Natural Synthesis of Aspirin, Part I: Synthesis of Salicylic Acid from Wintergreen Oil

Carl S. Lecher, Marian College, Indianapolis, IN, clecher@marian.edu

Chemical Concepts
Refluxing, vacuum filtration, recrystallization, melting point determination

Green Lessons
Use of natural product

IndianaAcademic Standards for Chemistry 1
Includes: C.1.1, C.1.2, C.1.3, C.1.4, C.1.5, C.1.8, C.1.9, C.1.11, C.1.12, C.1.13, C.15, C1.21, C1.27, C.1.35, C.1.44, C.1.45

Estimated Lab Time
Reaction = 50 minutes
Optional recrystallization (day 2) = 50 minutes

Synopsis:
This experiment is the first step of a natural synthesis of aspirin. The two steps found in this experiment, as well as the last step, can be done independently, or in conjunction with each other. The procedure is well optimized, and to our knowledge represents the greenest route to aspirin

Material List (per student):

Ring stand
Test tube clamp
Clamp holder
Large test tube (50 to 75 mL)
Stirring hot plate
Stir bar
400 mL beaker (for a hot water bath)
pH paper
Methyl salicylate (wintergreen oil) (1.52 g)
Aqueous sodium hydroxide solution (3 M) (10 mL)
Aqueous hydrochloric acid (3 M) (11 mL)
Distilled or de-ionized water
Ice
Filtration device (vacuum is superior to gravity)
For optional recrystallization:
Salicylic acid (synthesized or commercial)
100 mL beaker
Hot plate
Distilled or de-ionized water
Filtration device (vacuum is superior to gravity)



Safety Precautions:
Methyl salicylate: Methyl salicylate can irritate the eyes and skin

Sodium hydroxide: Caustic - avoid contact – it may damage clothing and skin.

Hydrochloric acid: Avoid contact – it may damage clothing and skin.

Scenario
New Age Pharmaceuticals has contacted Lecher Consulting Enterprises seeking our technical expertise in green synthesis techniques. New Age Pharmaceuticals is interested in developing a sustainable, environmentally benign synthetic route for the production of aspirin. The product is to be called New Age Organic Aspirin.

Background
Commercial aspirin is made by the acylation of salicylic acid. Salicylic acid is synthesized via the Kolbe-Schmitt reaction of phenol. Phenol can be synthesized by a variety of routes from benzene, which is a non-renewable resource obtained from crude oil. Alternatively, salicylic acid can be obtained by the hydrolysis of methyl salicylate. Oil of wintergreen, which contains methyl salicylate, is extracted from the leaves of the common wintergreen plant (gaultheria procumbens).[1] Wintergreen therefore represents a renewable source of salicylic acid.


Mechanism
The mechanism for the reaction is depicted in Scheme 2.



Note that the product of the initial reaction is a salt of salicylic acid (disodium salicylate) and not salicylic acid itself. Adding acid converts the disodium salicylate into salicylic acid. Salicylic acid is not very water soluble (especially in cold water), and precipitates out of the reaction mixture.

In the Lab
Lecher Consulting Enterprises has been hired to develop a reliable, cost effective procedure for the synthesis of natural aspirin. Our first objective is to optimize the hydrolysis of methyl salicylate and evaluate the procedure for greenness.



Reaction Table
Formula
Name Weight density eq mmol wt / vol

methyl salicylate 152.14 1.174 g/mL 1.00 7.7 1.17 g

aqueous sodium hydroxide (3.0 M) -- -- 3.00 23.1 8 mL

aqueous hydrochloric acid (3.0 M) -- -- 3.30 25.5 9 mL

Safety Precautions

Methyl salicylate: Methyl salicylate can irritate the eyes and skin

Sodium hydroxide: Caustic - avoid contact – it may damage clothing and skin.

Hydrochloric acid: Avoid contact – it may damage clothing and skin.

Experimental Procedure

Synthesis of Salicylic Acid

1. Set up ring stand and hot plate.

2. Set up a water bath on the hot plate; preheat a water bath to a gentle boil.

3. Pipette 1.0 mL of directly into a large test tube (50 to 75 mL). Add a stir bar.

4. Measure 8 mL of 3 M aqueous sodium hydroxide. Add to the test tube. Record any observation.

5. Clamp the test tube into the hot water bath.

6. Heat the reaction mixture with stirring (if possible) until all the solid has dissolved. This should take about 10 minutes.

7. Turn off the hot plate. Using the stir bar retriever, remove the stir bar.

8. Raise the test tube out of the hot water bath.

9. Slowly add 9 mL of aqueous 3 M hydrochloric acid. Mix with a stir rod, checking the pH by touching the stirring rod to a piece of pH paper.

10. Cool the mixture in an ice water bath for about 5 minutes.

Isolation
11. Collect the solid by vacuum filtration, washing it with a small amount of ice-cold DI water.

12. With the vacuum applied, allow the solid to air dry for 2 or 3 minutes.

13. Dispose of the aqueous filtrate via the drain with copious amounts of water.

14. Place the salicylic acid in a safe place and allow the crude product to dry to a constant mass.

15. Record the mass of the dry crude salicylic acid.




Carl S. Lecher, Marian College, Indianapolis, IN, clecher@marian.edu
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