Prozac is a famous antidepressant, also known as the “happy drug” as it can help alleviate depressio — Organic Chemistry Chemistry Question

Prozac is a famous antidepressant, also known as the “happy drug” as it can help alleviate depression. The active ingredient in Prozac is fluoxetine. Fluoxetine is prepared from β–dimethylaminopropiophenone in a four step sequence.

[VISUAL]

The target molecule can be obtained by a one–pot reaction involving three or more starting compounds also known as a multicomponent reaction (MCR). Among MCRs classic name reactions have developed into popular chemical reactions in the pharmaceutical industry for the preparation of compound libraries of low molecular drug–like compounds. For example, the Mannich reaction is a “one pot” combination reaction of three synthetic fragments to make a single product. This multicomponent reaction can be applied to the synthesis of β–dimethyl-aminopropiophenone, as paraformaldehyde and dimethylamine hydrochloride are combined in the presence of acetophenone to produce directly β–dimethyl–aminopropiophenone.

[VISUAL]

Experimental
Chemicals
• Acetophenone, liquid
• concentrated HCl aqueous solution
• dimethylamine hydrochloride, solid
• paraformaldehyde, solid
• ethanol, 95 % aqueous solution
• ethyl ether
• hexane
• methanol
• ethyl acetate
• acetone
• NaHCO₃, aqueous solution
• KMnO₄ , aqueous solution, 0.1 mol dm–3
• ZnCl₂, solid
• FeCl₃, 2.5% aqueous solution
• AgNO₃, 5% aqueous solution
• NaOH, 10% aqueous solution
• NH₃, aqueous solution (c = 2 mol dm–3)
• 2,4–dinitrophenylhydrazine
• conc. sulfuric acid

Apparatus and glassware
• round–bottomed flask, 25 cm₃
• Erlenmeyer flask, 50 cm₃
• stirrer
• temperature controller
• heating mantle
• sand
• support stand
• clamp and clamp holder
• melting point apparatus
• capillary tubes
• magnetic bar
• reflux condenser
• hose
• Büchner funnel
• suction flask
• glass rod
• filter paper
• beaker, 100 cm₃
• TLC plate (silica gel 60 F254, layer thickness: 250 µm, on glass support)
• micro–syringe
• developing chamber with a lid
• UV lamp

Procedure
Inside a fume hood, add 2 cm₃ of acetophenone, 0.65 g of dimethylamine hydrochloride and 1.76 g of paraformaldehyde into a 25 cm₃ round–bottom flask. Add 4 cm₃ of 95% ethanol to the flask, followed by 40 µdm₃ of concentrated HCl. Add your magnetic bar and equip the flask with a reflux condenser. Reflux the mixture for 2 hours by placing the flask in a sand bath preheated to 120 °C. Allow the reaction mixture to cool slightly (to 50~80 °C) and transfer it to a small Erlenmeyer flask (pour, do not pipette since the material may freeze in the pipette). Add 16 cm₃ of acetone and allow the flask to cool to room temperature. Mix thoroughly with a glass stirring rod. Cool the mixture in an ice–bath to complete the crystallization. Filter by suction using a Büchner funnel with a filter flask and wash the solids with 4 cm₃ of acetone. (You can use 1 cm₃ acetone to help transfer the last of the solid in the flask.) Let the product dry for at least 20 minutes on the funnel. Weigh the products and determine their melting point.

Extract a free amine into the organic solvent with aqueous NaHCO₃ solution for developing TLC. Dissolve about 0.1 g of the product with distilled water and then transfer the solution into a small separatory funnel. Add ethyl ether as an organic solvent. Neutralize the water layer with aqueous NaHCO₃ solution. Use a pH paper. Obtain the organic layer for TLC. Develop a TLC plate in ethyl acetate: hexane (2 : 1, v/v) or ethyl acetate: methanol (2 : 1, v/v).

Qualitative Tests
Perform the following tests with the product and report the observation.
1) The Bayer Test (Potassium permanganate); ALKENES AND ALKYNES
(This test is useful for indicating the presence of most olefinic or acetylenic functional groups.)
Dissolve 30 mg of the product in 2 cm₃ of water. Add dropwise aqueous solution of KMnO₄ (c = 0.1 mol dm–3) report the results.
2) Lucas test; ALCOHOLS
(This test is useful for distinguishing among lower molar mass of primary, secondary, and tertiary alcohols.)
Prepare Lucas’s reagent by dissolving 136 g of zinc chloride in 89 cm₃ of conc. HCl with cooling in ice bath. Add 2 cm₃ of Lucas’s reagent to 30 mg of the product in a test tube. Note the time required to form the insoluble alkyl chloride, which appears as a layer or emulsion.
3) Ferric chloride test; PHENOLS
(This test is useful for the recognition of phenols.)
Dissolve 30 mg of the product in 2 cm₃ of water or a mixture of ethanol and water, and add up to 3 drops of the 2.5% aqueous ferric chloride solution. Most phenols produce red, blue, purple, or green coloration; enols give red, violet, or tan coloration.
4) Tollen’s reagent (silver –ammonia complex ion); ALDEHYDES
(This test is useful for distinguishing aldehydes from ketones and other carbonyl compounds.)
To a clean test tube, add 2 cm₃ of the 5% silver nitrate solution and 1 drop of the 10% sodium hydroxide solution. Add aqueous ammonia solution (c = 2 mol dm–3) drop by drop with good shaking until the dark precipitated silver oxide just dissolves. Add 1 drop of the liquid or 30 mg of the product to be tested, shake the tube to mix, and allow it to stand at room temperature for 20 minutes. If nothing happens, heat the tube in a beaker of water at 35 °C for five minutes.
5) Test with 2,4 –dinitrophenylhydrazine; ALDEHYDES AND KETONES
(This test is useful for identifying aldehydes and ketones.)
Prepare 2,4–dinitrophenylhydrazine reagent by dissolving 3 g of 2,4–dinitrophenylhydrazine in 15 cm₃ of conc. sulfuric acid and adding this solution, with good stirring, to a mixture of 20 cm₃ of water and 70 cm₃ of 95% ethanol. Dissolve 100 mg of a solid product in 2 cm₃ of 95% ethanol, and add this solution to 2 cm₃ of the 2,4–dinitrophenylhydrazine reagent. Shake the mixture vigorously; if a precipitate does not form immediately, let the solution stand for 15 min.

Results
– Reagents & Products (Show calculations)
Reagents (compound names) | M (g mol–1) | m (g) or V (cm₃) used | mmole used | equivalent | physical properties
Product: [M = g mol–1]
Mass: g
Yield: %
– Melting Point : °C (Observed) | °C (Reported in the literature)
– Rf values (Record the Rf values and the size and shape of each spots):
(Show calculations)

Test result | Test Reagent | Observed | expected
1) KMnO₄ (Bayer’s test)
2) HCl, ZnCl₂ (Lucas’s test)
3) FeCl₃ (Ferric chloride solution)
4) AgNO₃ / NaOH / NH₃ (Tollen’s reagent)
5) 2,4–dinitrophenylhydrazine