Unit 5 Organic Synthesis

Organic synthesis refers to the preparation of useful substances from readily available raw
materials. Many useful substances contain complex organic molecules and several different
reactions may be needed to obtain the product.
Name three different types of product that would involve organic synthesis in its manufacture.
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Devising an Organic Synthesis
This is based on knowledge of organic reactions and the fact that functional groups usually react
in a similar way in more complex molecules. The starting material should be readily available.
For example, alcohols can easily be made from alkenes, obtained from crude oil. Alcohols are,
therefore, considered as readily available starting materials.
It is usually best to work backwards from the target molecule in order to identify the reactions
required to obtain the product from a particular starting material.
Example: Identify a sequence of reactions to produce 1,2 dibromobutane from butan-1-ol
Starting material

Target molecule

CH3CH2CH2CH2 OH

CH3CH2CHBrCH2Br
Br2

Heat/Al2O3
CH3CH2CH= CH2

Complete the boxes to show how you would synthesis 2-aminopropane from propene in two
steps. Work back from the amine. What could you make the amine from? Can this
be obtained from propene?
Starting material

Target molecule

CH3CH2=CH2

CH3CHNH2CH3

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In more complex synthesis there may be several alternative routes.

Factors which might affect decisions about the best route include
the number of reaction steps involved
the % yield at each stage
economic factors such as cost of reagents/reaction conditions
aspects of health and safety
% Yield Calculation when a number of steps are involved
The overall yield is reduced by the % yield involved at each stage.
For example: In a three stage reaction involving 90%, 50% and 80% yields, the total yield is
90/100 x 50/100 x 80/100 x 100 = 36 %
Q1. What is the overall yield in the following examples:
(a) 3 stage reaction involving 60% , 50% and 90% yields.
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(b) 4 stage reaction involving 70% , 50% , 60 % and 80 % yields
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Flow charts of Reactions required to solve Problems in Devising a Synthesis
Although you will have your books available to look up reactions from the flow charts on page
483, the reactants and reaction conditions are only provided in the relevant Topics. In order to
save time, it is best to learn the flow charts with the extra reaction details included.

Flow Chart 1

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Flow Chart 2

Flow Chart 3

Q2. Identify the organic compounds, reactants and conditions, as appropriate, for the following
steps in synthesis reactions.
(a) Three steps
CH3CH=CH2

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CH3COCH3

Name the type of reaction involved in each step.

Step 1 ___________________

Step 2 ____________________ Step 3____________________

(b) Three steps

CH3CH2CH2OH

CH3CHOHCH3

The required molecule in step 2 is the main product. Give the name and structural formula of an
alternative product
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Show how the reaction in step 2 occurs and suggest why the main product is formed.

(c) Two steps. Chlorination of a carboxylic acid is included.

CH3CH2OH

CH3CONHCH3

PCl5

CH3COCl

Q3. Fill in the boxes to complete the details of the synthesis involving the following reactions.
Then answer the related questions.
Complete this synthesis so the 1st step product is still an arene.
benzene

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cyclohexanol

-OH

Describe the type of reaction and attacking particle involved in

Step 1. ____________________

________________________

Step 3 ____________________

________________________

Describe the type of reaction involved in Step 2. __________________________

A catalyst is involved in Step 1. Name the catalyst and explain briefly the role it plays in the
reaction.
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A simple alternative to this sequence of reactions might be to react the benzene directly with KOH
to form cyclohexanol. Explain why this reaction is unlikely to occur.
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An alternative way of introducing a halogen atom in this reaction sequence might have been the
reaction of bromine with cyclohexane in the presence of UV light.
Write an equation for the reaction and describe the type of reaction and attacking particle
involved.
Eqn. __________________________________________________________________________
Reaction type and attacking particle ____________________

_________________________

Why would this reaction not be the best way to substitute a hydrogen atom with a single bromine
atom in the cyclohexane molecule.
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Benzene is no longer used in schools because of an associated health hazard. What is the health
hazard?
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Q4. Fill in the boxes to complete the details of the synthesis involving the following reactions.
C Hthe related questions.
CO2CH3
ThenCO
answer
2 2 5
Note: Step 2 involves electrophilic substitution in which the functional group, already present in
the benzene ring, is 3,5 directing.
-SO3H

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Name the type of reactions involved in

Step 1 _________________________________________________________________________
Step 3 _________________________________________________________________________
Explain what is meant by the functional group is 3,5 directing ___________________________
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Give the structural formula of one other product that might be formed in Step 2.

The molecule involved in the electrophilic substitution in Step 2 is SO3. Draw its displayed
formula, give its bond angles and describe its shape. Show the bond polarity in the molecule and
use it to explain which part of the molecule is involved in the electrophilic attack on the benzene
ring.

Explain why the molecule itself is non-polar. _________________________________________

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A 2-Stage Preparation of Nitrobenzene from benzene
An outline of the reactions involved is shown below:
conc HNO3/

-NO2

conc H2SO4

What do we call the type of reactions involved at each stage?

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tin/conc HCl

-NH2

Stage 1 _____________________

Stage 2 _______________________

In industry iron is used instead of tin in stage 2. Suggest why.

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Note: This preparation should not be carried out in school as benzene is carcinogenic.
There is also insufficient detail given in the outline procedure.

An outline of the preparation of nitro benzene is given below.

a. Slowly add conc nitric acid to the cooled sulphuric acid
b. Slowly add benzene to the cooled acid mixture. Shake the flask thoroughly.
c. Reflux the mixture at 60o C for 50 minutes. Nitrobenzene forms as a layer on top of the
acid mixture
d. Pour the contents of the flask into a large excess of water. The nitro benzene sinks to the
bottom.
e. Decant off most of the aqueous layer and separate the nitro benzene.
f. Wash the nitrobenzene with sodium carbonate and separate the nitrobenzene. Repeat until
there is no further reaction.
g. Transfer the nitro benzene to a flask and add anhydrous calcium chloride.
h. Filter the nitrobenzene into a flask and distil.
Concentrated nitric acid and concentrated sulphuric acid react as follows:
HNO3 + 2H2SO4 => NO2+ + H3O+ + 2HSO4What important particle is formed at this stage. What part does it play in the reaction?
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Why do you think it is necessary to shake the flask thoroughly in step b ?
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Why is the mixture refluxed for 50 minutes in step c?
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How could you reflux the reaction mixture and maintain the temperature at approximately 60 oC?
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Look up the density of nitrobenzene ____________ g/cm3
Why does the nitrobenzene form on top of the acid mixture, but sinks when it is diluted with an
excess of water? ________________________________________________________________
______________________________________________________________________________
What piece of apparatus is used for steps e-g _________________________________________
What is being removed from the nitrobenzene at
Step f _________________________________
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Step g _________________________________
How would you know when there was no further reaction in step f
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Use the data book to help suggest a range over which you would collect the nitrobenzene when it
is distilled.

___________ oC

The Preparation of phenylamine

This preparation is unsuitable as a class practical in schools. Nitrobenzene and phenylamine are toxic by
inhalation and by skin absorption. Ethoxyethane is very inflammable, volatile and explosive when mixed
with air.

Some of the steps involved in the preparation of phenylamine are given below.
a.
b.
c.
d.

Heat the tin, concentrated hydrochloric acid and nitro benzene for 20 minutes
Add sodium hydroxide and water. Steam distil the phenylamine.
Add sodium chloride solid to the distillate and shake.
Extract the product in ethoxyethane and allow it to stand in a flask containing a suitable
drying agent.
e. Procedure to obtain a sample of phenylamine.
As well as using safety glasses, give two essential safety precautions you would use to carry out
steps a-c in this experiment.
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Draw and label a diagram to show how you would carry out step a.

Give the structural formula of phenylamine in hydrochloric acid. __________________________

Write an equation to show what happens when this particle reacts with sodium hydroxide.
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Explain briefly how steam distillation separates the phenylamine from the reaction mixture.
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Why is sodium chloride added to the steam distillate?

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_______________________________________________________________________________
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What do we call the method of extracting phenylamine in ethoxyethane?
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Use the data book to help explain how you could obtain a sample of nitrobenzene in step e.
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What essential precautions would you take when carrying out this procedure?
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The Identification of Organic Compounds
Combustion Analysis
A weighed amount of an organic compound is burnt in oxygen. The amount of carbon dioxide,
water vapour and nitrogen formed is found from the increase in mass when they are absorbed in
different chemicals.
The empirical formula can be determined from the mass of the combustion products, using the
following guidelines.
- mass CO2/44 => moles CO2 = moles carbon (x12) => mass carbon
- mass H2O/18 => moles H2O (x 2) =>moles hydrogen = mass hydrogen
- mass nitrogen/14 = moles nitrogen
- mass oxygen = (mass organic compound (mass C + mass H + mass N)) /16 = moles oxygen
The empirical formula is then obtained from the ratio of moles of each element present.
Divide all the moles by the lowest number of moles and then multiply by a whole number to get
the simplest whole number ratio.

Q5. Combustion analysis showed that 0.173g of an organic compound produced 0.44g of CO2,
0.09g of water and 0.02g of nitrogen when burnt. What is the empirical formula of the organic
compound.
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_______________________________________________________________________________
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The empirical formula is also the molecular formula.
One structural isomer is shown below:
-NHCHO

What type of organic compound is this isomer? ________________________________________

Name the isomer. ________________________________________________________________
Suggest what pH you would expect, if this compound is shaken with a mixture of water and
universal Indicator solution. Explain your reasoning.
_______________________________________________________________________________
_______________________________________________________________________________
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Draw two other structural isomers, with familiar functional groups. Dont include two isomers,
which only vary in the position of a second functional group in the benzene ring.

Suggest a simple chemical test to distinguish between the two isomers. Give a positive result for
the test.
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Modern Analytical Techniques
Mass Spectrometry In a mass spectrometer organic compounds are vaporized and subjected to
electron bombardment. This removes electrons creating positive ions. The charged organic
molecules are unstable and break down into charged fragments, which reflect their structure. The
positively charged particles are accelerated through a magnetic field, where they are deflected
according to the mass of the positive ion. The ions are brought into detection with increasing
magnetic field, creating a spectrum of particles with increasing mass. Their abundance is also
recorded and represented on the spectrum
Example: Possible fragmentation of ethanol, C2H5OH
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C2H5+ ion detected at mass 29

C2H5OH

Electron
bombardment

C2H5OH+
OHo

free radical(not detected)

The C2H5+ can also fragment further, for example, by losing two H atoms to form C2H3+(mass 27)
Mass Spectrum of Ethanol

mass decrease of 15
from the molecular
ion - loss of CH3 gp

Relative
Abundance

31

Molecular or parent ion

46
0

10

20

30

40

50

60

70

80

mass/charge ratio

Features of the spectrum;

The peak with greatest mass(molecular ion) represents the molecular mass of the compound.
Other fragment peaks give an indication of the structure. For example, loss of CH3 in forming the
CH2OH+ peak(mass/charge 31) fits in with the known structure of ethanol.
Which ion is responsible for the peak at 45? __________________________________________
How could it be formed? __________________________________________________________
Sometimes a peak of low abundance occurs to the right of the molecular ion. What is responsible
for this peak? ___________________________________________________________________
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Q6. The key parts of a mass spectrum of a solid organic compound is shown below. Its %
composition is C 40.7 % H 8.5 % O 27.1 % N 23.7 % .
Work out its empirical formula. _____________________________________________________
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_______________________________________________________________________________
Use the mass spectrum to establish its molecular formula ________________________________
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Draw the displayed formulae of four structural isomers, which could have this molecular
formula.

59

44

Relative
Abundance

43

10

20

30

40

50

60

70

80

mass/charge ratio

Which species could be responsible for the peaks at the following mass/charge ratios?
44 _________________ through loss of a _________ group
43 _________________ through loss of a _________ group
Which structure do these fragments seem to match? ____________________________________
Infra Red
Infra Red spectra show absorptions of radiations associated with the natural bending and
stretching vibrations in organic molecules. Because of the number of different bonds the spectra
can be very complex. They provide a unique fingerprint of an organic molecule as well as
absorptions characteristic of specific bonds. You will need to use the data section 3.3 to identify
the bonds associated with absorptions at various wave numbers. You should also know that
hydrogen bonded atoms give broad peaks.
NMR
Nuclear magnetic resonance is an extremely powerful analytical technique. Hydrogen nuclei
absorb radio waves when subjected to a magnetic field and the exact frequency of absorption
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depends on the environment of the hydrogen atom. Absorptions by specific hydrogen atoms in
molecules are related to a standard (TMS) and identified by their chemical shift from this value.
The data book(section 3.4) shows the chemical shift of hydrogen atoms in particular functional
groups and also within different arenes. The spectra also show the intensity of absorption so that
the relative numbers of hydrogen atoms with a specific environment can be identified.
Example: propanal, CH3CH2CHO

Low Resolution nmr

absorption

3H

2H
1H

10

12

TMS

Chemical Shift / ppm fromTMS

The nmr shows that there are three hydrogen atoms with different environments in the molecule.
These match the structure and the proportions of each are in the ratio 3:2:1.
The data book (Section 3.4) shows that for the chemical shift values
1.0 - corresponds to a CH3 group next to other alkyl H atoms
2.5 - corresponds to alkyl H atoms next to a carbonyl group
9.7 - corresponds to an aldehyde H atom

absorption

Q7. A colourless organic liquid dissolves freely in water producing an acidic solution. Its
empirical formula is CH2O. Its mass spectrum shows a parent ion peak at 60 mass/charge units.
What is its molecular formula? _____________________________________________________
3H
_______________________________________________________________________________
An nmr spectrum of this compound is shown below.
1H

TMS
13

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12

10

Chemical Shift / ppm fromTMS

Use the nmr spectrum and information given to help identify the compound. Explain your
reasoning
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Use your data book to identify two peaks, which you would expect to see in the infra red spectrum
of this compound.
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Suggest two fragment ions that you would expect to see on the mass spectrum of the compound.
State how they would be formed.
_______________ due to loss of __________________________________________________
_______________ due to loss of __________________________________________________
Q8. A liquid hydrocarbon was analysed and found to contain 90.5% carbon. It burnt with a very
smoky flame and reaction with bromine in the presence of an iron catalyst, produced only one
mono-substituted structural isomer. Its mass spectrum showed a parent ion peak at 106
mass/charge ratio.
What is the empirical formula of the hydrocarbon?

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_______________________________________________________________________________
_______________________________________________________________________________
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What is its molecular formula? _____________________________________________________
What does the very smoky flame suggest about the hydrocarbon?
_______________________________________________________________________________
What type of hydrocarbon reacts with bromine in the presence of a iron catalyst? _____________
Suggest four possible structural isomers, which could react with bromine in this way.
1.

2.

3.

4.

Which of these isomers would produce only one possible mono-substituted isomer? __________
Name the hydrocarbon ___________________________________________________________
Give the mass/charge ratio and formula of a fragment ion that would be expected in its mass
spectrum.
__________
________________ due to loss of ___________________________________
Use your data book to help you represent a predicted nmr spectrum, on the chart below for this
hydrocarbon. The height of the peaks should represent the number of hydrogen atoms involved.
Label the number of hydrogen atoms for each peak.

absorption

TMS

12

10

Chemical Shift / ppm fromTMS

SYNOPTIC STYLE PRACTICE QUESTIONS

As in the actual exam you should get used to using your students and data book to help answer
these questions. Your written communication is also important and your ideas should be
explained clearly using equations and diagrams as appropriate.
The questions may also include work covered in Topics 1-15.
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Q1. Aspirin is a widely used painkiller made from

2-hydroxybenzoic acid. Combustion analysis of 0.09 g of aspirin produced 0.198 g carbon
dioxide and 0.036 g of water. The structure of aspirin is shown. A simplified mass spectrum and a
low resolution nmr are displayed opposite(page 17).
(a) What is the molecula formula of aspirin? _________________
Show that the combustion analysis results and mass spectrum parent ion are consistent with this
molecular formula.
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(b) Name the three functional groups in the aspirin molecule
1. _________________________ 2.________________________ 3. ______________________
(c) Draw the structure of 2-hydroxybenzoic acid.

Ethanoic anhydride and phosphoric acid can be used to convert 2-hydroxybenzoic acid into
aspirin.
Use structural formulae to represent an equation for the reaction.

______________________________________________________________________________
What is the function of the phosphoric acid? _________________________________________
Name the type of reaction involved. ________________________________________________
Aspirin Mass Spectrum - key peaks

Name another reagent, which could be used to convert 2-hydroxybenzoic acid into aspirin.
120
_____________________________________________________________________________
Relative
Suggest
Abundance

a reason why this is not used in the industrial manufacture.

%_____________________________________________________________________________
43

138
92

121
16

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20

40

60

80

100
mass/charge ratio

120

140

160

180

163

(d) Identify the most probable fragment ions responsible for

the peaks at the following mass/charge ratios. Show on the
aspirin molecule where bonds might break to form the
fragment ions.
43 _______________________________________
121 _______________________________________
163 _______________________________________
Suggest how the strong peak at 120 might have been
formed.
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(e) An nmr spectrum for aspirin(2-ethanolyoxybenzoic acid) is shown below. Use your data book
to help label the hydrogen atoms responsible for each peak, or set of peaks.
absorption

TMS

12

10

Chemical Shift / ppm fromTMS

What would be different about the spectrum, if the molecule was 4-ethanoyloxybenzoic acid?
______________________________________________________________________________
CH2CHNH2CH3
Q2. A possible synthesis of Amphetamine is considered, using benzene as a starting material.
benzene

amphetamine

17

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Step 2

Step 3

(a) Giving reagents and conditions devise a 4 step synthesis of amphetamine from benzene.
Draw the structural formula of an alternative product for step 2.

Draw the structural formula of two alternative products, which could be formed in step 3.

Suggest which product from step 2 is most likely to give the best yield in step 3. Justify your
answer.
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(b) In a series of experiments 2.3 g of amphetamine was obtained from 5 g of benzene. What was
the overall % yield.
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(c) Use the data book to identify three hazards associated with using benzene. Specify
precautions, which can be taken in each case.
Hazard
Precaution
1. _________________________________

______________________________________

2. _________________________________

______________________________________

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3. _________________________________

______________________________________

(d) Predict the solubility of amphetamine in water and hydrochloric acid. Explain your answer
fully, using equations as necessary.
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(e) The compound formed from step 3 could be converted into an alcohol and then a ketone.
Using structural formulae, show how this could be done, giving reagents and conditions for each
reaction.

Using the data book, explain how an IR spectrum would show that a ketone had been formed and
that no alcohol was present.
_______________________________________________________________________________
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How would an nmr spectrum show the difference between the two compounds?
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Describe a chemical test, which would enable you to confirm the presence of a C=O gp in the
ketone.
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