Chapter 9: 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)

1
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.

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.

A carbon with four different groups results in a chiral molecule and is

refered to as a chiral or asymmetric or stereogenic center.

2
 symmetry
plane

O
H H
H C O

H
C C H Achiral
H O

Not a
symmetry
plane

O
H
H OH CH3 Chiral
H C O
C C H
H H O

Chiral center (stereogenic, asymmetric)

Optical Rotation: molecules enriched in an enantiomer will rotate

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

Plane polarized light: light that oscillates in only one plane

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 0!° 0!°
H +a -a 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)

a: 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
(a) 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.

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

a= optical rotation in degrees

a l = path length in dm
[a]lT = c = concentration of sample in g/mL
l•c
T = temperature in °C
l= 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 [a]D may also depend upon solvent, therefore the solvent is
usually specified.

for alanine:
20
[a]D = +14.5° (c 10, 6N HCl)

4
Discovery of chirality in chemistry
L. Pasteur (1949)

Crystallization of sodium ammonium tartrate. Crystals were mirror

Images of each other and separated by tweezers under a microscope.
Each crystal was a enantiomerically pure.

Resolution: The process of separating racemates into pure enantiomers.

Crystallization is be a resolution process.

Assigning the Absolute Configuration

1. Use the Cahn-Ingold-Prelog priority rules (Chapter 6) to assign

priority (one through four) to the four groups on the “chiral” atom.

2. 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

clockwise = R counter clockwise = S

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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)

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 of the plane of the paper
HO2C
CH3 toward you

LINEAR ALKANES: You should draw the 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

6
Do the Double-Switch Trick!!
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
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 C Counterclockwise = S
O O C H3C Br
CH3 6-1 3 3 1

switch
H atomic # 1 priority 4
1 1
4 OCH3 1 4
OCH3 8-6-1
H H3CO H
HO C 2 OH 2 Counterclockwise = S
C OH 6-8-6 HO C OH
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 4 Clockwise = R
CH2CH3 6-6 2 1 HO H
H
CH2CH3 CH3
3
CH3 6-1 3

Note: assignment of R or S has NO relationship

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

7
Diastereomers: non-mirror image stereoisomers. Occurs when more
than one chiral centers are present in a molecule.

For a molecule with n chiral centers, there are 2n number of

stereoisomers possible, not including geometric stereoisomers of
double bonds.
OH O
Threonine- two chiral centers
*
* NH OH 22 = 4 possible stereoisomer
2

CO2H CO2H CO2H CO2H

R S S R
H C NH2 H2N C H H2N C H H C NH2
R S R S
H C OH HO C H H C OH HO C H
CH3 CH3 CH3 CH3

mirror images mirror images

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

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

8
Meso Compounds: molecules that contain chiral atoms but are
achiral because they also possess a plane of symmetry.
Tartaric acid:
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

superimposable

meso tartaric acid: The groups on the

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

H3C CH3 H3C CH3

no plane
meso (achiral)
of symmetry

Molecules with more than two chiral centers:

molecules with n chiral centers:
maximum of 2n stereoisomers
(excluding geometric isomers of double bonds)
maximum of 2(n-1) pairs of enantiomers

*
CH3
H Cholesterol: eight chiral centers
CH H * *
3
* * 28 = 256 possible stereoisomers
* * H *H
(only one of which is naturally occuring)
HO
H

9
Resolution of Racemates:
50:50 mixture of enantiomers is a racemic mixture or racemate,
denoted by (±) or (d,l)

Resolution: a process of separating a racemate into pure enantiomers.

The enantiomers of the racemate must be converted into
diastereomers.

Resolution of racemic acids by crystallization of their salts, using a

chiral counter ion

Diastereomeric salts
can be separated by
chiral crystallization
amine
base

Physical properties of Stereoisomers

Enantiomers have identical physical properties (such as mp, bp,

solubility, density, etc.) except for optical rotation

Diastereomers may have completely different physical properties

Racemates act as if they were a single pure compound. Some

physical properties of racemates may differ from those
of the pure enantiomer

Table 9.3: Some physical properties of stereoisomers of tartaric acid

Stereoisomer mp (°C) [a]D density (g/cm3) solibility (g/100mL H2O)

+ 168-170 +12 1.7598 139.0
- 168-170 -12 1.7598 139.0
meso 146-148 0 1.6660 125.0
± 206 0 1.7880 20.6

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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

Fischer Projections: representation of a three-dimensional molecule

as a flat structure

Tetrahedral carbon 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

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 Manipulation of Fischer Projections
1. Fischer projections can be rotate 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
steady CO2H CO2H
H OH HO CH3
CH3 H

(R) (R)

CO2H H
HO H HO2C OH

CH3 CH3
hold (S)
steady (S)

12
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

1-2-3 clockwise = R

Fischer projections with more than one chiral center:

1 CHO CHO
2
HO H HO H
3
H OH H OH

4 CH2OH CH2OH
Threose

2
CHO H4
1 2 1
2 4 S 2
HO H OHC OH
3 3
4 H OH 4 H OH 1
Hold Steady 1
3 CH2OH CH2OH
3

(2S, 3R)
H4
H4
Hold Steady 2 1
2
2
1
OHC
2 S OH
OHC OH
3 3
4 H OH 1 1 HO CH2OH
R 3
CH2OH H
3 4

13
Stereochemistry of Reactions: reactions may generate chiral centers
addition of HBr to alkenes

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

Any reaction between achiral reactants always leads to optically

inactive products, either a racemate of meso.
Must consider the reactants and mechanism of the reaction
Br
H H Br
Br2
CH3
H3C
CH3 + H3C
H3C CH3 Br
Addition of Br2 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)

1) OsO4 OH
OH
H H 2) NaHSO3 CH3
H3C
CH3 + H3C
Reaction of H3C CH3
OH OH

OsO4 with Meso (identical)

2-butene H CH3
1) OsO4
2) NaHSO3
OH
OH
CH3
(syn addition) H3C
CH3 + H3C
H3C H OH
OH
(2R, 3R) (2S, 3S)

14
Addition of HBr to a chiral alkene: reactions of a chiral reactant with
an achiral reagent gives diastereomeric products which may or
may not be formed in equal amounts. The intermediate
carbocation is asymmetric, therefore attack of Br- from the top
or bottom faces may not be equally probable. The two
transition states are diastereomeric and therefore may have
different activation energies

Chiral center of the reactant

is not involved during the
reaction and does not change

HO R CO H HO2C S OH
2

H NH2 H2N H
HO OH
O O O O
D-DOPA L-DOPA NH HN
no biological effect used for the treatment of
ParkinsonDisease N S O O R N
H H
O O
R CO2H HO2C S (S)-Thalidomide (R)-Thalidomide
teratogen sedative
H NH2 H2N H

D-phenylalanine L-phenyalanine O O
(controlled substance) naturally occuring amino acid H3C CH3

CH3 H3C
S CH3 H3C R

H N CH3 H3C N H (S)-(+)-carvone (R)-(-)-carvone

caraway seeds (rye) spearmint oil
H H
(S)-methampetamine (R)-methamphetamine
no biological effect F3C

HO H H OH O (±) - prozac
S CH3 S CH3
S R CH3 (S)-Fluoxetine
N
H N CH3 H N CH3 H
H H
Pseudoephedrine Ephedrine

15
Stereochemistry at atoms other than carbon: N, Si, P, S, and many
other atoms have the potential to be chiral (stereogenic) centers

H
H3C CH2CH3
N
••
Barrier to inversion is very low

Inversion is a racemization process

••
H N
CH2CH3
H3C

You will learn more about stereochemistry and the stereochemistry of reactions
next semester and in Chem 220c and 223

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