This article was first published inÂ
During the Second World War, American soldiers carried a first aid kit attached to their belt that contained a powder to be sprinkled on any open wound to prevent infection. That powder was sulfathiazole, synthesized by chemists from aniline, then already a compound of great commercial importance with a fascinating history.
Prior to the early 1800s, city streets were unlit at night, making for treacherous ventures into the darkness. Then along came gaslights. Lit at dusk by lamplighters, these produced a flame by burning “coal gas,” a mixture of hydrogen, methane, carbon monoxide and various hydrocarbons. The gas, generated by heating coal in the absence of air, was piped to street lamps and into the homes of the well-to-do. Left behind after the combustion of the coal was a thick, black goo called “coal tar” that accumulated in large amounts. Obviously, there was an interest in finding a use for the substance.
Distillation is a classic method, long practised by alchemists, of separating the components of a mixture by virtue of a difference in boiling point. In 1834, German chemist Friedlieb Runge distilled a sample of coal tar and isolated a liquid with a fishy smell that turned blue when treated with calcium hypochlorite. He named it kyanol, from the ancient Greek word for blue. Runge recognized the potential of this observation and proposed the building of a factory for the manufacture of synthetic dyes and other coal tar products, but the suggestion fell on deaf ears. This was more than a decade before William Henry Perkin was anointed as the discoverer of synthetic dyes.
Eight years before Runge’s experiment, Otto Unverdorben had isolated a substance he called crystalline from the destructive distillation of indigo, the blue dye produced from a plant originally native to India (hence the name). In 1843, August Wilhelm von Hofmann, who had studied under Justus von Liebig, the leading German chemist at the time, showed that kyanol and crystalline were one and the same. Thereafter, the compound came to be known as aniline, from “anil,” the common name for the plant that produces indigo.
In 1845, Hofmann was invited to be the first director of the Royal College of Chemistry in London, where he carried out further research on aniline and other compounds found in coal tar. The structure of molecules was unknown at the time, but chemists were able to determine the elements of which an unknown substance was composed. Aniline and quinine — which interestingly had also been isolated by Runge, from the bark of the Peruvian cinchona tree — both contained carbon, hydrogen and nitrogen, but quinine also contained oxygen. It seemed to Hofmann that using a reagent that adds oxygen to a molecule — in other words, an oxidizing agent — might convert aniline to quinine, which was much sought after as a treatment for malaria. He suggested that his 18-year-old student William Henry Perkin give this reaction a try.
In retrospect, the plan had no chance of coming to fruition since aniline and quinine have totally different chemical structures, so it is not surprising that Perkin became frustrated with his efforts. One day after dumping his latest attempt to oxidize aniline into the sink, and rinsing his flask with alcohol, he was astonished to find that the sink had turned a brilliant purple colour. Young Perkin had accidentally discovered the dye that would become known as mauve. He realized the commercial possibilities of his discovery, but distilling significant quantities of aniline from coal tar proved to be difficult. Then along came French chemist Antoine BĂ©champ, who found a way to convert benzene, readily available from coal tar, into aniline. The synthetic dye industry was underway.
Although Perkin did become wealthy from his discovery, it was in Germany that companies capitalized on aniline chemistry to create a massive dye industry. BASF (Badische Analin und Sodafabrik), now the largest chemical company in the world, got its start by producing dyes from aniline.
Besides dying fabrics, aniline derivatives also proved to be useful in staining microscope slides. Certain bacteria selectively absorb dyes, making them more visible under a microscope. This gave Paul Ehrlich the idea of incorporating a toxic substance, arsenic, into the dye, with hopes that it would kill the bacteria that absorb the dye. This led to the development in 1909 of Salvarsan, the first effective drug for the treatment of syphilis.
Given the success of Salvarsan, chemical companies began to experiment with the synthesis of all sorts of dyes that might act as antibacterial agents. Chemists Josef Klarer and Fritz Mietzsch at the Bayer laboratories of the IG Farben conglomerate in Germany synthesized an aniline derivative, sulfamidochrysoidine, that Dr. Gerhard Domagk found attacked streptococci bacteria in mice. Named Prontosil, the drug went on the market in 1935 in Europe and got a big boost in the U.S. when President Franklin Delano Roosevelt’s wife Eleanor had to miss Thanksgiving dinner to rush to Boston, where her son had been stricken with a strep infection. As Time magazine widely reported, Franklin Jr. made a remarkable recovery after his physician injected him with Prontosil.
Researchers at the Pasteur Institute in Paris went on to show that Prontosil breaks down in the body to release sulfanilamide, which is the actual active ingredient. This was easier to produce than Prontosil, but sulfanilamide’s reputation took a major blow in 1937 when the S.E. Massengill Co. formulated a liquid version using diethylene glycol as solvent without testing its toxicity. Before authorities were able to recall Elixir Sulfanilamide, 108 people, mostly children, had died as a result of diethylene glycol poisoning their liver and kidneys.
Since the problem was due to the solvent, not the active ingredient, the tragedy did not stop research into other “sulfa drugs.” By the early 1940s, around 500 sulfa drugs had been produced, including the sulfathiazole distributed to soldiers. However, by the end of the decade these had given way to the more effective antibiotic penicillin. Nevertheless, Prontosil is still regarded as the drug that ushered in the era of antibiotics.
Today, aniline is produced from benzene distilled from petroleum. It is still widely used to produce dyes for fabrics and hair, but has numerous other applications. Antioxidants to preserve rubber, the sweetener cyclamate, the painkiller acetaminophen (Tylenol), inks and polyurethane plastics all rely on aniline for their production. Indigo, from which Unverdorben first produced aniline, is now synthesized from aniline without the need to grow plants. Neither Unverdorben nor Runge (who, incidentally, was also the first to isolate caffeine from coffee beans) could have guessed where their discoveries of “crystalline” and “kyanol” would lead.
