In the Laboratory
W
Synthesis of the Sweetener Dulcin from the Analgesic
Acetaminophen
Brian D. Williams,* Birute Williams, and Louise Rodino
Department of Chemistry, Kings College, Wilkes-Barre PA 18711; *BDWillia@RS01.Kings.edu
Undergraduate organic chemistry students typically show
the greatest interest in laboratory experiments utilizing
familiar substances or compounds with a definite and readily
understood function, such as analgesics, sweeteners, or flavorings. Considering the common use of experiments involving
the analgesic aspirin, it is surprising that there have been few
synthetic procedures developed for the high school or undergraduate laboratory involving acetaminophen (I) (1–3).
This is notable because numerous experiments, concepts, and
techniques can be directly linked with acetaminophen and
its derivatives and would facilitate integration of its use in a
broader pedagogical strategy.1
This report describes the conversion of the analgesic acetaminophen to the artificial sweetener dulcin (IV). The experimental sequence is suitable for both high school and undergraduate laboratories and can be performed on either a
micro or macro scale. Phenacetin (II), also a physiologically
active analgesic, is an intermediate isolated during the sequence (2, 4 ). Consequently, the procedures described can
be adopted as a multistep synthesis of dulcin from acetaminophen or, alternatively as one-period conversions of either
acetaminophen to phenacetin or phenacetin to dulcin. A
Williamson-type synthesis of aromatic ethers is featured in
the former transformation, while the latter demonstrates an
amide hydrolysis followed by a nucleophilic addition reaction of an aryl amine with an isocyanate.2
The procedure described offers numerous advantages
over previously reported methods, making the experiment
suitable for student laboratories. Yields are high and crude
products are commonly isolated with sufficient purity that
refinement before analysis or use in subsequent reactions is
optional. Reaction conditions are optimized to provide adequate
time for product purification and characterization within each
3-hour laboratory period. Finally, halogenated solvents are
eliminated and the experiment can be run if desired on a
single Tylenol tablet, thus significantly minimizing chemical
use and wastes.
Procedural Overview
A well-known procedure for the conversion of I to II
involves a 1–3-h reflux of I, ethyl iodide, and K2CO3 catalyst
in methyl ethyl ketone followed by several extractions with
methylene chloride, producing crude yields ranging from 36
to 61% (2).
O
O
1. ethanol/NaOH
HO
N
CH3
2. CH3CH2I/reflux
CH3CH2CO
N
H
CH3
H
(I)
(II)
HC
l/H
O/
re
x
flu
2
O
NH3+Cl –
CH3CH2CO
1. solid NaHCO3
2. CH3COOH/urea/
reflux
CH3CH2CO
N
NH2
H
(III)
(IV)
The experiment described here involves reaction of I in
pure or tablet form with ethyl iodide in an ethanolic NaOH
solution. The formation of II is typically complete within a
15-minute reflux period.3 The phenacetin (II) is separated
from the insoluble tablet binder by a vacuum filtration into
an Erlenmeyer flask that contains a mixture of ice and water.
Phenacetin, upon contact with the cold water, will precipitate
from the filtrate as a white solid. This procedure simultaneously removes the tablet binder, precipitates the product, and
eliminates the use of chlorinated solvents. Students commonly
report isolating crude phenacetin in yields between 70 and
90%. A small portion of the sample is reserved for analysis.
The product is sufficiently pure to use in the synthesis of
IV.4 For the high school laboratory or those not interested in
a two-period multistep synthesis, the experiment can be
stopped at this point. Otherwise, phenacetin thus produced
or commercial phenacetin can be converted into dulcin (IV).
Many methods for the preparation of dulcin begin with
either p-phenetidine or its salt (6–8). In the procedure described,
p-phenetidine hydrochloride salt (III) is formed by hydrolysis
of II in excess acid and subsequently converted without isolation into IV, thereby eliminating both isolation and purification of the intermediate p-phenetidine or its salt.5 This is
accomplished by careful adjustment of the pH of the p-phenetidine hydrochloride solution with solid portions of NaHCO3
followed by addition of acetic acid and urea and refluxing.
The setting of the dulcin into a solid mass indicates completion
of the reaction. The mixture is chilled in an ice bath and the
dulcin is collected by vacuum filtration as a white crystalline
solid. Dulcin formed by this method is typically quite pure
and upon drying is suitable for analysis. It can be recrystallized
from a minimal amount of hot water.
JChemEd.chem.wisc.edu • Vol. 77 No. 3 March 2000 • Journal of Chemical Education
357
In the Laboratory
In our laboratories, GC analysis of active reaction mixtures
is used to determine adequate reaction times and temperatures,
although TLC can also be used.6 The completion of the final
reaction is often visible, since the dulcin sets into a solid mass;
therefore analysis is not usually required to determine the
reaction’s completion. If the monitoring of reactions is not
desired, the reaction conditions as reported in the student
procedure are adequate. In addition to TLC, GC, melting
point, and mixed melting point with genuine samples,
product identities can be readily assessed using IR and NMR
spectroscopy. Student yields for the conversion of phenacetin
to dulcin are reported between 70 and 90%, giving overall
yields for the two-step conversion of acetaminophen to dulcin
ranging from about 50 to 80%.
Discussion
The conversion of acetaminophen to dulcin is integrated
into our organic laboratory curriculum and is a very popular
experiment with our students. The chemical transformations
and conversion of “known solids into known solids” is particularly relevant. Students readily comprehend that one of
the two substituents on the aromatic ring is modified during
each step of the synthesis while the aromatic portion itself
remains unaffected. Each product is a white crystalline solid
similar to acetaminophen and cannot be differentiated by
simple inspection. This provides an excellent opportunity to
recognize that changes in just a portion or appendage of a
molecule may have little impact on the outward appearance
of the substance, while often causing dramatic differences
in spectroscopic and physical properties and physiological activity.7
The experimental sequence provides numerous learning
opportunities for students by introducing or reinforcing TLC
and GC analysis, recrystallization, vacuum filtration, melting
point, mixed melting point, IR, NMR, and analysis of active
reaction mixtures. Students gain proficiency with chemical
calculations, since the quantities of reagents used during the
conversion of phenacetin to dulcin must be calculated relative
to the amount of phenacetin isolated from Tylenol during
the first period.
Most students are familiar with acetaminophen. However, they are generally not aware of dulcin because it is no
longer used commercially as a sweetener. An examination of
sweetener theory (9) or dulcin’s discovery, development, and
ultimate removal from the market (10) provides excellent
associated reading. This multistep synthesis is preceded in our
laboratories by a related sequence that includes the extraction
of caffeine from tea, the synthesis of methyl salicylate from
aspirin, and the analysis of analgesic mixtures by TLC.
Acknowledgments
We are grateful to the Juniata College Science Outreach
program and The Camille and Henry Dreyfus Foundation
for their support and to Juniata College, Wilkes University,
and King’s College for the use of their facilities.
358
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Supplemental Material
Supplemental material for this article is available in this
issue of JCE Online.
Notes
1. For example, an experiment involving TLC analysis of analgesic mixtures can be performed before this experiment and students
can use the information obtained to follow the progress of the reaction (11). Work is in progress on a problem-based collaborative
learning project that incorporates the synthesis described here as
part of a greater sequence.
2. The reactive isocyanate is isocyanic acid that is generated
in situ by an acid-catalyzed elimination of ammonia from urea.
3. The appropriate amount of base can be calculated or titrated using thymol blue indicator (5).
4. Analysis of crude phenacetin by GC–MS occasionally revealed trace amounts of p-ethoxy aniline.
5. Alternatively, the phenetidine hydrochloride salt can be isolated as a stable solid by precipitating in an ice bath before addition of
NaHCO3.
6. In the interest of time, GC analysis was performed only on a
few reaction mixtures and the results were discussed with the class and
usually taken to be representative. Efforts were made to have each student or group contribute a sample for GC analysis at some time during one of the two periods. A HP model 6890 gas chromatograph
equipped with a 30-meter HP-5 column was used for analysis.
7. For example, for the conversion of acetaminophen to phenacetin, the melting points of the two compounds differ by about
32 °C. In addition, the 1H NMR spectra differ dramatically. Phenacetin shows a well-defined ethyl quartet and triplet from the ethoxy
substituent, whereas acetaminophen does not.
Literature Cited
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1978; p 288.
5. Ditts, K.; Durand, M. J. Chem. Educ. 1990, 67, 74.
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Journal of Chemical Education • Vol. 77 No. 3 March 2000 • JChemEd.chem.wisc.edu