Organic Synthesis

Histories of organic synthesis traditionally used to begin with Wöhler's preparation of artificial urea in 1828, which is supposed to have sent the enigmatic "vital force" into well-deserved oblivion. The situation was in fact extraordinarily complex, and a brief summary of this episode and its latter day interpretations is appropriate here.^[1]

We now know that there were as many varieties of "vitalism" as there were of "materialism" and of "mechanism" in the eighteenth and early nineteenth centuries; that there is no simple—nor even any sophisticated—correlation between vitalistic and metaphysical, teleological, or theological habits of thought; that there were examples of the artificial preparation of "organic" materials from inorganic ones before 1828; that "total" and "direct" syntheses were only performed long after that date; that many chemists—including many "vitalists"—expressed confidence in the future possibility of unlimited organic syntheses during the first three decades of the nineteenth century; and that Wöhler's accomplishment in no way refuted vitalism at a stroke,

nor could it have done so even in principle. The semantic problem alone is daunting, for it would require an army of interpreters to match the manifold senses of the word "synthesis" against the protean character of "vitalism," not to mention the necessity of a careful winnowing and analysis of historical events to judge which could be considered the critical tests. In conclusion, a full answer to the question "in what year and by what event was vitalism overthrown" is not possible and not worth the effort if it were.

All that said, with respect to the insignificance claim for Wöhler's urea, there is a danger in proving too much. Wöhler obviously thought that he had done something rather dramatic in his excited letter of 22 February 1828 to his mentor Berzelius, stressing that he could make urea without a kidney, or even a living creature. Berzelius' reply two weeks later is just as enthusiastic and just as focused on the issue of organic synthesis; Wöhler had produced a "jewel" for his "laurel-wreath" that would "immortalize" his name. Wöhler clearly noted in his letter that his accomplishment would fail to convert a committed skeptic, and his published article did not assert that vitalism had been refuted. Moreover, both Wöhler and Berzelius recognized that the reaction was very relevant to a separate issue, the emergent study of isomerism, for Wöhler had simultaneously discovered that urea and ammonium cyanate had identical compositions. However, these qualifications do not negate the fact that both men regarded the new reaction to be important for an evaluation of vitalist beliefs. Wöhler's pride in his feat was still in evidence thirty-five years later, when we find him urging his combative friend Liebig to respond to Berthelot's attempted usurpation of the entire field of organic synthesis, but modestly adding that Liebig should do this without explicit mention of the 1828 paper.^[2]

The "myth" of Wöhler's overthrow of vitalism in 1828 (and myth it surely was) was not created, as has been argued, in the spate of celebratory articles published during the centennial year, nor even in Hofmann's 1882 obituary of Wöhler. It was created in the immediate aftermath of the event itself. As early as 1843, Hermann Kopp, writing as a historian, urged that this was the deed that destroyed vitalist belief, and ignored the reaction's relevance for isomerism; Kopp's portrayal became an important source for later writers.^[3] The fact that most commentators on this "epochal" discovery during the first few years after the event emphasized its impact on the theory of isomerism may simply indicate an implicit recognition of the slippery character of the vitalist debate and simultaneous enthusiasm over a current live topic—not an assertion of its irrelevance for the demarcation between organic and inorganic chemistry.^[4] Relevant it was; a refutation of vitalism it was not. However, by the early 1850s, if not before, the myth of

a definitive refutation had become ensconced in the German textbook literature.^[5]

Even Wöhler and his most partisan mythologists recognized that urea had not represented a total or direct synthesis from the elements themselves, that this was a very simple organic substance whose physiological significance could easily be marginalized, and that the event represented at best a first hesitant step toward a distant goal. For the next quarter century, chemists were ambivalent, at times predicting a glorious future of artificial organic compounds creating better living through chemistry, at other times racked with doubt about the possibility of extending Wöhler's work to ever more complex substances.^[6]

Additional steps were eventually made, and here Wöhler's student Kolbe was in the forefront. We noted in chapter 3 that in 1845 Kolbe became the first to publish a total synthesis of an organic compound, namely, acetic acid from inorganic carbon and water, also using sulfur and chlorine. In this paper, Kolbe used the term synthesis perhaps for the first time in a chemical context and boldly predicted the artificial preparation of sugar, starch, and other organic products. A few years later, he and Frankland published what I have termed the first two important general synthetic manipulations (carboxylation through nitrile formation and the Kolbe electrolysis reaction).

From that time on, the synthetic repertoire of organic chemists quickly grew: Frankland's organometallic routes, Strecker's preparation of alanine and lactic acid from aldehyde, Hofmann's various eponymous amine reactions, Gerhardt's acid anhydrides, Williamson's ether synthesis, Kekulé's sulfurations, the Wurtz reaction and his glycol work, Wanklyn's preparation of propionic from carbonic acid, Berthelot's total syntheses of acetylene and other simple organics, the first commercial synthetic dyestuffs mauve and fuchsine, and so on. All of these examples are taken from the years 1847-1859; in the following decade the growing stream of organic-chemical novelties became a torrent. As late as 1850, Strecker thought it necessary to italicize his claim to have prepared artificial lactic acid; by 1858 Kolbe was confidently predicting that artificial indigo, alizarin, and quinine would soon make their appearance.^[7] By the latter date—about the time of the formulation of structure theory—expressions of caution and doubt disappeared from organic textbooks. In sum, what undid chemical vitalism was not a single discovery, nor any small handful of them, but rather a gradually increasing sense of the grand possibilities of organic-chemical manipulations, closely connected with fast-growing empirical success.

Kolbe remained in the vanguard of synthetic organic chemistry during his burst of research in the years 1858-1865—in fact, he was

arguably the leading personality. One of the most important of his contributions was a method for the preparation of salicylic acid from phenol, carbonic acid, and sodium metal, carried out in collaboration with his student Lautemann (this subject is explored in chap. 12). His role in the prediction and extended study of branched-chain secondary and tertiary alcohols and acids, and his participation in the further study of polyfunctional alcohols and acids, were discussed in chapter 9. Another instance began with Kolbe's published speculation that taurine, a component of a bovine bile acid discovered a generation earlier by Leopold Gmelin, was nothing other than aminoethylsulfonic acid. Since he regarded Magnus' isethionic acid (prepared from sulfuric acid and alcohol) as the analogous hydroxy compound, a reaction route was evident, and in 1862 he reported a synthesis of taurine from isethionic acid.^[8] He also succeeded in reversing Strecker's synthesis of lactic acid, by converting the latter to alanine.^[9] In both cases, he made important theoretical arguments, interrelating the constitutions of alanine and glycine with lactic, propionic, and acetic acids.

Jacob Volhard's project in Kolbe's lab in the eventful summer of 1862 was a study of sarcosine, long known as a hydrolysate of creatine (found in meat extract). Volhard proposed that sarcosine was N-methylglycine, and he proved the idea by preparing the compound from methylamine and Kekulé's monochloroacetic acid.^[10] With another junior colleague, Rudolf Schmitt, Kolbe carried out a modification of his salicylic acid synthesis by reacting carbonic acid with metallic potassium in the presence of water and isolating formic acid from the reaction mixture.^[11] In the same issue of the Annalen in which this paper appeared, Kolbe and Schmitt published a second article that signaled the isolation of a red dyestuff from the oxidation of commercial phenol by oxalic and sulfuric acids. The product, "rosolic acid," was subsequently shown to be identical to a compound first prepared by F. F. Runge many years earlier.^[12]

These events occurred just at that heady time when a new science-based industry was burgeoning: the coal tar dye trade. There are indications that Kolbe was quite interested in principle in taking economic advantage of this development however he could, but for whatever reason, he failed to follow up on his and Schmitt's discovery. A few years later, several scientists and industrialists (including Heinrich Caro, James Wanklyn, Carl Graebe, Carl Schorlemmer, R. S. Dale, and J. F. Persoz) investigated the compound further, and this work led to the commercial dyes known as corallin and aurine. Between 1876 and 1880, the cousins Emil and Otto Fischer elucidated the complex structures of these and related dyes. They are triphenylmethane derivatives, just like fuchsine (magenta)—the second commercially suc-

cessful color and the foundational product for several of the largest chemical companies today. Kolbe had failed to patent his method of preparing rosolic acid and his priority complaints were ignored. As for the Fischers' work, despite its structuralist basis Kolbe was "astonished" to find that it was "truly excellent." "It must only be translated into chemistry," he added.^[13]

Such generosity of sentiment did not characterize Kolbe's reaction to Adolf Baeyer's structural and synthetic work on indigo. Kolbe himself had long been interested in indigo, both scientifically and for its potential pecuniary rewards;^[14] he thought Baeyer's structural suggestions were unscientific absurdities. It must have bitterly rankled that Baeyer became the first to achieve a successful laboratory synthesis; mercifully, he did not live to see its lucrative commercial application.

After his transfer to Leipzig, Kolbe continued the sort of synthetic work that we have exemplified for the Marburg period; on the whole, however, his personal research activity declined. He did achieve fabulous financial success with one project, however—an improved version of his salicylic acid synthesis of 1859. This subject is covered in chapter 12.