In the Laboratory (Student Instructions) page 1

A Short, One-Pot Synthesis of Zyban (Wellbutrin, Bupropion)

[The following document consists of two parts: the Student Instructions, pp. 1-3, and the Guide for the Instructor,
pp. 4-22. Notes in the Student Instructions which are preceded by “Ins” are notes for the Instructor and can be
found at the end of the Guide for the Instructor, on pp. 20-21. Those notes preceded by “Student Notes” are for
the student and can be found at the end of the Student Instructions on p. 3.]

Student Instructions
Precautions: Wear gloves and carry out all steps in a well-functioning hood.
Bromine liquid and vapor are extremely caustic to skin and lungs, and should be
used only in the hood. Avoid breathing dichloromethane vapors, which are a
probable carcinogen; keep this solvent and all mixtures containing it in the hood at
all times. Ether vapors are extremely flammable; any open flame or spark can cause
a violent explosion. If you spill the contents of the reaction after the addition of the
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bromine but before the addition of the amine (during 2 3a), do not try to clean the
spill but tell your instructor immediately (Ins 1); the reaction mixture at this stage
contains intermediate 2, which is a lachrymator (irritates eyes and causes tears like

Cl Cl Cl Cl Cl
Br2 t-BuNH2 HCl

Br NH NH2
O O O O

1 2 3a [free base] 3b [HCl salt]

onions) .

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[ 1 2 ] Put 1.0 g (5.9 mmol) m-chloropropiophenone, 1, in a 50 mL round-bottom (RB) flask,
add 5.0 mL dichloromethane, CH2Cl2, and a magnetic stirbar and stir until the solid is dissolved.
Clamp the flask in the hood and attach a 50 mL pressure-equalizing dropping funnel. 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 RB. 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 RB 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

*Corresponding author; email: [email protected].

so that the color of the bromine has disappeared before the next drop is added (Student Note 1; Ins
2).
After all the bromine has been added, remove the dropping funnel and insert a simple distillation
apparatus. Distill the solvent from the reaction mixture by placing the stirred RB in a heated (55-60
(C) water bath. When all the dichloromethane 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
dichloromethane), remove the distillation apparatus (Ins 3).

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[ 2 3a ] The small amount of dense liquid remaining in the flask at this stage is 2 (2-bromo-31-
chloropropiophenone), which is a mild lachrymator (see Precautions above). Using a funnel, add to
the flask 10 mL of a 50:50 mixture of t-butylamine and N-methylpyrrolidinone (NMP), and heat the
(unstoppered) flask in a 55-60 (C water bath with stirring for 10 minutes (Student Note 2).
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 tap
water, and return the combined ether extracts to the separatory funnel. Shake the ether solution five
times with 25 mL portions of water, 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 K2CO3. You should add K2CO3 until new material
swirls freely in the solvent without clumping.

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[ 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.
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, K2CO3. Stir this powder 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 K2CO3
desiccant.
Using a Pasteur pipet, add a 20:100 v:v solution of conc. HCl:isopropyl alcohol dropwise with
In the Laboratory (Student Instructions) page 3

manual stirring to the chilled ether solution until the contents of the beaker are acid to pH paper (Ins
4). A few pipets-full will be needed; test the pH by touching a stirring rod moistened with the
solution to a small piece of pH paper moistened with water (Student Note 3).
About half way 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.
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 and calculate the percent yield. Your instructor
may wish you to determine the mp and/or run a TLC of your product (Ins 5).

Student Notes

Note 1. You should be able to see small bubbles forming where the bromine solution falls into the
flask; what do you think these are? 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 the Web.)
Note 3. The HCl solution was made by mixing 20 mL concentrated HCl (12.0 M) with 100 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 converted to 3a?)