Chirality

Recognition and Nomenclature

A molecule that cannot be superposed on its mirror image is said to be chiral.

A molecule that can be superposed on its mirror image is said to be achiral.

H H

H H Br
Br Cl
Cl

In the above molecule bromochloromethane the mirror image is the same

compound, thus the molecule is achiral. Also notice that a plane of symmetry or
mirror plane can be located in the molecule.
A plane of symmetry is defined as an imaginary plane that bisects a molecule in
such a way that the two halves of the molecule are mirror images of each other.
All molecules with a plane of symmetry are achiral.

Cl
plane
of
H H
symmetry
Br
Sec. 6 - Stereochemistry - 2 Forsey 1
 plane of symmetry
Another example
2-chloropropane
CH3CHClCH3
Cl

H C
CH3
H3C
achiral

Chiral Molecules F
F

C H C
H
Br Br
Cl Cl

Bromochlorofluoromethane is chiral because the mirror image is nonsuperposable,

also a plane of symmetry can not be located within the molecule. Thus the two
molecules are different.
These two stereoisomers are called enantiomers which is simply a pair of
stereoisomers that are nonposable mirror images.

Sec. 6 - Stereochemistry - 2 Forsey 2

Another example
2-butanol
CH3CHOHCH2CH3

Why is this important?

The molecules are different. They have the same physical properties such as boiling
and melting points but may act totally different biologically.

Sec. 6 - Stereochemistry - 2 Forsey 3

 stereogenic
CH3 carbons CH3

H H
H3C CH3
(S)-Limonene (R)-Limonene
Lemon smell Orange smell
Synthesized in 1953
Available in 46
countries until 1962

O O
H H

N N

O N O
N O O
H O O H

(R)- Thalidomide (S)- Thalidomide

Thalidomide used to alleviate symptoms teratogen: causes birth
of morning sickness- The two isomers sedative
defects
are interconverted (racemizes) in
biological conditions (H+) Sec. 6 - Stereochemistry - 2 Forsey 4
 Identification of chiral atoms

CH2CH3 CH2CH3

CH2CH3 CH2CH3
C C
Br Br
CH3 H3C
C C
Br Br BrH2CH2C CH2CH2Br
CH2CH2Br Br H2CH2C
BrH2CH2C CH2CH2Br
Mirror image
Mirror image

rotate rotate

To have a chiral carbon it must be bonded to four different groups.

 sp3 hybridized with four different groups attached. Thus –CH2- and -CH3
are not chiral carbons
CH2CH3
CH2CH3
CH3CH2CH2CH2 C CH3
CH3CH2CH2CH2 C CH3
CH2CH3
CH2CH2CH3

Sec. 6 - Stereochemistry - 2 Forsey 5

 Nomenclature of Enantiomers: The (R-S) system
Cahn-Ingold-Prelog Rules
CH3 CH3

HO H H OH
C C

CH2 CH2

CH3 CH3

2-butanol

Priority is first based on the atomic number of the atom that is

directly attached to the stereo center. The group with the lowest
atomic number is given the lowest priority and so on.
When a priority cannot be assigned on the basis of the atomic
number of the atoms that are directly attached to the stereocenter,
then the next set of atoms in the unassigned groups are
examined. Assign priority at the first point of difference

Sec. 6 - Stereochemistry - 2 Forsey 6

1. Assign priority based on atomic number

CH3 H
a H H
HO H C
C
HO H
C
CH2
H C H
CH3
CH3

Now rotate the structure so that the group with the lowest priority is directed away.
Then trace a path from the highest priority to the lowest priority. If the path is
clockwise, the enantiomer is designated (R) [Latin rectus meaning right]. If the path
is counterclockwise, the enantiomer is designated (S) [Latin sinister meaning left].
c
CH3
a d H3C OH
HO H C
C rotate so that the lowest
priority is at the back CH2
b CH2
CH3
CH3
Sec. 6 - Stereochemistry - 2 Forsey 7
 c
CH3
a d H 3C OH
HO H C
C rotate so that the lowest
priority is at the back CH2
b CH2
CH3
CH3

mirror images

c
CH3
a HO CH3
c H OH C
C rotate so that the lowest
priority is at the back CH2
b CH2
CH3
CH3

enantiomers

Sec. 6 - Stereochemistry - 2 Forsey 8

 If the groups attached to the chiral carbon contain double or triple bonds
the priority assigned is as if both atoms were duplicated.
R Y C
R
C Y R C Y R C Y R C Y
R
Y C Y C

CH3 H
C C H C H H2C HC OH
H2C HC C OH C
H2C C C OH
H3C C CH3 H H3C C CH3

H3C C CH3 CH3

CH3
CH3

H H
H H CH3
H
CH3 C C C C H
H C
HC C C C(CH3)3 H C C C C C H
HC C C(CH3)3
H
H C C H C
H H H

Sec. 6 - Stereochemistry - 2 Forsey 9

Do the following molecules have an R or S configuration?
Cl
H CH3
CH3
Rotate around bond
CH2 to get hydrogen to H3CH2C C H
the back CH2Cl
CH3

Sec. 6 - Stereochemistry - 2 Forsey 10

 Are the following pairs of molecules the same or enantiomers?

hydrogen at back already

hydrogen at back already
H F
OH H
F C CH3 H C Cl
H H3C
Cl CH3 CH2CH3 OH
H3C H3CH2C

Sec. 6 - Stereochemistry - 2 Forsey 11

 Properties of Enantiomers: Optical Activity
Enantiomers have almost all identical physical properties (melting point, boiling
point, density)
However enantiomers rotate the plane of plane-polarized light in equal but opposite
directions

Plane polarized light

Oscillation of the electric field of ordinary light occurs in all possible planes
perpendicular to the direction of propagation

If the light is passed through a polarizer only one plane emerges

Sec. 6 - Stereochemistry - 2 Forsey 12

The Polarimeter

Sec. 6 - Stereochemistry - 2 Forsey 13

Specific Rotation

An empty sample tube or one containing an achiral molecule will not rotate the
plane-polarized light
An optically active substance (e.g. one pure enantiomer ) will rotate the plane-
polarized light
The amount the analyzer needs to be turned to permit light through is called the 
observed rotation α
If the analyzer is rotated clockwise the rotation is (+) and the molecule is
dextrorotatory
If the analyzer is rotated counterclockwise the rotation is (-) and the molecule is
levorotatory

Sec. 6 - Stereochemistry - 2 Forsey 14

 The specific rotation of the two pure enantiomers of 2-butanol
are equal but opposite

There is no straightforward correlation between the R,S designation of an

enantiomer and the direction [(+) or (-)]in which it rotates plane polarized light

Racemic mixture
No net optical rotation
A 1:1 mixture of enantiomers
Often designated as (+)

Sec. 6 - Stereochemistry - 2 Forsey 15

Racemic Forms and Enantiomeric Excess

Often a mixture of enantiomers will be enriched in one enantiomer

One can measure the enantiomeric excess (ee)

Example : The optical rotation of a sample of 2-butanol is +6.76o. What is the

enantiomeric excess?

Sec. 6 - Stereochemistry - 2 Forsey 16

The Synthesis of Chiral Molecules

Most chemical reactions which produce chiral molecules produce them in

racemic form

Sec. 6 - Stereochemistry - 2 Forsey 17

Molecules with More than One Stereogenic Center

The maximum number of stereoisomers available will not exceed 2n,

where n is equal to the number of tetrahedral stereogenic centers

* *
CH3CHCHCH2CH3 2,3-Dibromopentane. Two chiral centers therefore
4 stereoisomers
Br Br

CH3 CH3 CH3 CH3

H C Br Br C H Br C H H C Br

H C Br Br C H H C Br Br C H

CH2CH3 CH2CH3 CH2CH3 CH2CH3

1 enantiomers 2 3 enantiomers 4

1 and 2 are enantiomers, as is 3 and 4, but what are 1 and 3 or 1 and 4. They are
stereoisomers because they have the same connectivity. These are called
diastereomers.
Sec. 6 - Stereochemistry - 2 Forsey 18
Diastereomers
Diastereomers: stereoisomers which are not mirror images of each other
They have different physical properties and unlike enantiomers can be more
readily separated or isolated from each other
CH3
CH3 CH3 CH3
Br C H
H C Br Br C H H C Br
Br C H
H C Br H C Br Br C H
CH2CH3
CH2CH3 CH2CH3 CH2CH3
enantiomers enantiomers

Connectivity is
the same
and the
orientation in
space is different
∴stereoisomers
Diastereomers but they are not
mirror images

Sec. 6 - Stereochemistry - 2 Forsey 19

 Nomenclature
1 CH
3 CH3
2 CH3
H C Br Br C H
3 Br C H
H C Br Br C H
H C Br
CH2CH3 CH2CH3
4 5
CH2CH3

-2,3-dibromopentane

CH3

H C Br

Br C H

CH2CH3

-2,3-dibromopentane

-2,3-dibromopentane
-2,3-dibromopentane Sec. 6 - Stereochemistry - 2 Forsey 20
Fisher Projections

Each intersection of the horizontal and vertical lines represents a chiral carbon.
Each horizontal line represents a bond coming toward the viewer.
Each vertical line represents bonds going back away from the viewer.
O O
O O
CH CH
CH CH
Fisher H C OH Fisher H OH
H C OH H OH
projection projection
H C OH H OH
CH2OH CH2OH
glyceraldehyde CH2OH CH OH
2
O erythrose

1 CH

2
H OH Which carbons are chiral?
3
H OH
4
HO H
5 CH2OH
Sec. 6 - Stereochemistry - 2 Forsey 21
As stated in the above slides there are 2n optical isomers, where
n is the number of chiral carbons. But what about tartaric acid?
CO2H CO2H
R H OH HO H
enantiomers
R HO H H OH

CO2H CO2H
mp = 168° mp = 168°

[α ] 20
D = + 12 o [α ] D20 = − 12o
CO2H CO2H
mp = 200°
same
R H OH HO H S
[α ] D20 = 0
S H OH HO H R Thus there are only
CO2H 3 stereoisomers not 4
CO2H
Are these two mirror images enantiomers?
What do you call a compound that has chiral carbons but its mirror image is
exactly the same molecule. You call that molecule a meso compound
Sec. 6 - Stereochemistry - 2 Forsey 22
 How many stereoisomers does 2,3,4-trihydroxy-pentanedioic acid have?
OH OH
2n possible isomers = 8
HO2CCHCHCHCO2H
OH
CO2H CO2H CO2H CO2H
1 and 2 are the same
H OH HO H Meso compound or achiral H OH HO H
and optically inactive
H OH HO H HO H H OH
3 and 4 are the same
H OH HO H H OH HO H
Meso compound
CO2H CO2H CO2H CO2H
5 and 6 are non-
1 2 superposable mirror images 3 4

CO2H CO2H Therefore enantiomers CO2H CO2H

7 and 8 are the same as 5 H OH HO
H OH HO H H
and 6
H OH HO H HO H H OH

HO H H OH HO H H OH

CO2H CO2H CO2H CO2H

7 8
5 6 Sec. 6 - Stereochemistry - 2 Forsey 23
 How many stereoisomers does 2,3,4-trijydroxy-pentanedioic acid have?
4 and not 8 stereoisomers because of the meso compounds and
both ends of the molecule have the same substituents
1 2 3 4 5 6
CO2H CO2H CO2H CO2H CO2H CO2H

H OH HO H H OH HO H H OH HO H

H OH H OH H OH HO H HO H H OH

H OH HO H HO H H OH HO H H OH

CO2H CO2H CO2H CO2H CO2H CO2H

meso meso
(±) enantiomers but
Plane of symmetry (±) enantiomers the same as 3 and 4
Meso compounds contain 2 or more chiral carbons atoms (stereogenic carbons)
but have at least one conformation that is achiral, usually by virtue of a plane of
symmetry. Remember you can only get a meso compound when the “top” and
“bottom” halves have the same substituents.
Pairs of enantiomers have identical physical and chemical properties except for
interactions with other chiral molecules and with polarized light.
Diastereomers however are chemically and physically different. They have different
melting points and different solubilities and often undergo chemical reactions in a
different fashion. Sec. 6 - Stereochemistry - 2 Forsey 24
 Diastereomers and alkenes

same connectivity same orientations same connectivity different orientations

Cl Cl I
F
C C C C
Br F Structural isomers
Br I
different
connectivity Diastereomers

Cl Br Cl I

C C C C

F I F Br

Diastereomers have the same connectivity (stereoisomers) but have a

different spatial arrangement and are therefore different compounds.
Structural isomers have the same molecular formula but the
connectivity is different and therefore not stereoisomers

Sec. 6 - Stereochemistry - 2 Forsey 25

Cycloalkanes and stereochemistry
How many isomers are there for the following cycloalkanes?

C3H5X – only one

C3H4X2 – 4 isomers – what are they?

1,1 cis-1,2 trans-1,2

enantiomers

C4H7X – only one

Sec. 6 - Stereochemistry - 2 Forsey 26

C4H6X2 – 6 isomers – what are they?

1,1 cis-1,2 trans-1,2 flip

plane of symmetry
enantiomers
plane of symmetry same
no plane of symmetry

Notice how the meso compounds have a plane of symmetry

Sec. 6 - Stereochemistry - 2 Forsey 27

 Cyclohexane

1,4-dimethylcyclohexane

What is the isomeric

relationship between
the cis and trans
structures ?

Diastereomers

Neither the cis not trans isomers is optically active

Sec. 6 - Stereochemistry - 2 Forsey 28

1,3-dimethylcyclohexane
Two stereogenic carbons therefore the possibility of 4 stereoisomers, but there
is only three because one structure is a meso compound.

enantiomers

H3C CH3 H3C CH3

Sec. 6 - Stereochemistry - 2 Forsey 29

1,2-dimethylcyclohexane
Two stereogenic carbons therefore the possibility of 4 stereoisomers, but there
is only three because one structure is a conformation stereoisomer.

trans-1,2-dimethylcyclohexane

enantiomers

cis-1,2-dimethylcyclohexane
The cis mirror images are not identical eq eq
and are enantiomers but one molecule ax ax
readily interconverts to the other by a
ring flip and at room temperature so both conformations have one axial
rapidly that the two forms are and equatorial methyl group and are
indistinguishable. Structures c and d of equal energy
are conformational stereoisomers.
Sec. 6 - Stereochemistry - 2 Forsey 30
Not all stereogenic centers are carbon atoms

Reactions and stereogenic centers. Very important later.

chiral carbon
retention of configuration note: optical activity may
change direction

If a reaction takes place in a way so that no bonds to the stereogenic carbon

are broken, the is said to proceed with retention of configuration

Sec. 6 - Stereochemistry - 2 Forsey 31

Retention of configuration will not always maintain its (R) or (S) designation.

chiral carbon
retention of configuration

Reaction at
stereogenic
center
Something to
look forward
too

Sec. 6 - Stereochemistry - 2 Forsey 32

Chiral compounds with no chiral atoms.
Allenes R1 R3

What is the hybridization of each carbon?

C C C

sp2 sp sp2
R2 R4

enantiomers

Sec. 6 - Stereochemistry - 2 Forsey 33

Helicenes
The helicenes, first synthesized in 1956 by Newmann, are a fascinating class of chrial
molecules. Helicenes are benzologs of phenanthrene in which a regular cylindrical
helix is formed through an all-ortho annelation of the aromatic rings. Their structure
is a consequence of the repulsive steric interaction between terminal aromatic rings.
Helicenes have large optical rotation for example hexahelicene has an enormous
optical rotation: [α ] D20 = 3700 o
These spirals are unusual molecules because there are "right-" and "left-" handed
forms. Helicenes are "chiral" because they have right and left isomers. The two
forms can be differentiated by imagining that the spiral is the inclined plane of a
screw. If you rotate a screw clockwise and it advances, it is right-handed. If you
rotate it counterclockwise and it advances, it is left-handed. The conversion between
right- and left-handed forms is called racemization

phenanthrene

Sec. 6 - Stereochemistry - 2 Forsey hexahelicene 34

 Review and Additional Examples

Structural isomers: Different compounds with the same molecular formula

or Constitutional isomers but with different order of attachment.
Stereoisomers: Different compounds which have the same structure,
differing only in the arrangement of the atoms in space.
Geometric isomers: Stereoisomers that differ by groups being on the same
side or on opposite sides of a site of rigidity in a molecule.
Chiral: Any object that cannot be superposed on its mirror image.
Achiral: Any object that can be superposed on its mirror image.
Enantiomers: A pair of stereoisomers that are nonsuperposable mirror
images.
Diastereomers: Any pair of stereoisomers that are not enantiomers.
Meso form: A stereoisomer that contains chiral carbons but can be
superposed on its mirror image

Sec. 6 - Stereochemistry - 2 Forsey 35

 Methodology for the Determination of Chirality

How many chiral centers

Zero One Two or more

Is there a mirror plane? Is there a mirror plane?

Chiral

Yes No No Yes

No Are they non- Are they non- No Achiral

Achiral identical mirror identical mirror (meso)
images? images?

Yes Yes
Chiral Chiral

Sec. 6 - Stereochemistry - 2 Forsey 36

 Methodology for the Classification of Stereoisomers
Two structures with same
molecular formulas

Yes same connectivity No

Yes are they superimposable? No Constitutional isomers

Stereoisomers
structures are the
same compounds

are they mirror

Yes images of each No
other?

Enantiomers Diastereomers

Sec. 6 - Stereochemistry - 2 Forsey 37

 Identify the following as diastereomers, enantiomers,
or meso compounds.

CO2H CO2H

H2N C H H C NH2

CH2OH CH2OH

Is the connectivity the same?

H3C CH3 H3C H
C C C C
H H H CH3 Are they mirror images of
each other?

O O
C H C H Is the connectivity the same?

H OH H OH
Are they mirror images of
H OH HO H each other?
CH2OH CH2OH
Sec. 6 - Stereochemistry - 2 Forsey 38
 Identify the following as diastereomers, enantiomers, or
meso compounds.
Is the connectivity the same?
CHO CHO
H OH HO H
Are they mirror images of
H OH HO H each other?
H OH HO H Can one image be superposed on
CH2OH CH2OH the other?

Is the connectivity the same?

CH2OH CH2OH
H OH HO H
Are they mirror images of
H OH HO H each other?
H OH HO H Can one image be superposed on
CH2OH CH2OH the other?

Is the connectivity the same?

CHO CHO
HO H H OH
H OH HO H Are they mirror images of
each other?
H OH HO H
Can one image be superposed on
CH2OH CH2OH the other?

Sec. 6 - Stereochemistry - 2 Forsey 39

Identify the following as diastereomers, enantiomers,
or meso compounds.

CO2H CO2H CO2H

H OH H OH HO H
HO H H OH H OH
HO H H OH H OH
CO2H CO2H CO2H
1 2 3

Enantiomers

Diastereomers

Meso compound

Sec. 6 - Stereochemistry - 2 Forsey 40

Sec. 6 - Stereochemistry - 2 Forsey 41