Jce1098 p1261 synthesis of aspirin: a general chemistry experiment
In the Laboratory Synthesis of Aspirin John Olmsted III Department of Chemistry and Biochemistry, California State University, Fullerton, Fullerton, CA 92834
In recent years, examples from organic chemistry have
recognition, as the reactions modify the periphery of a struc-
come to play increasingly prominent roles in the first-year
tural core common to the starting material, intermediate
university general chemistry course. The American Chemical
product, and final product (Fig. 1).
Society has recommended more integration of biological
Viewed from another perspective, this sequence exem-
concepts into college-level introductory general chemistry
plifies two of the most common types of chemical reaction,
courses. Following this recommendation, at least two current
general chemistry textbooks make liberal use of organic examples
(1), and some universities are bringing organic chemistry
much more into the forefront of the introductory course (2).
At California State University, Fullerton, the first-semester
general chemistry laboratory has been redesigned over the past
several years. The redesign has added an organic component
As illustrated in Figure 2, the hydrolysis reaction pro-
and provided students with explicit examples of several types of
ceeds in several steps involving deprotonation and protona-
operations in which chemists engage: observation, synthesis,
tion as well as cleavage of a C-O bond (7 ). These encom-
quantitative measurements, construction of apparatus, and
pass examples of Brønsted acid-base proton transfer, another
chemical analysis. Our experiment that accentuates accurate
quantitative measurements was reported earlier (3).
These structural changes manifest themselves through
Over the course of the first semester and the beginning
readily observed macroscopic changes as the synthesis pro-
of the second, our general chemistry students synthesize two
ceeds. Addition of aqueous base to syrupy, fragrant oil of
organic substances (aspirin and methyl orange) and two
wintergreen yields a white odorless solid. Upon heating, this
inorganic substances (alum and potassium ferrioxalate). Anearlier paper described our ferrioxalate synthesis experiment(4). This paper describes the first of our organic synthesis
experiments, the synthesis, purification, and qualitative spec-
troscopic characterization of aspirin.
Aspirin (acetylsalicylic acid) is a pain-relieving compound
familiar to virtually all students. The synthesis of aspirin from
oil of wintergreen is an example of one of the most prevalent,
profitable, and honored activities of chemists: the conversionof a naturally occurring substance into one with therapeutic
value. Simple enough to be accomplished and understood
by beginning students, this synthesis nevertheless serves as a
paradigm for the pharmaceutical industry, from tranquilizers and
antibiotics to yet-undiscovered agents for treating cancer,
The two-step conversion of oil of wintergreen (methyl 2-
hydroxybenzoate) into salicylic acid (5) and then into aspirin
(6 ) serves as an introductory example of multistep sequen-
tial synthesis. It also provides practice in molecular pattern
Figure 1. The structural core common to oil of wintergreen, salicylic
Figure 2. Reaction mechanism for the conversion of oil of winter-
JChemEd.chem.wisc.edu • Vol. 75 No. 10 October 1998 • Journal of Chemical Education
In the Laboratory
solid reacts further to yield a solution, from which a differentwhite solid precipitates upon acidification. On heating withacrid liquid acetic anhydride, salicylic acid reacts and dissolves. Dilution with water and cooling results in precipitation ofaspirin, yet another white solid.
Synthesis must always be accompanied by isolation and
purification of the product. Both salicylic acid and aspirinare sparingly soluble in water, making these procedures readilyaccessible to the general chemistry student. Isolation is easilyaccomplished by suction filtration using a Büchner funnelapparatus, and purification is equally easily accomplished bydissolving the crude product in hot water and chilling torecrystallize the pure product.
A newly synthesized chemical substance must be appro-
priately characterized before the synthesis can be judged a
Figure 3. FTIR spectra of oil of wintergreen, salicylic acid, and aspirin.
success. While characterization is multifaceted and typicallyinvolves techniques well beyond the scope of general chemistry,FTIR spectrophotometry is well suited to characterization ofaspirin and its precursors. By taking FTIR spectra of their
deionized water. Cool the beaker in an ice bath until it is just
products, our students not only "see" that their white solids
warm to the touch. Without removing the beaker, slowly add,
are distinctly different but also become familiar with one of
with continuous stirring, 50 mL of 8 M H2SO4 (precipitate
the most prevalent instruments of the contemporary laboratory.
forms). After chilling in the ice bath, isolate the product.
Figure 3 shows actual FTIR spectra taken under the same
Rinse the beaker with iced deionized water, pour over the
conditions that are used by our students. The three compounds
precipitate, and continue suction for about 10 minutes.
share spectral features due to their common framework, for
Transfer the crude solid to a 250-mL beaker containing
example the aromatic C-H bending vibrations in the 600-
100 mL of deionized water. Heat to a gentle boil until the
800 cm᎑1 region. They differ substantially in the absorptions
solid dissolves completely. Allow the beaker to cool (crystals
form), then transfer the beaker to an ice bath and chill thor-
the broad hydrogen-bonded OH absorption that is promi-
oughly. Isolate the product. Rinse the beaker with 50 mL of
nent in oil of wintergreen and salicylic acid between 3000
iced deionized water, pour over the precipitate, and continue
and 3500 cm᎑1. On the other hand, whereas oil of winter-
suction for 15 minutes. Spread the solid on a watch glass,
green and salicylic acid have a single C=O absorption at about
cover with filter paper, and store overnight until dry.
1700 cm᎑1, aspirin has two distinct peaks arising from its ester
Conversion of Salicylic Acid into Aspirin
Weigh 1.4 g of salicylic acid and transfer to a clean, dry
125-mL Erlenmeyer flask. Add 3.0 mL of acetic anhydride (CAUTION: caustic vapors: use a hood) and 5 drops of con-
Outlined here is a compact version of the procedure
centrated H3PO4. Stopper with a one-hole rubber stopper
carried out by our students and the instructions for their
fitted with 2 cm of plastic tubing. Float the Erlenmeyer flask
laboratory report. The procedure given to the students includes
in an 800-mL beaker containing 250 mL of water. Heat this
more detailed specifications for standard techniques with
beaker to 85 °C and maintain between 85 and 90 °C for five
which they may not be sufficiently familiar. Pan balances
minutes (CAUTION: do not boil; steam baths may be used if
provide sufficient accuracy for all weighings, and graduated
available). Discontinue heating and immediately use a Pasteur
cylinders provide sufficient accuracy for volume measurements.
pipet to deliver 2 mL of deionized water through the plastic
Glassware can be cleaned by rinsing with deionized water and
tubing (CAUTION: hot acid vapors). When the flask is suffi-
need not be dry except when explicitly noted. Isolation of
ciently cool, remove it using a towel, remove the stopper, and
solids is accomplished by cold suction filtration using a
add 20 mL of deionized water. Allow to stand at room
temperature until crystals begin to form. Then add 10 mL
The filtrate from the first synthesis procedure is substan-
of deionized water, swirl, and place the flask in an ice bath.
tially acidic and should be disposed of properly following
After chilling, isolate the product. Rinse the flask with 15
procedures for acidic aqueous waste. All other liquid waste
mL of iced deionized water, pour over the precipitate, and
is relatively benign and can be rinsed down the sink.
continue suction for about 10 minutes.
Conversion of Oil of Wintergreen to Salicylic Acid
Weigh the solid in a clean, dry 50-mL beaker and add
to the beaker 10 mL of deionized water per gram of solid.
0.2 mL of oil of wintergreen to a previously
Heat with continuous stirring until all solid dissolves. Transfer
weighed clean, dry 250-mL beaker and reweigh. Add, with
the beaker to an ice bath and chill (crystals form) until precipi-
stirring, 40 mL of 6 M NaOH (precipitate forms). Heat with
tation appears complete. Isolate the product and continue
occasional stirring to a gentle boil, reduce the heating rate to
suction for an additional 10 minutes. Then transfer the solid
avoid "bumping", and continue boiling gently for 15 min-
to a clean, dry 50-mL beaker and oven-dry at 80 °C (CAUTION:
utes. Midway through heating, rinse any solids adhering to
aspirin melts and decomposes at 100 °C) for one hour. Remove,
the beaker walls into the solution with a small quantity of
Journal of Chemical Education • Vol. 75 No. 10 October 1998 • JChemEd.chem.wisc.edu
In the Laboratory
The use of FTIR in undergraduate laboratories is becom-
Prepare a solution of each solid (salicylic acid and aspirin)
ing increasingly prevalent as this technique becomes routine
by placing about 1 mL of ethyl acetate in a clean, dry test
and instruments are more affordable. Others have described
tube, adding a spatula-tip amount of solid, and stirring to
experiments using FTIR spectroscopy in general chemistry
dissolve. Using a Pasteur pipet, transfer 4-5 drops of this
for smog analysis (9) and for exploring Lewis structures (10).
solution to a salt plate and allow the solvent to evaporate.
The technique also finds applications in the organic laboratory
Place the salt plate on the mount in the sample compartment
(11) and throughout the undergraduate curriculum (12). At
of an FTIR spectrophotometer. Scan the spectrum and print
Fullerton we make use of FTIR not only in general chemistry
a copy. Clean the salt plate three times by placing several
laboratory but also in our undergraduate organic, analytical,
drops of ethyl acetate on its surface and wiping thoroughly
and physical chemistry laboratories; and our students often
use the instruments in the course of their undergraduate
Include in your report for this experiment a one-paragraph
abstract, brief procedure, data and results, and discussion. In
The use of FTIR spectroscopy to differentiate aspirin from
the procedure, describe the details of what you did and
other substances is not unique to this instructional exercise
observations you made, but do not reproduce the procedure
in chemical synthesis. Procedures for quantitative analysis of
from the laboratory manual. Data and results should include
aspirin using FTIR have been reported for pharmaceutical
all masses used, the theoretical yields of products, and the
preparations (13) and drug testing (14). Furthermore, con-
percent yields of products. In the discussion, answer the
temporary research utilizes FTIR to study aspirin-DNA (15)
question "What explains why my yields are different from
and aspirin-RNA interactions (16 ). Thus, the qualitative
theoretical yields?" Also compare the IR spectra of oil of
identification of aspirin by FTIR serves as a representation
wintergreen and your two products and identify the peaks
of how modern spectroscopic techniques facilitate analytical
that are unique to each of the products. Discussion Acknowledgments
The FTIR instrument used for this work, a Perkin-Elmer
The one-step synthesis of aspirin from salicylic acid is
Model 1600 with 2 cm᎑1 resolution, was purchased using
described in many general chemistry laboratory manuals (8)
funding provided by NSF-ILI grant USE-9250902, FTIR
and may be traced to a report by Brown and Friedman (6 ). in Undergraduate Chemistry Laboratories.
The experiment described here differs from these typical syn-theses in three respects. First, it is a more elaborate two-step
synthesis that starts from a common natural substance. Second,it is designed to be carried out early in the general chemistry
1. Olmsted, J., III; Williams, G. M. Chemistry: the Molecular Sci-ence, 2nd ed.;W. C. Brown: Dubuque, IA, 1997. Moore, J. W.;
laboratory rather than toward the end, where more typical
Stanitski, C. L.; Wood, J. L.; Kotz, J. C. The Chemical World:
organic syntheses are placed. Third, it incorporates the use
Concepts and Applications, 2nd ed.; Saunders: Ft. Worth, TX, 1998.
of FTIR spectroscopy for qualitative identification of the
2. Rettich, T. R.; Bailey, D. N.; Frank, F. J.; Frick, J. A. J. Chem.
chemical changes that have occurred. Educ. 1996,73, 638. E᎑ge, S. N.; Coppola, B. P.; Lawton, R. G.
The two-step synthesis requires more than one laboratory
J. Chem. Educ. 1997,74, 74-83.
period. This is in keeping with our laboratory design, in which
3. Olmsted, J., III. J. Chem. Educ. 1986,63, 538-540. 4. Olmsted, J., III. J. Chem. Educ. 1984,61, 1098-1099.
students perform a small number of extended experiments
5. Khan, M. N.; Olagbemiro, T. O. J. Org. Chem. 1982,47,
with a thread of continuity that reflects actual laboratory
practice. However, the synthesis/characterization experiment
6. Brown, D. B.; Friedman, L. B. J. Chem. Educ. 1973,50, 214-215.
can easily be segmented into three single-period experiments:
7. March, J. Advanced Organic Chemistry, 4th ed.; Wiley: New York,
the conversion of oil of wintergreen into salicylic acid, synthesis
1992; pp 378-383 and references cited therein.
of aspirin from salicylic acid, and IR characterization of these
8. For example: Modular Laboratory Program in Chemistry; Neidig, H.
substances. Such segmentation would allow simple air-drying
A., Ed.;Chemical Education Resources: Palmyra, PA, 1980. Lippincott, W. T.; Meek, D. W.; Gailey, K. D.; Whitten, K. W. Ex-
of the aspirin product in place of the oven-dry procedure de-
perimental General Chemistry;Saunders: Philadelphia, 1984. Marcus,
scribed here. In addition, melting point characterization of
S.; Sienko, M. J.; Plane, R. A. Experimental General Chemistry;
salicylic acid and aspirin can easily be added to the charac-
McGraw-Hill, New York, 1988. Hall, J. F. Experimental Chemistry;
D. C. Heath: Lexington, MA, 1989. Beran, J. A. Laboratory Manual
Placing an organic synthesis experiment early in the gen-
for Principles of General Chemistry, 5th ed.; Wiley: New York, 1994.
eral chemistry laboratory emphasizes that the principles of
9. Amey, R. J. Chem. Educ. 1992,69, A148-A151.
10. Swartz, J. E.; Schladetzky, K. J. Chem. Educ. 1996,73, 188-189.
chemical reactivity and stoichiometry apply equally to organic
11. Hammond, S.; Straus, D. A. J. Chem. Educ. 1993,70, A79.
and inorganic materials. Additionally, this synthesis has a
12. Bezoari, M. D. Chem. Educator 1996, 1; http://journals.springer-
strong practical appeal. Students enjoy the fragrance of oil
of wintergreen (which may remind them of the kitchen, the
13. Bouhsanin, Z.; Garrigues, S.; de la Guardia, M. Analyst1996,
athletic locker room, or both) as well as the production of a
staple pharmaceutical product. While they are unlikely to ap-
14. Walters, M. J.; Ayers, R. J.; Brown, D. J. J. Assoc. Off. Anal. Chem.1990, 73, 904-926.
preciate the nuances of organic functional groups early in
15. Neault, J. F.; Naoui, M.; Manfait, M.; Tajmir-Riahi, H. A. FEBS
their course, the simplicity of the reaction mechanisms makes
Lett. 1996, 382, 26-30.
it possible for them to understand the chemistry taking place
16. Neault, J. F.; Tajmir-Riahi, H. A. J. Phys. Chem. B 1997, 101,
JChemEd.chem.wisc.edu • Vol. 75 No. 10 October 1998 • Journal of Chemical Education
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