Investigation: Investigate the optical isomerism in Ibuprofen.

Name: Yuntong Guo

Candidate Number: 0109

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Content
Abstract …………………………………………………………………………………………3
Introduction……………………………………………………………………………………4
Why I investigated Ibuprofen………………………………………………………………………4

Why is ibuprofen crucial……………………………………………………………………………4

Literature Review……………………………………………………………………………5
General chemical information of ibuprofen …………………………………………………………6

The significance of optical isomerism in drugs ………………………………………………………6

Comparative Pharmacology of optical Ibuprofen isomers ………………………………………….7

Pharmacokinetics of anti-inflammatory activity …………...………………………………………8

The usefulness of pure s-ibuprofen (dexibuprofen) ………………………………………………9

Additional Account of Methodology in Research and the Preparation of Experiment ……….……9

Practical …………………………………………………………………………………………11
Aim/hypothesis …………………………………………………………………………………….11

Procedure of Ibuprofen Synthesis ………………………………………………………………….11

Chemical material……………………………………………………………………………………12

Equipment……………………………………………………………………………………………13

Risk Assessment………………………………………………………………………………………14

Overall scheme & method…………………………………………………………………………….15

Test for optical activity……………………………………………………………………………….18

Photograph of the experiment ………………………………………………………………………19

HNMR Scan-Chloride Substitution…………………………………………………………………...25

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HNMR Scan-Ibuprofen………………………………………………………………………………26

Results & Conclusion……………………………………………………………………………….27

Experiment Evaluation …………………………………………………………………………….27

EPQ Self-evaluation…………………………………………………………………………………27

Bibliography……………………………………………………………………………………29
Appendices…………………………………………………………………………………….33

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Abstract

This paper will introduce a chemical with molecular name isobutylphenylpropionic acid, or more
commonly known as Ibuprofen. In introduction and literature review, they detailed as following: the
chemical identity of Ibuprofen, the significance of optical isomerism in drugs, optical stereochemistry,
Comparative Pharmacology of Optical Ibuprofen Isomers, Ibuprofen Pharmacokinetics for Anti-
Inflammatory activity, and the methodology of my experiment. In practical section, I will elaborate the
methodology of how Ibuprofen is synthesized in Changzhou University Chemical Engineering Lab.
Moreover, I will include a discussion section of the experiment result as well as evaluating this
experiment and a bibliography at the end.

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Introduction

Ibuprofen (a.k.a. Advil, Motrin) is regarded as a better alternative to aspirin. “Ibuprofen has been rated
as the safest conventional NSAID by spontaneous adverse drug reaction reporting systems in the UK.”
(Bushra and Aslam, 2010)
Despite ibuprofen’s great reputation, the chemistry of Ibuprofen is intriguing since it exhibits optical
isomerism which makes it unique to NSAIDs such as aspirin.
Finding an interest in optical isomerism and inspired by my chemistry tutor who did a PhD in
biochemistry field, I decided to investigate further the optical isomerism in drugs. Optical Isomerism is
briefly covered in my A-course, it seems to be a minor structural isomerism to learn but has a large
impact on organisms in terms of their biochemistry.
Later, I developed an idea of making pure active form of Ibuprofen after understand its pharmacology.
Eventually, I narrow this aim down to find the step in Kjonaas’ synthesis scheme introducing the optical
isomerism. (Kjonaas et al., 2011)

Why I investigated Ibuprofen?

Ibuprofen exhibits an exceedingly fascinating stereochemistry called optical isomerism (Adams, Bresloff
and Mason, 1975) which I have studied only a corner of an ice burg in A2
Moreover, I always have a curiosity to know how exactly chemists do in a pharmaceutical company
because it is likely to be my future career plan. Plus, it is my personal interest to investigate various kinds
of organic synthesis.
To conclude, this investigation provides me a precious opportunity to look at how the more complicated
pharmaceutical drug is synthesis and to apply the core concept in chemistry in real life. Furthermore, this
project surprised me that I used all physics, biology, and most essentially chemistry to give a bigger
image of ibuprofen optical isomerism.

Why is Ibuprofen Crucial?

1. Ibuprofen is ranked between 29th-38th of the most commonly prescribed medication from 2006
to 2016. (Kane, 2016) It is used both over the counter and under prescription thanks to its good
tolerance and safety.
2. It is One of the three most essential non-steroidal anti-Inflammatory drug. (WHO, 2013)
3. It is very affordable and can cost as little as 0.05USD per tablet. (Amazon,2019)
4. It has some unexpected but potentially important properties. For instance, ibuprofen has shown its
ability to extend the lifespan in some organisms. (He et al.,2014)

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Literature Review
This section accounts how I conducted research for my investigation and shows evaluations for the
sources I have used. I have started the research with the basic chemical information of Ibuprofen,
followed by the stereochemistry and pharmacokinetics of Ibuprofen. Lastly, a methodology for my
research is summarized at the end of this section.

General chemical information of Ibuprofen

I began with the molecular geometry of Ibuprofen since my project is highly related with structure of
Ibuprofen and I can deduce some chemical properties about Ibuprofen by analyzing structure along. (i.e.
carboxylic acid functional group makes Ibuprofen acidic)

By looking at the skeletal formula of ibuprofen below, I found it exhibits optical isomerism.
(Nugrahani and Kartini, 2015)

IUPAC Name 2-[4-(2-methylpropyl)phenyl]propanoic acid

Molecular Formula C13H18O2

Molecular Weight 206.285 g/mol

Hydrogen Bond Donor Count 1

Hydrogen Bond Acceptor Count 2

Rotatable Bond Count 4

(National Center for Biotechnology Information,2018)

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First, I did some very primary through the use of few common search engine Google, Bing, and Baidu. I
did not have a very clear and detailed idea of which part of Ibuprofen I should study. Afterwards, I
decided to do some general background knowledge on Ibuprofen based on Wikipedia. (Wikipedia, 2018)
However, I did not know the Wikipedia can be not very reliable at that time. Although Wikipedia is not a
suitable source for in-depth research, it is a perfect point to start with. After noticing this, I deleted all the
information obtained from Wikipedia from my EPQ draft and tried to find the similar text from other
high-level resources to verify and replace deleted part.

I found National Centre for Biotechnology Information through reading a similar EPQ produced by
Yanzhen Ong. (Ong, 2017) Much of the chemical information I used was verified via National Center for
Biotechnology Information. It is a governmental Biology and Chemistry database containing adequate
essays and Information including the structure, physical and chemical properties, toxicity, and safety of
Ibuprofen. Moreover, the site has its own individual researchers and science professions to peer review
the articles published on their web so that the error is reduced to minimum and the center has both
primary and secondary data. In conclusion, National Center for Biotechnology Information has been a
very reliable source and helped me with understanding the molecular structure of Ibuprofen. (National
Center for Biotechnology Information, 2018)

Then, I found this site (NCBI) has well organized data base containing countless biochemical
information. Followed that I found another useful source PubChem (Pubchem.ncbi.nlm.nih.gov, 2018)
which is also regulated by government and most webpages are reviewed by the high degree researcher.
There is also hazardous chemical information on that web which I have used later in my risk assessment
in practical session.

The significance of optical isomerism in drugs

This section explains why optical isomerism is so important in pharmaceutical drug chemistry.

Unlike Aspirin, Ibuprofen exhibits optical isomerism since it has 4 different groups attached to the chiral
carbon. (i.e. COOH, CH3, H, isobutyl benzene) The isomer of Ibuprofen is S-Ibuprofen which can rotate
the plane of light clockwise and R-Ibuprofen which is able to rotate the plane of light anticlockwise due
to their optical activity. (Hinselwood, 2018) This form of isomerism is crucial since each S and R form
isomer performs differently in human body.

Previously, Thalidomide was discovered as an extremely useful drug that treats pregnant women’s
morning sickness and was used in worldwide in last century. Afterwards, a large portion of users of
Thalidomide had their babies born with deformity.

(Vargesson, 2015)
For this reason, I initiate the research into the optical isomer of Ibuprofen research. As usual, I performed
some elementary research on Bing with the key word optical isomerism and Ibuprofen to seek some

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background knowledge. Meanwhile, in our A-level Chemistry lesson, Dr. Hinselwood have went through
the optical isomerism briefly so I used some notes from him in the form of class notes. (Hinselwood,
2018)

R-form Ibuprofen is biologically less active than S-form Ibuprofen (aka. Dexibuprofen). However, in
human body, the R-form Ibuprofen is slowly converted to the active form S-Ibuprofen via an enzyme
catalyzed reaction. (Kumaresan, 2010)

Comparative Pharmacology of Optical Ibuprofen Isomers

This section compares in detail how R and S form ibuprofen actually work differently in human body.

At clinical concentration, S (+) form Ibuprofen acts as a cyclooxygenase (COX) inhibitor while R (-)
form Ibuprofen is not capable of inhibiting the activity of COX. Since R (-) form Ibuprofen is involved in
lipid metabolism and it may be incorporated into triglycerides in the presence of endogenous fatty acid
which is very rare, it can be considered as another type of drug. It is worth to note that S (+) form
Ibuprofen cannot participate in this event, so racemic Ibuprofen can be regarded as two different drugs.
(Evans, 2001)

Racemic Ibuprofen has been used as non-steroid anti-inflammatory drug for over 40 years and I wonder if
it is better to use pure S (+) form Ibuprofen as a painkiller since the R (+) form Ibuprofen gives an
unwanted effect.

“When racemic ibuprofen is given to humans, a substantial fraction of the dose of R( -)-ibuprofen
(50%-60%) undergoes 'metabolic inversion' to yield S(+)-ibuprofen.” (Evans, 2001)
In other words, if a patient takes in a dose of 400mg racemic Ibuprofen, this person should receive an
effect of about 75% or 300mg effect of pure S (+) Ibuprofen theoretically. However, in Evens’ article, the
author claimed that 200mg pure Ibuprofen is even more effective than 400mg racemic Ibuprofen in
studies around 2000 which implies pure S (+) form has greater than expected efficacy. (Evans, 2001)

This section based primarily on “Comparative Pharmacology of S(+)-Ibuprofen and (RS)-Ibuprofen”

(Evans, 2001) and I am very glad I had found this source through the use of Baidu search engine. (Baidu,
2018) Baidu is not regarded as the most reliable source since all the users can upload journals and most of
them are not peer-reviewed. I would therefore have to check the article by searching the key word
Ibuprofen comparative Pharmacology. Fortunately, I found the same article on another source, namely
research gate. The article provides me with a strong support of why optical isomerism of Ibuprofen is
worth further investigating. Surprisingly, it gives more detail about the metabolic conversion of R(-)
Ibuprofen to S(+) Ibuprofen which is in supplement to my previous chapter. However, the article is
updated lastly in 2001 which might have become invalid as the quick development of modern
pharmacology.

Pharmacokinetics for Anti-Inflammatory activity

This section is intended to show the different pathways for R-Ibuprofen and S-Ibuprofen to work in
human biological system. This section helps me to understand what the usefulness of a pure solution of
active form of Ibuprofen.

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 (Rainsford, 2009)

As seen in the diagram, the main mechanism of Ibuprofen is the non-selective, reversible inhibition of
cyclooxygenase enzyme COX-1 and COX-2. (Mazaleuskaya et al., 2015)
The more potent optical isomer, S-Ibuprofen have about 15 times more effective than R-form.
Essentially, the pharmacodynamic effect ibuprofen is directly connected to the inhibition of prostanoid
synthesis. Single and repeated oral dose can inhibit the production of COX-1-derived TxB2 by over 90
percent. Similarly, the production of COX-2 derived PGE2 was inhibited by over 85 percent.

“PGE2 and PGI2 are proinflammatory prostanoids that enhance edema formation, increase vascular
permeability, and promote leukocyte infiltration.” (Mazaleuskaya et al., 2015)

To understand the pharmacodynamics of Ibuprofen, I did not perform elementary research but went
through the high reliability resources directly. i.e. the resource is not editable and contain a complete
bibliography and author info.
I put Ibuprofen mechanism as my key words into the search engine Bing international edition. After my
own filtration of useful information I found a PPT very useful but its author info is not identified and it
does not have a bibliography. On the other hand, it is not editable and the pdf consists of numerous

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annotated graphs to illustrate the relationship between NASIDs and Cyclooxygenase. (Albany Education,
2018) Afterwards, I checked the knowledge on the other website, and the info in the pdf found previously
was verified. Above all, it is a very useful source that focus much on the COX and NASID. It might not
suit university level researcher as the knowledge is not very steep.
Although it will be very clear if I used the diagram in the pdf which is discussed beforehand, it might not
be 100% true. I would therefore stick on the diagram in the journal written by Rainsford.
(Rainsford, 2009)

The usefulness of pure s-ibuprofen (dexibuprofen)

After all the complex stereochemistry of Ibuprofen, why should we explore the synthesis of S-from
Ibuprofen even it will involve expensive synthesis procedure.
1. Dexibuprofen is more effective for inhibiting acute pain since it contains active form of Ibuprofen
only. It will be released at greater rate to inhibit the activity of cyclooxygenase 2 compared to the
same dose of racemic Ibuprofen. (Derry, Best and Moore, 2013)
2. Studies show that different ethnics may have different biological ability to convert inactive form
Ibuprofen to active Ibuprofen via the catalytic activity of CoA. i.e. The study in Chinese reveals
that around 25% of R-from Ibuprofen will be converted to S- form Ibuprofen. (Zheng et al., 2008)
If dexibuprofen is used, the dose will be exact, so it is easier for doctor to control the dose and
avoid any side effect that may arise if overdose.
3. If an efficient industrial synthesis scheme is developed, it can improve the atom economy of
synthesis Ibuprofen I theory. The product is active Ibuprofen only so it will lead to a virtually
100% increase in yield.

Additional Account of Methodology in Research and the Preparation of

Experiment
In order to find the method of Ibuprofen synthesize, I started with checking the articles online via Google
first (Google.com, 2019) to give a rough insight of the experiment I am going to conduct in the school
lab. I found various way to synthesize Ibuprofen on the Internet, yet many require sophisticated reagents
that our school lab do not have. (i.e. Boot’s and Hoechst synthesis of Ibuprofen) (Ahmadi et al., 2014)
Followed by the primary research on Google Reminded by Dr. Hinselwood, I realized I could try to do
my EPQ experiment in a more advanced lab. Then I discussed with our school lab technician who has a
contact in Changzhou University about the possibility of doing my experiment there. After I successfully
got access to Changzhou University lab, I began to put more attention on academic journals to come up
with a feasible experiment plan that can be done in the university laboratory. I tried to filter the result
with the restriction that it must be reviewed and practiced. Eventually, a two-day lab scheme was picked,
namely, Synthesis of Ibuprofen in the Introductory Organic Laboratory (Kjonaas et al., 2011) through the
use of springer online data base. (Link.springer.com, 2018) and was verified to be a feasible experiment.
(Hinselwood, 2018)

Synthesis of Ibuprofen in the Introductory Organic Laboratory accounts the theoretical mechanism of the
synthesis of Ibuprofen which has been divided into four steps (Kjonaas et al., 2011), each step involving
one or multiple common chemical reagent (e.g. NaBH4, a common reducing agent in step one). It is a
two-day lab with an optional stop point between step two and step three, and the expected lab work hours
is 6hrs in total. (Kjonaas et al., 2011)

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Furthermore, Synthesis of Ibuprofen in the Introductory Organic Laboratory is a very brief article that
accounts all the chemical needed for the experiment and all of these chemicals can be easily found in a
high school lab. (Kjonaas et al., 2011) Moreover, the lab procedures are carefully stated and a brief risk
assessment is included. On the other hand, there is not any diagram for the experiment setup and
experimental apparatus remain unidentified which make my experiment setup challenging. This is also
why I requires a preliminary trial before the final experiment. Moreover, in this synthesis scheme, H-MRI
(magnetic resonance imaging) is needed to determine whether the final product is pure. (Kjonaas et al.,
2011) However, our high school does not have a HNMR scanner since it is beyond the A level study. As
a result, I begin to find the other lab which I have HNMR scanner that I can use.

As PDF can be uploaded or intentionally modified by anyone, so I did an information accuracy check by
finding the same process from its original source, American Chemical Society. (American Chemical
Society, 2018)
I therefore checked if there were other sources giving the same or very similar procedure. (e.g. same
chemical mechanism but slightly different chemicals such distinct reducing agents) It turned out research
gate which is a very reliable scientific journal article web possesses the identical process of Ibuprofen
synthesis procedure so that I decided the lab process is reliable.

Subsequently, I discussed the experiment detail with Dr. Hinselwood and our lab technician to schedule
the preliminary experiment. It is vitally important to do a small-scale pre-test since we can find the
procedure(s) can be improved so that I can have less waste in the final experiment.
Learning from Ong who did an EPQ investigation project in synthesis of Aspirin (Ong, 2017), I decided
to do a preliminary research to find any experiment procedure that need to be improved or improvised.

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Practical
In the detailed description below, it is an account of experimental procedure in a standard scientific
format. It begins with the aim and includes all the reactants and apparatus needed and a methodology.

Aim: Determine the step which introduces optical activity in the chosen scheme.

(Somogyi, Bochner, and David, 2004)

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Chemical Materials:
1. P – isobutylacetophenone (Kjonaas et al., 2011)
2. Sodium Borohydride (Kjonaas et al., 2011)
3. Methanol (Kjonaas et al., 2011)
4. Distilled water (Guo, 2019)
5. Ethyl Acetate (Guo, 2019)
6. Saturated Sodium Chloride Solution (Guo, 2019)
7. Anhydrous Sodium Sulphate (Guo, 2019)
8. Thin piece of Magnesium (Guo, 2019)
9. Tetrahydrofuran (Kjonaas et al., 2011)
10. 10% HCl solution (Guo, 2019)
11. Carbon dioxide (Guo, 2019)

Equipment:
1. Thermometer (Guo, 2019)
2. Long arm electric stirrer (Guo, 2019)
3. Stirrer head (Guo, 2019)
4. Büchner funnel (Guo, 2019)
5. Conical seal (Guo, 2019)
6. Vacuum pump (Guo, 2019)
7. Filter Paper (Guo, 2019)
8. Separating funnel (Guo, 2019)
9. Magnetic Stirrer + its magnetic component (Guo, 2019)
10. Rotary Evaporator (Guo, 2019)
11. Measuring Cylinder (Guo, 2019)
12. Low Temperature Water Bath (Guo, 2019)
13. Clamp (Guo, 2019)

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14. TLC plate (Kjonaas et al., 2011)
15. Capillary tube (Guo, 2019)
16. Carbon dioxide supply (Kjonaas et al., 2011)
17. Molecular sieve (to dry Tetrahydrofuran in advance) (Guo, 2019)
18. Petroleum ether (Kjonaas et al., 2011)
19. 300ml flask (Guo, 2019)
20. 4-neck 150ml flask (Guo, 2019)
21. Transferring pipette (Guo, 2019)
22. Electric balance (Guo, 2019)

Risk Assessment
Chemical Hazard Safety Precaution

Hydrochloric Acid Corrosive Liquid (Pubchem, 2018) Wear glove, lab coat, and safety
googles.

Sodium Borohydride Corrosive, flammable, irritant, Wear glove, lab coat, and safety
acute toxic googles.
(Pubchem, 2018)

P-isobutylacetophenone Flammable Avoid the contact with fire

(Pubchem, 2018)
Use under fume hood

Methanol Flammable, acute toxic Avoid the contact with fire

(Pubchem, 2018)
Use under fume hood

Petroleum Ether Flammable, irritant Avoid the contact with fire

(Pubchem, 2018)
Use under the fume hood

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 Wear facial masks

Reduce the time working with it

Thionyl Chloride Highly toxic, cause death in short Full laboratory dressing and gas
exposure (Pubchem, 2018) masks.

Work under fume cupboard,

quickly remove any Thionyl
Chloride at work place.

Sodium Hydroxide Solution Corrosive (Pubchem, 2018) Wear glove, lab coat, and safety
googles.

Tetrahydrofuran Flammable, Irritant, health Avoid the contact with fire

hazard (Pubchem, 2018)
Use under fume hood

The corrosive liquids are also volatile, so they must be handled under a fume hood throughout the
experiment. Safety googles, nitrile gloves, and laboratory coat should be worn at all times.

Overall Scheme:

Method:

(Guo, 2019)

1. Carefully pour 257 ml of methanol into the 4-neck flask. (Guo, 2019)

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 2. Weigh 8.81g P-isobutylacetophenone and use a transferring pipette to transfer it into the 4-neck
flask. (Guo, 2019)
3. Insert thermometer (with seal), long arm stirrer head (with seal), and büchner funnel(with seal)
into the 4-neck flask. (Guo, 2019)
4. Clamp the 4-neck flask and adjust the position of 4-neck flask so that the 4-neck flask is emerged
in the liquid in the low temperature(273K) water bath. (Guo, 2019)
5. Connect the Long arm stirrer with the stirrer head inserted and turn on the stirrer. (Guo, 2019)
6. Weigh 3.79g of Sodium Borohydride and divide it into 0.79g, 1.0g, 1.0g,1.0g portions, then add it
to the 4-neck flask one portion per time. (Guo, 2019)
7. After adding all the Sodium Borohydride into the solution rinse the neck where we added the
Sodium Borohydride with minimum amount of methanol. (Guo, 2019)
8. Seal the 4-neck flask and allow the stirrer to work for 10 more minutes. (Guo, 2019)
9. After 10 minutes, get 4-neck flask out of the low temperature water bath and leave the stirrer to
stir the reactant mixture at room temperature for further 10 minutes. (Guo, 2019)
10. Perform a TLC Chromatography to check if the product mixture contains desired product before
the extraction procedure. First, sample 0.5ml of product mixture from the product mixture and
dissolve it into 1ml distilled water. Add ethyl acetate to extract the organic impure product. Draw
the base line on the TLC plate and use capillary tube to transfer a small amount of product
mixture on to the marked TLC plate put the plate into a small container with 2ml petroleum ether.
After the solvent stop climbing, measure the distance climbed by the solvent and by the organic
mixture. (Guo, 2019)
11. Pour 150ml water into the 300ml flask and add the product mixture to the beaker. (Guo, 2019)
12. Put the flask on the magnetic stirrer. [Optional Rest Point, 45mins] (Guo, 2019)
13. Divide the reaction mixture into two portions and add 200ml of ethyl acetate to extract three
times for each portion, the organic layer is wanted. (Note to open the stopper to release the
pressure regularly. (Guo, 2019)
14. Wash the organic layer with 100ml saturated NaCl solution for each portion of extracted organic
liquid. (Guo, 2019)
15. Obtain the organic layer and dry by adding drying agent anhydrous Sodium Sulfate. (Guo, 2019)
16. Use vacuum filtration to filter out hydrous Sodium Sulfate and excess anhydrous Sodium
Sulphate. (Guo, 2019)
17. Obtain the pure product by rotary evaporator. (Guo, 2019)

(Guo, 2019)

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 18. Add 4g product from the previous step into the round bottom flask, then add 120ml
dichloromethane and place the flask submerged to a 273K low temperature water bath. (Guo,
2019)
19. Weigh and add 4g of Thionyl Chloride to the system and get the flask out of the low temperature
water bath so that the reaction liquid rises to the room temperature. (Guo, 2019)
20. Leave the reaction liquid to react for 24hrs. (Guo, 2019)
21. The reaction is carefully quenched with 50ml distilled water, the organic layer was extracted and
shaken with 0.2M Disodium hydrogen phosphate and neutralized with NaOH (aq) until the
solution is neutral. The organic layer is extracted again and dried over Sodium sulphate. (Guo,
2019)
22. Use vacuum filtration and rotary evaporation to obtain the title compound which is a pale-yellow
viscos liquid. (Guo, 2019)

23. Check the product purity by a HNMR scan. (Guo, 2019)

(Guo, 2019)

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 24. Weight 2.0g of thin pieces of magnesium and cut them into smaller pieces. (Do not use fine
Magnesium powder, otherwise the reaction will be too vigorous.) (Guo, 2019)
25. Weight 0.986g product from the previous stage into the four-neck flask, add Mg pieces
afterwards. (Guo, 2019)
26. Measure 40ml of dried Tetrahydrofuran into the four-neck flask. (Guo, 2019)
27. Use a magnetic stirrer incorporated with a water bath to stir the reaction mixture. (Guo, 2019)
28. Carefully add 3-4 drops of 1-2dibromoethane to initiate the reaction. Once the reaction is
initiated, it will give a lot of heat due to its exothermic nature. (Guo, 2019)

29. Heat and reflux using the incorporated water bath at 348K-353K for 45mins. (Guo, 2019)

30. Turn
off
the

(Guo, 2019)

heater of the water bath and wait the system to drop to the room temperature and connect the
carbon dioxide supply with a flow rate of 0.3L/hour for 30 mins. (Guo, 2019)
31. Add 40ml of ether followed by 40ml 10%HCl and extract organic layer. Extract using 40ml ether
each time for two more times. (Guo, 2019)
32. Add 100g 5%NaCl solution, shake and obtain the aqueous layer, discard the organic layer. (Guo,
2019)
33. To the aqueous layer, putting 100ml 10%HCl and stir using a magnetic stirrer. (Guo, 2019)
34. Extract again using 60ml ether for three times, add anhydrous sodium sulphate and stir. (Guo,
2019)
35. Vacuum Filtration and rotary evaporation to obtain he final product. (Guo, 2019) (Kjonaas et al.,
2011)

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Testing Optical Activity

Material:
1. Two polarizing filters (Szulc ,2017)
2. A transparent liquid tank
3. A protector or a more precise angle measuring instrument (Szulc ,2017)
4. Synthesized Ibuprofen Solution of a known (if the exact value needed, this is not compulsory in my
experiment) concentration (Szulc ,2017)

Method:
1. Put each of the polarizing filters on the opposite side of the transparent water tank. (Szulc ,2017)
2. Adjust on of the polarizing filter until no light can pass through. (Szulc ,2017)
3. Pour Ibuprofen Solution into the water tank (Szulc ,2017)
4. Adjust the polarizing filter again till no photo can transmit through (Szulc ,2017)
5. Measure the angle of second adjustment (Szulc ,2017)
6. Repeat the experiment to obtain an average. (Szulc ,2017)
7. If the angle of second adjustment is less than 5 degrees, this means the plane of polarization is not
changed or changed exactly multiples of 180 degrees (Szulc ,2017)

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 Photographs of experiment:

Step 9. After 10 minutes, get 4-

neck flask out of the low
temperature water bath and leave
the stirrer to stir the reactant
mixture at room temperature for
further 10 minutes. (Guo, 2019)
(Below)

(Guo, 2019)

Step 4. Clamp the 4-neck flask and

adjust the position of 4-neck flask
so that the 4-neck flask is emerged
in the liquid in the low
temperature(273K) water bath.
(Guo, 2019) (Above)

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21 | P a g e
Step 10. Perform a TLC Chromatography to check if the product mixture contains desired product
before the extraction procedure. First, sample 0.5ml of product mixture from the product mixture and
dissolve it into 1ml distilled water. Add ethyl acetate to extract the organic impure product. Draw the
base line on the TLC plate and use capillary tube to transfer a small amount of product mixture on to
the marked TLC plate put the plate into a small container with 2ml petroleum ether. After the solvent
stop climbing, measure the distance climbed by the solvent and by the organic mixture. (Guo, 2019)
(During TLC chromatography, Left) (TLC Chromatography Result, Right)

(Hinselwood, 2019)

Step12. Put the flask on the magnetic

stirrer. (Guo, 2019) (Above)

Step13. Divide the reaction mixture into

two portions and add 200ml of ethyl
acetate to extract three times for each
portion, the organic layer is wanted. (Guo,
2019) (Right)

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 Step16. Use vacuum filtration to filter out hydrous Sodium Sulfate and excess
anhydrous Sodium Sulphate. (Guo, 2019) (Above)
Step17. Obtain the pure product by rotary evaporator. (Guo, 2019) (Below)

(Hinselwood, 2019)

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 Step 26. Measure 40ml of dried
Tetrahydrofuran into the four-neck
flask. (Guo, 2019) (Below)

Step 24. Weight 2.0g of thin pieces

of magnesium and cut them into
smaller pieces. (Guo, 2019)
(Above)

24 | P a g e
 Step 30. Turn off the heater of the water bath and wait the system to
drop to the room temperature and connect the carbon dioxide supply
with a flow rate of 0.3L/hour for 30 mins. (Guo, 2019)

HNMR Scan-Chloride Substitution

25 | P a g e
 (ChemDraw®, 2019)

Analysis:
1H NMR (300 MHz, CDCl3) δ 7.25-7.23 (d, J = 6 Hz, 2H), 7.06-
7.04 (d, J =6 Hz, 2H), 5.04-4.97 (m, 1H), 2.41-2.37 (m, 2H), 1.82-
1.73 (m, 4H), 0.83-0.78 (m, 6H) ppm.

26 | P a g e
Analysis:
1H NMR (300 MHz, CDCl3) δ 7.23-7.20 (d, J = 9 Hz, 2H), 7.11-
7.08 (d, J =9 Hz, 2H), 3.74-3.67 (m, 1H), 2.45-2.43 (d, J = 6 Hz，
2H), 1.86-1.77 (m, 1H), 1.51-1.43 (m, 3H),0.90-0.83 (m, 6H)
ppm.
27 | P a g e
28 | P a g e
Results of my experiment
Product Whether or not optically active
After step1 Not significant
After step2 Not significant
After step3 Not significant
After step4 Not significant

Conclusion
Each step in my chosen synthesis scheme in my product may have introduced optical isomerism in
Ibuprofen since all the optical activity tests after each step have shown the reaction mixture were not
significantly optically active which means the reaction mixture after each step contains equal amount of R
and S form product.

Future work
The general limitation of this EPQ are funding and time. The experiment design is valid according to my
chemistry teacher and chemistry expert at Changzhou University.
Moreover, the disappointing result is primarily due to the lack of monitoring equipment. I have only
tested the optical activity of the product mixture after finishing each step as the current Changzhou
University lab equipment has not allowed me to test the optical activity continuously. If I can get access
to an equipment that can continuously monitor the change in optical activity during the reaction, I may
give a much stronger conclusion and even suggest a new mechanism for each step.
Alternatively, I could enlarge the scale of Ibuprofen synthesis then take a sample with a fixed time
interval to obtain continuous data. However, this would be very manually demand and it is hard to quench
the reaction.

Experiment Evaluation
*Strength:
1.I followed a reliable method for my investigation experiment and I have discussed with subject expert
in both my high school and Changzhou University.
2.I have used advanced methods i.e. TLC Chromatography and HNMR scan to control the purity.
3. I have recorded every step of experiment procedure in a lab record book in a standard form.
*Points can be improved:
I could have repeated experiment to increase the reliability of my results and could have obtained more
data for statistical analysis.

EPQ Self-evaluation

29 | P a g e
*Strength:
1. I have used a wide range of resources (e.g. Interviews with Dr. Szulc and Dr. Hinselwood, journals and
webpages)
2. A great independence was shown to conduct my experiment in Changzhou university.
3. I have evidently improved my chemistry practical skills through this opportunity.
4. I have learned a lot about the pharmaceutical drugs mechanisms which is not in the curriculum.
5. I realized that recording every lab procedure in a standard form makes tracking back much easier.
6. I practiced to use some common organic chemistry synthesis apparatus and analysis equipment and
software.
*Points can be improved:
1. I should have built more connections between each part of my EPQ. EPQ is not a fiction, as much as
possible readers should be able to follow the direction of this article easily.
2. More experiment could be done and data would be sufficient for a statistical test.
3. I should concentrate more on Ibuprofen synthesis at the beginning of my EPQ investigation.

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Appendices
Here are some notes taken when I interviewed Dr. Hinselwood.

I. The synthesis of Ibuprofen will normally give a racemic product solution.

II. The purity of the product can be checked in each step via NMR.
III. The final yield of Ibuprofen synthesis using this scheme 1(shake with HCl only) might be very
low, less than 5%.

Followed by the notes taken with Dr. Szulc.

I. The optical activity is a bulk quantity and can be measured with a polarimeter.

35 | P a g e