Synthesis of Aspirin Course Notes

The History of Aspirin

Aspirin has a long past. In the 5th century B.C. Hippocrates first used a bitter powder obtained from ground willow bark to ease aches and pains and to reduce fever. In Northern America, the American Indians chewed on willow bark to obtain these same results. In the 1700s, the scientist Reverend Edmund Stone wrote about the success of the bark and the willow in a cure of the "agues", or fevers with aches. The substance in the willow bark that was 1) bitter and 2) good for fever and pain and that made these people feel better is salicin, the pharmacological ancestor of a family of drugs called salicylates which include aspirin. Salicin can be converted by the body after it is eaten to another chemical, salicylic acid.

In 1829 the pharmacist Leroux showed that salicin is this active willow ingredient. For many years salicylic acid and its close relatives were used at high doses to treat pain and swelling in diseases like arthritis and to treat fever in illnesses like influenza.

salicyclic acid structure

salicylic acid

The problem with these chemicals was that they upset the user's stomach badly. Some people had bleeding in their digestive tracts from the high doses of these chemicals needed to control, pain and swelling. One of these people was a German named Hoffmann. Over 100 years ago, a German industrial chemist, Felix Hoffmann set about to find a drug to ease his father's arthritis without causing severe stomach irritation that was associated with sodium salicylate, the standard anti-arthritis drug of the time. The large doses, 6 - 8 grams, of sodium salicylate that was used to treat arthritis commonly irritated the stomach lining and many patients, including Hoffmann's father could not tolerate the drug.

Figuring that the acidity made salicylates hard on the stomach, Hoffmann started looking for a less acidic formulation. His search lead him to synthesize acetylsalicylic acid, a compound that shared the therapeutic properties of other salicylates and might cause less stomach irritations. He did this by putting the compound through a couple of chemical reactions that covered up one of the acidic portions, leaving the carboxylic acid group, with an ACETYL group converting it into acetylsalicylic acid.

acetylsalicylic acid structure

acetylsalicylic acid

The new compound reduced fever, relieved moderate pain and at higher doses alleviated rheumatic and arthritic conditions. Hoffman was confident that his new compound would be more effective than the salicylates then in use.

His superiors did not share his enthusiasm. They doubted that acetylsalicylic acid would ever become a valuable commercially successful drug because in large doses salicylates commonly produced shortness of breath and an alarmingly rapid heart rate. It was taken for granted that acetylsalicylic acid would weaken the heart and that physicians would be reluctant to prescribe it.

In 1899, Dreser, a top chemist with Friedrich Bayer and Co., gave acetylsalicylic acid the now familiar name aspirin, but in 1897 Bayer didn't think aspirin had much of a future. Little did they know what the future held for aspirin.

Today, Americans consume an estimated 80 billion aspirins a year and the physicians desk reference lists more than 50 over the counter drugs which contain aspirin as the principle active ingredient.

Enough Already! You're Giving Me a Headache

No one understands how pain works completely. A lot is known about pain, but the more that is found out about pain, the more questions that arise. Here is a simplified view. Pain is really something you feel in your brain. Lets say you hit your finger with a hammer (don't try this at home!). The part of your finger that is damaged has nerve endings in it that detect things like heat, light touch from things you hold and of course, big crushing shocks like hammers. There are different receptors for each of these types of sensations. The damaged tissue in your finger also releases some chemicals which make those nerve endings register the crushing shock even stronger -like turning up the volume on the TV so you can hear it better. Some of these chemicals are prostagladins and working cells in the damaged tissues make those chemicals using an enzyme called cyclooyxgenase 2 (or COX-2).

Because of the prostagladins, the nerve endings that are involved now send a strong signal through nerves in your hand, then through your arm, up your neck and into your brain, where your mind decides this signal means, "PAIN!!!". The prostagladins seem to contribute just a portion of the total signal that means pain, but this portion is an important one. In addition to helping you feel the pain, prostagladins also cause your finger to swell up (inflammation) to bathe the tissues in fluid from your blood that will protect it and help it heal. Thats the simplified story.(1)

Aspirin achieves some of its effects by inhibiting the enzymes that produce prostagladins. Prostagladins are hormone-like substances that influence the elasticity of blood vessels, control uterine contractions, directs the functioning of blood platelets to help stop bleeding and regulates numerous other activities in the body. Remember the enzyme COX-2? It is the protein made by your body's cells whose job is to take chemicals floating around in your tissues and turn them into prostagladins. COX-2 can be found in lots of normal tissues, but much more of it is found in damaged tissue. Aspirin it turns out, sticks to COX-2 and won't let it do its job. It's like a lock you put on a bicycle. The bicycle won't move with the lock on, and COX-2 can't work with aspirin stuck to it.

(1) Howstuffworks "How Aspirin Works"

In the 1970's a British pharmocologist John Vane, Ph.D. noted that many forms of tissue injury were followed by the release of prostagladins. In laboratory studies he found that 2 groups of prostagladins cause fever and redness, common signs of inflammation. Vane and his co-workers showed that by blocking the synthesis of prostagladins, aspirin prevented blood platelets from aggregating, one of the initial steps in the formation of blood clots.

Since aspirin lowers the amount of prostagladins, it can help alleviate conditions like pain, fever and the discomfort of menstrual cramps. Aspirin is an analgesic (relieves pain without loss of consciousness), an antipyretic (fever reducer),an anti-inflammatory, and an anti-platelet.

The Esterification Process

Aspirin can be made by using a process called esterification. Esterification occurs when a carboxylic acid and an alcohol combine in a reaction to produce an ester. This reaction can be used to synthesize aspirin from salicylic acid. In the lab, the carboxylic acid alcohol mixture is heated in the presence of H2SO4, sulfuric acid, which acts as a catalyst. During the reaction process, a molecule of water splits off and the remaining carboxylic acid and alcohol fragments become attached producing an ester.

General Esterification Reaction

General Reaction of Esterification

Esterification of Aspirin

Esterification of Aspirin Usng Acetic Acid

What We Are Doing In The Lab

You start by weighing out a sample of salicylic acid into an Erlenmeyer flask. To the sample you will add acetic anhydride. We are using acetic anhydride instead of acetic acid because acetic anhydride has a faster reaction time. The catalyst concentrated H2SO4 is added to speed up the reaction. The flask containing this solution is then heated in a boiling water bath for about 15 minutes. This process is called esterifcation.

Esterification of Aspirin In Lab

Esterification of Aspirin In Our Lab Using Acetic Anhydride

The flask is then removed and allowed to cool. Ice cold distilled water is slowly added to the flask to decompose any unreacted acetic annhydride.

Decomposition of acetic anhydride

Decomposition of Unreacted Acetic Anhydride

Ice cold distilled water is added to the flask again. The flask is then chilled in an ice-water bath for about 10 minutes until crystallization of the aspirin is complete. The aspirin crystals are collected on a Buchner funnel and washed with additional ice cold distilled water. You are using ice cold distilled water instead of room temperature distilled water because aspirin is insoluble in cold water and you would not be dissolving any of your aspirin product. The acetic acid and H2SO4 are water soluble, in any temperature water, and can be removed by washing the aspirin with the chilled water. Salicylic acid is only slightly soluble in water and any unreacted salicylic acid cannot be removed completely in the washing process. Once the aspirin crystals are purified they are allowed to dry. They are then weighed and tested for purity.

Why We Use Ice Cold Distilled Water

1) Aspirin is insoluble in cold water.

2) Acetic anhydride decomposes to water soluble acetic acid.

3) H2SO4, sulfuric acid, is soluble in water.

4) During the washing process impurities (acetic acid and H2SO4, sulfuric acid) are removed.

Testing For Impurities

We use iron III chloride to determine the purity of our aspirin. Iron III chloride combines with the phenol group to form a purple complex. If salicylic acid is present (impurity) the product will turn purple when FeCl3 is added, because salicylic acid is a phenol.

Purple color when FeCl3 added - impure product, salicylic acid present. Unreacted salicylic acid is present. Salicylic acid is NOT water soluble and cannot be removed by using cold distilled water. If you do not heat the solution long enough the reaction will not be complete.

No color change, appearance of yellow color, or a faint purple tinge - pure product, no unreacted salicylic acid present.

Purity test

LEFT - pure (no phenol present), RIGHT - impure (phenol present)

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last updated: January 22, 2015