Symmetry

Monarch butterfly:
bilateral symmetry=
mirror symmetry

Whenever winds blow

butterflies find a new place
on the willow tree
-Basho (~1644 - 1694)

153

Chapter 7: Stereochemistry - three-dimensional arrangement

of atoms (groups) in space
Stereoisomers: molecules with the same connectivity but
different arrangement of atoms (groups) in space
H3C CH3 H3C H

H H H CH3

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

H H H CH3

H3C CH3 H3C H

cis-2-butene trans-2-butene

geometric isomers (diastereomers)

154

1
7.1: Molecular Chirality: Enantiomers
Enantiomers: non-superimposable mirror image isomers.
Enantiomers are related to each other much like a right hand
is related to a left hand
Enantiomers have identical physical properties, i.e., bp, mp, etc.
Chirality (from the Greek word for hand). Enantiomers are said
to be chiral.

155

Molecules are not chiral if they contain a plane of symmetry: a

plane that cuts a molecule in half so that one half is the mirror
image of the other half. Molecules (or objects) that possess a
mirror plane of symmetry are superimposable on their mirror
image and are termed achiral.
7.2: The Chirality Center - A molecule containing a carbon with
four different groups results in a chiral molecule, and the carbon
is referred to as a chiral, or asymmetric, or stereogenic center.

156

2
Enantiomers: non-superimposable mirror image isomers

7.3: Symmetry in Achiral Structures - Any molecule with a

plane of symmetry or a center of symmetry must be achiral.
achiral chiral
Not a
symmetry symmetry
plane plane
O O
H OH H
H H CH3
H C O
H C O C C H
C C H H H O
H H O

Chiral center
(stereogenic, asymmetric) 157

7.4: Optical Activity - molecules enriched in an enantiomer will

rotate plane polarized light are said to be optically active. The
optical rotation is dependent upon the substance, the
concentration, the path length through the sample, and the
wavelength of light.
Polarimeter

589 nm -
D-line of
a sodium
lamp

Plane polarized light: light that oscillates in only one plane

158

3
 0 ° 0 °
H +α -α H
HO C HO2C C
CH3 CH3
HO2C HO

dextrorotatory (d): rotates light levororotatory (l): rotates light

to the right (clockwise) to the left (counterclockwise)

α : angle (# of degrees) plane polarized light is rotated by an

optically active sample. Expressed in degrees.
Enantiomers will rotate plane polarized light the same magnitude
(α) but in opposite directions (+ or -)
90% (+) + 10% (-) will rotate light 80% of pure (+)
75% (+) + 25% (-) will rotate light 50% of pure (+)
50% (+) + 50% (-) will be optically inactive
50:50 mixture of enantiomers (+/-): racemate or racemic mixture
Each individual molecule is chiral, however the bulk property
of the substance is achiral, if it is in an achiral environment.
159

Specific Rotation [α]D : a standardized value for the optical rotation

α  = optical rotation in degrees

100 α l = path length in dm
[α]λT = c = concentration of sample in g/100 mL
l•c
T = temperature in °C
λ  = wavelength of light, usually D for the
D-line of a sodium lamp (589 nm)

The specific rotation is a physical constant of a chiral molecule

The [α]D may also depend upon solvent, therefore the solvent is
usually specified.
H NH2

for alanine: HO2C

20
[α]D = +14.5° (c 10, 6N HCl)
160

4
 CH3 CH3
H O
H O H
CH3 CH3 O CH3

[α]D= +33.0 [α]D= -7.0

There is NO correlation between the sign of the optical rotation

and the three-dimensional arrangement of atoms 161

7.6: The Cahn-Ingold-Prelog R-S Notational System

Assigning the Absolute Configuration
1.  Use the Cahn-Ingold-Prelog priority rules (Chapter 5) to
assign priority (one through four) to the four groups on the
“chiral” atom.
3.  Orient the molecule so that the lowest priority atom is in the
back (away from you). Look at the remaining three groups
of priority 1-3. If the remaining three groups are arranged so
that the priorities 1→2→3 are in a clockwise fashion, then
assign the chiral center as R (“rectus” or right). If the
remaining three groups are arranged 1→2→3 in a
counterclockwise manner, then assign the chiral center as
S (“sinister” or left)
1 1 1 1
OH OH OH
2 3 orient lowest priority OH
orient lowest priority H
CO2H 4 H CH3 H
4 H group away group away
CH3 H3C CO2H 2 CO2H HO2C CH3 3
3 2
3 2

162
clockwise = R counter clockwise = S

5
 3.  Or use the “Hand Rule.” Orient the lowest priority group up.
Point your thumb in the direction of the lowest priority
group. If you need to use your right hand so that your
fingers point in the direction of the group priorities in the
order 1→2→3, then the stereogenic center is assigned R
(“rectus” or right). If your left hand is required so that your
fingers point in the direction of the group priorities 1→2→3,
the the stereogenic center is assigned S (“sinister” or left).

4 4
H H
1 1
2 HO 2
OH
HO2C CO2H
CH3 H3C
3 3
(R)-(-)-Lactic acid (S)-(+)-Lactic acid
(Right Hand) (Left Hand)

163

You must be able to draw tetrahedral carbons properly!!

In the plane of the paper Dash: projecting behind
and in the same plane the plane of the paper Dash and Wedge are on
as the tetrahedral carbon away from you adjacent position off the
(adjacent position off the tetrahedral carbon
tetrahedral carbon) H
Wedge: projecting out
C OH
HO2C of the plane of the paper
CH3
toward you

LINEAR ALKANES: You should draw the carbon backbone in the plane of
the paper, and draw substituents either coming towards you (with wedges)
or going away from you (with dashes). Note that each carbon should look
like a tetrahedron.
Correct ••
Incorrect ••

H H H
Br
C OH HO C C OH Br
HO2C CO2H HO2C
CH3 H3C CH3

Cl Br Cl
OH OH
Cl O OH
Cl Br H
164

6
Do the Double-Switch Dance!!
In order to assign the stereochemistry you
must be able to manipulate the structure
on paper so that the lowest priority group
is in the proper orientation (back for the
steering wheel rule or up for the hand rule)
Interchanging any two groups inverts the stereochemistry. So
switch the lowest priority group to the desired position. Then
switch the other two groups. The “double-switch” does not
change the stereochemistry.
3 CH3
CO2H CO2H switch the clockwise = R
switch the H and OH CH3 and CO2H H C
HO C H C OH 1
H OH HO2C
H3C H3C 2
inverts the
inverts the
stereochemistry
stereochemistry

switch the
CH3 H H
switch the H and CH3 OH and CO2H 2 left hand = S
C OH C OH C CO2H
HO2C HO2C HO
H CH3 1 CH3
inverts the 3
stereochemistry inverts the 165
stereochemistry

switch Br atomic # 35 priority 1

1 3
Br CH3 H 1 4
O
C 2 OH 2 2 H4
H C OH 6-8
HO
switch 4
O O C H3C
C
Br
Counterclockwise = S
CH3 6-1 3 3 1

switch
H atomic # 1 priority 4
1 1
4 4
OCH3 OCH3 8-6-1 1
H H3CO H
HO C 2 OH C OH 6-8-6 2 HO C OH Counterclockwise = S
3 O C 2 3
O O
CH2OH 6-8-1 3
switch

switch H atomic # 1 priority 4

switch
OH 8 1 2
CH3 CH2CH3
C OH 2 1 HO H
4 Clockwise = R
H CH2CH3 6-6
CH2CH3 CH3
3
CH3 6-1 3

Note: assignment of R or S has NO relationship

with the optical rotation (+) or (-). 166

7
7.7: Fischer Projections - representation of a three-dimensional
molecule as a flat structure. A tetrahedral carbon is represented
by two crossed lines:
horizontal line is coming vertical line is going back
out of the plane of the behind the plane of the
page (toward you) paper (away from you)

substituent carbon

CO2H CO2H CO2H

H OH H OH
OH
(R)-lactic acid H3C
H CH3 CH3

CO2H CO2H CO2H

(S)-lactic acid H3C
H HO H HO H
OH CH3 CH3

167

Manipulation of Fischer Projections

1.  Fischer projections can be rotated by 180° only!
CO2H CH3 CO2H CH3
180 ° H OH HO H 180 ° HO H H OH
CH3 CO2H CH3 CO2H

(R) (R) (S) (S)

a 90° rotation inverts the stereochemistry and is illegal!

90 ° CO2H OH
H OH ≠ HO2C CH3
CH3 H

(R) (S)

2.  If one group of a Fischer projection is held steady, the other

three groups can be rotated clockwise or counterclockwise.
hold CO2H CO2H CO2H H
steady HO H HO2C OH
H OH HO CH3
hold CH3 CH3
CH3 H
steady
(R) (R) (S) (S)
168

8
Assigning R and S Configuration to Fischer Projections
1.  Assign priorities to the four substitutents according to the
Cahn-Ingold-Prelog rules
2.  Perform the two allowed manipulations of the Fischer
projection to place the lowest priority group at the top
(or bottom).
3.  If the priority of the groups 1→2→3 are clockwise then assign
the center as R, if 1→2→3 are counterclockwise then assign
the center as S.
2
place at
CO2H the top 4
H
1 H2N H 4 2 HO2C NH2 1
hold steady CH3
CH3
rotate other 3 3
three groups
counterclockwise
1-2-3 counterclockwise = S

2
4 2
CO2H
H CO2H
4 H 1 2
NH2 1 H2N
H2N CO2H CH3
CH3 1 3
CH3 H
3 4
3
169
1-2-3 clockwise = R

7.8: Properties of Enantiomers

In general, enantiomers have the same physical properties
(bp, mp, density, etc). Enantiomers will rotate plane polarized
light the same magnitude (α) but in opposite directions (+ or -).
O O R CO H
HO 2 HO2C S OH
H3C CH3
H NH2 H2N H
CH3 H3C HO OH
D-DOPA L-DOPA
(R)-(-)-carvone no biological effect used for the treatment of
(S)-(+)-carvone
spearmint oil ParkinsonDisease
caraway seeds (rye)
O O O O
NH HN
S CH3 H3C R
N S O O R N H N CH3 H3C N H
H H H H
O O
(S)-Thalidomide (S)-methampetamine (R)-methamphetamine
(R)-Thalidomide
teratogen no biological effect
sedative

Enantiomers can have significantly different biological properties

170

9
7.10: Chiral Molecules with Two Chirality Centers
CO2H CO2H CO2H CO2H
OH O
H2N H H NH2 H NH2 H2N H

*
* NH OH H OH HO H H OH HO H

2 CH3 CH3 CH3 CH3

Threonine (2S, 3R) (2R, 3S) (2R, 3R) (2S, 3S)

mirror images mirror images

(enantiomers) (enantiomers)
Natural threonine
possesses the 2S, 3R
stereochemistry
non-mirror image
(diastereomers)

171

Enantiomers must have the opposite configuration at all

chiral centers.
In general, enantiomers have identical physical properties
except optical rotation (which is equal in magnitude but opposite
in sign). Diastereomers may have completely different physical
properties.
For a molecule with n chiral centers, there are 2n number of
stereoisomers possible, not including geometric stereoisomers
of double bonds.

Erythro: substituents on same side of a Fischer projection

i.e., (2R, 3R)- and (2S, 3S)-threonine
Threo: substituents on opposite sides of a Fischer projection
i.e., (2S, 3R)- and (2R, 3S)-threonine

172

10
 Br H H Br Br Cl Cl Br

H Cl Cl H H H H H

(1S,2S)-1-bromo-2- (1R,2R)-1-bromo-2- (1S,2R)-1-bromo-2- (1R,2S)-1-bromo-2-

chlorocyclopropane chlorocyclopropane chlorocyclopropane chlorocyclopropane

mirror images mirror images

(enantiomers) (enantiomers)

non-mirror image
(diastereomers)

7.11: Achiral Molecules with Two Chirality Centers

Br Br Br Br Br H H Br

H H H H H Br Br H

meso (achiral) chiral

Meso: molecules that contain chiral atoms but are achiral
because they also possess a plane of symmetry. 173

CO2H CO2H CO2H CO2H

R S R S
H C OH HO C H H C OH HO C H rotate 180°
R S S R
HO C H H C OH H C OH HO C H
CO2H CO2H CO2H CO2H

mirror images Identical

(enantiomers)

CO2H CO2H
diastereomers R R
H C OH H C OH
S S
H C OH H C OH
CO2H CO2H

meso tartaric acid: The groups on the

top carbon reflect (through the
symmetry plane) onto the groups on
the bottom carbon

174

11
 7.12: Molecules with Multiple Chirality Centers
Maximum number of stereoisomers = 2n.
where n = number of structural units capable of
stereochemical variation.
Structural units include chiral centers and cis (E)
and/or trans (Z) double bonds.
*
CH3
H Cholesterol: eight chiral centers
CH H * *
3
* * 28 = 256 possible stereoisomers
* * H *H
(only one of which is naturally occurring)
HO
H

H H
(E) (E)
H3C (R) H3C (S)

H H OH H HO H
OH
H3CHC C C CH3 H H
H (Z)
H H (R)
H (Z) (S)

H3C H OH H3C HO H 175

A Brief Review of Isomerism

Isomers: compounds with the same chemical formula, but

different arrangement of atoms
Constitutional isomer: have different connectivities (not limited
to alkanes)
C5H12 C4H10O C4H11N
NH2
O
OH
NH2
butanol diethyl ether

different carbon skeleton different functional group different position of FG

Stereoisomers: Atoms connected in the same way, but different

three-dimensional arrangement of atoms or groups (topology)
enantiomers: non-superimposable mirror image isomers
diastereomers: non-superimposable, non-mirror image
isomer (more than one chiral center.
geometric isomers (diastereomers): E / Z alkene isomers
176

12
7.9: Reactions That Create a Chirality Center - reactions of
achiral reactants may generate product with chiral centers
H
Br
C H H-Br
H3CH2C C H3CH2C C CH3
H H
1-butene 2-bromobutane
(achiral) (chiral)

However, the products of such reactions with be optically inactive

(racemic)
Br - Top Face

bottom
H face top Br
H3CH2C H face
CH3 H3CH2C C C
C CH3 H3CH2C H
Br CH3

Br - Bottom Face (S)-2-bromobutane

(R)-2-bromobutane
(50%) (50%)

There is an equal chance for Br- to add from the top face or the
bottom face resulting in a 50:50 mixture. The two products are
enantiomers. The two transitions states are enantiomeric and
have identical activation energies 177

O
H3CCO3H *
chiral but racemic

OH
Br2, H2O
Br
*
chiral but racemic

H3C OH HBr H3C Br

* *

racemic chiral but racemic

H3C OH H3C Br
HBr
(S)

chiral but racemic

178

13
 Br
H H Br
Br2
CH3
H3C
CH3 + H3C
H3C CH3
Addition of Br2 Br
Br

to 2-butene (2R, 3R) (2S, 3S)

(anti-addition) Br
Br
H CH3 Br2 CH3
H3C
CH3 + H3C
H3C H Br
Br
Meso (identical)

O O
H H H H H3C CH3
H3CCO3H
+
Epoxidation H3C CH3 H3C CH3 H H
to 2-butene Meso (identical)
(syn-addition) O
H CH3 H3CCO3H O
H CH3 H3C H
+
H3C H H3C H H CH3
(2R, 3R) (2S, 3S)
179

A reaction of a chiral reactant with an achiral reagent may give

diastereomeric products, which may or may not be formed in
equal amounts.
H3C H HBr H3C H Br H H3C H H Br
+
(R) (R) (S) (R) (R)

(R)-4-methyl-1-hexene (2S,4R)-2-bromo- (2R,4R)-2-bromo-

4-methylhexane 4-methylhexane

Br - Top Face

bottom H3C H
H face top H3C H Br
H face C
C CH3 C H
H CH3 Br CH3 CH3

Br - Bottom Face (2S,4R)-2-bromo-

(2R,4R)-2-bromo-
4-methylhexane 4-methylhexane

7.14: Resolution of Enantiomers (please read) - a process of

separating a racemate into pure enantiomers. The enantiomers of
the racemate must be temporarily converted into diastereomers.
50:50 mixture of enantiomers is a racemic mixture or racemate,
denoted by (±) or (d,l) 180

14
Resolution of a racemic amino acids by crystallization of their
salts, using a chiral counter ion H
H H NH2
H NH2 H NH2 N H3O C
C C CH3 CO2H
CH3 CO2H CH3 CO2 N
H (R)-(-)
(±) (R)-(-) (-)
+
H Diasteromeric salts
N +
(separate)

N H
H H H3N H
(-)-sparteine H2N H N H3O C
(chiral base) C CH3 CO2H
CH3 CO2 N
H
(S)-(+) (-) (S)-(+)

7.15: Stereoregular Polymers (please read)

7.16: Chirality Centers Other Than Carbon (please read)
Stereochemistry at atoms other than carbon: N, Si, P, S, and
H C
3
H
N
CH CH other atoms have the potential to be
2 3

•• chiral (assymmetric, stereogenic) centers

Barrier to inversion is very low

••
H N
H3C
CH2CH3 Inversion is a racemization process 181

15