The Salicylic Acid Craze

Kolbe proposed his benzene theory on the very day his new laboratory opened, and for the first few years thereafter it was all he could do to keep up with the crush of students. The number of papers emanating from his institute mushroomed, but virtually all of the research was performed and much of it was also designed by his students and junior colleagues. Finally in mid-September 1873, refreshed by a long vacation on the Baltic Sea, he set to work with great enthusiasm and optimism to crack Kekulé's theory and prove his own. He opined to Volhard that

. . . Kekulé's benzene theory (which is indeed very beautifully contrived and invented, but not discovered) with everything that follows from it, will sooner or later be disproven. In ten years it will be as little discussed as Gerhardt's type theory has been ignored these many years. This winter I intend with my students to carry out a major study of the derivatives of salicylic acid... I do in fact believe that [salylic] is not identical with benzoic acid, but rather is easily converted to the latter. Establishing this isomerism would overthrow Kekulé's benzene theory. Perhaps I shall also succeed in forming an isophenol.^[50]

Fourteen years earlier, Kolbe and Lautemann had tried and failed to synthesize salicylic acid by reacting phenol with carbon dioxide and sodium hydroxide; they had then turned with success to the much more expensive sodium metal itself. Within two weeks of starting his new investigation, Kolbe discovered the conditions under which the sodium hydroxide route would work. An equimolar solution of phenol and sodium hydroxide was dried under heat to a fine powder (sodium phenolate) and protected from moisture. The powder was then placed in an iron retort on an oil bath, and a stream of dry carbon dioxide was introduced. The retort was heated over the course of twelve hours, starting at 100ºC and gradually increasing to 250º. During the process, half of the original phenol distilled off, so that the stoichiometric yield was fifty percent; in practice, it was about forty percent, still an efficient process. The residue was then dissolved in water, acidified with mineral acid, and extracted and recrystallized to obtain the free salicylic acid.

By this new process, salicylic acid could be obtained far more quickly and easily, and in far larger batches, than by the earlier synthesis. Moreover, whereas salicylic acid prepared from willow bark or wintergreen oil—or by the 1859 synthesis—cost around 50 thalers per pound, the new process could produce pure product at around a thaler per pound. This cost saving opened up scientific as well as entrepreneurial vistas. For example, one barrier to a thorough exploration of the nature of salylic acid had always been the high cost of the starting material from which it is made, salicylic acid. With the new process on line, Kolbe could make almost any quantity desired and could mount a definitive assault on the compound. A second point of scientific interest was Kolbe's mystifying discovery that simply substituting caustic potash for soda results in the formation of paraoxybenzoic instead of salicylic acid.

A third point of interest was potentially the most important of all. Kolbe found that when the phenol that distills off during the reaction is reused with fresh caustic soda and carbon dioxide, the yield of product was much reduced, and even further reduced the third time around. He came to the ready conclusion, as he wrote Varrentrapp, that he was here dealing with a hitherto unknown isomer of phenol that is unreactive with carbon dioxide. Viewing commercial phenol as a mixture of two isomers would also explain why nitrating the substance yields two isomeric nitrophenols and why the yield of picric acid (trinitrophenol) is always so poor.^[51] Certainly Kolbe knew very well that other circumstances, such as the constant sharp melting point of phenol, spoke against his conjecture. As hard as he tried—for the discovery would destroy Kekulé's theory at a stroke—he was unable to prepare two distinct phenols. He eventually gave up on this idea, after publishing only a preliminary note on the subject.^[52] He was never able to unravel the mysteries of his reaction; even today the mechanism is not fully understood. As for his definitive assault on salylic acid, despite his disappointed private assessment in 1873 that "proof" of its non existence had been established, he continued to work on the putative compound for the rest of his life, but was never able to demonstrate its real existence.^[53]

But even if the scientific content of his discovery did not have the explosive impact Kolbe had hoped, the technological interest did not escape him, even from the very beginning. He thought first of the possibilities of using his salicylic acid to make inexpensive artificial oil of wintergreen of hitherto unattainably high purity, and he also considered possible applications to dyes.

Within weeks of developing the new reaction, Kolbe entered into partnership with Dr. Friedrich von Heyden (1837-1926), a student of Rudolf Schmitt, who told Kolbe that he himself had neither the time

nor the resources for the endeavor. Heyden set up an industrial lab in the carriage house of a family estate on the outskirts of Dresden. After several months of intense labor, he began to produce and sell product in the spring of 1874, at which time a decision was made to build a proper factory in Radebeul, seven miles northwest of Dresden. Heyden provided most of the development work and all of the capital, around 15,000 thalers in all. Production at Radebeul began early in 1875. The two entrepreneurs took out patents in eighteen German and ten additional foreign states, issued licenses to other producers, and began to build further capacity. By 1878 the factory employed twenty-seven workers and six managers and was producing 50,000 pounds annually.^[54]

The Radebeul firm expanded and diversified repeatedly in the last quarter of the century, growing rapidly even in the midst of the depression of the late 1870s and 1880s. In 1899, then the largest chemical factory in Saxony, it was transformed into a joint stock company. The next year the company had five million marks of stock capital and 780 employees, and it was producing no fewer than fifty-six products. The company advertised at the Paris Exposition of 1900 that their salicylic acid had enjoyed "a true victory march through the entire civilized world." Be that as it may, the Radebeul factory had become the preeminent site for the Saxon chemical industry, and it made both Heyden and Kolbe a great deal of money. At the time of German reunification in 1989, the company was a state-owned pharmaceutical works.^[55]

It is possible to come up with at least a rough estimate of how lucrative the undertaking was for Kolbe. He mentioned to Frankland his expectation that the product could be obtained for about 1 thaler per pound, and Kolbe and Heyden established their initial retail price at 5 thalers per pound.^[56] Combining an estimate for Kolbe's share of per-pound profit with the known capacity figures, it would appear that from around 1878, Kolbe may have earned on the order of 10,000 thalers per year from salicylic acid manufacture. Such an amount would double the income from his already lucrative salary and student fees; it alone was several times his total income in Marburg. This sort of calculation can only be extremely approximate, but what it can do is make clear that in the last decade of his life Kolbe became a wealthy man.

This calculation does not include income from licensing the process. A few entrepreneurs who wanted to produce salicylic acid without paying fees to Kolbe and Heyden attempted to have the patent declared invalid because, as they claimed, it was based on an existing process, namely, the 1859 Kolbe-Lautemann synthesis. After Kolbe

successfully argued in Prussian court that the 1873 reaction was distinct, the same problem arose in England and in Belgium. Kolbe enlisted Frankland's and Armstrong's aid for the English litigation.^[57] Wurtz supported Kolbe in Belgium, even though Wurtz had been directly approached by the patent infringer. Kolbe was surprised and appreciative, but not so grateful as to cease his polemical attacks on Wurtz in his journal.^[58]

Kolbe's reaction remained limited by the fifty percent stoichiometry until Rudolf Schmitt found how to avoid distilling off unreacted phenol (by lowering the temperature and increasing the reaction time). The yield doubled, and the cost of production nearly halved, which dramatically increased income from the process. Schmitt's paper was dated five months after Kolbe's death. Today the synthesis is known to organic chemists as the "Kolbe-Schmitt reaction," and it has proven to be a flexible and important synthetic route to aromatic carboxylic acids.^[59]

What fueled the increasingly strong demand for salicylic acid was aggressive market-oriented research and promotion by Kolbe. He made for himself several useful products: a tooth powder containing salicylic acid and its methyl ester (oil of wintergreen); a mouthwash with the same ingredients that he proclaimed to be an instant cure for bad breath; a foot powder to prevent sweating and odor, which he thought should be mandatory for all soldiers; a bath salt formulation that he found extremely refreshing; and a tonic. In his reports in the Journal für praktische Chemie , he was careful to specify from whom salicylic acid could be purchased inexpensively. He found by experiments on himself and eight volunteers among his assistants and advanced Praktikanten that the human body could tolerate daily salicylic acid consumption of at least 1 to 1½ grams. In 1877 he began to drink as much as one liter of "salicylated water" per day, amounting to ingesting close to a gram of salicylic acid per day. He testified that this habit cured his digestive upset, blisters on his mouth and tongue, and his kidney stones and that it gave him a feeling of general vigor and well-being. This was not hucksterism; he believed it. "With this treatment I hope to grow very old," he wrote Heinrich Vieweg.^[60] Curiously, considering his regular bouts with severe rheumatism, he never mentioned any anti-inflammatory or analgesic effect of the compound.

All of these uses were relatively minor compared to the two largest potential markets for salicylic acid: as an antiseptic and a food preservative. The formula for salicylic acid exhibits a family relationship both to the strong disinfectant phenol (a.k.a. Dr. Lister's carbolic acid) and to benzoic acid, which had already had various applications in pharmaceuticals and food technology. This gave Kolbe the idea to test salicylic acid for similar properties. Examples of pure chemist-entre-

preneurs such as Liebig, who had made large profits from his extract of beef, and Hofmann, who had a number of lucrative dye patents, must also have been in his mind.

Asking his assistant Ernst von Meyer to collaborate with him, Kolbe began these investigations in March 1874. They found that very small amounts of the substance would halt, retard, or prevent fermentations or spoilage in a variety of materials, including amygdalin, urine, milk, butter, beer, wine, eggs (treated by soaking in salicylated water), bread, fruits, and meats. Kolbe's optimism soared, for the need for food preservation has been constant throughout history, and salicylic acid appeared to be far more innocuous and bland and just as efficacious as such obviously toxic and unpalatable additives as phenol, boric acid, and formaldehyde—all of which found application in nineteenth-century food technology.

Kolbe's initial optimism was tempered by some of his subsequent findings. He persuaded a sea captain to take salicylated water on a voyage to the tropics, but the crew found that this water went bad just as quickly as untreated water (Kolbe concluded that the salicylic acid became bound to the wood of the casks). Similarly, despite his promising initial experiments and much subsequent effort, by 1882 Kolbe reluctantly gave up on developing a commercially attractive process to preserve fresh meat using salicylic or carbonic acid. The preservatives did retard putrefaction remarkably well, but after only a few days the meat acquired an unpleasant aroma and taste (not from spoilage, Kolbe carefully noted, but problematical nonetheless) that survived cooking.^[61] He had better luck with bread, butter, beer, and wine, and for these products salicylic acid successfully entered the food industry. Even so, some governments were unconvinced of the safety of the additive; for example, although approved in the Imperial German food law, it was refused entry into Bavarian foods. Hermann Ost regarded this as a foolish prejudice and predicted in 1885 that reason would soon prevail.^[62] Salicylic acid as a food preservative was most successful in Germany; in most other countries, however, benzoic acid was preferred for its gentler action on the stomach.

Application as an antiseptic carried a different set of standards and problems. Lister's innovations of the 1860s were more rapidly adopted in Germany than in Britain; Carl Thiersch, professor of surgery at Leipzig, was one of the first prominent surgeons after Lister himself to adopt antiseptic techniques using phenol. In the late 1860s, shortly after Thiersch's arrival, the Surgical Institute was built just a few steps from Kolbe's institute, and Kolbe and Thiersch maintained cordial relations. In April 1874, Thiersch began a series of clinical trials with salicylic acid, at Kolbe's behest. Bandages soaked in a salicylate solu-

tion appeared to maintain antisepsis as well as phenol, with far less irritation to the skin or the nose, and Thiersch became an enthusiastic proponent of the new application.^[63] The Leipzig professor of gynecology, C. S. F. Credé, adopted the new antiseptic for his clinic as well and reported excellent results. Kolbe publicly recommended salicylated water as a disinfecting agent for hospitals and sickrooms (its disadvantages compared to phenol were lower solubility as well as higher price, and so it found no market in this application). Thiersch and others began to explore possible pharmacological application as an internal bactericide. Kolbe also contacted Max von Pettenkofer in Munich about the same time, but without result.^[64]

On 31 July 1875, Kolbe's eighteen-year-old daughter (and Ernst von Meyer's fiancée) Johanna became seriously ill with diphtheria. Since the family doctor (Thiersch) was not immediately available, Kolbe began treating her himself. He had her take 0.3 grams of salicylic acid every one and a half hours, gave her salicylated water with which to gargle, and sprayed it topically on her throat. When Thiersch arrived, he let Kolbe's cure proceed, and Johanna quickly recovered.^[65] This experience convinced Kolbe that salicylic acid would become an invaluable internal medicine against a number of epidemic diseases: in addition to diphtheria, it was tested against cholera, typhus, and a number of animal diseases. However, the results were negative, and Kolbe's hopes were not fulfilled. Moreover, after a few years of enthusiasm, most Listerian surgeons decided that antisepsis using salicylic acid was not as reliable as that using phenol, and by the early 1880s, most were returning to Lister's original material.^[66]

In the short term, salicylic acid proved to be an important antiseptic, food preservative, and antipyretic and analgesic. Even more important for the long term, it became an indispensable intermediate in the manufacture of a wide variety of perfumes, flavors, pharmaceuticals, and dyes. It was a principal element in the rise of the German fine chemical industry during the last quarter of the century. Thirteen years after Kolbe's death, a Bayer company chemist named Felix Hoffmann acetylated Kolbe's compound, and the most widely used (and least expensive) pharmaceutical in history was born: aspirin.^[67]