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.

Investigation: Investigate the optical isomerism in Ibuprofen.

Name: Yuntong Guo

Candidate Number: 0109

(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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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)

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 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

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 (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.

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HNMR Scan-Ibuprofen
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.
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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.

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