Laboratory Reference Manual, Chemistry 201/202
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Experiment 3   Synthesis of Salicylic Acid from Oil of Wintergreen (Methyl Salicylate)

OVERVIEW | BACKGROUND | PROCEDURE | NOTES | REPORT

Background

Methyl salicylate and salicylic acid are naturally occurring compounds with medicinal uses. The procedure used here to convert methyl salicylate into salicylic acid is called saponification. It is chemically related to the process used to convert natural fats into soap.

Salicylic acid and aspirin

Many plants produce salicylic acid naturally. Among these, willow trees have been recognized since antiquity as a potent source of medicine. Hippocrates encouraged the pregnant women of ancient Greece to chew willow leaves and drink willow tea to alleviate labor and birth pains. Chinese, Native Americans, and others also used willow.

Salicylic acid is found mainly in the willow's leaves and bark. The pure acid possesses several useful medicinal properties. It is an antipyretic (a fever reducer), an analgesic (a pain reducer), and an anti-inflammatory (a swelling reducer).

Unfortunately, pure salicylic acid and even the concoctions derived from willow, make for an extremely unpleasent medicine. The salicylic acid molecule contains two acidic functional groups, the phenol group (PhOH) and the carboxylic acid group (-CO2H). These groups make salicylic acid an irritating substance that burns the sensitive linings of the mouth, throat, esophagus, and stomach. (Interestingly, salicylic acid's ability to burn living tissue makes it useful for other applications. Salicylic acid is the active ingredient in Compound W, an over-the-counter wart remover.)

The best way to mitigate salicylic acid's harsh qualities is to replace the acidic hydrogens with less reactive groups of atoms. For example, replacing the phenolic hydrogen with an acetyl group, -COCH3, gives acetylsalicylic acid or "aspirin".

salicylic acid v. aspirin

Acetylsalicylic acid does not occur naturally. It contains only one acidic functional group, and bypass most of the digestive system without causing burns. Eventually, acetylsalicylic acid reacts with water, mainly in the bloodstream, to regenerate salicylic acid.

The story of aspirin's discovery. Aspirin is a fascinating substance for many reasons. I have discovered a wealth of information on aspirin by typing "aspirin" and another keyword ("discovery", "patent", etc.) into web search engines. Here are two interesting sidelights on aspirin:

  • Friedrich Bayer & Co., the first company to test aspirin as a commercial product, did not allow its release initially because the head of Bayer's pharmacology lab was convinced that aspirin would damage the human heart (this person had a clause in his contract that allowed him to blackball any compound that he didn't trust). Many years later it was discovered that a daily aspirin pill helped prevent heart attacks.
  • Bayer was forced to relinquish its aspirin patent as part of the Treaty of Versailles following World War I. This action was demanded by the Allies as part of the war reparations.

Perhaps the most interesting story concerns the discovery of aspirin. Several times over the last 30 years, I had encountered a story (and repeated it in earlier versions of this lab manual) that now turns out to be work of fiction with an interesting twist.

The standard story claims that Felix Hoffmann, a young Bayer chemist, had been encouraged by his ailing father to look for compounds that would alleviate the latter's arthritis pains. The result was aspirin, which Hoffmann first prepared and gave to his father in 1897.

Some versions of the story say it was an accident that Hoffmann decided to make aspirin. Other versions say he made aspirin because earlier chemists had already reported some medical success with impure aspirin. In any case, the story did not get told until 1934 (and even then it only appeared in a footnote in a German book describing the history of chemical engineering).

Shortly after World War II, another version of aspirin's discovery was published by a Jewish colleague of Hoffmann's, Arthur Eichengruen. Dr. Eichengruen was a survivor of the Theresienstadt concentration camp, and after the war he told his story: he had planned and directed the synthesis of aspirin along with the synthesis of several related compounds, and he was responsible for aspirin's initial surreptitious clinical testing (remember that the head of the Bayer pharmacology lab was against testing). Hoffmann's role was relegated to the initial lab synthesis and nothing more (Hoffmann probably didn't even know why he was preparing the compound).

The Eichengruen version was ignored by historians and chemists until 1999, when another scientist, Walter Sneader, re-examined all of the documents involved and published an analysis of the historical record (BMJ, 2000, 321, 1591). His research revealed that the "original" 1934 footnote did not fit the known facts, whereas Eichengruen's "new" account was convincing on all counts.

It may seem surprising that the original story of aspirin's discovery did not emerge until 1934, more than 30 years after the first commercial sale of aspirin. It may seem even more surprising that Eichengruen waited an additional 15 years before publishing his story. However, both events can be explained by the rise and fall of Nazi Germany.

German life was controlled by the Nazi party in 1934. They had already taken steps to remove Jews from many professions, and they had taken it upon themselves to rewrite German history (to "Aryanize" it), including German scientific history. Contradicting Nazi propaganda at that point in time would have been a one-way ticket to oblivion for a Jewish chemist. Sadly, as of this writing (Aug. 2003), the Bayer company still fails to acknowledge the contributions of Arthur Eichengruen.

Methyl salicylate

Methyl salicylate, like salicylic acid, is produced by many plants. It was first isolated from wintergreen leaves, Gaultheria procumbens, and is often called oil of wintergreen.

Methyl salicylate is similar to acetylsalicylic acid in that it masks one of the acidic hydrogens in salicylic acid. Methyl salicylate replaces the carboxylic acid hydrogen with a methyl group, -CH3. The result is a relatively unreactive compound that does not liberate salicylic acid efficiently in the body. Consequently, methyl salicylate is not an effective analgesic.

Methyl salicylate has other uses, including its distinctive fragrance, and is added to many commercial products, including root beer and Ben-Gay ointment.

Saponification

Natural fats are called triglycerides because they contain glycerol and three fatty acids. The functional group that links glycerol with each fatty acid is called a carboxylic acid ester. Thus, a triglyceride contains three ester groups. (Loudon p. 948-952, 986-988 and 1036 describe how to name carboxylic acids and related compounds).

glycerol v. fatty acid v. triglyceride

Fats can be converted into fatty acids and glycerol by boiling fat with lye (aqueous NaOH). This process is called saponification (Loudon p. 1004) because the products make a nice soap. Notice that the chemical equation drawn below is not balanced; more atoms are needed on the reactant side of the equation (lye contributes the missing atoms).

fat saponification

A completely analogous process converts methyl salicylate into salicylic acid. Methyl salicylate is a carboxylic acid ester too, and it reacts with lye to make a carboxylic acid (salicylic acid) and an alcohol (methanol).

methyl salicylate saponification

The analogous chemical behavior of "triglyceride + lye" and "methyl salicylate + lye" illustrates a widespread chemical phenomenon: functional groups, like carboxylic acid esters, react in pretty much the same way regardless of their molecular surroundings. This principle, which we might call the "functional group principle" is probably the most important mental tool in all of organic chemistry. When an organic chemist looks at the formula of an unfamiliar compound, the first thing he or she does is look for familiar functional groups.

Saponification reactions will be studied in detail during Chemistry 202, so only a few points will be mentioned here.

  • The saponification reaction occurs in several "steps". Each step makes or breaks one or two bonds, and generates one or more new compounds called intermediates. An intermediate is a compound that persists anywhere from a few microseconds to several minutes, but always decays into other molecules.
  • The sequence of reaction steps that molecules follow as they change from reactants to products is called a reaction mechanism. The reaction mechanism for saponification is shown at the bottom of Loudon, p. 1005.

    Notice that Loudon's mechanism presents the carboxylic acid as a reaction intermediate (eq. 21.9a). The carboxylic acid is unstable in the reaction mixture because the mixture contains a large number of strongly basic molecules. To actually obtain a carboxylic acid, we must "work up" the basic reaction mixture by adding a stronger acid. This acid converts all of the hydroxide ions into water molecules, and the carboxylate ions (RCO2-) into neutral carboxylic acid molecules.
  • The saponification of methyl salicylate requires even more steps than the mechanism shown in Loudon. Methyl salicylate contains an acidic phenol group (PhOH). This group reacts immediately with aqueous lye to give an insoluble white goo. The ions in this goo subsequently undergo saponification a la Loudon (this is discussed in the Procedure and Notes).

OVERVIEW | BACKGROUND | PROCEDURE | NOTES | REPORT

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