In the Laboratory
page 1
(Student Instructions)
A Short, One-Pot Synthesis of Zyban (Wellbutrin, Bupropion)
Daniel M. Perrine,* Jason T. Ross, Stephen J. Nervi, and Richard H. Zimmerman
Department of Chemistry, Loyola College in Maryland, 4501 N. Charles St., Baltimore, MD 21210-2699
[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
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
t-BuNH2
Br2
O
Br
O
1
Cl
2
Cl
HCl
O
NH
3a [free base]
O
NH2
3b [HCl salt]
onions) .

[ 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: dmp@loyola.edu.
In the Laboratory
(Student Instructions)
page 2
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).

[ 2 3a ] The small amount of dense liquid remaining in the flask at this stage is 2 (2-bromo-31chloropropiophenone), 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.

[ 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 cottonplugged 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.
Note 2.
Note 3.
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?
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.)
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?)
In the Laboratory
page 4
(Guide for the Instructor)
Guide for the Instructor
Cl
Cl
Cl
t-BuNH2
Br2
O
Cl
Br
O
HCl
O
1
2
C9H9ClO
168.62
C 64.11% H 5.38%
Cl 21.03% O 9.49%
C9H8BrClO
247.51
C 43.67% H 3.26%
Br 32.28% Cl 14.32% O 6.46%
Cl
NH
3a [free base]
C13H18ClNO
239.74
C 65.13% H 7.57%
Cl 14.79% N 5.84% O 6.67%
O
NH2
3b [HCl salt]
C13H19Cl2NO
276.20
C 56.53% H 6.93%
Cl 25.67% N 5.07% O 5.79%
Background
Some time ago, over the course of writing a book on the chemistry of psychotropic drugs,1 it
occurred to the principal author, DMP, that the structures of some widely prescribed drugs, in
particular some of the antidepressant and antipsychotic drugs, were simple enough that it might be
possible to develop a laboratory procedure allowing students in the introductory organic chemistry
course to synthesize them. This led eventually to a publication in this journal 2 of a synthesis of “Nmethyl Prozac,” the immediate precursor of fluoxetine (Prozac). As had been hoped, many students
who were otherwise bored or unmotivated by organic chemistry became intrigued by the idea of being
able to use their new knowledge to synthesize a drug as widely used and as widely discussed as
Prozac.
The structure of bupropion, 3b, which is the HCl salt of (±)-2-(tert-butylamino)-31chloropropiophenone, is even simpler than that of fluoxetine, and the recently discovered and unique
application of bupropion as an aid in smoking cessation (Zyban) greatly enhances student interest in
its synthesis. How Zyban works is not fully understood, but it probably involves an interaction with
CNS receptors for norepinephrine and dopamine (the drug does not interact with receptors for
serotonin or nicotine); its principal metabolite, hydroxybupropion (formed by reduction of the ketone
function to an alcohol) is also active 3. Since there is some evidence that nicotine, cocaine, and other
addictive drugs owe their reinforcing properties to eventual interaction with dopamine receptors in
the mesotelencephalic (ventral tegmental) area of the brain 4, it was hoped that bupropion might be
useful in suppressing the craving for cocaine as well as nicotine. However, an extensive double-blind
trial of bupropion (300 mg/day) for this use among cocaine-dependant patients showed that it had
no benefit over placebo 5. (But it is interesting to speculate whether larger doses of bupropion might
have shown some benefit; unfortunately, doses greater than 400 mg/day cause a significant increase
In the Laboratory
page 5
(Guide for the Instructor)
in the risk of seizures.)
The only synthesis of (±)-2-(tert-butylamino)-31-chloropropiophenone we found in the literature
is the Burroughs-Wellcome (BW) patent of Mehta 6. A later publication from BW workers Hill and
Scharver, which describes the synthesis of 14C- and 3H-labeled forms of the drug, follows essentially
the same procedure as the patent 7. Neither was very promising for our purposes: in the patent
literature (4) step 2 3a alone takes over 24 hours to carry out, and in the procedure of Hill et al.
(5), it takes over 3 days! This and other aspects of the Hill procedure in particular seemed to invite
maximum decomposition of the labile free base 3a. Features of the bromination step (1
2) as
described in these references also seemed peculiar, such as using nearly 2 equivalents of Br2 and
refluxing: in our hands, GC-MS showed that these conditions result in the formation of considerable
amounts of unwanted ,-dibromopropiophenone. Finally, the BW procedures involved lengthy and
cumbersome workup procedures for both steps.
In the event, we found that the bromination step 1
2 worked quite well in CH2Cl2 at ice
temperature with one equivalent of bromine. This is essentially the method used by Boyer and Straw
for the bromination of (unsubstituted) propiophenone 8, except that these workers used CCl4 as a
solvent. While the bromination of 1 was marginally more rapid in CCl4 than in CH2Cl2, current
concerns about the toxicity of this solvent ruled out its use. The additional hour of reaction time
employed by Boyer and Straw we found to be unnecessary for 1.
In an effort to find other reaction conditions for step 2
3a, we searched the literature for
syntheses of -tert-butylaminopropiophenone, the ring-unsubstituted analog of bupropion. We found
only one reference 9 to the synthesis of this compound, and it prescribed 5 hours reflux in benzene
and resulted in only a 37% yield. We then tried N-methylpyrrolidinone (NMP) as a solvent and found
that the reaction of t-butyl amine and 2 at room temperature in this solvent was noticeably exothermic
and went to completion (as judged by disappearance of 2 by GC-MS) in less than 0.5 hours. Out of
consideration for the impatience of youth, we tried warming the reaction in a 60 (C water bath and
found it was complete in less than 10 min. By contrast, when the reaction is carried out in
acetonitrile, the solvent used by the BW workers, it is not exothermic, considerably slower, and
according to Hill et al. (7) resulted in only a 43% yield, while our yields averaged 75-85%.
A final improvement was to dispense with the isolation of lachrymatory 2. Unfortunately, NMP
cannot be used for step 1 2(bromine reacts violently with NMP) and step 2 3 will not take place
in CH2Cl2, but it is quite easy to distill off the CH2Cl2 after step 1 2 (the distillation also serves to
remove any HBr) and immediately add the amine and NMP to the residue in the flask. With all these
improvements incorporated, the majority of students are able to complete this one-pot, two-step
synthesis including the isolation of the HCl salt, in less than two hours.







Identification of Product
The following data is presented in considerable detail because we thought aspects of it (for
example the high-field NMR and DEPT spectra) could be used by many instructors in a useful way
to supplement the laboratory experiment (for instance as quiz or exam material) and to allow it to be
integrated with the organic lecture material.
•
Analytically Pure Material. Since an excess of t-butyl amine is used in the reaction, care must
be taken to thoroughly wash the ether solution of 3a with water to remove this reactant.
Otherwise, when the hydrochloride salt is formed by addition of HCl to the ether solution of 3a,
t-butylamine HCl (TBHCl), which is much less soluble in ether than bupropion HCl, will
In the Laboratory
page 6
(Guide for the Instructor)
precipitate before or with 3b, the HCl salt of bupropion. If there is any more than a very small
percentage of TBHCl contaminating 3b, even repeated conventional recrystallization (dissolving
the amine salt in EtOH and adding ether to induce precipitation) may fail to remove it. We
initially sent out for elemental analysis what we thought was a very pure sample of 3b, only to
be disappointed by the following results:
Bupropion HCl
C
H
N
Cl
O
Calculated
56.53
6.93
5.07
25.67
5.79
Found
54.43
7.40
6.17
26.93
54.53
7.67
6.23
27.18
Tert-Butyl HCl (TBHCl)
Calculated
43.84
11.04
12.78
32.35
When we realized that the most likely contaminant was TBHCl, we reformed the bupropion free
base, washed its ether solution several times with water, and again formed the HCl salt. We also
carried out a final recrystallization by chilling a hot saturated solution of 3b in sec-butyl alcohol.
(This is the solvent used by Hill (7). Crystallization from this viscous solvent is slow and it is best
to let the solution stand overnight in the freezer; the crystals can then be collected and washed
with cold sec-butyl alcohol, then ether.) Material so purified resulted in analytically pure
material: C 56.50, H 6.78, N, 5.00% [Quantitative Technologies, Inc., Whitehouse, NJ]. Note
that the presence of TBHCl contaminating 3b is not easy to detect. It has no absorption in the
UV, so is invisible with most HPLC detectors. Small amounts merge with the large t-butyl peak
of 3b on PNMR. It stays at the baseline on TLC (below); on GCMS it elutes in the first few
minutes with the solvent peak, when the detector is off. Since 3b decomposes on heating (see
below) its melting point is a poor index of purity.
•
Melting Point. It would be best if students could allow their product to dry and determine the
melting point as the simplest means of identification. However, we were unable to reproduce the
literature melting point, which is given in the patent (6) and the Merck Index 10 as 233-234 (C.
Material which had been recrystallized several times to analytical purity, as well as an authentic
sample from Sigma, turns brown at about 196 (C and then darkens and decomposes with
evolution of gas at 214 (C. It is possible that when bupropion is crystallized from our solvent
system (ether, i-PrOH, water) it emerges as in a different crystalline form than when the patent
process (from water) is followed 11. More likely, the patent data is a typo or an error.
•
TLC. Hill et al. do not give a mp for their product, but they do give an identification by TLC.
Using an eluant of CHCl3:Et3N 19:1 (v:v) they report an Rf of 0.61-0.63 (7). We found this was
quite reproducible (Rf of 0.62) when we used the same eluant system and J. T. Baker SG IB-F
flexible TLC sheets (“Baker flex”). These sheets are inexpensive and some laboratory instructors
might wish to assign this to their students as a way of identifying their product.
In the Laboratory
(Guide for the Instructor)
page 7
•
HPLC. Less convenient as a method of student identification is an HPLC method we developed.
Using a Whatman Partisil 10 ODS-3 column with an eluant of 43:40:17 MeOH:MeCN:buffer
[0.012 M KH2PO4] (v:v:v) with a flow rate of 1.0 mL/min, bupropion HCl has an Rt of about 6.6
min. Using this method, we obtained a 100% peak at identical Rt for a) our product, for b) an
authentic sample purchased from Sigma, and for c) a extract made from the center of a Bupropion
sustained-release 150 mg tablet. (To ensure separation from excipients, the tablet contents were
stirred with water, filtered, made basic, extracted into CH2Cl2, the solvent removed and the
residue taken up in the eluant for analysis.)
•
GC-MS. Both the free base of bupropion and the HCl salt (which dissociates in the column into
HCl gas and the free base and has identical GC and MS properties as the free base) decompose
slightly on the column so that two peaks are evident, a major peak at about 9.05 min for
bupropion [M/z 240 (M++ 1, 1%), 100 (C6H14N, 33%), 44 (C2H6N, 100%)] followed by a small
“shoulder” at 9.25 min [M/z 57 (C3H5O?, 100 %)]. An authentic sample from Sigma as well as
the extract of a Bupropion tablet have the identical GC-MS. In an effort to run the column at a
low enough temperature to prevent decomposition, we found that a column temperature of 135
(C considerably reduced the relative size of the second peak, but at the cost of broadening the
major peak and slowing retention time to about 45 minutes. At lower temperatures, the
compound would not come off the column.
•
FTIR. On page 9 are two superimposed FTIR spectra using Nujol mulls. The upper spectrum
used authentic material from Sigma, the lower was our product. Our FTIR has a variation in
precision of about ±10 cm-1: the spectra are numerically the same within the precision of the
instrument.
•
1
H-NMR. On pages 10 and 11 is the proton NMR at 400 MHZ of our product. (All of the
following high-field NMR spectra were run by Spectral Data Services of Champaign, IL.) The
small numbers above each absorption identify the H atoms most likely involved. (To suggest
some explanation for the splitting pattern for the signals we have identified as coming from
protons 1 and 2, we have drawn the structure in what we propose may be a particularly stable
conformation, recognizing the likely hydrogen bonding interaction between the protonated
nitrogen and the carbonyl. Our material is not chiral, of course, and we have arbitrarily chosen
to portray the R enantiomer.) (DMSO-d6) 1.33 (s, 9H), 1.55 (d, 3H, J = 7.1 Hz), 5.32 (m, 1H),
7.67 (t, 1H, J = 7.8), 7.86 (d, 1H, J = 7.8), 8.18 (d, 1H, J = 7.8), 8.28 (s, 1H), 8.63 (m, 1H), 9.79
(m, 1H). Musso et al. 12 provide data on a 100 MHZ proton NMR analysis of each of the
enantiomers of bupropion (which should be identical to each other and to our data on the
racemate) and their results are consistent with ours except that their lower field strength did not
allow the aromatic protons to be differentiated.
•
13
C-NMR. On page 12 is the carbon-13 NMR of our product (run in D2O), and on page 13 is an
expansion of the region between 126 and 136 . On the first of the three structures drawn on
page 12 each carbon atom has been given a number; the small numbers above each absorption
identify the carbon atoms most likely involved. The second structure on page 12 has the chemical
shift for each carbon atom in the structure as predicted by the BioRad ChemWindow 6
In the Laboratory
(Guide for the Instructor)
page 8
Spectroscopy program. The third structure has the actual experimental chemical shift. As can
be seen, the BioRad program performed quite well except for carbon atoms 8 and 10, which seem
to be reversed (see DEPT below).
•
DEPT. On pages 14 and 15 is a DEPT (Distortionless Enhancement by Polarization Transfer)13
experiment with our product. This procedure allows the number of protons on each carbon to
be determined. The top spectrum of the three on page 14 is a 135( angle proton pulse and will
display as a positive (upwards directed) signal any methyl (CH3) or methyne (CH) carbons and
as a negative (downwards directed) signal any methylene carbons (CH2). Signals for carbons
bearing no proton will disappear. As can be seen, the signals for carbons 4 and 11 have
disappeared. On page 15 is an expansion of the 135( angle proton pulse showing that the signals
for carbons 8 and 9 have also disappeared. These four carbons have no hydrogens bonded to
them (showing that the BioRad assignment for carbon 10 is certainly in error; presumably it
should be switched with 8). The middle spectrum on page 14 is a 90( angle proton pulse and
allows methyl carbons to be distinguished from methynes; at this angle, only methynes should
appear (as upwards directed signals) while methyl carbons should disappear or, as in our
experiment, be diminished by several orders of magnitude.
In the Laboratory
(Guide for the Instructor)
FTIR
Upper trace: authentic sample (Sigma)
Lower trace: our product
page 9
In the Laboratory
(Guide for the Instructor)
1
H-NMR (400 MHZ)
1
3
(CH3)3C
H
2
4
H
N H
O
5
H3C
6
9
H
H
7
H
Cl
8
H
page 10
In the Laboratory
(Guide for the Instructor)
1
H-NMR (400 MHZ)
1
3
(CH3)3C
H
2
4
H
N H
O
5
H3C
6
9
H
H
7
H
Cl
8
H
page 11
In the Laboratory
page 12
(Guide for the Instructor)
13
C-NMR
C-13 NMR
4
H
O
2
27.07
N H
H
3
O
1
11
7
10
59.97
27.07
N H
56.05
195.83 17.04
H
O
6
126.40
128.30
127.37
9
129.90
134.90
130.90
Cl
132.20
Cl
58.91
25.39
25.39
135.92
8
5
25.39
27.07
2
2
(Actual)
(BioRad)
N H
53.50
195.72 17.67
132.96
128.48
134.78
135.14
Cl
In the Laboratory
(Guide for the Instructor)
13
C-NMR
page 13
In the Laboratory
(Guide for the Instructor)
2
4
2
H
O
2
N H
3
1
11
8
6
5
9
7
10
Cl
13
C-NMR-DEPT
page 14
In the Laboratory
(Guide for the Instructor)
13
C-NMR-DEPT
page 15
In the Laboratory
(Guide for the Instructor)
page 16
Notes for the Instructor
Ins 1
Ins 2
Ins 3
Ins 4
Ins 5
These Notes are keyed to (Ins #) within the Student Instructions.
The -bromoketone 2 does not seem to be a particularly potent lachrymator. In
preliminary studies of this reaction, when we were regularly isolating 2 (without
further purification) as a dense yellowish oil, some burning in the eyes and tearing was
occasionally noticed at the end of the day if we had forgotten to wear gloves or had
been careless in handling the materials. There is no need for any concern beyond the
ordinary if a student spills their reaction mixture after the addition of the t-butyl amine
since, even at room temperature, the reaction will proceed to completion within 20
minutes and the products (t-butylammonium bromide and bupropion) are not
particularly worrisome. If a student spills their reaction mixture after adding the
bromine but before adding the amine, the best way to neutralize the spill is to add
some of the t-butyl amine/NMP mixture to the spill before mopping it up in order to
get as much 2 as possible transformed into bupropion.
This note is intended to suggest to the student that an initially slow rate of reaction
(the “induction time”) can be explained by autocatalysis, namely that once some HBr
has been formed by an initially slow process, it catalyzes the enolization of the ketone,
which is the rate-determining step in the bromination process. (Most of the student
notes are intended as questions to encourage the students to be thinking why they are
performing each step as they do so, rather than mindlessly following the written
procedures. Actually, it is rarely possible to succeed in following an experimental
procedure if the reader does not understand (and want to understand) what he or she
is being asked to do and why. In our experience, the problem with “cookbook
chemistry” lies not in having a cookbook but in not knowing how to be a cook, which
is partly a matter of desire and partly an innate gift. Julia Child owned many
cookbooks (as did my maternal grandmother) but knew how to use them creatively
and with understanding. As for my grandmother . . . nil de mortuis nisi bonum.)
After the CH2Cl2 has distilled, there is nothing left in the pot which will volatilize at 60
(C, and the thermometer will begin to revert to room temperature. Despite having
this explained to them numerous times, some students (cookbook chemists like my
grandmother) will continue to warm their flask for another hour (or century), earnestly
awaiting a final 0.1000 mL of solvent.
Unlike many amines, bupropion has no tendency to oil out if excess acid is added.
Caution the students not to dip the pH paper directly into the beaker since the organic
dyes will dissolve in the ether.
The first time we had a class do this experiment, we asked them to report the mp of
their product, without mentioning the problems we had reproducing the patent and
Merck Index data. We were curious to see how many students would opt for the
unethical shortcut of reporting the published value. To our surprise, most were
honest.
In the Laboratory
(Guide for the Instructor)
page 17
Literature Cited
1.
Perrine, D. M. The Chemistry of Mind-Altering Drugs: History, Pharmacology, and Cultural
Context; American Chemical Society: Washington, DC, 1996.
2.
Perrine, D. M.; Sabanayagam, N. R.; Reynolds, K. J. J. Chem. Educ. 1998, 75, 1266.
3.
Ascher, J. A.; Cole, J. O., et al. J. Clin. Psychiatry 1995, 56, 395-401.
4.
Perrine, D. M. The Chemistry of Mind-Altering Drugs, p 22-23.
5.
Margolin, A.; Kosten, T. R.; et al. “A multicenter trial of bupropion for cocaine dependence in
methadone-maintained patients,” Drug and Alcohol Dependence 1995, 40, 125-131.
6.
Mehta, N. B. “Meta Chloro Substituted--butylaminopropiophenones,” U.S. Patent 3 819 706,
Jun 25, 1974.
7.
Hill, J. A.; Scharver, J. D., J. Labeled Compd. Radiopharm. 1988, 25, 1095-1104. A later
publication by Burroughs Wellcome workers (11) starts with preformed (±) bupropion.
8.
Boyer, J. H.; Straw, D. J. Am. Chem. Soc. 1953, 75, 1642-1644.
9.
Müller, v.H.K.; Müller, E.; Baborowski, H. J. prakt. Chem. 1971, 313, 1-16.
10.
The Merck Index, 12th ed.; Budavari, S.; O’Neil, M. J.; et al., Eds.; Merck: Rahway, NY, 1996,
(monograph number) 1523.
11.
But then our crystals should be the metastable form which would revert to the more stable
allomorph over time, making it doubly unlikely that the Sigma material would have the same mp as
our material. See Jacques, J.; Collet, A.; Wilen, S. H. Enantiomers, Racemates, and Resolutions,
Wiley: New York, 1981, pp 131-133. The enantiomers of bupropion show a large difference in
mp for a quite small difference in specific rotation: (+) bupropion mp 217-219 []D20( +40.21; (-)
bupropion mp 188-190 []D20( -39.64 (12).
12.
Musso, D. L.; Mehta, N. B.; et al. “Synthesis and evaluation of the antidepressant activity of the
enantiomers of bupropion,” Chirality 1993, 5, 495-500.
13.
Silverstein, R. M.; Webster, F. X. Spectrometric Identification of Organic Compounds; 6th, John
Wiley & Sons: New York, 1998, p. 236.