Topic 3 - Stereochemistry

Manipal International University

1
 - Stereochemistry
• Optical isomerism-elements of symmetry, chirality,
enantiomers, optical activity, properties of
enantiomers- chiral & achiral molecules with 2 stereo-
genic centres- E.g., Lactic acid and Tartaric acid..
• Diastereomers-definition & examples, threo and
erythro diastereomers, meso compounds-definition
and examples,
• Resolution of enantiomers – mechanical, chemical
and biochemical methods.
• Relative and absolute configuration, sequence rules,
D&L, R&S systems of nomenclature. Geometrical
isomerism, cis-trans, E-Z, syn-anti configurations 2
 Stereochemistry
The Shapes of Molecules
• Stereochemistry: the branch of chemistry
concerned with the three dimension shapes
of molecules

The most stable shape of Decane.

 Isomers
• Isomers: different compounds with the
same molecular formula
• Constitutional isomers: isomers with a
different connectivity
• Stereoisomers: isomers with the same
connectivity but a different orientation of
their atoms in space
 Constitutional Isomers
• Have same molecular
CH2 CH3
form but different
H3C CH2
structural formula
butane
• Both isomers to the B.P = -0.5C
right are C4H10 CH3
• These have different
CH
chemical and physical H3 C CH3
properties
isobutane
B.P = -11.7 C
 Isomers
Nonidentical compounds having the same molecular
formula
Cis-Trans Isomers
 Stereoisomers
• Appear to have same structure in 2D, in 3D have
different structures
• Are non-superimposable mirror images of each
other

• With modeling kit build a model: carbon atom with four

different colors attached (use same size bonds!)
• Look at your model in a mirror, build what you see in the
mirror.
• Are the two superimposable?
Achiral compounds have superimposable mirror images

Chiral compounds have nonsuperimposable mirror

images
 Chirality
• Chiral: from the Greek, cheir, hand: an object that is
not superposable on its mirror image
• Achiral Compounds have superimposable mirror
images
• an achiral object has at least one element of
symmetry
– plane of symmetry: an imaginary plane passing
through an object dividing it so that one half is the
mirror image of the other half
– center of symmetry: a point so situated that
identical components are located on opposite
sides and equidistant from that point along the axis
passing through it
 Elements of Symmetry
• Symmetry in objects
 Elements of Symmetry
• Plane of symmetry (cont’d)
mirror
plane

HO OH
 Chiral centers
• Carbon attached to 4 different substituent
groups
– Even if two substituent groups start with C,
they could still be different.
H H

H3CH2C OH CH2CH3
HO
CH3 H3C

• C=O, never chiral (C only attached to 3 things)

• CH3, CH2 groups, never chiral because they are
symmetric:
 Vocabulary
• Stereoisomers have chiral centers.
• Carbon atoms can be
– chiral or achiral
– Asymmetric or symmetric
• If two molecules are stereoisomers, they
are also called enantiomers
• Chiral molecules are optically active
• Enantiomers are optical isomers
 Enantiomers
nonsuperimposable mirror-image molecules
Drawing Enantiomers

Perspective formula

Fischer projection
A stereocenter (stereogenic center) is an atom at which
the interchange of two groups produces a stereoisomer
 Naming Enantiomers
The R,S system of nomenclature
Rank the groups (atoms) bonded to the chirality center
Orient the lowest priority (4) away from you

Clockwise = R configuration

Counterclockwise = S configuration
R,S Convention
 Priority rules
1. Each atom bonded to the chiral center is
assigned a priority based on atomic number;
the higher the atomic number, the higher the
priority
(1) (6) (7) (8) (16) (17) (35) (53)
-H -CH3 -N H2 - OH - SH - Cl - Br -I
Increasing priority

2. If priority cannot be assigned per the atoms

bonded to the chiral center, look to the next set
of atoms;(1) priority(6)is assigned (7)
at the first
(8)
point
of difference
- CH 2 -H - CH 2 -CH 3 - CH 2 -N H2 - CH 2 -OH
Increasing priority
3-20
Naming from the Perspective Formula
1. Rank the groups bonded to the asymmetric carbon
1

2
3

2. If the group (or atom) with the lowest priority is

bonded by hatched wedge,
3. If necessary, rotate the molecule so that the lowest
priority group (or atom) is bonded by a hatched wedge

4. You can draw group 1 to group 2, passing group 4,

but never 3
 Naming from the Fischer Projection
1. Rank the groups (or atom) that are bonded to the asymmetric
carbon and draw an arrow with the highest priority to the lowest
priority
Cl

CH3CH2 CH2CH2CH3
(R)-3-chlorohexane
H
2. If the lowest priority is on a horizontal bond, the naming is
opposite to the direction of the arrow
CH3

H OH (S)-2-butanol
CH2CH3
3. The arrow can go from group 1 to 2, passing group 4, but not
group 3
CO2H

H CH3
(S)-lactic acid
OH

A Fischer projection can only be rotated 180 ° in the plane

of the paper to yield the same molecule
Enantiomers
 2-Butanol
• has one chiral center
• here are four different representations for one
enantiomer
OH H OH
H OH OH
C H C
H3 C H3 C CH2 CH3
CH2 CH 3
(1) (2) (3) (4)
• using (4) as a model, here are two different
representations for the enantiomer of (4)
OH OH OH

(4) representations for the

enantiomer of (4)
3-25
Enantiomers
 The enantiomers of lactic acid
• drawn in two different representations

O OH HO O
C C

C C
H OH HO H
CH3 CH3

O O
OH HO
OH OH

3-26
Enantiomers
 3-Chlorocyclohexene
Cl Cl

3-27
R,S Convention
 Priority rules
1. Each atom bonded to the chiral center is
assigned a priority based on atomic number;
the higher the atomic number, the higher the
priority
(1) (6) (7) (8) (16) (17) (35) (53)
-H -CH3 -N H2 - OH - SH - Cl - Br -I
Increasing priority

2. If priority cannot be assigned per the atoms

bonded to the chiral center, look to the next set
of atoms;(1) priority(6)is assigned (7)
at the first
(8)
point
of difference
- CH 2 -H - CH 2 -CH 3 - CH 2 -N H2 - CH 2 -OH
Increasing priority
3-28
R,S Convention
3. Atoms participating in a double or triple
bond are considered to be bonded to an
equivalent number of similar atoms by
single bonds
C C
is treated as
-CH= CH2 -CH-CH2

O O C
is treated as
-CH C O
H
C C
is treated as
C CH C C H
C C

3-29
Naming Chiral Centers
1. Locate the chiral center, identify its four
substituents, and assign priority from 1
(highest) to 4 (lowest) to each substituent
2. Orient the molecule so that the group of
lowest priority (4) is directed away from you
3. Read the three groups projecting toward you in
order from highest (1) to lowest priority (3)
4. If the groups are read clockwise, the
configuration is R; if they are read
counterclockwise, the configuration is S
1
S
H Cl
(S)-2-Chlorobutane 2 3

3-30
Naming Chiral Centers
• (R)-3-Chlorocyclohexene

Cl 3
1
H
2
R
• (R)-Mevalonic acid
1
1 4
HO CH3 O R

3 2
HO OH
3 2

3-31
Enantiomers & Diastereomers
 For a molecule with 1 chiral center, 21 = 2
stereoisomers are possible
 For a molecule with 2 chiral centers, a
maximum of 22 = 4 stereoisomers are
possible
 For a molecule with n chiral centers, a
maximum of 2n stereoisomers are possible

3-32
Enantiomers & Diastereomers
 2,3,4-Trihydroxybutanal
• two chiral centers
• 22 = 4 stereoisomers exist; two pairs of
enantiomers
CHO CHO CHO CHO
H C OH HO C H H C OH HO C H

H C OH HO C H HO C H H C OH

CH2 OH CH2 OH CH2 OH CH2 OH

A pair of enantiomers A pair of enantiomers
(Erythreose) (Threose)

 Diastereomers:
• stereoisomers that are not mirror images
• refers to the relationship among two or more
3-33
Enantiomers & Diastereomers
 2,3-Dihydroxybutanedioic acid (tartaric
acid)
• two chiral centers; 2n = 4, but only three
stereoisomers
COOH exist
COOH COOH COOH

H C OH HO C H H C OH HO C H

H C OH HO C H HO C H H C OH

COOH COOH COOH COOH

A meso compound A pair of enantiomers
(plane of symmetry)

 Meso compound: an achiral compound

possessing two or more chiral centers that
3-34
 Meso Compounds
Have two or more asymmetric carbons and a plane of
symmetry

They are achiral molecules

Enantiomers & Diastereomers
 2-Methylcyclopentanol

CH3 OH HO H3 C

H H H H
cis-2-Methylcyclopentanol
(a pair of enantiomers) diastereomers

CH3 H H H3 C

H OH HO H
trans-2-Methylcyclopentanol
(a pair of enantiomers)
3-37
Enantiomers & Diastereomers
 1,2-Cyclopentanediol

OH HO OH HO

H H H H
cis-
1,2-Cyclopentanediol
(a meso compound)
diastereomers

OH H H HO

H HO OH H
trans-
1,2-Cyclopentanediol
(a pair of enantiomers)

3-38
Enantiomers & Diastereomers
 cis-3-Methylcyclohexanol

H3 C OH HO CH3

3-39
Enantiomers & Diastereomers
 trans-3-Methylcyclohexanol

H3 C CH3

OH HO

3-40
Isomers
rotation about
Compounds with the single bonds
same molecular formula
Conformations
same different
connectivity connectivity rotation
restricted

Stereoisomers Constitutional Conformational

Isomers Isomers
stereoisomers
but no chiral centers with chiral centers
Atropisomers
Cis,Trans m ore than
(E,Z) Isomers one chiral center one chiral center
(can be called achiral chiral
diastereomers)
Enantiomers
not mirror mirror
Meso
images images
Compounds

Diastereomers Enantiomers 3-41

Properties of Stereoisomers
 Enantiomers have identical physical and
chemical properties in achiral
environments
 Diastereomers are different compounds
and have different physical and chemical
properties
• meso tartaric acid, for example, has different
physical and chemical properties from its
enantiomers

3-42
Chiral compounds are optically active; they rotate the
plane of polarized light.

Clockwise (+) Counterclockwise (-)

Different from R,S configuration

Achiral compounds do not rotate the plane of polarized

light. They are optically inactive.
Plane-Polarized Light
 Ordinary light: light vibrating in all planes
perpendicular to its direction of
propagation
 Plane-polarized light: light vibrating only in
parallel planes
 Optically active: refers to a compound that
rotates the plane of plane-polarized light

3-44
Plane-Polarized Light
• plane-polarized light is the vector sum of left
and right circularly polarized light
• circularly polarized light reacts one way with
an R chiral center, and the opposite way with
its enantiomer
• the result of interaction of plane-polarized light
with a chiral compound is rotation of the plane
of polarization

3-45
Plane-Polarized Light
 Polarimeter: a device for measuring the
extent of rotation of plane-polarized light

3-46
Optical Activity
• observed rotation: the number of degrees, ,
through which a compound rotates the plane of
polarized light
• dextrorotatory (+): refers to a compound that
rotates the plane of polarized light to the right
• levorotatory (-): refers to a compound that
rotates of the plane of polarized light to the left
• specific rotation: observed rotation when a
pure sample is placed in a tube 1.0 dm in
length and concentration in g/mL (density); for
a solution, concentration is expressed
COOH COOH in g/ 100
mL C H H C
H3 C CH3
OH HO
(S)-(+ )-Lactic acid (R)-(-)-Lactatic acid
21 21
[ ] D = + 2.6° [ ] D = -2.6° 3-47
A racemic mixture, which contains an equal amount of
the two enantiomers, is optically inactive

optical purity = observed specific rotation

specific rotation of the pure enantiomer

excess of a single enantiomer

enantiomeric excess =
entire mixture
Optical Purity
 Optical purity: a way of describing the
composition of a mixture of enantiomers
[ ]sam ple
Percent optical purity = x 100
[ ]pure enantio mer

 Enantiomeric excess: the difference

between the percentage of two
enantiomers in a mixture
[R] - [S]
Enantiomeric excess (ee) = x 100 = %R - %S
[R] + [S]

• optical purity is numerically equal to

enantiomeric excess, but is experimentally
determined 3-49
Enantiomeric Excess
Example: a commercial synthesis of naproxen, a
nonsteroidal anti-inflammatory drug (NSAID),
gives the S enantiomer in 97% ee
CH3

COOH
H3 CO
(S)-Naproxen

Calculate the percentages of the R and S

enantiomers in this mixture

3-50
Resolution
 Racemic mixture: an equimolar mixture of
two enantiomers
• because a racemic mixture contains equal
numbers of dextrorotatory and levorotatory
molecules, its specific rotation is zero
 Resolution: the separation of a racemic
mixture into its enantiomers

3-51
Discrimination of Enantiomers by
Biological Molecules
Resolution
 One means of resolution is to convert the
pair of enantiomers into two
diastereomers
• diastereomers are different compounds and
have different physical properties
 A common reaction for chemical resolution
- +
is saltRCOOH
formation
+ :B RCOO HB
(R,S)-Carboxylic (R)-Base (R,R)-Salt + (S,R)-Salt)
acid

• after separation of the diastereomers, the

enantiomerically pure acids are recovered

3-53
 Resolution of a Racemic Mixture
(S)-base
(R)-acid (S)-acid (R,S)-salt (S,S)-salt
enantiomers diastereomers

(R,S)-salt (S,S)-salt
HCl HCl

(S)-baseH+ (S)-baseH+
+ +
(R)-acid (S)-acid
Resolution
• Racemic acids can be resolved using
commercially available chiral bases such as 1-
phenylethanamine
NH2 NH2

(S)-1-Phenylethanamine (R)-1-Phenylethanamine

• Racemic bases can be resolved using chiral

acids
OH such
O as O H3 C CH3
HO HO HOOC COOH
OH OH
CH3
O OH O OH
(2R,3R)-(+)-Tartaric acid (S)-(-)-Malic acid (1S,3R)-(+)-Camphoric acid

3-55
Resolution
 Enzymes as resolving agents
O OEt EtO O

CH3 H3 C
+
H3 CO OCH3
Ethyl ester of (S)-naproxen Ethyl ester of (R)-naproxen
(not affected by the esterase)
1. esterase NaOH, H2 O
2 . HCl, H2 O

O OH

CH3

H3 CO
(S)-Naproxen
3-56
Amino Acids
• the 20 most common amino acids have a
central carbon, called an a-carbon, bonded to
an NH2 group and a COOH group
• in 19 of the 20, the a-carbon is a chiral center
• 18 of the 19 a-carbons have the R configuration,
one has the S configuration
• in the D,L system, all have the L configuration
• at neutral pH, an amino acid exists as an
internal salt
side chainformula, O
• in this structural the symbol R = a side
chain H3 N
O-
R
Ionized or zwitterion
form of an amino acid
3-57
Chirality in the Biological World
 Except for inorganic salts and a few low-
molecular-weight organic substances, the
molecules of living systems are chiral
 Although these molecules can exist as a
number of stereoisomers, generally only
one is produced and used in a given
biological system
 It’s a chiral world!

3-58
Chirality in the Biological World
 Consider chymotrypsin, a protein-digesting
enzyme in the digestive system of animals
• chymotrypsin contains 251 chiral centers
• the maximum number of stereoisomers
possible is 2251
• there are only 238 stars in our galaxy!

3-59
Chirality in the Biological World
 Enzymes are like hands in a handshake
• the substrate fits into a binding site on the
enzyme surface
• a left-handed molecule will only fit into a left-
handed binding site and
• a right-handed molecule will only fit into a
right-handed binding site
• enantiomers have different physiological
properties because of the handedness of their
interactions with other chiral molecules in
living systems

3-60
Chirality in the Biological World
• a schematic diagram of an enzyme surface
capable of binding with (R)-glyceraldehyde but
not with (S)-glyceraldehyde

3-61