Page 1 of 10
Version 2002
From: http://www.bayeraspirin.com/
ASPIRIN
SYNTHESIS OF A USEFUL ANALGESIC
EXTRA BONUS: SYNTHESIS OF A PLEASANT NATURAL PRODUCT: OIL OF WINTERGREEN
Objectives: Synthesize two useful organic compounds;
Assess the purity of aspirin by titration against standardized NaOH;
Standardize NaOH and perform a titration;
Enjoy making a natural product.
THE SALICYLATES, ASPIRIN, AND THE BIRTH OF ORGANIC SYNTHESIS:
Organic compounds were so called originally because they were made by living organisms. Now, it
is possible to make millions of organic compounds in the laboratory. What they all have in common
is a carbon backbone.
FIGURE 1. Aspirin (acetyl salicylic acid): Its Associated Bells & Whistles.
O
H
C
O
C
C
C
H
H
C
C
C
C
O
H
C
O
C
C
C
C
O
O
O
C
H
O
C
CH 3
H
C
-CH3
O
CH3
C
H
Acetyl Salicylic acid
The carbon
backbone
of the salicylates
an acetyl Group
A carboxylic acid
Can you find it on aspirin?
A Hydroxyl
Group
A methyl
group
Page 2 of 10
Version 2002
Aspirin is one of a class of remarkable analgesic (pain relieving) drugs called the
salicylates: (SEE FIGURE 2)
FIGURE 2: SOME OF THE SALICYLATES
H OH
O
O
CH 3
C
H
C
H
C
CH2C
HO
H
C
O
C
C
H
C
C
H
OH
H
H
C
H
O
C
HO
O
H
C
C
O
C
H
C
H
Salicylin
O
C
H
C
C
H
C
Salicylic acid
H
O
O
CH 3
C
OH
C
H
C
O
O
H
C
O
C
C
H
C
C
C
CH 3
H
C
H
C
C
O
Methyl salicylate, Oil of Wintergreen
H
H
C
C
C
H
Acetyl salicylic acid, aspirin
H
BEFORE YOU COME TO LAB:
1. Identify the ACETYL GOUP, THE CARBOXYLIC ACID GROUP, the HYDROXYL GROUP AND THE
METHYL GROUP on aspirin and methyl salicylate.
2. Trace the salicylate carbon skeleton on salicylin.
Page 3 of 10
Version 2002
The following essay was written by Professor A.C. Gibson for his course in Economic Botany at UCLA:
SALICACEAE, Willow Family
The history of medicine has been enriched by thousands of plant species, but one plant--the willow-has probably been used and prescribed more than any other powdered drug. Willow is the original
source of aspirin. Even today, when aspirin substitutes are available, up to 80 million tablets of aspirin
are used each day in North America, and up to 50 million pounds each year are swallowed
throughout the world. Now aspirin can be easily made [industrially] by reacting phenol and carbon
dioxide.
Hippocrates of Cos (460-377 B.C.) noted that chewing leaves of willow (Salix) reduced pain, and he
prescribed this remedy for women in labor. Hippocrates certainly did not discover this drug, which
was used for centuries earlier in European folk medicine. (We should be cautious in crediting
Hippocrates with everything because researchers have suggested that the extensive collection of
medical writings found in Alexandria, formerly ascribed to Hippocrates, may have been written by
several people, the most influential of whom was Hippocrates.) Subsequent ancient Greek physicians
recommended willow for alleviating pain and reducing fever and inflammation. In North America,
probably even before the Greeks, the Alabama, Chickasaw, and Montagnai Indians used willow to
relieve fevers, aches, and pains, and the beneficial effects were also known to the Hottentots of
southern Africa.
Advocates of the Doctrine of Signatures described how willow worked to reduce inflammation of joints
because the "weeping" branches were very flexible, like human limbs. As late as 1763, an English
clergyman named Edward Stone (also known as Edmund Stone) wrote that willow is useful for
lowering fever because both willow and fever thrive in damp regions.
In the 1820s, European chemists, eagerly studying the chemistry of plants, were able to isolate from
willow a glycoside, which was named salicin, after the genus. Salicin was also discovered in poplars
and aspens (also Salicaceae). In the laboratory, Karl Löwig (1839) treated salicin with acid--as salicin
is acted on in the human stomach--to make salicylic acid, and about that time salicylic acid was also
discovered occurring naturally in a European species of Spiraea (dropwort). Salicylic acid had major
medicinal uses and soon became a panacea. A related compound being used at that time was methyl
salicylate, found in an oil from birch bark (Betula lenta) and oil of wintergreen (Gaultheria
Page 4 of 10
Version 2002
procumbens), long used to relieve aches. In this century, oil of wintergreen was formerly used in
"analgesics" (rubefacients) for athletes. [And still is in SportsBalm]
The problem with salicylic acid was that, for many, it caused nausea and great gastric discomfort. A
different compound was synthesized in 1853 by Carl von Gerhardt by putting an acetyl group on
salicylic acid, making acetylsalicylic acid, which is a chemical salt (solid). Nonetheless, no one was
aware of the more gentle properties of this compound until 1893, when Felix Hoffman, an employee
of Friedrich Bayer and Company, found an easier way to make this salt and then tested it on his
father, who had arthritis. In 1899, Bayer, which started in 1863 as a dye production company,
marketed this medicine as "aspirin"--coming from the words 'acetyl' and Spiraea. The price of aspirin
initially was expensive until Bayer learned how to mass produce tablets. Aspirin was thus the first
major medicine in the world to be sold in tablet form.
As the ancients already knew, aspirin is a remarkable painkiller, i.e., an analgesic. Research indicates
that painkilling results from the depressant action of aspirin on the central nervous tissue, somehow
by reducing mild to moderate pain messages from reaching the brain. A very important use of aspirin
is as an antipyretic, i.e., to lower body temperature (fever), via the dissipation of heat through effects
on the hypothalamus, increasing sweating. The third major use of aspirin is as an anti-inflammatory
agent (reduce swelling), as for victims of arthritis and "rheumatism."
American consumers spend $700,000,000 to $800,000,000 per year on painkillers (excluding
opiates), especially aspirin and acetaminophen, the very common alternative that is marketed under
names such as Tylenol, Datril, and Liquiprin. Both chemicals allay pain, but there are important
differences. Aspirin, which is significantly cheaper, has the additional anti-inflammatory effects and
therefore is critical for arthritis patients (much cheaper than the competing drugs). However, as
arthritis pain intensifies, aspirin dosages must also be made stronger, and high dosages are
potentially more dangerous. Maximum aspirin daily dosage should be 60 grains per 24 hours.
Medical studies on the effect of aspirin on breaking up blood clots (an antithrombotic drug) are now
fairly conclusive, and many physicians prescribe daily aspirin after heart attacks or even as a
preventative program because aspirin inhibits release of prostaglandin and thereby platelet
agglutination. There are more effective, but not cheaper, antithrombotic drugs, e.g., sulfinpyrazone.
There are over 500 aspirin deaths in this country every year, from large accidental (child) or mostly
suicidal (adult) overdoses or, rarely, from allergic reactions. [In 1989, there were 1.28 million ingestion
Page 5 of 10
Version 2002
poisonings, of which 5889 were of aspirin, and ten times more of acetaminophen.] Actually, in the
United States, children aspirin deaths have declined from 40 to just 2 within the last 20 years. The
dangerous side effect of aspirin is gastrointestinal irritation and stomach bleeding, which contribute to
stomach ulcers (caused by bacteria). For treating simple aches and pains, painkilling pills that
combine aspirin with acetaminophen do not appear to be any more useful than a single chemical.
Perhaps a piece of judiciary history is needed here. Aspirin was a patented name by Bayer, but this
German company had conflicts with France and Great Britain, who fought against Germany in World
War I and did not acknowledge that patent. Australia also began its own production when aspirin
could not be supplied there. A legal battle ensued when Monsanto in the United States began its own
production in 1917, and this eventually reached the U.S. Supreme Court, which ruled that "aspirin"
had become so widely advertised and common that Bayer no longer owned the name. Hence, aspirin
is now a vernacular name, which is why large companies of other products now aggressively take
anyone to court when a popular product name is unlawfully used.
Excerpted from: Gibson, A. C. Economic Botany, UCLA,
http://www.botgard.ucla.edu/html/botanytextbooks/economicbotany/Salix/
See also: Insel, Paul, “Analgesic-Antipyretics and Antiinflaamatory Agents” in: Goodman &Gilman’s The
Pharmacological Basis of Therapeutics, 8th ed.,A. G. Goodman, T.W. Rall, A. S. Nies and P. Taylor, eds.
McGraw-Hill, NY, 1993.
In this lab, you will synthesis aspirin and oil of wintergreen from salicylic acid:
Balanced equation for the reaction of salicylic acid and acetic anhydride
O
H
O
C
C
H C
H
C
H C
O
C
O
+
CH 3
C
O
CH 3
C
C
O
H
H
Acetic anhydride
H+
To make aspirin, you will react salicylic acid
with a source of acetyl groups called acetic
anhydride. An acetyl group from acetic
anhydride reacts with the hydroxyl group on
salicylic acid, making an ester, which you will
come to know and love in Organic next year.
Salicylic acid
O
O
H
C
O
C
H
C
C
C
H
An ester group
O
O
+
H
C
C
C
C
O
H
H3C
H
O
C
O
Acetyl salicylic acid
CH 3
Acetic acid
In the presence of acid and some heat, this
reaction occurs quickly. Aspirin is less soluble
in water than salicylic acid, and will precipitate
out of solution, making it easy to isolate and
Page 6 of 10
Version 2002
purify. It won’t be pure enough to use against a headache, however.
BEFORE YOU COME TO LAB:
IDENTIFY THE ESTER GROUP ON ASPIRIN.
Next week you will assess the purity of your aspirin by titration.
O
H
C
C
H C
H
C
H C
OH
O
+
CH 3
To make oil of wintergreen, you will use methanol to
make an ester, but this time on the carboxylic acid
group of salicylic acid. You will find that many esters
smell good, and oil of wintergreen is no exception.
C
C
O
H
H
Methanol
H+
Salicylic acid
O
H
C
C
H
C
C
H
C
C
BEFORE YOU COME TO LAB:
Where does the methyl group on methanol end up?
CH 3
O
+
C
OH
H
H
We won’t do anything further with oil of wintergreen.
O
H
Methyll salicylate
Water
Balanced equation for the reaction of salicylic acid and methanol
BEFORE LAB PREPARATION:
Set up a Table of Reagents in your lab notebook, and in Excel. See page 10.
THE EXPERIMENT:
I. SYNTHESIS OF ASPIRIN FROM SALICYLIC ACID:
A. FIRST things first:
i. Set up a boiling water bath in a 400 or 600 mL beaker on a
hot plate.
ii. Start chilling about 100 mL of ice water in a 250 mL beaker.
B. Get the REACTION going:
i. Weigh out 4.0 grams (+/- 0.0001 g) of salicylic acid.
(SalH). What is means is: you need more than 3.9 grams and less
than 4.1 grams of salicyclic acid, and DO NOT waste your time
trying to get exactly 4.0000 grams of salicylic acid. DO record the
exact mass of salicylic acid you use, to the nearest 0.0001 g., in your
notebook.
Page 7 of 10
Version 2002
Caution: Salicylic acid is a skin irritant. Don’t breathe the dust, clean up the balance area and
wash your hands.
ii. Clean up the balance.
iii.The TA or lab instructor will dispense for you, in the hood, 10 mL of acetic anhydride.
Swirl the flask to mix the SalH, add 10 drops of 18 M (conc) H2SO4, and heat the flask in
your boiling water bath for about 15 minutes. Keep an eye out for bumps.
Caution: Acetic anhydride is an eye irritant. Avoid contact with skin & eyes.
Conc. H2SO4 is strongly corrosive. Keep it off your skin, out of your eyes, and in the glass portion of
the Pasteur pipet. Keep the pipet straight up & down. Don’t tilt it and let sulfuric acid run into the
bulb. If you spill any on yourself, wash up with lots of water.
C. While you WAIT: Set up the Oil of Wintergreen prep (part 2).
D. CRYSTALLIZE out the aspirin you made from the rest of the stuff:
Carefully take the reaction flask out of the boiling water bath and add 20 mL of ice water to it. This will
decompose excess acetic anhydride:
O
O
O
+
C
C
H
H
Put your flask on ice and stir it occasionally
water
H3C
O
CH 3
until the acetyl salicylic acid has come out of
O
acetic anhydride
solution. Aspirin (acetyl salicylic acid) is
much less soluble in cold water than salicylic
C
H
2
H3C
O
acid, which will stay in the supernatant.
acetic acid
Crystallization can be speedy and dramatic,
with large white crystals crashing out of solution; it can also be spectacularly slow. In general, fast
crystallization, while satisfying to the Type A Personality, results in less pure crystals. If you don’t see crystals
in 5 minutes or so, consult your instructor for tips. If you don’t get crystals at all, but see “oiling out”, put the
flask back in the boiling water bath, reheat it until it no longer looks oily, and cool it again on ice (don’t add
more ice water).
E. FILTER the solid aspirin away from the rest of the stuff:
i.
Set up a vacuum filter apparatus (there will be a demo apparatus on the front bench),
using a Büchner funnel and side arm flask. Put in a piece of filter paper, start the vacuum,
and moisten the filter paper with distilled water to seal it down.
ii.
Pour the contents of your reaction vessel onto the filter paper. You’ll notice that the 2nd
law of Lab Science is in effect, namely that a lot of aspirin is sticking to the glass. Rinse
the reaction vessel with 10 mL of ice cold water, swirl it around to get the aspirin, and add
that to the filter. Repeat one or two more times to get the rest of the aspirin.
If you see any crystals forming in your side arm flask, pour t he filtrate into your
reaction vessel , re-assemble the filter, and re-filter.
iii.
Wash the aspirin crystals on the filter paper with about 10 mL of ice cold water.
Page 8 of 10
Version 2002
F. RECRYSTALLIZE the aspirin:
The aspirin sitting on your filter paper is mixed with unreacted salicylic acid, and acetic acid and sulfuric acid
that haven’t washed away. To clean it up:
i.
Scrape the crystals into a 100 mL beaker. Add ethanol, 1 mL at a time, with VIGOROUS
SWIRLING…(3rd Law of Lab Science…STIR IT UP!) until the aspirin dissolves. Don’t add any
more ethanol than you need to (20 mL should do it) and STIR between ethanol additions.
Start about 50 mL of water warming up on a hot plate.
Warm the ethanol/aspirin solution on a hot plate (NO OPEN FLAME) to about 60oC. Pour in about
50 mL of warm water into the ethanol/aspiring solution, stir it, cover it with a watch glass, and set it
in an ice bath to crystallize. Aspirin is much less soluble in water than ethanol, and much less soluble
in cold water than hot. Salicylic acid is more soluble than aspirin in water, and will stay in solution.
You will lose some aspirin in this step, but what you have left will be purer.
Be sure you describe in your notebook what the color and shape of the aspirin crystals are.
ii.
iii.
iv.
G.
RECOVER your aspirin, DRY it, WEIGH it and SAVE it for next week.
i. Vacuum filter your crystals, and wash them with two 10 mL portions of ice cold water.
ii.
Scrape your crystals into a clean 100 mL beaker, LABEL THE BEAKER with your name &
section, cover it with parafilm with holes punched in it, and place it in the area provided.
Next week, you will get the mass of the aspirin, calculate the % yield, and assess the purity
of your product by titration against standard NaOH.
II. SYNTHESIS OF OIL OF WINTERGREEN:
A. SYNTHESIZE Oil of Wintergreen:
i.
ii.
In a 10 mL Ehrlenmeyer flask, mix 0.10 g of salicylic acid with 10 drops (< 0.5 mL) of
anhydrous methanol.
Add 1 drop concentrated (18 M ) H2SO4 and a boiling chip, and heat the mixture gently
for about 5 minutes.
B. DETECT the product.
Remove the reaction vessel from the heat, stir the mixture with a clean stirring rod, and carefully smell
what you have made.
ALL WASTE FROM THIS EXPERIMENT GOES IN THE JUG LABELLED “ORGANIC
WASTE” IN THE HOOD
Page 9 of 10
Equipment for 2 students
ASPIRIN
400 or 600 mL Beaker for boiling water bath
(larger size preferred)
250 mL beaker for ice water
125 mL Ehrlenmeyer
Ring stand
Hot plate
Clamp for Ehrlenmeyer neck
Ice bath in grey plastic tub
Buchner funnel & collar
+ filter paper to fit
250 mL Side arm flask & tubing
Wash bottles of water
100 mL beaker
Watch glass
10 mL grad cylinder
OIL OF WINTERGREEN
10 mL Ehrlenmeyer flask
Boiling chip
Pastuer pipet & bulb
Version 2002
1
Demos: Vacuum filtration apparatus
1
1
1
1
1
1
1
1
1
2
1
1
1
1
1
Reagents needed (for 2 students)
ASPIRIN
Salicylic acid
2g
Acetic anhydride
5 mL
(dispense small volume for each
section, keep vial tightly closed)
Conc. H2SO4
1 plastic
dropper bottle
Ethanol
1 wash bottle
OIL OF WINTERGREEN
Salicylic acid
0.100 g
Methanol
1 plastic dropper bottle
Conc. H2SO4
1 plastic
dropper bottle
Page 10 of 10
SAMPLE REAGENT TABLE FORMAT:
Version 2002