol
A B
C D
erythro enantiomers
threo enantiomers

A&C
A&D
diastereomers
B&C
47
B&D
 Tartaric acid
HOOC-CH(OH)-CH(OH)-COOH 22 = 4 stereoisomers ?

OH OH

R HO2C R S
HO2C R
CO2H CO2H

OH diastereomers OH
?
enantiomers
OH OH

S HO2C S R
HO2C S
CO2H CO2H

OH OH

HO2C CO2H
R S
COOH COOH HO OH COOH
H OH HO H
H OH
HO H H OH
H OH
COOH COOH
COOH
pair of enantiomers 48
meso compound
 Stereochemistry
Meso Compounds

49
 Stereochemistry
Disubstituted Cycloalkanes
• Consider 1,3-dibromocyclopentane. Since it has two
stereogenic centers, it has a maximum of four stereoisomers.

• Recall that a disubstituted cycloalkane can have two

substituents on the same side of the ring (cis isomer, A) or on
opposite sides of the ring (trans isomer, B). These
compounds are stereoisomers but not mirror images.

50
 Stereochemistry
Disubstituted Cycloalkanes
• To draw the other two stereoisomers if they exist, draw mirror
images of each compound and determine whether the
compound and its mirror image are superimposable.

• The cis isomer is superimposable on its mirror image, making

the images identical. Thus, A is an achiral meso compound.
51
 Stereochemistry
Disubstituted Cycloalkanes
• The trans isomer is not superimposable on its mirror image,
labeled C, making B and C different compounds. B and C are
enantiomers.

• Because one stereoisomer of 1,3-dibromocyclopentane is

superimposable on its mirror image, there are only three
stereoisomers, not four.
52
53
Problem: Draw all the isomers with mol. formula C 6H-12 that
contain a cyclobutane ring, and comment on their chirality

Hint: the base structure is dimethyl cyclobutane [1,2 (cis & trans) and
1,3 (cis & trans) also 1,1]; there also exist 1ethyl cyclobutane.

Me Me Me Me
Me

Me

54
Cis-2,4-dimethylcyclobutanone on LAH reduction provides two alcohols, write down their
structures and comment on their chirality. The trans isomer on the other side yields only
one alcohol. Explain the phenomena?

Me O

Me
Hint:

OH OH
O
LAH
+

Both are achiral (meso)

OH OH
O
LAH
=

55
chiral
Problem: 2,5-dimethyl-1,1-cyclopentane dicarboxylic acid exist as two isomers
(A & B; differ in mp; A is optically inactive but B is not)),Upon heating (mono decarboxylation)
A yields two 2,5-dimethylcyclopentanecarboxylic acid (optically inactive) and
B yields one (optically active). Assign structures of A & B.

HO2C CO2H

HO2C CO2H
Hint:
CO2H CO2H
heat
A + Me Me

CO2H CO2H
HO2C CO2H
heat
or

B
same
A & B are diastereomers
56
Enantiomers and Chiral Resolution

Why the smells of Orange and lemons are different?

R- (+)-limonene S- (-)-limonene
smell of orange smell of lemons

Enantiomeric smell !!!

57
 Perfumery compounds from jasmine
O

Jasmone

Cis-jasmone is the main compound in jasmone perfume

O
O

S
R CO2Me
CO2Me

strong odour odourless

(+)-Z-methyl epijasmonate (-)-Z-methyl epijasmonate
58
 Me
*
COOH

Ibuprofen
Anti-inflammatory drug, used to relieve pain, inflammation
500 mg of one tablet contains only half of its as active drug

Me
Me
COOH
COOH

S is active R is inactive

59
 HO HO
Drug for the treatment of NH2
NH2
Parkinson’s disease
Only L-dopa can restore
HO CO2H HO CO2H
the nerve function.
L-dopa D-dopa
marketed as a toxic
single enantiomer

Me
Me
NMe2
Me2N C
C O
O
O
O

Novrad 60
Darvon
(anticough agent)
(Pain killer)
 Stereochemistry
Physical Properties of Stereoisomers
• Enantiomeric excess (optical purity) is a measurement of
how much one enantiomer is present in excess of the
racemic mixture. It is denoted by the symbol ee.

ee = % of one enantiomer - % of the other enantiomer.

• Consider the following example—If a mixture contains
75% of one enantiomer and 25% of the other, the
enantiomeric excess is 75% - 25% = 50%. Thus, there is a
50% excess of one enantiomer over the racemic mixture.
• The enantiomeric excess can also be calculated if the
specific rotation [] of a mixture and the specific rotation
[] of a pure enantiomer are known.
ee = ([] mixture/[] pure enantiomer) x 100.
61
 Enantiomeric Excess
When a mixture of enantiomers is neither
enantiomerically pure (all one enantiomer) nor
racemic (equal amounts of two enantiomers), the
relative amounts of the enantiomers in the mixture
can be expressed as the enantiomeric excess (optical
purity).

e.e.= d - l x 100
d + l
(excess of one over the other) x100
= (entire mixture)
62
 Resolution of Enantiomers

Enantiomers have the same physical properties so they can not be separated directly.

A possible technique for separation is chemical modification into diastereomers, which

possess different physical properties. Once in hand, diastereomers can be separated
by physical means, such as boiling point or recrystallization and then converted back
into enantiomers.

Two key requirements:

1. The reaction must be reversible so that the enantiomers can be released.
2. The reagent that reacts with the enantiomers must be stereochemically pure.

Example: The resolution of (S) and (R)-2-butanol via esterification with

enantiomerically pure (R,R)-tartaric acid.

Key reaction: Esterification

O + O
H
R-C-O-H + H-O-R' R-C-O-R' + H2O
acid alcohol ester 63
 Reaction Scheme

CH2CH3
S
O H separate
CH2CH3 O C CH3 then H+
H R OH CH2CH3
HO H
H2O
HO
CH3 RH HO H
CO2H + CO2H CH3
(S)-2-butanol H CO2H
H OH (S)-2-butanol
+ H OH
HO H +
HO H
CO2H CH2CH3
CH2CH3 CO2H
(R,R)-tartaric acid H R O separate CH2CH3
H OH (R,R)-tartaric acid
CH3 CH3C O then H+ H OH
H R OH
CH3
(R)-2-butanol H2O
HO RH (R)-2-butanol
CO2H

The initial product esters are diastereomers of each other and can be separated by
selective recrystallization (i.e. different solubilities in a solvent). The alcohols are
recovered by hydrolysis of the esters (reversible reaction).
64