Organic-Synthesis & Chirality

1 of 34 © Boardworks Ltd 2010

Light waves
Light can be considered as a series of

transverse waves, oscillating at 90° to
the direction the light is moving.
Transverse waves can be modelled by

moving one end of a Slinky up and down.
direction of wave
propagation
Polarized light

Optically active compounds
Optically active compounds have the ability to rotate the
plane of polarized light.
Optically active compounds exist as two isomers, known as
enantiomers. One rotates the plane of polarized light
clockwise: the + or d isomer. The other rotates the plane of
polarized light anticlockwise: the - or l enantiomer.
l enantiomer polarized light d enantiomer

Chiral carbon atoms
For a compound to be optically active it must contain a carbon
atom to which four different groups are attached.
Such a carbon atom is called a chiral carbon, and is denoted
by a *.
glycine alanine
The amino acid glycine does not contain a chiral carbon
whereas alanine does. Alanine would be therefore be optically
active but glycine would not.

Mirror images
If a chiral compound is drawn in 3D it is possible to see how
the two enantiomers are different:
optical isomers of alanine

The two enantiomers are mirror images of each other. No
matter how you rotate the molecules, it is impossible to
superimpose them on top of each other.

Identifying chiral carbons

Measuring optical activity

Properties of optical isomers
Optical isomers have identical physical and chemical
properties, but their biological activity may be different due to
the shape specificity of biological receptors.
For example, limonene is an

optically active compound.
The d isomer is found in the peel
of citrus fruit and has an orange
smell. The l isomer is found in
pine needles and cones and has
a refreshing pine-like smell.
d-limonene l-limonene
Smell receptors in our nose are able to distinguish between the
two different isomers.

Optically active amino acids
Other than glycine, alpha amino acids
are all optically active because they
contain a chiral carbon.
There are therefore two possible

isomers of all the optically active
amino acids.
Usually, only one type
of optical isomer is
produced by an
organism. In general,
only the l-isomers of
amino acids occur
in nature.
d-isomer l-isomer
Synthesis of lactic acid

Optical isomers in drug manufacture
If a drug is optically active, different enantiomers may bind
differently (or not at all) to target receptors in the body.
One enantiomer can have a desired effect, while the other
may have either no effect at all, or a different effect entirely.
A racemic mixture is often used in drug manufacture because

it is difficult and expensive to separate the two isomers.
For example, ibuprofen is optically

active. Only d-ibuprofen is
pharmaceutically active, but
l-ibuprofen is not harmful so
ibuprofen tablets contain a racemic
mixture of the two enantiomers.

Thalidomide and optical isomerism
Thalidomide was used as a tranquilizer and painkiller in the
1950s. It was sold as a ‘wonder drug’ also effective at reducing
morning sickness, and was prescribed to pregnant women.
The birth of a large number of babies with severe birth defects

was subsequently linked to thalidomide use during pregnancy.
This is because thalidomide is racemic drug. The d-enantiomer
is effective against morning sickness, but the l-enantiomer is
teratogenic (causes birth defects).
d-thalidomide l-thalidomide
Separating optical isomers
When optically active substances are made in the lab,
the usual result is a racemic (50:50) mixture of the two
different enantiomers.
If one enantiomer is harmful, or causes

unpleasant side effects, the different
optical isomers must be separated.
This is difficult to achieve as the

enantiomers have identical chemical
and physical properties.
Separating optical isomers is therefore

time-consuming and expensive, but
can improve pharmacological activity.

Obtaining optically pure compounds
Optically pure compounds can be obtained from some racemic
mixtures with biological methods. These natural pathways
involve microorganisms and promote stereoselectivity.
For example, lactic acid is found in milk and can be prepared

in the lab, but in both cases a racemic mixture is the result.
d-lactic acid is found in muscle but pure l-lactic acid does not
occur naturally and must be obtained from the racemic mixture.
This can be done with the mould

Penicillium glaucum, used to make
blue cheese. Given a racemic mixture,
the mould feeds only on d-lactic acid,
leaving pure l-lactic acid behind.

Synthesizing optically pure compounds
An alternative to separation is to synthesize an optically pure
product. This has the advantage that no separation is required.
For example, a group can be attached to the starting material

that physically blocks one of the approaches the other reagent
can make, so only one enantiomer is formed.
Another approach is to use naturally-occurring chiral

molecules – for example l-amino acids or sugars – as the
starting point for synthesis.
This technique is sometimes known as chiral pool synthesis,

as it makes use of a ‘pool’ of optically-pure reactants to ensure
that only one type of optical isomer is present in the products.

Chiral catalysts
An alternative method is the use of a chiral catalyst. Chiral
catalysts transfer their chirality to reactants so that only a
single type of isomer is synthesized.
Examples of chiral catalysts include transition metal
complexes prepared using chiral ligands, chiral organic
compounds and biological molecules such as enzymes.
In 1968, William Knowles

created one of the first chiral
catalysts from a transition
metal complex. He used this
technique to synthesize L-
DOPA, a treatment for
Parkinson’s disease.

Optical isomerism: true or false?

Importance of organic synthesis
Chemists are able to construct synthetic pathways to prepare
a desired compound. They design a molecule and then work
out how to make it from readily available precursors.
This is of particular use in the

pharmaceutical industry, where a
molecule can be designed to
have specific functional properties.
A series of reactions is worked out in which each stage

modifies the starting compound in a particular way; for
example, adding a functional group. It is vital for each stage in
the synthesis to be carried out under the right conditions.

Functional groups

Identify the functional groups

Multiple functional groups
Some compounds, for example paracetamol, contain more
than one functional group.
N-substituted
amide
phenyl
hydroxyl
The chemical reactivity of each functional group is usually
the same as it would be on its own.

Predicting compound properties

Summary of organic synthesis reactions

Devising a synthetic route (1/2)
1. Write down the possible products that can be made

from the starting material in one step.
2. Write down the possible chemicals that can synthesize
the desired product in one step.
3. Identify possible synthetic pathways.
For example, synthesizing ethylamine from ethanol:
CH3CHO CH3CH2CN
CH3CH2OH CH3COOH CH3CH2NH2
CH3CH2Cl CH3CH2Cl
CH3CH2OOR
Devising a synthetic route (2/2)
Synthesis of propanoic acid (CH3CH2COOH) from ethyl chloride
(CH3CH2Cl):
1. Write down the possible products that can be made from
the starting material in one step.
As the carbon chain increases in length the reaction must
be via a nitrile.
CH2CH2 CH3CH2COOH
2. Write down possible
products from the nitrile. CH3CH2CN
CH3CH2Cl CH3CH2CH2NH2
3. Identify possible CH3CH2NH2
synthetic pathways.
CH3CH2OH
Complete the synthetic route

Glossary

What’s the keyword?

Multiple-choice quiz

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What is polarized light?

What is polarized light?

What is optical activity?

What is optical activity?

1 of 34 © Boardworks Ltd 2010

2 of 34 © Boardworks Ltd 2010

Light can be considered as a series of

Transverse waves can be modelled by

4 of 34 © Boardworks Ltd 2010

l enantiomer polarized light d enantiomer

6 of 34 © Boardworks Ltd 2010

optical isomers of alanine

7 of 34 © Boardworks Ltd 2010

8 of 34 © Boardworks Ltd 2010

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For example, limonene is an

10 of 34 © Boardworks Ltd 2010

There are therefore two possible

13 of 34 © Boardworks Ltd 2010

A racemic mixture is often used in drug manufacture because

For example, ibuprofen is optically

14 of 34 © Boardworks Ltd 2010

The birth of a large number of babies with severe birth defects

If one enantiomer is harmful, or causes

This is difficult to achieve as the

Separating optical isomers is therefore

16 of 34 © Boardworks Ltd 2010

For example, lactic acid is found in milk and can be prepared

This can be done with the mould

17 of 34 © Boardworks Ltd 2010

For example, a group can be attached to the starting material

Another approach is to use naturally-occurring chiral

This technique is sometimes known as chiral pool synthesis,

18 of 34 © Boardworks Ltd 2010

In 1968, William Knowles

19 of 34 © Boardworks Ltd 2010

20 of 34 © Boardworks Ltd 2010

This is of particular use in the

A series of reactions is worked out in which each stage

22 of 34 © Boardworks Ltd 2010

23 of 34 © Boardworks Ltd 2010

24 of 34 © Boardworks Ltd 2010

25 of 34 © Boardworks Ltd 2010

26 of 34 © Boardworks Ltd 2010

27 of 34 © Boardworks Ltd 2010

1. Write down the possible products that can be made

For example, synthesizing ethylamine from ethanol:

CH3CH2OH CH3COOH CH3CH2NH2

30 of 34 © Boardworks Ltd 2010

32 of 34 © Boardworks Ltd 2010

33 of 34 © Boardworks Ltd 2010

34 of 34 © Boardworks Ltd 2010

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