L

TOPIC 4. STEREOCHEMISTRY
(Chapter 5)

OBJECTIVES
1. Discuss the three-dimensional structure of organic molecules
2. Recognize enantiomers, diastereomers, meso compounds
3. Provide R/S designations of stereocenters
4. Calculate optical rotations, enantiomeric excesses
5. Use molecular models to determine the 3D arrangement of atoms in
chiral molecules

D.M. Collard 2007

 S:5.1-2

RECOGNIZING ISOMERS

Isomers
Compounds with same molecular formula,
but different structures

Constitutional Isomers Stereoisomers

Different connectivity Same connectivity, different
three dimensional arrangement

Diastereomers Enantiomers
Stereoisomers which are Non-superposable
not enantiomers, mirror images
includes geometic isomers

S:5.3
5.5-5.7
CHIRALITY: ENANTIOMERS Prob
5.30,31,33
35a,b,f
An object (molecule) which has a non-superposable* mirror image is
chiral (the opposite of chiral is “achiral”).

* Important small print:

In spite of Solomon and Fryhle’s foonote regarding the dictionary definition of superposable and
superimposable (and their preference for the former), most chemists refer to non-superimposability
of mirror images as a requirement for chirality. This instructor will undoubtedly use
“superimposability” in lecture and on exams.

D.M. Collard 2007

 Symmetry: Mirror Planes and Centers of Inversion
Another test for chirality is to assess whether the object itself has a mirror plane
of symmetry or point of symmetry (point of inversion). Objects (molecules) with
mirror planes or centers of inversion are achiral (NOT chiral)

CH3
COOH
C Cl H3C
H3C
Cl
H3C

Objects (molecules) without a mirror plane or point of inversion are chiral. They
are non-superposable on their mirror images.

Enantiomers
Molecules can be chiral. Pairs of molecules which are non-superposable
mirror images of one another are called enantiomers. Enantiomers are
examples of stereoisomers: molecules which differ only in the spatial
arrangement of atoms.

Molecules with a single carbon atom bearing four different substituents can
exist as a pair of enantiomers which differ in the arrangement
(“configuration”) of these substituents.
A A
The carbon is stereogenic
The carbon is a stereocenter
D D
B B
C C

A 1:1 mixture of enantiomers is called a

racemic mixture

You must be able to recognize when pairs of

molecules are identical (superposable) or
entaniomers (non-superposable mirror images)

D.M. Collard 2007

 Problem: Which of the following are identical to the first structure?

Problem: Which of the following are identical to the first structure?

H CH3 COOH

OH COOH H
H3 C COOH HO H H3C OH

Problem: Which of the following are identical to the first structure?

COOH H COOH

OH OH CH3
H3 C H HOOC CH3 H OH

D.M. Collard 2007

 Designating Configuration
Stereocenters are designated as having either R- or S-configurations….
- Assign priorities to the substituents using the Cahn-Ingold-Prelog
system (briefly, atoms are ranked in order of atomic number (if
isotopes are present, the heavier isotope has higher priority); if two
atoms are identical, the next set of attached atoms is considered).
- View the molecule with the lowest priority (4) substituent pointing away
from you.
- Trace from highest priority (1) to second priority (2), to third (3)….

Clockwise = R
Counterclockwise = S
e.g., F D
D = deuterium = 2H;
Br H CH3 D>H
HO
Cl H

Ranking Substituents
If the atoms joined to the chiral center are identical, you must consider the
set of three atoms connected to them:
C(CH3)3 CH(CH3)2 CH2CH3 CH3
> > >
C(C,C,C) C(C,C,H) C(C,H,H) C(H,H,H)

CH2OH C(CH3)3
>
C(O,H,H) C(C,C,C)

A double bond is considered to be two bonds to the next atom:

H H
C O > CH2OH > C CH2

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

D.M. Collard 2007

 Examples of Chiral Molecules

CH3

CH3 CH2CO2H

H H
H2N CO2H CO2H
HO H CH2

H3C

S-alanine S-malic acid R-carvone

(an α-amino acid) (from apples) (spearmint)

Problem: What is the configuration of each stereocenter (chiral carbon

atom) in each of the following compounds?

CH3 N
O
H

NH2
H CH2 H
H3C H O O
H 3C O O O
H

D.M. Collard 2007

 L S:5.13
FISCHER PROJECTIONS Prob:
5.35k-l
(molecules with one stereocenter)

Orient the molecule so that substituents oriented up and down are

pointing away from you and then apply a steamroller.

C http://www.r-r-a.org.uk/aandp.html

D B
A

Converting a Fischer projection back into a 3D tetrahedral representation.

CH3
HO H
CH2CH3

Problem: Which of the following represent the S-enantiomer of 2-phenyl-1-

ethanol, which ones are R?

Me Ph OH
Ph OH H Me H Me
H OH Ph
OH H Ph

Ph Me HO Me
H

D.M. Collard 2007

 Problem: Which of the following are identical to the first structure? [You should
be able to work out how Fischer projections can be redrawn without inverting
the configuration]
COOH H CH3 OH

H OH H3C COOH HO H HOOC CH3

CH3 OH COOH H
r otate by 90o rotate by 180o r otate by
270o

COOH COOH COOH

HO H H OH H3C H
CH3 CH3 OH
swap hor izontal swap vertical rotate set of
substit uent s substituents subst ituents

S:5.1; 5.4;
WHY IS STEREOCHEMISTRY 5.11

IMPORTANT?
Chirality in Nature
Most biomolecules are chiral and only exist as one enantiomer in nature. NH2

H OH N
O
H O
HO O N
H2N HO
OH HO O
H
H OH H H
H CH(CH3)2
H HO H H
OH H
Amino acids Carbohydrates Nucleotides
(in proteins) (sugars) (in DNA)
e.g., valine e.g., glucose e.g., cytosine

Problem: What is the configuration of each stereocenter (chiral carbon

atom) in each of the above compounds?

D.M. Collard 2007

 Interaction between the Body (Receptors) and Chiral
Drugs

R R

Chiral Pharmaceuticals: Thalidomide

The racemate of thalidomide was marketed in Europe in early 1960s for
treatment of morning sickness. One enantiomer is a sedative. However, the
other causes birth defects.
Today, both enantiomers of any pharmaceutical must be tested for efficacy
and side effects. Recent studies have shown that thalidomide may be effective
against HIV, cancer, leprosy and other inflammatory disorders.

O
H
O
NH
O O

Problem: Which enantiomer of thalidomide is shown above?

D.M. Collard 2007

 S:5.8-5.9

ROTATION OF PLANE-POLARIZED LIGHT Prob:5.42;

43

Enantiomers have identical physical and chemical properties in the

absence of other chiral molecules, except for their influence on plane-
polarized light.

Polarimetry

Optical Rotation
The observed rotation is: α
The observed specific rotatation is: [α] = α / c·l
where c = concentration of solution (in g/mL) and l = pathlength in dm
(1 dm = 10 cm = 10-1 m)

α and [α] depend on solvent, temperature and wavelength of the

polarized light. Generally the sodium D line is used for the light source
and the experiment is done at room temperature, 25 °C.

The specific rotation is then noted as

25
[α] D (conc./solvent)
The specific rotation of an optical pure chiral compound is a “property”
(like melting point or boiling point)

The specific rotation, [α],of a given sample depends on its “optical

purity”. Only the excess of one enantiomer over the other gives rise to a
rotation.

D.M. Collard 2007

 Optical Purity
The rotation of enantiomers are equal but opposite. If the [α] of the R-
enantiomer of compound A is +100°, the [α] of the S-enantiomer is _____

The [α] of a equal mixture of the R- and S-enantiomers (racemic mixture)

is _____

The % excess amount of one enanatiomer over the other is called the
enantiomeric excess (ee). e.g.,
100% R, 0% S: ee = ____
50% R, 50% S: ee = ____
70% R, 30% S: ee = ____

Problem: The [α] of the R-enantiomer of compound A is +100°. The [α] of a

certain mixture of R- and S-enantiomers of compound A is -50°. What is
the ee of this mixture? What is the % R-enantiomer in this mixture?

D.M. Collard 2007

 Other Terminology
Review: The terminology “R-enantiomer of compound A” refers to its
absolute configuration using the Cahn-Ingold-Prelog system

If the [α] of (R)-A, is (+) we can also refer to it as (+)-A or (d )-A, where d
stands for dextrorotatory (clockwise).

In this case, the [α] of (S)-A, would be (-) and we can also refer to it as
(-)-A or (l )-A, where l stands for levotrorotatory (counterclockwise).

Thus, (+) = (d), and (-) = (l)

An equal mixture of the R- and S-enantiomers of compound A, is called

a racemic mixture and is noted as (R/S)-A, or (±)-A or (d,l )-A.

Problem: Both enantiomers of chiral pharmaceuticals must be tested

independently. Many chiral drugs must be prescribed as a single
enantiomer. Naproxen is an anti-inflammatory, prepared as a single
enantiomer (shown). A regulatory agency mandates that this drug be
sold at greater than 97% e.e. The specific rotation of the R-enantiomer
(in CHCl3) is +65.5°. A production engineer samples the latest 50 kg
batch of Naproxen produced at the plant. She dissolves 2.6 g of product
in 10 mL of chloroform and measures an optical rotation of +15.2° in a 10
cm (1 dm) polarimeter. CH(CH3)CO2H
(i) Draw the R-enantiomer of Naproxen. *
(ii) Can this sample be marketed? MeO
(iii) What mass of the 50 kg batch is
actually the (+)(R)-enantiomer?

D.M. Collard 2007

 S:5.10;
5.15
SYNTHESIS OF CHIRAL MOLECULES
Most syntheses are not enantiospecific: if a reaction forms a stereocenter,
it will proceed to give a racemic mixture of two enantiomers.
achiral achiral product racemic
starting materials → or ← starting materials
racemic mixture

Chiral catalysts (such as enzymes) can be used to induce chirality

Chiral starting materials can be transformed to:

Molecules with the same stereochemistry
(e.g., R → R, “retention of stereochemistry”)
Molecules with the opposite stereochemistry
(i.e., R → S, “inversion”)
Racemic mixture
(i.e., R → [R/S or (d,l ) or (±)], “racemization”)

S:5.12-13
STEREOISOMERS WITH MORE THAN Prob:
ONE STEREOCENTER 5.33,34,
35c-e,41

For Fischer projections of compounds with more than one stereocenter,

remember that each represents and consider each

stereocenter one at a time.

` ``

D.M. Collard 2007

 Problem: Complete the Fischer projection on the right to represent the molecule
on the left. Consider the configuration of the two carbon atoms independent of
one another. Provide a complete name for this compound (including
stereochemistry!) Is this compound chiral?

H3C H CH3
Br
C C
Br H CH3
CH3

Diastereomers
Problem: Draw all the stereoisomers of CH3CH(OH)CH(OH)COOH:

H3C H COOH COOH

OH
C C
HO H COOH

CH 3 CH 3

COOH COOH

CH3 CH3

If the sets of substituents on stereogenic centers are different there will be 2n

stereoisomers.
Stereoisomers which are not mirror images of each other are called
diastereomers.
Diastereomers have different properties from each other (e.g., solubility, mp,
bp, polarity). They can be separated by recrystallization, distillation or
chromatography.

D.M. Collard 2007

 Problem: Complete the Fisher projection of the following compound

Ph H CH3
OH
C C
Br H CH3
Ph
Problem: Draw the enantiomer of the compound shown above

CH3

Ph

Problem: Draw two diastereomers of the molecule shown above.

CH3 CH3

Ph Ph

Problem: What is the relationship between the first structure and each of the
others (identical, enantiomers, diastereomers)?

COOH CH3 COOH

R
H OH HO H HO H
R
H OH HO H H OH
CH3 COOH CH3
r otate by 180o swap one set
of horizontal
substituents

COOH COOH
HO H H OH
HO H HO CH3
CH3 H
swap both set s
r otate one set of
of hor izont al substituents
substituents

D.M. Collard 2007

 L

Meso Compounds
If the sets of substituents on stereogenic centers are identical there will be
fewer than 2n stereoisomers.

H3C H CH 3 CH3
Br
C C H Br

Br H CH 3 Br H
CH 3 CH3

CH3 CH3

CH3 CH3

Compounds with stereogenic centers which are not chiral are called meso
compounds.
Meso compounds possess a point or plane of symmetry (in at least one
conformation)

S:5.16
SEPARATION OF ENANTIOMERS
Enantiomers have identical physical properties. Racemic mixtures of
carboxylic acids can be treated with a pure enantiomer of an amine to
form a pair of diastereomeric ammonium carboxylates which has different
properties
general reaction:
O
H O
H + R' N H
R O R' N H
H R O
H

e.g., Me
O O
Ph H
Ph H H Ph NH2 (R)-B (R)-B
O O (S)-A +
+ (R)-A
Me H H Me (R)-B
salt salt
(S)-A (R)-A

D.M. Collard 2007

 The pair of diastereomeric ammonium carboxylates can usually be
separated by recrystallization (with hard work and luck) and the two acids
(and the amine) recovered.
e.g., (R)-B (R)-B
(S)-A +
(R)-A
salt salt

separate by
crystallization
O
O
Ph H HCl (R)-B (R)-B
O HCl H Ph
(S)-A (R)-A O
Me H
salt salt H Me
(S)-A
Me (R)-A

H is recovered for reuse

Ph
NH2
(R)-B

acid-base chemistry to convert diastereomeric

ammonuim carboxylate to carboxylic acid:
RCOO- R'NH3+ + HCl RCOOH + R'NH3+Cl-

S:5.14
CYCLIC COMPOUNDS Prob:
5.35h,j,o,p;
37-40
e.g., trans- and cis-1,2-dimethylcyclobutane

CH3
CH3
H3C

CH3

e.g., trans-1,2-dimethylcyclohexane

CH3

CH3

D.M. Collard 2007

 Problem: Is cis-1,2-dimethylcyclohexane chiral?

CH3 CH3

CH3 H3C

CH3
CH3

CH3 H3C

S:5.17-5.18
OTHER CHIRAL COMPOUNDS Prob:
5.35q,36
Non-Carbon Stereocenters
R1 O
X R2 S
R4 Me Et
R3
X = Si, N+, P+, etc

Chiral molecules without stereocenters: Allenes (C=C=C)

H H
CH3 CH3
C C C C C C C C C
H H3C H
H3C

Problem: Which of the following are chiral?

H H H
H CH3 CH3
C C C C C C C C C
H CH3 H CH3 H3C CH3

D.M. Collard 2007

 TOPIC 4 ON EXAM 2

Types of Questions
- Recognize enantiomers, diastereomers, meso compounds
- Provide R/S designations of stereocenters
- Calculate optical rotations, enantiomeric excesses
The problems in the book are good examples of the types of
problems on the exam.

Preparing for Exam 2:

- Work as many problems as possible.
- Work in groups.
- Do the “Learning Group Problem” at the end of the chapter.
- You may bring models to the exam, but are limited to two chiral
carbon atoms.
YOU MAY USE A SMALL MODEL KIT AND A CALCULATOR
DURING EXAM 2.
You will NOT have access to these on the final.

D.M. Collard 2007