Chemistry can be roughly divided into two branches, analysis and synthesis. Chemists either try to identify existing substances or make new ones. By the early 19th century, a number of substances had been isolated from plants, with morphine from the poppy, quinine from cinchona bark, and coumarin from tonka beans being examples. However, given that these substances were derived from living species, they were believed to be endowed with a “life force” that could not be duplicated in the lab, and that such “organic” substances could not be synthesized.
That belief was eventually dispelled, starting with Friedrich Wohler’s classic accidental discovery in 1828 that heating ammonium cyanate, a chemical with no living ancestry, was converted it into urea, which he showed to be identical to urea extracted from his own urine. Since it was present in urine, urea obviously came from a living system, nevertheless it could be produced in the laboratory! Although Wohler’s urea synthesis marks the first time that a compound identical to one produced in nature was replicated in the laboratory, it did not precipitate widespread efforts to synthesize new compounds. That only happened after William Henry Perkin’s classic accidental discovery.
One of the most often told stories, at least by me, is the accidental discovery of mauveine, the first synthetic dye, by Perkin in 1856 at the ripe old age of eighteen. During a futile attempt to synthesize quinine from compounds found in coal tar, young Perkin accidentally produced a substance that had a stunning mauve colour. Up to that time, all dyes were extracted from a natural source, but the discovery of mauveine changed that. Before long, a number of other “coal tar” dyes appeared in the marketplace, many produced by Perkin who with financial help from his father and brother opened a dye factory.
By the time he reached his thirties, Perkin was wealthy enough to retire from the dye business to devote all his efforts to chemical research. His main interest, as one would expect, focused on synthetic chemistry, that is using chemical reactions to make novel compounds. One of his targets was coumarin, much desired by the perfume industry. A synthetic version would make perfume production much easier than extraction of coumarin from its main natural source, the tonka bean. In 1868 Perkin managed to make coumarin from compounds isolated from coal tar using a reaction he invented. Later christened the “Perkin reaction,” it is widely used, and is a staple in organic chemistry courses.
Synthetic coumarin first appeared on the market in 1882 in Fougere-Royal, the highly successful perfume that became the prototype for a host of “Fougeres” linked by the inclusion of coumarin. The compound didn’t get much attention outside the perfume industry until the 1920s when cattle in Canada and the Northern U.S. began to die from some mysterious condition that caused them to bleed to death. The connection turned out to be the consumption of moldy silage made from sweet clover. Before long researchers showed that moldy hay, but not regular hay, had an anticoagulant effect in rabbits and by 1940 the chemical responsible was isolated. While coumarin was found to have no anticoagulant effect, chemicals in mould converted it into a novel compound that caused excessive bleeding. Somehow it interfered with the action of Vitamin K, the compound that prevents bleeding by coagulating blood when necessary. Named dicoumarol, the newly isolated anticoagulant’s molecular structure was confirmed when it was independently synthesized. Dicoumarol found a use as a rat poison.
Karl Link at the University of Wisconsin continued working on developing more potent coumarin-based anticoagulants for use as rodent poisons and came up with a derivative of dicoumarol that was named “warfarin” from the acronym for Wisconsin Alumni Research Foundation. Warfarin was first registered for use as a rodenticide in the US in 1948 and caught pharmaceutical chemists’ attention in 1951 when an American soldier tried to commit suicide with warfarin and was saved when given vitamin K. The success with an antidote suggested that warfarin could be used as a drug in humans when blood clot formation needed to be prevented. It was found to be generally superior to dicoumarol, and in 1954 was approved for medical use in humans. An early recipient of warfarin was US president Dwight Eisenhower who was prescribed the drug after having a heart attack in 1955.
Isn’t it interesting how a story that starts with an accidental discovery of a dye leads down a path that ends with the synthesis of a life-saving drug?
