456

Chapter 30:
organic synthesis
Learning outcomes
You should be able to:
■■ state that most chiral drugs extracted from ■■ for an organic molecule containing several
natural sources often contain only a single functional groups:
optical isomer – identify organic functional groups using key
■■ state reasons why the synthetic preparation of drug reactions
molecules often requires the production of a single – predict properties and reactions
optical isomer, e.g. better therapeutic activity, ■■ devise multi-stage synthetic routes for
fewer side effects preparing organic molecules using key reactions.
 Chapter 30: Organic synthesis

Introduction
Chemists play a vital role in developing new materials
to improve our lives. In this chapter you can find out
about their work in developing new medicinal drugs.

Figure 30.1  Chemists around the

world work in large teams to model,
develop and test new medicines.

Designing new medicinal drugs
How do we go about designing new molecules to fight
diseases? One way is to identify the structural features the
new drug will need to stop particular bacteria or viruses
working. The structural features may be associated with
the active site on a particular enzyme needed for an
essential function of the pathogen. Once these structural
features have been identified we can then predict the shape
of a molecule that would fit into, and hence block, the
active site.
The functional groups present would also be crucial to
ensure the drug could bind into the active site effectively.
The intermolecular bonds formed between the drug and
its target molecule could involve:
■■ hydrogen bonding
■■ ionic attraction
■■ dipole–dipole forces
■■ instantaneous dipole–induced dipole forces (van der Waals’
forces, see Chapter 4, page 62).
Computers are now used to judge the fit between a
potential drug molecule and a receptor site on its
target molecule. Such molecular modelling has greatly
speeded up the process of designing new medicines.
The interactions and fit of a potential medicine with
a biological receptor molecule can be studied before
the medicine is ever made in the lab. Before molecular
modelling became available, the synthesis of a new
medicine involved far more trial and error. Chemists had
to prepare many more possible medicines for testing.
With molecular modelling, only those molecules that 457
are definite possibilities are made and tested. Molecular
modelling on a computer is now a powerful tool, used
when designing medicines and many other compounds
(e.g. pesticides and polymers).
This type of research was used in the fight against
AIDS in the late 1980s and 1990s. Scientists using
X-ray crystallography (a method in which a sample is
irradiated with X-rays and the pattern is analysed by
computer) worked out the shape of HIV protease in
1988 (Figure 30.2). This enzyme plays an important role
when the virus becomes infectious. Researchers realised
that, if a molecule could be discovered that could block
its active site, this might be one step on the route to
finding a cure for AIDS. Knowing the molecule that the
enzyme worked on (its substrate), researchers were able
construct similar molecules on the computer screen to fit
the active site.
The first attempts fitted perfectly, but were not water
soluble. This meant the drug could not be delivered to its
target, the HIV protease. Eventually a soluble molecule
that would interfere with the enzyme was found. In less
than 8 years pharmaceutical companies had developed
three new anti-viral drugs for people with HIV/AIDS.
This would have taken about twice as long if the structure
of HIV protease had not been determined. Traditional
 Cambridge International A Level Chemistry
active site
Figure 30.2  A symmetrical HIV protease molecule, with its
active site in the centre of the molecule. Knowing its structure
made the search for a drug to fight AIDS much quicker and
cheaper than traditional trial-and-error methods.
trial-and-error methods involve the testing of many
thousands of possible drugs.
The death rate from AIDS dropped significantly.
However, the virus developed resistance to the new drugs
as it mutated. So scientists now have to model the new
drug-resistant strains of the infection and are developing
new drugs to inhibit the mutant versions of HIV protease.
These inhibitors are one part of a cocktail of drugs that
458
can be used to treat the disease now.
Identifying macromolecules
NMR spectroscopy is also used extensively in finding
out the structures of biological macromolecules such
as proteins and nucleic acids. As well as identifying the
different types of 1H atoms present, more sophisticated
data can yield, for example, the distance between atoms in
macromolecules. Large amounts of data are collected and
analysed by computer programs to reveal the shape of the
molecules under investigation.
Figures 30.3 and 30.4 show images obtained from
NMR analysis of two protein molecules made up from
over 100 amino acids. These are called ribbon diagrams.
Figure 30.3  A protein made up of
106 amino acid residues.
Figure 30.4  A protein made up of 153 amino acid residues.
This NMR analysis takes place in solution, so it is
particularly useful for medical research. Many human
proteins exist in solution in the body so we can mimic the
interactions that take place in cells or in the bloodstream.
question
1 a Which method was used to determine the
structure of HIV protease in 1988?
b Which method could be used to show the shape of
the enzyme in solution?
c What type of natural polymer is an enzyme such as
HIV protease?
d How did the new anti-viral drugs work?
Chirality in pharmaceutical synthesis
The pharmaceutical industry is constantly searching for
new drugs. Their research chemists have discovered that
most of these drugs contain at least one chiral centre (see
page 195). Remember that a molecule containing a carbon
atom bonded to four different atoms or groups of atoms
can exist as two non-superimposable mirror images.
These two isomers are called enantiomers and they will
be optically active. They differ in their ability to rotate the
plane of polarised light to the left or to the right.
Using conventional organic reactions to make the
desired product will yield a 50 : 50 mixture of the two
enantiomers. We call this a racemic mixture. Although the
physical properties of the enantiomers will be identical,
each differs in its ‘pharmaceutical activity’, i.e. the effect
the drug has on the body. For example, naproxen is a drug

used to treat the pain caused by arthritis (Figure 30.5).
One enantiomer will ease the pain but the other can cause
liver damage.
As another example, one enantiomer of a drug used
to treat tuberculosis (TB) is effective, whereas the
other can cause blindness. Therefore, chemists ideally
need a single pure enantiomer to put in their drug
product. Note that about 80% of new drugs patented are
single enantiomers.
Using pure enantiomers will be beneficial as it:
■■ reduces the patient’s dosage by half as the pure enantiomer
is more potent, i.e. has better therapeutic activity (thereby
cutting costs of production)
■■ minimises the risk of side effects (thereby protecting
patients from further problems and drugs companies
from possible legal action for damages if serious side effects
do occur).
There are three ways to prepare pure enantiomers:
■■ optical resolution
■■ using optically active starting materials
■■ using a chiral catalyst.
Optical resolution
This method involves the chemists following a traditional
synthetic route to make the compound, resulting in a
racemic mixture. Then they separate the two enantiomers
in a process called optical resolution. This involves using
a pure enantiomer of another optically active compound
(called a chiral auxiliary) that will react with one of the
isomers in the mixture. The new product formed will
now have different properties and so can be separated
by physical means. For example, the solubility in a
given solvent will differ so the unwanted enantiomer
and the new product can be separated by fractional
crystallisation. The new product is then converted back
to the desired enantiomer in a simple reaction (e.g. by
adding dilute alkali).
The crystallisation is repeated many times to ensure
purity. This method is difficult, time-consuming, uses
extra reagents and involves the disposal of half the original
racemic mixture.
Large volumes of organic solvents (often harmful
to the environment) are used in the process. However,
chemists are now using supercritical carbon dioxide as a
solvent, which is much safer. At 31 °C and 73 atmospheres
pressure, CO2 is a suitable non-polar solvent for many
drug derivatives in the racemic resolution process. The
solubility of the derivatives can be changed, simply by
varying the density of the solvent. The solvent, which is
Chapter 30: Organic synthesis
non-toxic, is easily removed by reducing the pressure and
then recycling it to use in the process again.
We can also use high-performance liquid
chromatography (HPLC, see page 436) to separate a
racemic mixture, as long as the stationary medium (e.g.
the solid that packs the column) is itself optically active.
Using optically active starting materials
This technique uses starting materials that are themselves
optically active and in the same orientation as the desired
product. These are often naturally occurring compounds
such as carbohydrates or L-amino acids. The biochemist
will choose from this ‘chiral pool’. The synthetic route is
designed to keep any intermediates and the final product
formed in the same enantiomeric form. As a result, there is
no need to carry out the costly separation process needed
when a racemic mixture is produced.
Chiral catalysts
Chemists are also developing new chiral catalysts that
ensure only one specific enantiomer is formed in a
reaction. The benefits of these catalysts are that only small
quantities are needed and they can be used over and
over again, although the catalyst itself can be expensive.
A ruthenium (Ru) organometallic catalyst is used in the 459
production of naproxen (see Figure 30.5).
Often a combination of optical resolution and
chiral synthesis is needed in the production of a
pharmaceutically active, pure enantiomer.
H H
C
C
COOH
+ H2
CH3O
organometallic
⎯⎯→
ruthenium catalyst
(a chiral catalyst)
CH3
H
C
* COOH
CH3O
naproxen
(drug for arthritis)
Figure 30.5  The chiral catalyst (an organometallic ruthenium
compound) ensures only the desired enantiomer is formed –
in this case, naproxen for the treatment of arthritis. The chiral
centre in naproxen is marked with an asterisk. The marked
carbon atom is known as an ‘asymmetric carbon’.
 Cambridge International A Level Chemistry

The pharmaceutical industry can also use enzymes to

promote stereoselectivity and produce single-enantiomer
products. The specific shape and the nature of the
molecular interactions at the active site of an enzyme
ensure only one enantiomer will be formed (as in living
things). The enzymes are often immobilised (fixed in
place) on inert supports. This enables the reactants to be
passed over them without the need to separate the product
from the enzymes after the reaction.
However, it can be expensive isolating enzymes from living
things. Using whole organisms, such as bacteria, can reduce
this cost. Nowadays, synthetic enzymes can also be made,
designed for a particular synthesis. Therefore a search for a
suitable enzyme from the limited pool available from natural
sources is not always necessary.
Overall, using an enzyme process might take longer
to develop than a conventional synthetic route, but
in the long run the benefits generally outweigh the
disadvantages. There are fewer steps needed in the
synthesis route, resulting in a ‘greener’ process.
question
460
2 a Why are pure enantiomers rather than
racemic mixtures the better option for use as
pharmaceutical drugs from the point of view of:
question (continued)
b Why are modern enzyme-based processes
for manufacturing pure enantiomers more
sustainable (environmentally friendly) than
traditional synthetic routes used by the
pharmaceutical industry?
c Find out why the drug thalidomide resulted in legal
action against its manufacturer.
Synthetic routes
When research chemists want to make a new compound,
they usually work backwards from the desired compound
to create a series of reactions, starting with a compound
extracted from a commonly available raw material. In
industry, common starting materials are hydrocarbons
from crude oil and its refining, and compounds extracted
from plants, such as esters from fats and vegetable oils.
You will need some of the skills of a research chemist
when tackling questions that involve:
■■ predicting the reactions of complex molecules you
have never seen before, containing more than one
functional group
■■ suggesting a series of reactions to make a given compound
from a given starting compound.

 i a patient In order to be successful in answering these questions,

 ii a pharmaceutical company? you will need to be familiar with all the reactions and
conditions of each homologous series mentioned in the
syllabus. The flow chart in Figure 30.6 is a summary of

alkanes
H2(g), heat ultraviolet
under pressure light with amines
with nickel halogen, room heat with
catalyst temperature
heat under pressure alcohol
and pressure and acid
with ammonia in alcohol
catalyst
alkenes halogenoalkanes carboxylic acids esters
treat with HX(aq),
warm with heat with water
room temperature
distil from mixture NaBH4 in and acid catalyst
and pressure
of alcohol, conc. water
heat with dilute H2SO4 and KX(s) reflux with excess
aqueous alkali acidified potassium
hot pumice aldehydes dichromate(VI)
pass alkene and warm with NaBH4
steam over heated and AI2O3 in water heat with
phosphoric acid catalyst distil on adding to water and
under pressure alcohols acid catalyst
acidified potassium dichromate(VI)

Figure 30.6  Some of the important organic reactions you have to remember.
 Chapter 30: Organic synthesis

some of the most useful reactions you need to know,
but you could be asked about others, so it is a good idea
to make your own summary spider charts for all the
reactions in Chapters 15 to 28. For example, for Chapter 16
write the word ‘Halogenoalkane’ in a box and draw arrows
radiating out from the box to the products made in their
reactions, labelling the arrows with other reactants and the
reaction conditions. Displaying these on a wall and using
different colours will help you remember them.
Adding carbon atoms
The RCN molecule can be either hydrolysed to make
a carboxylic acid (by refluxing with dilute hydrochloric
acid) or reduced to make an amine (by adding LiAlH4 in
dry ether).
We can add an alkyl or acyl side-chain to a benzene
ring by carrying out a Friedel–Crafts reaction, which is
another useful reaction when planning synthetic routes.
For example:
AlCl3 catalyst
C6H6  +  CH3CH2Cl C6H5CH2CH3  +  HCl
benzene ethylbenzene

Sometimes the starting compound from a raw material

does not have enough carbon atoms in its molecules to
make the desired product. An extra carbon atom can be
added by adding the nitrile functional group,  C   N.
Remember that these can be made from halogenoalkanes:
reflux with ethanolic KCN
RBr  +  HCN RCN  +  HBr

where R is an alkyl group, so RCN has an extra

carbon atom.

question
461
3 a Name the functional groups in the molecules of: 4 a Name the organic products A to D in the synthetic
 i aspirin route below:
boil with NaOH(aq) add excess HCl(aq)
 ii paracetamol.
C2H5COOC3H7 A B
O add PCl5 add conc. ammonia
C H C D
O H H
H b i Devise a three-stage synthetic route to convert
O N
O benzene into benzenediazonium chloride.
C C H
C H  ii How would you convert the benzenediazonium
O H
O C chloride into an orange dye?
H H
aspirin paracetamol

b i Both the molecules in part a are broken down


when refluxed with dilute hydrochloric acid. Write
an equation each for the reaction of aspirin and
paracetamol with H2O.
 ii What do we call the type of reaction in b i ?
 Cambridge International A Level Chemistry

Summary
■ Both natural biochemicals and modern medicinal
drugs contain chiral molecules. Generally, only one
of the enantiomers of a drug is beneficial to living
organisms and the other isomer may have undesirable
effects. The beneficial isomer has the appropriate
shape and pattern of intermolecular forces to interact
with a receptor molecule in a living organism.
■ Chemists are now producing drugs containing
single enantiomers rather than a racemic mixture
of isomers. This enables the dose to be halved,
improves pharmacological activity (behaviour of
molecule in an organism), reduces side effects and
minimises litigation against manufacturers.
■ Molecular design of a new medicinal drug is
made possible with a sound understanding of the
structural features that produce beneficial effects.
The computerised study of the interactions between
molecules and biological receptors has become a
powerful tool in the search for new medicines.
■ Recognising the functional groups in a given organic
molecule enables us to predict its reactions.
■ Knowing the reactions of the different functional
groups in organic reactions enables us to devise
synthetic routes to make given compounds.

End-of-chapter questions
1 A sample of lactic acid (CH3CH(OH)COOH) was extracted from a natural source and found to be optically active. It
462 was then subjected to two reactions, as shown below.
step A step B
CH3CH(OH)COOH CH3COCOOH CH3CH(OH)COOH
sample 1 sample 2

Sample 1 was optically active but sample 2 was not optically active.
a i Give the systematic name for lactic acid. [1]
ii The structure of one optical isomer of the lactic acid is:
OH

C
H3C H

COOH
Draw the other optical isomer. [1]
iii Explain why lactic acid can form optical isomers. [1]
b i Give the reagents and conditions necessary for step A. [2]
ii Give the balanced equation for the reaction. [2]
c i Give the reagents and conditions necessary for step B. [2]
ii Give the balanced equation for the reaction. [2]
d i Give the mechanism for step B. The first step involves nucleophilic attack on the carbon of the
ketone group by an H– ion from NaBH4. [5]
ii Explain why sample 2 does not show any optical activity – it does not rotate plane-polarised light. [3]
e i Explain why lactic acid can be polymerised. [2]
ii State the type of polymerisation reaction that this an example of. [1]
iii Draw the repeat unit of poly(lactic acid). [1]
Total = 23
 Chapter 30: Organic synthesis

2 Explain how 2-aminopropanoic acid can be prepared from lactic acid in two steps. You should give
the reagents and conditions necessary plus balanced symbol equations for the reactions taking place. [9]
Total = 9

3 Write short notes on the following methods of synthesising chiral molecules:

a using a chiral auxiliary [3]
b use of a chiral pool. [3]
Total = 6

4 The structure of the compound known as thalidomide can be shown as:

O

N O
N
H
O O
a Copy the molecule and mark the chiral centre on your drawing. [1]
b Name two functional groups found in a molecule of thalidomide. [2]
c Suggest the type of reaction that might change the molecule into an alcohol and any reagents needed. [2]
d Explain why the chirality of drugs has been such an important issue in the pharmaceutical industry,
giving one benefit to patients and one benefit to pharmaceutical companies of using pure enantiomers. [3]
Total = 8

5 The flow charts below show how poly(ethene) can be obtained by two different routes. 463

process 1 process 2 poly

Route I decane ethene
(ethene)

substance
A

substance process 3 process 2 poly

Route II ethene
B (ethene)

H2O

a i Identify substance A and give the equation for the reaction taking place in process 1. [3]
ii What term is used to describe process 1? [1]
b i Name substance B and give the equation for the reaction taking place in process 3. [3]
ii What term is used to describe process 3? [1]
Total = 8