by Isaac Asimov
This notion of improving on nature in one fashion or another, rather than merely supplementing it, has grown to colossal proportions since Berthelot showed the way. The first fruits of the new outlook were in the field of dyes.
THE FIRST SYNTHESIS
The beginnings of organic chemistry were in Germany. Wöhler and Liebig were both German, and other men of great ability followed them. Before the middle of the nineteenth century, there were no organic chemists in England even remotely comparable to those in Germany. In fact, English schools had so low an opinion of chemistry that they taught the subject only during the lunch recess, not expecting (or even perhaps desiring) many students to be interested. It is odd, therefore, that the first feat of synthesis with worldwide repercussions was actually carried through in England.
It came about in this way. In 1845, when the Royal College of Science in London finally decided to give a good course in chemistry, it imported a young German to do the teaching. He was August Wilhelm von Hofmann, only twenty-seven at the time, and he was hired at the suggestion of Queen Victoria’s husband, the Prince Consort Albert (who was himself of German birth).
Hofmann was interested in a number of things, among them coal tar, which he had worked with on the occasion of his first research project under Liebig. Coal tar is a black, gummy material given off by coal when it is heated strongly in the absence of air. The tar is not an attractive material, but it is a valuable source of organic chemicals. In the 1840s, for instance, it served as a source of large quantities of reasonably pure benzene and of a nitrogen-containing compound called aniline, related to benzene, which Hofmann had been the first to obtain from coal tar.
About ten years after he arrived in England, Hofmann came across a seventeen-year-old boy studying chemistry at the college. His name was William Henry Perkin. Hofmann had a keen eye for talent and knew enthusiasm when he saw it. He took on the youngster as an assistant and set him to work on coal-tar compounds. Perkin’s enthusiasm was tireless. He set up a laboratory in his home and worked there as well as at school.
Hofmann, who was also interested in medical applications of chemistry, mused aloud one day in 1856 on the possibility of synthesizing quinine, a natural substance used in the treatment of malaria. Now those were the days before structural formulas had come into their own. The only thing known about quinine was its atomic composition, and no one at the time had any idea of just how complicated its structure is. (It was not till 1908 that the structure was correctly deduced.)
Blissfully ignorant of its complexity, Perkin, at the age of eighteen, tackled the problem of synthesizing quinine. He began with allyltoluidine, one of his coal-tar compounds. This molecule seemed to have about half the numbers of the various types of atoms that quinine has in its molecule. If he put two of these molecules together and added some missing oxygen atoms (say, by mixing in some potassium dichromate, known to add oxygen atoms to chemicals with which it is mixed), Perkin thought he might get a molecule of quinine.
Naturally this approach got Perkin nowhere. He ended with a dirty, red-brown goo. Then he tried aniline in place of allyltoluidine and got a blackish goo. This time, though, it seemed to him that he caught a purplish glint in it. He added alcohol to the mess, and the colorless liquid turned a beautiful purple. At once Perkin thought of the possibility of his having discovered something that might be useful as a dye.
Dyes had always been greatly admired, and expensive, substances. There were only a handful of good dyes—dyes that stained fabric permanently and brilliantly and did not fade or wash out. There was dark blue indigo, from the indigo plant and the closely related woad for which Britain was famous in early Roman times; there was Tyrian purple, from a snail (so called because ancient Tyre grew rich on its manufacture; in the later Roman Empire, the royal children were born in a room with hangings dyed with Tyrian purple, whence the phrase “born to the purple”); and there was reddish alizarin, from the madder plant (alizarin came from Arabic words meaning “the juice”). To these inheritances from ancient and medieval times, later dyers had added a few tropical dyes and inorganic pigments (today used chiefly in paints).
Hence, Perkin’s excitement about the possibility that his purple substance might be a dye. At the suggestion of a friend, he sent a sample to a firm in Scotland which was interested in dyes, and quickly the answer came back that the purple compound had good properties. Could it be supplied cheaply? Perkin proceeded to patent the dye (there was considerable argument about whether an eighteen-year-old could obtain a patent, but eventually he obtained it), to quit school, and to go into business.
His project was not easy. Perkin had to start from scratch, preparing his own starting materials from coal tar with equipment of his own design. Within six months, however, he was producing what he named aniline purple—a compound not found in nature and superior to any natural dye in its color range.
French dyers, who took to the new dye more quickly than did the more conservative English, named the color mauve, from the mallow (Latin malva); and the dye itself came to be known as mauveine. Quickly it became the rage (the period being sometimes referred to as the Mauve Decade), and Perkin grew rich. At the age of twenty-three, he was the world authority on dyes.
The dam had broken. A number of organic chemists, inspired by Perkin’s astonishing success, went to work synthesizing dyes, and many succeeded. Hofmann himself turned to this new field and, in 1858, synthesized a red-purple dye which was later given the name magenta by the French dyers (then arbiters of the world’s fashions). The dye was named for the Italian city where the French defeated the Austrians in a battle in 1859.
Hofmann returned to Germany in 1865, carrying his new interest in dyes with him. He discovered a group of violet dyes still known as Hofmann s violets. By the mid-twentieth century, no less than 3,500 synthetic dyes were in commercial use.
Chemists also synthesized the natural dyestuffs in the laboratory. Karl Graebe of Germany and Perkin both synthesized alizarin in 1869 (Graebe applying for the patent one day sooner than Perkin); and in 1880, the German chemist Adolf von Baeyer worked out a method of synthesizing indigo. (For his work on dyes, von Baeyer received the Nobel Prize in chemistry in 1905.)
Perkin retired from business in 1874, at the age of thirty-five, and returned to his first love—research. By 1875, he had managed to synthesize coumarin (a naturally occurring substance which has the pleasant odor of new-mown hay)—and thus began the synthetic perfume industry.
Perkin alone could not maintain British supremacy against the great development of German organic chemistry; and by the turn of the century, “synthetics” became almost a German monopoly. It was a German chemist, Otto Wallach, who carried on the work on synthetic perfumes that Perkin had started. In 1910, Wallach was awarded the Nobel Prize in chemistry for his investigations. The Croatian chemist Leopold Ruzicka, teaching in Switzerland, first synthesized musk, an important component of perfumes. He shared the Nobel Prize in chemistry in 1938. However, during the First World War, Great Britain and the United States, shut off from the products of the German chemical laboratories, were forced to develop chemical industries of their own.
ALKALOIDS AND PAIN DEADENERS
Achievements in synthetic organic chemistry could not have proceeded at anything better than a stumbling pace if chemists had had to depend upon fortunate accidents such as the one that had been seized upon by Perkin. Fortunately the structural formulas of Kekulé, presented three years after Perkin’s discovery, made it possible to prepare blueprints, so to speak, of the organic molecule. No longer did chemists have to prepare quinine by sheer guesswork and hope; they had methods for attempting to scale the structural heights of the molecule step by step, with advance knowledge of where they were headed and what they might expect.
Chemists learned how to alter one group of atoms to another; to open up rings of atoms and to form rings from open chains; to split groups of atoms in two; and to add carbon atoms one by one to a chain. The specif
ic method of doing a particular architectural task within the organic molecule is still often referred to by the name of the chemist who first described the details. For instance, Perkin discovered a method of adding a two-carbon atom group by heating certain substances with chemicals named acetic anhydride and sodium acetate. This is still called the Perkin reaction. Perkin’s teacher, Hofmann, discovered that a ring of atoms which included a nitrogen could be treated with a substance called methyl iodide in the presence of a silver compound in such a way that the ring was eventually broken and the nitrogen atom removed. This is the Hofmann degradation. In 1877, the French chemist Charles Friedel, working with the America~ chemist James Mason Crafts, discovered a way of attaching a short carbon chain to a benzene ring by the use of heat and aluminum chloride. This is now known as the Friedel-Crafts reaction.
In 1900, the French chemist Victor Grignard discovered that magnesium metal, properly used, could bring about a rather large variety of different joinings of carbon chains; he presented the discovery in his doctoral dissertation. For the development of these Grignard reactions he shared in the Nobel Prize in chemistry in 1912. The French chemist Paul Sabatier, who shared it with him, had discovered (with Jean Baptiste Senderens) a method of using finely divided nickel to bring about the addition of hydrogen atoms in those places where a carbon chain possessed a double bond. This is the Sabatier-Senderens reduction.
In 1928, the German chemists Otto Diels and Kurt Alder discovered a method of adding the two ends of a carbon chain to opposite ends of a double bond in another carbon chain, thus forming a ring of atoms. For the discovery of this Diels-Alder reaction, they shared the Nobel Prize for chemistry in 1950.
In other words, by noting the changes in the structural formulas of substances subjected to a variety of chemicals and conditions, organic chemists worked out a slowly growing set of ground rules on how to change one compound into another at will. It was not easy. Every compound and every change had its own peculiarities and difficulties. But the main paths were blazed, and the skilled organic chemist found them clear signs toward progress in what had formerly seemed a jungle.
Knowledge of the manner in which particular groups of atoms behave could also be used to work out the structure of unknown compounds. For instance, when simple alcohols react with metallic sodium and liberate hydrogen, only the hydrogen linked to an oxygen atom is released, not the hydrogens linked to carbon atoms. On the other hand, some organic compounds will take on hydrogen atoms under appropriate conditions while others will not. It turns out that compounds that add hydrogen generally possess double or triple bonds and add the hydrogen at those bonds. From such information a whole new type of chemical analysis of organic compounds arose; the nature of the atom groupings was determined, rather than just the numbers and kinds of various atoms present. The liberation of hydrogen by the addition of sodium signified the presence of an oxygen-bound hydrogen atom in the compound; the acceptance of hydrogen meant the presence of double or triple bonds. If the molecule was too complicated for analysis as a whole, it could be broken down into simpler portions by well-defined methods; the structures of the simpler portions could be worked out and the original molecule deduced from those.
Using the structural formula as a tool and guide, chemists could work out the structure of some useful naturally occurring organic compound (analysis) and then set about duplicating it or something like it in the laboratory (synthesis). One result was that something which was rare, expensive or difficult to obtain in nature might become cheaply available in quantity in the laboratory. Or, as in the case of the coal-tar dyes, the laboratory might create something that fulfilled a need better than did similar substances found in nature.
One startling case of a deliberate improvement on nature involves cocaine, found in the leaves of the coca plant, which is native to Bolivia and Peru but is now grown chiefly in Java. Like the compounds strychnine, morphine, and quinine, all mentioned earlier, cocaine is an example of an alkaloid, a nitrogen-containing plant product that, in small concentration, has profound physiological effects on man. Depending on the dose, alkaloids can cure or kill. The most famous alkaloid death of all times was that of Socrates, who was killed by coniine, an alkaloid in hemlock.
The molecular structure of the alkaloids is, in some cases, extraordinarily complicated, but that just sharpened chemical curiosity. The English chemist Robert Robinson tackled the alkaloids systematically. He worked out the structure of morphine (for all but one dubious atom) in 1925, and the structure of strychnine in 1946. He received the Nobel Prize for chemistry in 1947 as recognition of the value of his work.
Robinson had merely worked out the structure of alkaloids without using that structure as a guide to their synthesis. The American chemist Robert Burns Woodward took care of that. With his American colleague William von Eggers Doering, he synthesized quinine in 1944. It was the wild-goose chase after this particular compound by Perkin that had had such tremendous results. And, if you are curious, here is the structural formula of quinine:
No wonder it stumped Perkin.
That Woodward and von Doering solved the problem is not merely a tribute to their brilliance. They had at their disposal the new electronic theories of molecular structure and behavior worked out by men such as Pauling. Woodward went on to synthesize a variety of complicated molecules which had, before his time, represented hopeless challenges. In 1954, for instance, he synthesized strychnine.
Long before the structure of the alkaloids had been worked out, however, some of them—notably cocaine—were of intense interest to medical men. The South American Indians, it had been discovered, would chew coca leaves, finding it an antidote to fatigue and a source of happiness-sensation. The Scottish physician Robert Christison introduced the plant to Europe. (This is not the only gift to medicine on the part of the witch doctors and herb women of prescientific societies. There are also quinine and strychnine, already mentioned, as well as opium, digitalis, curare, atropine, strophanthidin, and reserpine. In addition, the smoking of tobacco, the chewing of betel nuts, the drinking of alcohol, and the taking of such drugs as marijuana and peyote are all inherited from primitive societies.)
Cocaine was not merely a general happiness-producer. Doctors discovered that it deadened the body, temporarily and locally, to sensations of pain. In 1884, the American physician Carl Koller discovered that cocaine could be used as a pain deadener when added to the mucous membranes around the eye. Eye operations could then be performed without pain. Cocaine could also be used in dentistry, allowing teeth to be extracted without pain.
This effect fascinated doctors, for one of the great medical victories of the nineteenth century had been that over pain. In 1799, Humphry Davy had prepared the gas nitrous oxide (N2O) and studied its effects. He found that when it was inhaled, it released inhibitions so that anyone breathing it would laugh, cry, or otherwise act foolishly. Its common name is laughing gas, for that reason.
In the early 1840s, an American scientist, Gardner Quincy Cotton, discovered that nitrous oxide deadened the sensation of pain; and, in 1844, an American dentist, Horace Wells, used it in dentistry. By that time, something better had entered the field.
The American surgeon Crawford Williamson Long in 1842 had used ether to put a patient to sleep during tooth extractions. In 1846, the American dentist William Thomas Green Morton conducted a surgical operation under ether at the Massachusetts General Hospital. Morton usually gets the credit for the discovery, because Long did not describe his feat in the medical journals until after Morton’s public demonstration, and Wells’s earliest public demonstrations with nitrous oxide had been only indifferent successes.
The American poet and physician Oliver Wendell Holmes suggested that pain-deadening compounds be called anesthetics (from Greek words meaning “no feeling”). Some people at the time felt that anesthetics were a sacrilegious attempt to avoid pain inflicted on human beings by God; but if anything was needed to make anesthesia respectable, it was
its use by the Scottish physician James Young Simpson for Queen Victoria of England during childbirth.
Anesthesia had finally converted surgery from torture-chamber butchery to something that was at least humane and, with the addition of antiseptic conditions, even life-saving. For that reason, any further advance in anesthesia was seized on with great interest. Cocaine’s special interest was that it was a local anesthetic, deadening pain in a specific area without inducing general unconsciousness and lack of sensation, as in the case of such general anesthetics as ether.
There are several drawbacks to cocaine, however. In the first place, it can induce troublesome side effects and can even kill patients sensitive to it. Second, it can bring about addiction and has to be used skimpily and with caution. (Cocaine is one of the dangerous drugs that deaden not only pain but other unpleasant sensations and give a user the illusion of euphoria. The user may become habituated to the drug so that he may require increasing doses and, despite the actual bad effect upon his body, become so dependent on the illusions the drug carries with it that he cannot stop using it without developing painful withdrawal symptoms. Such drug addiction for cocaine and other drugs of this sort is an important social problem. Up to twenty tons of cocaine are produced illegally each year and sold with tremendous profits to a few and tremendous misery to many, despite worldwide efforts to stop the traffic.) Third, the molecule is fragile, and heating cocaine to sterilize it of any bacteria leads to changes in the molecule that interfere with its anesthetic effects.
The structure of the cocaine molecule is rather complicated:
The double ring on the left is the fragile portion, and that is the difficult one to synthesize. (The synthesis of cocaine was not achieved until 1923, when Richard Willstatter managed it.) However, it occurred to chemists that they might synthesize similar compounds in which the double ring was not closed, and so make the compound both easier to form and more stable. The synthetic substance might possess the anesthetic properties of cocaine, perhaps without the undesirable side effects.
