To this day the structure of mauveine remains a bit of a mystery. Perkin’s starting materials, isolated from coal tar, were not pure, and it is now thought that his purple color was obtained from a mixture of very closely related compounds. The following is presumed to be the major structure responsible for the color:
Part of the mauveine molecule, the major contributor to Perkin’s mauve color
Perkin’s decision to manufacture the mauve dye commercially was undoubtedly a leap of faith. He was young, a novice chemistry student with little knowledge of the dye industry and absolutely no experience of large-scale chemical production. As well, his synthesis had a very low yield, at best maybe 5 percent of the theoretically possible amount, and there were real difficulties associated with obtaining a steady supply of the coal tar starting materials. For a more experienced chemist these problems would have been daunting, and probably we can attribute Perkin’s success in part to the fact that he did not let his lack of experience deter him. With no comparable manufacturing process as a guide, Perkin had to devise and test new apparatus and procedures. Solutions to problems associated with scaling up his chemical synthesis were found: large glass vessels were made, as the acid in the process would attack iron containers; cooling devices were used to prevent overheating during the chemical reactions; hazards such as explosions and toxic fume releases were controlled. In 1873 Perkin sold his factory after operating it for fifteen years. He retired a wealthy man and spent the rest of his life studying chemistry in his home laboratory.
THE LEGACY OF DYE S
The dye trade, which now mainly produces chemically synthesized artificial dyes, became the forerunner to an organic chemical enterprise that would eventually produce antibiotics, explosives, perfumes, paints, inks, pesticides, and plastics. The fledgling organic chemistry industry developed not in England—the home of mauve—or in France, where dyes and dyeing had been of crucial importance for centuries. Rather, it was Germany that developed a huge organic chemical empire along with the technology and science on which it was based. Britain already had a strong chemical industry, supplying the raw materials needed for bleaching, printing, pottery, porcelain, glassmaking, tanning, brewing, and distilling, but these compounds were mainly inorganic: potash, lime, salt, soda, acid, sulfur, chalk, and clay.
There are several reasons why Germany—and to a lesser extent Switzerland—became major players in synthetic organic chemicals. By the 1870s a number of British and French dye manufacturers had been forced out of business as a result of an endless series of patent disputes over dyes and dye processes. Britain’s major entrepreneur, Perkin, had retired, and no one else with the requisite chemical knowledge, manufacturing skills, and business talents replaced him. So Britain, perhaps not realizing it was against the country’s interests, became an exporter of the raw materials for the growing synthetic dye industry. Britain had gained industrial supremacy on the basis of importing raw materials and converting them into finished goods for export, so its failure to recognize the usefulness of coal tar and the importance of the synthetic chemical industry was a major mistake that benefited Germany.
Another important reason for the growth of the German dye industry was the collaborative effort between industry and universities. Unlike other countries where chemical research remained the prerogative of universities, German academics tended to work closely with their counterparts in industry. This pattern was vital to the success of the German chemical industry. Without knowledge of the molecular structures of organic compounds and a scientific understanding of the chemical steps in the reactions of organic synthesis, scientists could not have developed the sophisticated technology that eventually led to modern-day pharmaceuticals.
The chemical industry in Germany grew from three companies. In 1861 the first company, Badische Anilin und Soda Fabrik (BASF), was established at Ludwigshafen on the Rhine River. Although it was originally formed to produce inorganic compounds such as soda ash and caustic soda, BASF soon became active in the dye industry. In 1868 two German academics, Carl Graebe and Carl Liebermann, announced the first synthetic alizarin. BASF’s head chemist, Heinrich Caro, contacted the chemists in Berlin and collaborated with them to produce a commercially viable synthesis of alizarin. By the beginning of the twentieth century BASF was producing around two thousand tons of this important dye and was well on its way to becoming one of the big-five chemical companies that dominate the world today.
The second big German chemical company, Hoechst, was formed only a year later than BASF. Originally established to produce aniline red, a brilliant red dye also known as magenta or fuchsine, Hoechst chemists patented their own synthesis for alizarin, which proved very profitable. Synthetic indigo, the product of years of research and considerable financial investment, was also very lucrative for both BASF and Hoechst.
The third big German chemical company shared in the synthetic alizarin market as well. Although the name of Bayer is most often associated with aspirin, Bayer and Company, set up in 1861, initially made aniline dyes. Aspirin had been synthesized in 1853, but it was not until around 1900 that profits from synthetic dyes, especially alizarin, allowed Bayer and Company to diversify into pharmaceuticals and to market aspirin commercially.
In the 1860s these three companies produced only a small percentage of the world’s synthetic dyes, but by 1881 they accounted for half of the global output. At the turn of the century, despite a huge increase in overall world production of synthetic dyes, Germany had gained almost 90 percent of the dye market. Along with domination of dye manufacturing went a commanding lead in the business of organic chemistry as well as a heavy role in the development of German industry. With the advent of World War I the German government was able to enlist dye companies to become sophisticated producers of explosives, poisonous gases, drugs, fertilizers, and other chemicals necessary to support the war.
After World War I the German economy and the German chemical industry were in trouble. In 1925, in the hopes of alleviating stagnating market conditions, the major German chemical companies consolidated into a giant conglomerate, Interessengemeinschaft Farbenindustrie Aktiengesellschaft (Syndicate of Dyestuff Industry Corporation), generally known as IG Farben. Translated literally, Interessengemeinschaft means “community of interest,” and this conglomeration was definitely in the interest of the German chemical-manufacturing community. Reorganized and revitalized, IG Farben, by now the world’s largest chemical cartel, invested its considerable profits and economic power into research, diversified into new products, and developed new technologies with the aim of achieving a future monopoly of the chemical industry.
With the arrival of World War II IG Farben, already a major contributor to the Nazi Party, became a major player in Adolf Hitler’s war machine. As the German army advanced through Europe, IG Farben took over control of chemical plants and manufacturing sites in German-occupied countries. A large chemical plant to make synthetic oil and rubber was built at the Auschwitz concentration camp in Poland. Inmates of the camp labored in the plant and were also subjected to experimentation with new drugs.
After the war nine of IG Farben’s executives were tried and found guilty of plunder and property crimes in occupied territories. Four executives were convicted of imposing slave labor and of treating prisoners of war and civilians inhumanely. IG Farben’s growth and influence was halted; the giant chemical group was split up, so that the major players again were BASF, Hoechst, and Bayer. These three companies have continued to prosper and expand and today constitute a sizable portion of the organic chemical industry, with interests ranging from plastics and textiles to pharmaceuticals and synthetic oil.
Dye molecules changed history. Sought after from their natural sources for thousands of years, they created some of humankind’s first industries. As the demand for color grew, so did guilds and factories, towns and trade. But the appearance of synthetic dyes transformed the world. Traditional means of obtaining natural dyes vanished. In their place, l
ess than a century after Perkin first synthesized mauve, giant chemical conglomerates dominated not only the dye market but also a burgeoning organic chemistry industry. This in turn provided the financial capital and the chemical knowledge for today’s huge production of antibiotics, analgesics, and other pharmaceutical compounds.
Perkin’s mauve was only one of the synthetic dye compounds involved in this remarkable transformation, but many chemists consider it the molecule that turned organic chemistry from an academic pursuit into a major global industry. From mauve to monopoly, the dye concocted by a British teenager on his vacation had a powerful influence on the course of world events.
10. WONDER DRUGS
IT PROBABLY WOULD not have surprised William Perkin that his synthesis of mauve became the basis for the huge commercial dye enterprise. After all, he had been so sure that the manufacture of mauve would be profitable that he had persuaded his father to finance his dream—and he had been extremely successful in his lifetime. But even he likely could not have predicted that his legacy would include one of the major developments evolving from the dye industry: pharmaceuticals. This aspect of synthetic organic chemistry would far surpass the production of dyes, change the practice of medicine, and save millions of lives.
In 1856, the year when Perkin prepared the mauve molecule, the average life expectancy in Britain was around forty-five years. This number did not change markedly for the rest of the nineteenth century. By 1900 the average life expectancy in the United States had only increased to forty-six years for a male and forty-eight years for a female. A century later, in contrast, these figures have soared to seventy-two for males and seventy-nine for females.
For such a dramatic increase after so many centuries of much lower life expectancies, something amazing had to have happened. One of the major factors in longer lifespans was the introduction, in the twentieth century, of molecules of medicinal chemistry and in particular of the miracle molecules known as antibiotics. Literally thousands of different pharmaceutical compounds have been synthesized over the past century, and hundreds of them were life changing for many people. We will look at the chemistry and development of only two types of pharmaceuticals: the pain-relieving molecule aspirin, and two examples of antibiotics. Profits from aspirin helped convince chemical companies that there was a future in pharmaceuticals; the first antibiotics—sulfa drugs and penicillins—are still prescribed today.
For thousands of years medicinal herbs have been used to heal wounds, cure sickness, and relieve pain. Every human society has developed unique traditional remedies, a number of which have yielded extremely useful compounds or have been chemically modified to produce modern medicines. Quinine, which comes from the South American cinchona tree and originally used by the Indians of Peru to treat fevers, is still today an antimalarial. Foxglove containing digitalis, which is still prescribed as a contemporary heart stimulant, has long been used in western Europe to treat heart ailments. The analgesic properties of sap from the seed capsules of a poppy plant were well known from Europe to Asia and morphine extracted from this source still plays a major role in pain relief.
Historically, however, few if any effective remedies were known for treating bacterial infections. Until relatively recently even a small cut or a tiny puncture wound could, if infected, become life threatening. Fifty percent of soldiers wounded during the American Civil War died of bacterial infections. Thanks to antiseptic procedures and molecules like phenol, introduced by Joseph Lister, this percentage was smaller during the First World War. But although use of antiseptics helped prevent infection from surgery, it did little to stop an infection once it had started. The great influenza pandemic of 1918-1919 killed more than twenty million people worldwide, a far greater toll than that of World War I. The influenza itself was viral; the actual cause of death was usually a secondary infection of bacterial pneumonia. Contracting tetanus, tuberculosis, cholera, typhoid fever, leprosy, gonorrhea, or any of a host of other illnesses was often a death sentence. In 1798 an English doctor, Edward Jenner, successfully demonstrated for the smallpox virus the process of artificially producing immunity to a disease, although the concept of acquiring immunity in this way had been known from earlier times and from other countries. Starting in the last decades of the nineteenth century, similar methods of providing immunity against bacteria were investigated as well, and gradually inoculation became available for a number of bacterial diseases. By the 1940s fear of the dreaded childhood duo of scarlet fever and diphtheria had receded in countries where vaccination programs were available.
ASPIRIN
In the early twentieth century the German and Swiss chemical industries were prospering from their investment in the manufacture of dyestuffs. But this success was more than just financial. Along with profits from dye sales came a new wealth of chemical knowledge, of experience with large-scale reactions, and of techniques for separation and purification that were vital for expansion into the new chemical business of pharmaceuticals. Bayer and Company, the German firm that got its start from aniline dyes, was one of the first to recognize the commercial possibilities in the chemical production of medicines—in particular aspirin, which has now been used by more people worldwide than any other medication.
In 1893 Felix Hofmann, a chemist working for the Bayer company, decided to investigate the properties of compounds that were related to salicylic acid, a molecule obtained from salicin, a pain-relieving molecule originally isolated from the bark of trees of the willow genus (Salix) in 1827. The curative properties of the willow and related plants such as poplars had been known for centuries. Hippocrates, the famed physician of ancient Greece, had used extracts from willow bark to reduce fevers and relieve pain. Although the bitter-tasting salicin molecule incorporates a glucose ring into its structure, the rest of the molecule overwhelms any sweetness from the sugar part.
The salicin molecule
Like the glucose-containing indican molecule that produces indigo, salicin breaks into two parts: glucose and salicyl alcohol, which can be oxidized to salicylic acid. Both salicyl alcohol and salicylic acid are classified as phenols because they have an OH group directly attached to the benzene ring.
These molecules are also similar in structure to isoeugenol, eugenol, and zingerone from cloves, nutmeg, and ginger. It is probable that like these molecules, salicin acts as a natural pesticide to protect the willow tree. Salicylic acid is also produced from the flowers of meadowsweet or Spiraea ulmaria, a wetlands perennial native to Europe and western Asia.
Salicylic acid, the active portion of the salicin molecule, not only reduces fever and relieves pain but also acts as an anti-inflammatory. It is much more potent than the naturally occurring salicin, but it can be very irritating to the lining of the stomach, reducing its medicinal value. Hofmann’s interest in compounds related to salicylic acid arose out of concern for his father, whose rheumatoid arthritis was little relieved by salicin. Hoping that the anti-inflammatory properties of salicylic acid would be retained but its corrosive properties lessened, Hofmann gave his father a derivative of salicylic acid—acetyl salicylic acid, first prepared by another German chemist forty years previously. In ASA, as acetyl salicylic acid has come to be called, the acetyl group (CH3CO) replaces the H of the phenolic OH group of salicylic acid. The phenol molecule is corrosive; perhaps Hofmann reasoned that converting the OH attached to the aromatic ring into an acetyl group might mask its irritating characteristics.
Hofmann’s experiment paid off—for his father and for the Bayer company. The acetylated form of salicylic acid turned out to be effective and well tolerated. Its potent anti-inflammatory and analgesic properties persuaded the Bayer company, in 1899, to begin marketing small packets of powdered “aspirin.” The name is a combination of the a from acetyl and the spir from Spiraea ulmaria, the meadowsweet plant. The Bayer company name became synonymous with aspirin, marking Bayer’s entrance into the world of medicinal chemistry.
As the popularity of aspirin incre
ased, the natural sources from which salicylic acid was produced—meadowsweet and willow—were no longer sufficient to satisfy world demand. A new synthetic method using the phenol molecule as the starting material was introduced. Aspirin sales soared; during World War I the American subsidiary of the original Bayer company purchased as much phenol as possible from both national and international sources in order to guarantee an adequate supply for the manufacture of aspirin. The countries that supplied Bayer with phenol thus had reduced capacity to make picric acid (trinitrophenol), an explosive also prepared from this same starting material (see Chapter 5). What effect this may have had on the course of World War I we can only speculate, but aspirin production may have reduced reliance on picric acid for munitions and hastened the development of TNT-based explosives.
Today aspirin is the most widely used of all drugs for treating illness and injury. There are well over four hundred aspirin-containing preparations, and over forty million pounds of aspirin are produced in the United States annually. As well as relieving pain, lowering body temperature, and reducing inflammation, aspirin also has blood-thinning properties. Small doses of aspirin are being recommended as a preventive against strokes and for deep-vein thrombosis, the condition known as “economy class syndrome” in long-haul airline passengers.
THE SAGA OF SULFA
Around the time of Hofmann’s experiment on his father—a drug-trial procedure that is not recommended—the German doctor Paul Ehrlich was conducting experiments of his own. Ehrlich was, by all accounts, a truly eccentric character, said to smoke twenty-five cigars a day and spend many hours in philosophical discussions in beer halls. But along with his eccentricity came the determination and insight that gained him the 1908 Nobel Prize in medicine. Despite having no formal training in experimental chemistry or applied bacteriology, Ehrlich noted that different coal tar dyes would stain some tissues and some microorganisms but not others. He reasoned that if one microorganism absorbed a dyestuff and another did not, this differentiation might allow a toxic dye to kill tissue that absorbed it without damaging nonstaining tissue. Hopefully the infecting microorganism would be eliminated while the host was unharmed. Ehrlich termed this theory the “magic bullet” approach, the magic bullet being the dye molecule targeting the tissue it stained.
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