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Acetyl salicylic acid – Aspirin

A molecule of acetyl salicylic acid (aspirin) in front of a willow, with a beaker and tablets on the side.

A molecule of acetyl salicylic acid (aspirin) in front of a willow, with a beaker and tablets on the side.

Picture It… is very pleased to introduce the first of our school student authored posts! Today’s post is co-authored by Anya Appoo, a student at The Ridings’ Federation, Winterbourne International Academy. It is also our first venture into the chemistry inside your medicine cabinet, with Molecules of Medicine.

The willow has many sinister associations in myth. In English folklore, the willow was believed to uproot itself and follow unwary travellers. Japanese tradition associates the willow with ghosts. However, this creepy tree also contains useful chemical compounds. Willow bark has been used as a pain reliever for thousands of years and the chemicals responsible have led to the discovery of aspirin, which has recently been found to have multiple medicinal applications (Jefferys, D., 2005, Aspirin: The Extraordinary Story of a Wonder Drug. New Edition. London: Bloomsbury Publishing PLC).

The different structures of salicin, salicylic acid and aspirin.

The different structures of salicin, salicylic acid and aspirin.

1) People of the ancient cultures of Egypt, Assyria and Sumer chewed willow bark as a relief from fever and pain. This unusual property of the plant was recorded in 400BC by the Greek physician Hippocrates; for whom the Hippocratic Oath, of modern medical practice, is named. The chemical study of medicinal plants began in earnest in the 1800s and, in 1829, the active ingredient of willow bark was isolated. Although naturally occurring in willow bark, salicin is not present in high amounts, so high doses are required to achieve pain relief.

In 1859, German chemist Hermann Kolbe synthesised salicylic acid. However this was found to be an irritant to the stomach and so was not all that useful.  In fact many patients who tried Kolbe’s new salicylic acid preferred their headaches to the severe heartburn they experienced as a side-effect (Warner, S., 2004, The Tribulations of Clinical Trials. The Scientist Magazine, 26 Apr).

It was another German scientist, Felix Hoffman, who made the first true aspirin – acetyl salicylic acid. In the same fortnight he also synthesised heroin, but that is another and entirely different chemical story. Hoffman’s company, Bayer, developed a process for synthesising the drug in large quantities and in 1899 the drug was patented. Aspirin was now available to people in powder form through a prescription. It wasn’t until later that imprinted tablets were used, to prevent problems with false substances. For the first fifty years aspirin was used purely as a pain killer, anti-inflammatory drug and a way to control fever. It wasn’t until the 21st century that other uses became known. Aspirin is now thought to be effective in treating many conditions including heart attacks and strokes (Circulation, 1993, 87659 – 675), schizophrenia  (J. Clin. Psychiatry, 2010, 71, 520 – 527), Alzheimer’s (Aging Dis., 2010, 1, 37 – 59) and several types of cancer (Epidemiology, 1994, 5, 138 – 146).

2) With 100 billion tablets consumed annually, aspirin is now one of the most commonly consumed drugs in the world (Rainsford, K.D., ed.,Aspirin and Related Drugs, 2004,  London, Taylor & Francis; Laurence, J., Focus: Aspirin – The Secret History of a Wonder Drug. The Independent, 17 Apr, 2005). Aspirin is most well known for being an analgesic drug – a painkiller. One role of prostaglandins is sensitizing our nerve endings, to increase the effect of pain eliciting chemicals which send signals through the nervous system to the brain, to make us feel pain. When production of prostaglandins is decreased less of these chemicals reach the brain, so the sensation of pain is less intense. Prostaglandins are also inflammatory mediators, meaning aspirin also acts as an anti-inflammatory drug. It is also an antipyretic drug, meaning it can be used to control fever. Following a bacterial infection, prostaglandins are produced in an area of the brain which controls body temperature – they cause an increase in temperature. When aspirin is being taken this temperature increase is prevented. As well as decreasing prostaglandin production, aspirin also reduces the production of thromboxane. Thromboxane is a hormone-like substance which signals for blood platelets to bind together – causing a blood clot or thrombus to be formed. A thrombus may be responsible for a heart attack or a stroke, by stopping blood flow, and therefore oxygen supply, to the heart or brain, when becoming lodged in an artery. Aspirin has an anti-platelet affect, preventing platelets from sticking together and forming clots. So aspirin is given to patients during and after a heart attack to increase survival rate.

A sprig of willow together with a molecule of salicylic acid.

A sprig of willow together with a molecule of salicylic acid.

The medicinal use of aspirin is hindered by some nasty side-effects. Salicyclic acid caused severe heartburn in patients when it was first introduced as a pain killer. Modern aspirin still lists side-effects such as gastrointestinal irritation, which may lead to ulcers and bleeding in severe cases. So why do these chemicals cause these symptoms? Part of the reason is due to acidity. Acidity is the ability of a compound to donate hydrogen ions, known as protons. Salicylic acid has two protons available, one on the carboxylic acid group and another from the alcohol group, it is a diprotic organic acid. Aspirin, on the other hand, only has one proton available, as the other is replaced by an acetyl group. Aspirin is a monoprotic organic acid. Salicylic acid is more acidic than aspirin and is more acidic than the human stomach, after digestion. So, introducing salicylic acid to the stomach increases the acidity, leading to symptoms such as heartburn.

3) Today aspirin is completely chemically synthesised without use of natural sources. One method starts from petroleum, which is refined by distillation to obtain benzene. Benzene is reacted sequentially with sulphuric acid and sodium hydroxide to give sodium phenolate.  This undergoes the Kolbe-Schmidt reaction (Chem. Rev., 1957, 57, 583 – 620), utilising carbon dioxide at high temperature and pressure, to give sodium salicylate, which is acidified to give salicylic acid. Salicylic acid is then reacted with acetic anhydride in the presence of an acid catalyst, usually sulphuric or phosphoric acid, to give acetyl salicylic acid, aspirin (Pavia, D.-L., Lampman, G.-M., Kriz, G.-S., Introduction to Organic Laboratory Techniques; A Contemporary Approach, Philidelphia, 1976, 72; Miller, J.-A., Neuzil, E.-F.,Modern Experimental Organic Chemistry, Heath Lexington, MA, 1982, 192).

The steps involved in the synthesis of aspirin.

The steps involved in the synthesis of aspirin.

Whilst this method uses only simple and relatively cheap chemicals, it has numerous problems. The initial benzene starting material is refined from petroleum, a depleted resource, and benzene itself is highly toxic. The acid catalysts are highly corrosive and must be handled with caution. Due to this necessity for highly toxic and corrosive chemicals, people have speculated whether aspirin would be allowed on the market, if it was newly introduced as a commercial pharmaceutical today (American Scientist, 1991, 79, 11 – 14).

Preyssler's anion, [NaP5W30O110]14-

Preyssler’s anion, [NaP5W30O110]14-

To avoid the use of corrosive acids, for the acetylisation of salicylic acid, research groups have investigated using acetyl chloride-pyridine as the acetylating agent (J. Chem. Ed., 1998, 75, 770). However the bad smell and irritant nature of the reagents mean this method isn’t suitable for the industrial scale. Solid acid catalysts, such as Preyssler’s Anion, have been investigated as green alternative catalysts, since they are recyclable (J. Chinese Chem. Soc., 2007, 54, 1017 – 1020).

The difficulties of industrial scale synthesis do not end with concerns regarding starting materials. Once the reaction is complete the reaction mixture contains aspirin but also unreacted acid catalyst and acetic anhydride, as well as undesired waste product, acetic acid. Unreacted acetic anhydride is decomposed to from acetic acid by addition of water. Aspirin is isolated from the mixture by filtering a cooled solution of the reaction mixture, as aspirin is insoluble in cold water, whereas acetic acid and phosphoric acid are soluble in water.

The aspirin then needs to be purified to make sure there is no excess salicylic acid present, as this is the unwanted substance which causes extreme side effects. Excess salicylic acid is not completely removed by washing with cold water, so purification is achieved through recrystallization. Aspirin recrystallises out of solution after being added to ethanol and cooled – this leaves impurities in the solution and allows pure, solid aspirin to be removed. The purity of aspirin can then be tested by checking the melting point of the substance. Once a high enough purity has been achieved, the chemical can be sent out to be manufactured into pills.

As aspirin ages, it may decompose and return to salicyclic acid and acetic acid. So, if you open an old bottle of aspirin at home and they smell of vinegar, they are probably no longer safe to use.

Contributors: Anya Appoo (writing and research), Jenny Slaughter (writing and research) and Natalie Fey (images and photography).