The synthesis of Ibuprofen PDF

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The synthesis of Ibuprofen...

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Name: Febin Xavier

Date: 29/10/20

Experiment 5 – Planning a synthesis – The synthesis of Ibuprofen Introduction and Safety Data: Aims of the experiment were to determine possible synthetic routes from pure sample of Isobutylbenzene in order to form Ibuprofen using Scifinder and google scholar for an experimental method. Factors taken into account were expenses, atom economy, hazard risk and efficiency of the reaction.

Chemical

Volume (mL)

Aluminium chloride Hydrogen chloride Isobutylbenzene

420

Mass (g)

405

Dichloromethane Acetic Anhydride

Concentrati Hazard on (moldm3 )

302

3.04 0.3 2.25

230

1.71

150

Sodium sulfate Petroleum Ether

450

Sodium Hydroxide Methanol

270 450

0.10

Sodium borohydride

18.0

magnesium 1,2-dibromomethane

0.476

80.0 dropwise

Brine (sodium chloride)

150

0.50

Corrosive, irritant Corrosive, Acute toxic Flammable, irritant, Environmental hazard Health hazard, Irritant Flammable, Corrosive, Irritant Corrosive, Irritant Flammable, Irritant, Health hazard, Environmental hazard Corrosive Flammable, Acute toxic, Health hazard Flammable, Corrosive, Acute toxic, Irritant, Health hazard Flammable, irritant Acute toxic, Irritant, Health hazard, Environmental hazard Irritant

Experimental Method: +

+

Isobutylbenzene AlCl3

+

Name: Febin Xavier

Date: 29/10/20 CH3COOH

HCl

H3O

H2O

H3 O

NH2OH

Ibuprofen Preparation of sample to be separated into aqueous and organic layers: An ice bath was prepared containing AlCl3 (405g) and CH2Cl2 (150mL) in a round bottom flask which were transferred simultaneously. Isobutylbenzene (302g) and acetic anhydride (230g) were combined with the previous solution, resulting sample being stirred for ~2 hours at 0°C. This is where the Friedel-Crafts acylation takes place. Once the sample reached room temperature, the reaction was quenched using HCl (150mL) and the aqueous layer was separated using CH2Cl2 (150mL). The organic layer being relatively less dense was then washed NaOH (150mL) followed by NaCl (150mL) and H2O (!50mL) before separation. The separated solution was then dehydrated with Na2SO4. Synthesis of 1-(4-isobutylphenyl) ethanol: Methanol (450mL) was used to dissolve p-isobutylacetophenone (92.25g) which then followed by addition of Sodium Borohydride (18g) where the solution was left for ~10 minutes. This sample was then reacted with HCl (150mL) where the dense aqueous layer extracted via petroleum ether (1.125L) whilst organic layer once again dehydrated using Na2SO4 with solvent undergoing evaporation. Synthesis of 1-chloro-1-(4-isobutylphenyl) ethane: In a separating funnel HCl (150mL) and 1-(4-isobutylphenyl) ethane were combined and vigorously shaken for mixture to undergo complete reaction. Petroleum ether was once again used to extract the organic product as in the previous stage. Synthesis and purification of Ibuprofen 2-(4-isobutylphenyl) propanoic acid: 1-chloro-1-(4-isobutylphenyl) ethane, magnesium (80g) and 1,2-dibromomethane (~25 drops) were collectively combined in a flask and refluxed for ~60 minutes. Once the solution attained room temperature the solution mix was decanted into separating funnel with petroleum ether (750mL) and HCl (150mL) for extraction of the aqueous layer. HCl (150mL) was used to acid wash the organic layer and then separated with Petroleum ether which gave the desired product Ibuprofen in the process. Results and Discussion:

Table of Costs: Chemical Aluminium chloride Hydrogen chloride Isobutylbenzene Dichloromethane Acetic Anhydride Sodium sulfate Petroleum Ether

Cost per Gram (£ g1 )/mL/L

Total Cost (£) for practical

0.237 0.194 0.204 0.313 0.0950 0.02948 0.0298

95.985 81.48 61.608 46.95 21.85 0.2948 13.41

Name: Febin Xavier Sodium Hydroxide Methanol Sodium borohydride magnesium 1,2-dibromomethane Brine (NaCl) Total Cost = £564.14

Date: 29/10/20 0.0904 0.187 5.40 0.289 0.113 0.0535

24.408 84.15 97.20 23.12 5.65 8.025

The chosen reaction scheme for synthesis of Ibuprofen involved Friedel – Crafts acylation mechanism which included fewer steps i.e., 2 and 4 for both synthesis routes. The chosen pathways also had higher atom economy, making it efficient and hence more sustainable. It posed no threat as an environmental hazard either due to its less hazardous reactants. The experiment was altered, and measurements were scaled up by a factor of 75 to ensure the approximate yield of ~10g was achieved. The literature yield for the synthesis gives 13.8g. Any deviations included the non-use of nitrogen gas in consideration of the nature of lab and the scaling of measurements to ensure the approximated yield. Analytical techniques: Spectroscopic analysis – Infra red spectrum of the Ibuprofen could be obtained, and the resulting spectra compared to a known literature spectrum of pure Ibuprofen for comparison and to determine the purity and identity of the final product. Any impurities can be observed by the abnormalities in the peaks for specific functional groups in the spectrum of the product. Melting point determination – This technique could also be used to assess the purity of the synthesised Ibuprofen once again comparing to literature values of melting point for ibuprofen (75-77°C). If lower, than stated melting point then gives indication of possible impurities in the synthesised molecule. Conclusion: The reaction scheme chosen was the best and optimal reaction pathway as it had few steps and giving high atom economy. It was also efficient both economically as well as environmentally.

References: Gharib, A., Noroozi Pesyan, N., Vojdani Fard, L. and Roshani, M., 2014. Synthesis of Ibuprofen Using Silica-Supported Preyssler Nanoparticles as an Eco-Friendly, Inexpensive, and Efficient Catalyst. Organic Chemistry International, 2014. Dr D.R. Snead and Prof.Dr.T.F. Jamison, A three-minute synthesis and purification of Ibuprofen: Pushing the Limits of Continuous-Flow Processing, 2014. Tumusiime, Shakirah and Mandebvu, Tinodaishe Antoinette, "Four step synthesis of Ibuprofen" (2014). Sr. Seraphim Gibbons Undergraduate Symposium. 27. Mc.Kilburg & R. Tyler, Ibuprofen Synthesis, 2017.

Name: Febin Xavier

Date: 29/10/20...