- Jul 19, 2021
- Reaction score
Step 1: 1 -> 2
Synthesis of 2: From the stockroom, obtain a 14/20 50 mL round-bottom (RB) flask and 14/20 side-arm addition funnel to fit. In a good hood, put 1.0 g (5.9 mmol) m-chloropropiophenone, 1, into the 50 mL round-bottom (RB) flask (obtain from stockroom) clamped above a magnetic stirrer, add 5 mL dichloromethane, CH2Cl2, and a magnetic stir bar and stir until the solid is dissolved. Place the addition funnel on the flask. Put 6.0 mL (6.0 mmol) of a 1.0 M solution of Br2 in CH2Cl2 in the funnel and add a few drops to the flask. If the reaction does not begin immediately (as judged by the disappearance of the color of the bromine), warm the flask briefly with your hand or a warm-water bath. Once the reaction begins, the color of the bromine will rapidly disappear, and the flask should be placed in an ice bath. The bromine solution can now be added dropwise to the flask with stirring; add the bromine solution just rapidly enough so that the color of the bromine has disappeared before the next drop is added (Note 1).
Isolation of 2: After all the bromine has been added, remove the dropping funnel, add two boiling chips and set up a simple distillation apparatus by replacing the addition funnel with a microscale distillation head obtained from the stockroom. Insert the special ground joiner thermometer and connect the condenser to the water. Distill the solvent from the reaction mixture by placing the stirred flask in a beaker of warm water kept at about 55-70 °C by a hot plate. When all the CH2Cl2 has distilled over (a little less than 10 mL will be collected due to evaporative loses; the temperature of the distillate should rise to 40 °C the bp of CH2Cl2 and then fall when the CH2Cl2 stops distilling Don’t keep heating after this happens.), remove the distillation apparatus.
Step 2: 2 -> 3a.
Synthesis of 3a: The small amount of dense liquid remaining in the flask at this stage is 2 (2-bromo-3’- chloropropiophenone), which is a mild lachrymator (see Cautions above). Using a funnel, add to the flask 10 mL of a 50:50 mixture of 5 mL t-butylamine and 5 mL N-methylpyrrolidinone (NMP), and heat the (unstoppered) flask in a 55-60 °C water bath with stirring for 10 minutes (Note 2).
Isolation of an ether solution of 3a: The flask now contains 3a, the free base form of bupropion. (Although most of the lachrymatory 2 has been consumed in forming 3a, you should continue to work in the hood.) There are two other substances, besides 3a in the flask: the excess t-butylamine and the NMP solvent. All three substances are soluble in ether, but the last two are also soluble in water, while 3a as the free base is not. We will take advantage of these solubility differences to isolate our product in pure form. Transfer the contents of the flask to a separatory funnel, add 25 mL water and extract the mixture 3 times with 25 mL portions of ether, collecting and combining the ether extracts in a beaker. Remember to shake the separatory funnel well during each extraction and to wait for the layers to fully separate. (Caution! Ether is very volatile and pressure will develop!) The ether layer(s) will be on top and contain your product, 3a, while the aqueous layer will be at the bottom. The water layer contains the NMP solvent and excess t-butylamine; discard this layer, rinse the funnel with water, and return the combined ether extracts to the separatory funnel. Shake the ether solution five times with new 25 mL portions of water each time, allowing the layers to separate each time and then discarding the water layer. Transfer the ether solution to a clean, dry Erlenmeyer flask and remove any remaining water by stirring it in the beaker with anhydrous Na2SO4. You should add Na2SO4 until new material swirls freely in the solvent without clumping. Remove 2 to 3 mL (a Pasteur pipetful) of this ether solution into a vial and allow the ether to evaporate in your locker, until next time so that you can run an NMR on the free amine 3a in CDCl3. Run the C-13 NMR if instructed to do so.
Step 3: 3a -> 3b.
At this point, your beaker contains a solution of the free base of bupropion, 3a, in ether. Like most amines, the free base of this compound is soluble in ether and insoluble in water. But when 3a is reacted with an acid, it will form a salt which will have opposite solubility properties, being insoluble in ether but soluble in water. Most pharmaceuticals are amines like bupropion, and they are nearly always marketed and administered in their salt form, usually the chloride. Following an ancient convention, amine chlorides in pharmacy and medicine are referred to as the “hydrochloride”: e.g., morphine hydrochloride, fluoxetine (Prozac) hydrochloride. We will form the hydrochloride salt in a solvent mixture consisting mostly of ether, so that it will precipitate out in crystalline form.
Synthesis of 3b: Decant the ether solution through a funnel loosely plugged with cotton into a dry beaker chilled in an ice bath. The white powder remaining behind is the drying agent, Na2SO4. Wash any residual 3a from this powder by stirring it with enough fresh ether to cover it, allow it to settle, and decant the ether through the same cotton-plugged funnel into the beaker in the ice bath. You can then discard the cotton plug and the Na2SO4 desiccant. Using a Pasteur pipet, add a 2:10 v:v solution of conc. HCl:isopropyl alcohol dropwise with manual stirring to the chilled ether solution until the contents of the beaker are acid to pH paper. A few pipets-full will be needed (Note 3); test the pH by touching a stirring rod moistened with the solution to a small piece of pH paper moistened with water. About halfway to the equivalence point, sparkling white crystals of bupropion hydrochloride, 3b, will begin to form in the beaker. When the pH of the beaker is < 3 enough acid has been added.
Isolation of 3b: Cover the beaker loosely with a watch glass, and allow it to chill thoroughly for 5-10 minutes in the ice bath. Collect the crystals by gentle vacuum filtration, wash them twice with small portions of ether, and let them air dry. (Do not force a rapid stream of air through the crystals during vacuum filtration; if you do, they may develop a static electric charge, and when approached with a spatula will leap around the bench like Mexican jumping beans.) When the crystals are dry, determine the mass, calculate the percent yield, and determine the mp.
Note 1. You should be able to see small bubbles forming where the bromine solution falls into the flask. What do you think these bubbles consist of? If the humidity is high enough, you may notice a fog or fumes coming from the mouth of the flask as the reaction takes place: what is this? Alpha halogenations are acid-catalyzed; does this explain why this reaction is often slow at first, but then proceeds rapidly?
Note 2. The displacement of a bromine atom by an amine is usually an SN2 process. Why would you expect that the reaction you are carrying out, using t-BuNH2, might be much slower than the same reaction using methyl amine? What other reactions would be expected to compete with the SN2 reaction, which forms bupropion? The choice of solvent in these reactions can be very significant. Try to find a discussion of solvent effects in SN2 reactions in your textbook, in the library, or in the Web.
Note 3. The HCl solution was made by mixing 2 mL concentrated HCl (12.0 M) with 10 mL isopropyl alcohol. Assuming there is no contraction or expansion of volume on mixing, what is the molarity of the resulting solution? How many mL should you need if all your starting material (5.9 mmol 1) has been entirely converted to 3a?
The aqueous extracts can be washed down the drain with lots of COLD water. Discard the ether filtrate in the appropriate waste container in the hood.
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