Week 4/Lecture 1:

Stereochemistry
Weekly objectives

1. Define and understand the concepts of chirality and enantiomers

2. Identify centers of chirality in organic molecules
3. Understand the importance of chirality in biology and medicine
4. Apply the Cahn-Ingold-Prelog rules to assign stereocentres
5. Identify meso compounds and classify types of stereoisomers
6. Understand the use of polarimetry to differentiate enantiomers
The concept of chirality

• 3D structure of molecules

• Two molecules with

• Same molecular formula
• Same connectivity of atoms
• Different spatial arrangement of the atoms

• A molecule or object that is not superimposable

on this mirror image
 Individual
ACTIVITY 1: Alkene addition and stereochemistry
Draw the product of the addition HCl to the alkene 1.
Use wedged and hashed bonds to represent this product in 3D.

5 mins

CH3
H 3C H-Cl
1
 Individual
ACTIVITY 1: Discussion and feedback
• Think about the shape of the alkene.

5 mins
 Individual
ACTIVITY 1: Discussion and feedback
• Think about how the nucleophile can approach the carbocation.

5 mins
 Individual
ACTIVITY 1: Discussion and feedback
• In this product the chloride anion has approached from above the page.

5 mins

H Cl
CH3
H 3C
 Individual
ACTIVITY 1: Discussion and feedback
• In this product the chloride anion has approached from behind the page.

5 mins

Cl H
CH3
H 3C
Enantiomers
How are these two structures related to each other?

H Cl Cl H
CH3 H 3C
H 3C CH3

These mirror images are called enantiomers

Types of isomers
Are they Isomers?
Different compounds with same molecular formula.

Are they Constitutional Isomers? Are they Stereoisomers?

Different order of attachment of atoms Same order of attachment, different position of
atoms in space

Are they Enantiomers? Are they Diastereoisomers

None superimposable mirror images. All other stereoisomers

• Alkenes isomerism is
diastereoisomerism.
• Described as trans (or E) and cis (or Z)
If a molecule can exist as two enantiomers then it is chiral.
Chiral molecules contain a stereogenic centre.
• This is the carbon to which the bold and hash lines are attached.
• Whenever a carbon has 4 different substituents the molecule is chiral.
When is a molecule achiral?
If a molecule has only 3 different groups then it is achiral (means “lacking chirality”).
Consider the following example.

• These mirror images are superimposable

 Individual
ACTIVITY 2: Identify the stereogenic centres.
Mark the stereogenic centre(s) on each of the following molecules.

10 mins

O O
H 3C H 3C
OH OH
NH2 OH

Alanine Lactic acid

 Individual
ACTIVITY 3: Identify the stereogenic centres.
Mark the stereogenic centre(s) on each of the following molecules.

10 mins
HO
CH3 O Cl
CH3 H
H 3C OH O
NH2 Br H
N
CH3
Valine 2-Bromo-1-chloropropyl- HO
cyclopentane Morphine
(Bonus question)
 Individual
ACTIVITY 3: Discussion and feedback
Mark the stereogenic centre(s) on each of the following molecules.

10 mins

O O
H 3C H 3C
OH OH
NH2 OH

Alanine Lactic acid

 Individual
ACTIVITY 3: Discussion and feedback
Mark the stereogenic centre(s) on each of the following molecules.

10 mins
HO
CH3 O Cl
CH3 H
H 3C OH O
NH2 Br H
N
CH3
Valine 2-Bromo-1-chloropropyl- HO
cyclopentane Morphine
(Bonus
question)
The Importance of Chirality in Nature

Enzymes are chiral molecules which only produce or react with substances
that match their stereochemical requirements.
• Enzymes can distinguish between different enantiomers of glyceraldehyde.
Stereochemistry: Using the correct enantiomer matters!
HO OH O O O O
NH HN
N O O N
H H

N N O O
CH3 H 3C Thalidomide Mutagen
Sedative/ antinausea
Levomethorphan Dextromethorphan
Opoid analgesic Cough suppressant
(No analgesic activity)

H3C CH3 O O H3C CH3

HS OH HO SH
NH2 NH2
Penilillamine Neurotoxin
Treats copper metabolism
disorder (Wilson’s disease)
Summary

Today we have:
• Introduced the concepts of chirality and enantiomers.
• Practiced identifying chiral objects.
• Practiced identifying centers of chirality.
• Discussed the importance of chirality in drugs and biology.
Week 4/Lecture 2:
Stereochemistry
Types of isomers
Are they Isomers?
Different compounds with same molecular formula.

Are they Constitutional Isomers? Are they Stereoisomers?

Different order of attachment of atoms Same order of attachment, different position of
atoms in space

Are they Enantiomers? Are they Diastereoisomers

None superimposable mirror images. All other stereoisomers

• Alkenes isomerism is
diastereoisomerism.
• Described as trans (or E) and cis (or Z)
How do we name enantiomers? Cahn-Ingold-Prelog rules

Stereogenic centers can be assigned as either (R) or (S).

This allows for the unambiguous assignment of stereochemistry.

COOH COOH
H H
H 3C OH HO CH3

(S)-lactic acid (R)-lactic acid

How do we name enantiomers? Cahn-Ingold-Prelog rules
Three steps to assign (R) or (S)

1) Identify the stereogenic centre.

COOH
H
H 3C OH
How do we name enantiomers? Cahn-Ingold-Prelog rules
Three steps to assign (R) or (S)

1) Identify the stereogenic centre.

2) Assign priority to each group attached to the stereogenic centre.

Next two groups are carbon based.

Carboxylate has higher priority as it is Hydrogen has lowest mass.
attached to oxygen. 2 Assigned # 4.
COOH
4
3 H
H 3C OH
Methyl has lower priority as it 1 Oxygen has the highest mass.
is attached to hydrogens. Gets #1
How do we name enantiomers? Cahn-Ingold-Prelog rules
Three steps to assign (R) or (S)

1) Identify the stereogenic centre.

2) Assign priority to each group attached to the stereogenic centre.
3) Orient lowest priority group (4) to the back and draw arrow from 1-3.
Clockwise = R
Anticlockwise = S

COOH
4
3 H
H 3C OH
1
(S)-lactic acid
 Individual

ACTIVITY 4: Assigning stereocentres

Assign the stereocenter(s) in each of the following molecules as (R) or (S).

5 mins

O H Cl
H 3C CH3
OH
H NH 2 Br H

Alanine 2-Bromo-1-chloropropyl-cyclopentane
 Individual
ACTIVITY 4: Discussion and feedback

5 mins

O
3
2
H 3C
OH
H NH 2
4 1

Anticlockwise - (S)

(S)- alanine
 Individual
ACTIVITY 4: Discussion and feedback

5 mins

4 1
H Cl
2 CH 3
3
Br H

clockwise (R)
 Individual
ACTIVITY 4: Discussion and feedback

5 mins

Now the second stereocentre

3 Cl H H Cl 3
H 3C CH3
2 2
H Br Br H
4 1 1 4

Anticlockwise - (S)
Flip the molecule so that
group 4 is at the back.
More than one stereogenic centre - diastereoisomers.
The molecule from our previous example had 2 stereogenic centres, how many stereoisomers?

R S S R R S
R S
H Cl H Cl H Cl H Cl
CH3 CH3 CH3 CH3
Br H Br H Br H Br H

This is a pair of enantiomers AND a second pair of enantiomers

If we switch both stereogenic centres we have its mirror images ∴ enantiomers.

Switch one we have stereoisomers that are not mirror images ∴ diastereoisomers.
More than one stereogenic centre.

R S S R R S
R S
H Cl H Cl H Cl H Cl
CH3 CH3 CH3 CH3
Br H Br H Br H Br H

This is a pair of enantiomers AND a second pair of enantiomers

These are diastereosiomers

A molecule with n stereogenic centres has up to 2n stereoisomers.

Types of isomers
Are they Isomers?
Different compounds with same molecular formula.

Are they Constitutional Isomers? Are they Stereoisomers?

Different order of attachment of atoms Same order of attachment, different position of
atoms in space

Are they Enantiomers? Are they Diastereoisomers

None superimposable mirror images. All other stereoisomers

• Alkenes isomerism is an example of

diastereoisomerism.
• If a molecule has multiple stereogenic
centers and we change one that is another
example of a diastereoisomerism.
 Meso compounds have a plane of symmetry.
A molecule with n stereogenic centres has up to 2n stereoisomers.

OH OH OH OH
R S R S
S R R S
OH OH OH OH

• Plane of symmetry and chiral centres

• We call it a meso compound.
OH

OH
OH HO
R S
S R This molecule can exist as 1 of 3 stereoisomers:
OH • two enantiomers.
HO • 1 meso compound.
ACTIVITY 5 - Assigning stereocentres, trickier examples

H OH H OH
H OH
HO CH3 H 3C OH
CH3
CH3
H3C CH3 O CH3
ACTIVITY 6 – Are these molecules chiral?

OH
OH OH
Cl H HO OH
H H CH3
OH H H 3C
H Cl HO OH
H OH
OH
How do we differentiate enantiomers?
The enantiomers of a chiral molecule will have the exact same physical properties
• Melting/boiling point
• IR spectra
• NMR spectra etc.
Chiral molecules can differentiate between the enantiomers of other chiral molecules.
The smell receptors in our nose are chiral proteins, which can detect the different
enantiomers of carvone.

H 3C H 3C
H H
CH3 CH3
O O

(R)-(-)-carvone (S)-(+)-carvone
How do we differentiate enantiomers?
Enantiomers can be distinguished by how they interact with a plane of polarised light

• Plane polarised light: consists of waves vibrating only in one plane

• Polarimeter: a device for measuring the extent of rotation of plane
polarised light.
Summary

Today we have:
• Introduced the Cahn-Ingold-Prelog rules.
• Practiced assigning stereogenic centres as (R) or (S).
• Learnt to identify meso compounds.
• Learnt about ways to differentiate enantiomers.
Stereochemistry and the origin of life.

Why is life one

“handedness”
and not the
other?

CH3
OH
CH3 CH3 OH
OH OH OH
H 2N H 2N H 2N HO O
HO
O O O HO
OH

“L” amino acids “D” sugars

Stereochemistry and the origin of life.

Several theories exist:

• Random chance and autocatalysis

• Circularly polarised light

• Asymmetry in fundamental forces (spin

of electrons)