12—
Aromatic Chemistry
Present-day organic chemists divide their millions of known compounds into two broad categories, aliphatics ("fatty" substances) and aromatics (compounds based on the benzene family, some of which have notable aromas). Aromatic substances are important both because they are the larger class and because they have more general application to chemical industry, being essential for most important dyes and pharmaceuticals. Up until Kolbe's entry into the science circa 1840, most organic chemical research had been devoted to what later became known as aliphatic compounds, and the few aromatics known were not thought to be taxonomically distinct. This began to change in the 1840s. Hofmann's first major research (1842) was a pathbreaking investigation of compounds in coal tar, many of which are aromatic.[1] In the years that followed, aromatics were aggressively pursued in many laboratories, notably by Hofmann, Laurent, and Gerhardt. It was noticed that these compounds appeared to have a minimum carbon content (twelve equivalents or six atoms), that they had far less hydrogen relative to carbon than most other organic substances, and that they had a distinctive set of chemical characteristics.
In 1855 Hofmann introduced the term aromatic to signal these distinctions, and the term quickly spread.[2] By this time, the isomeric relationships of aromatic compounds were becoming interesting, and investigations into the constitutions of organic molecules were becoming widespread and successful. But the constitutional question regarding aromatic compounds proved intractable: the base radical for aromatics consisted of C12 H5 in equivalents or C6 H5 in atoms, but how were these
atoms configured? Kekulé simply side-stepped the issue in his structure theory of 1857-1858, devoting himself almost entirely to aliphatic compounds. Only A. S. Couper and J. Loschmidt proposed possible structures for benzene during this time period, but these were only speculations for which neither man offered any empirical justification. Their proposals were not influential.[3]
Early Work on Salicylic and Salylic Acids
Salicylic acid (2-hydroxybenzoic acid), a constituent of a number of plant extracts with noted febrifugal properties, had been studied since the late 1820s, as had the related substance phenol (carbolic acid or hydroxybenzene). Benzoic acid (benzene carboxylic acid) had long been known. For some reason, Kolbe became interested in these compounds shortly after his arrival in Marburg.
Since salicylic acid was known to decarboxylate easily (mild heating converted the substance to phenol, with evolution of carbon dioxide), Kolbe speculated that salicylic acid might be simply an ester of phenol and carbonic acid. Accordingly, it should have been possible to synthesize the acid by esterifying the two components (e.g., reacting sodium phenolate with phosgene, then hydrolyzing the remaining chlorine). Repeated experiments along this line consistently failed, but without shaking Kolbe's assumption.[4]
Kolbe put his first Ph.D. student, Wilhelm Gerland, to work on closely related problems. Gerland succeeded in making a second aminobenzoic acid, "benzaminic acid" (the first such was anthranilic acid). Since anthranilic acid could be oxidized smoothly to salicylic acid, Kolbe suggested publicly that these two compounds had analogous structures, that is, the former must be an amide if the latter (as he still assumed) was an ester. This would explain the isomerism of anthranilic with benzaminic acid, the latter being the true aminobenzoic acid. But Kolbe confessed continued failure in proving this notion by making salicylic acid through esterification.[5] Gerland then found that oxidation of benzaminic produced an isomer of salicylic acid, which he named "Oxybenzoësäure." He suggested that it was this new isomer, not salicylic acid, that was the carbonic acid ester. This seems to have been Gerland's proposal and not Kolbe's.[6]
By 1859, after a hiatus caused partially by his ill health, Kolbe had put two new students to work on related problems. One was Rudolf Schmitt, not yet Ph.D. but already an assistant, who attempted to expand the isomerism of anthranilic/benzaminic acids to analogous aromatic sulfoacids. The other was Eduard Lautemann, then an ad-
vanced Praktikant, who was assigned the study of a number of salicylic acid homologs.[7] This work was going on simultaneously with Kolbe's attempts, with Lautemann's and Carl Ulrich's help, to show that glycolic and lactic acids were monobasic hydroxy derivatives of acetic and propionic acids, respectively, to counter Wurtz' contentions that they were dibasic, or rather (as Wurtz later argued) diatomic and monobasic.
I have suggested in chapter 9 that Kolbe's discomfort with the idea of polybasic organic acids originated in his theoretical commitments to radical theories and the earliest version of the type theory. Kolbe himself stated that his effort to show that salicylic acid was an ester was motivated not so much by an otherwise unexplained isomerism but by his disagreement with those who viewed the compound as dibasic.[8] Piria's demonstration in 1855 of double salts of salicylic acid appeared to provide an irrefutable demonstration of its dibasic character. However, late in 1859 Kolbe and Lautemann finally succeeded in synthesizing sodium salicylate from phenol by simultaneously introducing gaseous carbon dioxide and finely divided sodium metal into hot phenol.[9]
Kolbe initially thought that this synthesis demonstrated his ester hypothesis.[10] However, by April 1860 he abandoned that idea because he realized that his conjectural structure could not account for the known reduced forms of salicylic acid: salicylaldehyde, and salicyl alcohol. Nonetheless, the new synthesis provided proof (he thought) that salicylic acid was indeed monobasic. The substance was, in fact, entirely analogous to glycolic and lactic acids, in that it consisted of benzoic acid in which one hydrogen atom of the phenyl radical was substituted by the radical HO2 . That the hydrogen of this "hydrogen peroxide" radical could be replaced by a metal atom in the double salts of salicylic acid did not mean that the acid was dibasic. He went so far as to assert that only monoacids, such as salicylic acid, have corresponding aldehydes and alcohols and that any assertions to the contrary were "unscientific frivolities" that did not even deserve to be discussed. This remarkable statement contradicted Kolbe's own published views, and he soon had to retract it.[11]
Kolbe's new view of the constitution of salicylic acid seemed to have solved one problem, but it created another: now Kolbe was designating both salicylic and its isomer oxybenzoic acid by the same rational formula and so the cause of the isomerism was mysterious. Fortunately, a recent discovery by Lautemann suggested a resolution. Reduction products of salicylic acid included not only salicylaldehyde but also what appeared to be an isomer of benzoic acid, for which Lautemann and Kolbe suggested the name "salylic acid." Thus, benzoic acid could
be converted to benzaminic and then to oxybenzoic acid, whereas salylic acid was related genetically to both anthranilic and salicylic acids. There were therefore two independent isomeric series. All of this could easily be explained if there were two isomeric parent aromatic hydrocarbons having the equivalent formula C12 H6 , and Kolbe suggested precisely that. The parent radical of the salylic acid series Kolbe suggested should be called "phenyl," which is the radical in phenol; the progenitor of the benzoic acid series could then be called "benzyl," the radical of benzoic acid. Such a hypothesis could also explain the known isomerism of benzyl alcohol versus cresol.[12]
Kolbe admitted that there were problems with this suggestion. No second isomer of benzene was actually known (decarboxylation of salylic acid, for instance, apparently yielded ordinary benzene), and there was no second phenol. Moreover, there should be a distinct salyl aldehyde and salyl alcohol, a sulfosalylic acid, and so on. Nor was there any way to know in what the isomerism of the parent hydrocarbon may consist. However, Kolbe was willing to speculate: benzyl may be
while phenyl could be (C10 H5 )'"C2 . One radical thus has a structure in which one or two additional functional groups may substitute for two hydrogens of methylene, while the other contains a carbon (C2 ) that is bound only to a single triatomic group; he symbolized these isomeric radicals as b(C12 H5 ) and p(C12 H5 ). Kolbe offered no empirical justification for these structural details, nor is one evident to the historian.
Kekulé's former roommate in London, Hugo Müller, verified the existence of salylic acid soon thereafter, or so he thought at the time, and wrote Kekulé about it.[13] Kekulé then published an article that followed up on Kolbe's research, expanding Kolbe's suggestion of two isomeric series to include such compounds as the two known chlorobenzoic acids. He stated that the existence of an isomer of benzoic, i.e., salylic acid, was no longer in doubt, and he thought that there may also be two isomers of benzene.
However, I consider it inappropriate even now to enter into a theoretical discussion, since the necessary factual foundation for this is missing. Even Kolbe, who has to date penetrated the furthest toward true knowledge of the actual arrangements of atoms, was able to discover no other difference in the constitutions of these substances than that, in addition
to the elements that otherwise compose organic compounds, the first contains a soft "b," the other a hard "p."
Kekulé had evidently been dismayed by Kolbe's public charge (presumably directed at Wurtz, but arguably also at Kekulé) of "unscientific frivolities," for he followed this little witticism with a more direct barb:
But what further deters me from discussing this question is the circumstance that I probably could not do that without criticizing Kolbe's theoretical views (which hitherto from one paper to the next have constantly changed), and also his manner of dealing with other chemists in his publications—a critique I wish to avoid, if possible entirely, or at least as long as possible.[14]
Since 1857 Kekulé had been working with benzoic and salicylic acids himself, and he had hinted at a "denser" and "next-simplest" arrangement of the carbon skeleton of benzene in his structure theory paper of 1858. But he was not yet ready to enter into an explicit theoretical discussion, presumably for the reason stated—the still scanty empirical record. It is probable that he had not yet formed any satisfactory hypothesis regarding the isomerisms.[15]
Kolbe's conjecture that his "phenyl" (in contrast to his "benzyl") radical had a carbon with no hydrogen atoms suggested to him that one might be able to hydrogenate this carbon, producing compounds with more hydrogen than aromatic compounds but less than any aliphatic compounds. He had had good results with sodium amalgam as a reducing agent, and so in December 1860 he tried it on phenol, salylic acid, and salicylic acid, and other "phenyl" compounds. In February 1861, he reported excitedly to Liebig that he thought he had succeeded in his goal and that the discovery promised to yield years worth of exciting research. Reduction of salylic acid yielded much aldehyde, but also a certain percentage of a weakly smelling liquid that appeared to be an acid with a larger percentage of hydrogen than the starting material.[16] Liebig was enthralled; this was an "extremely fortunate idea, which opens up a treasure-trove of new discoveries."[17]
Kolbe published a short preliminary communication in the Annalen on this subject and tried to follow it up, but he was unable to isolate enough of the compound to prove his idea of an intermediate link between aromatic and aliphatic compounds. As he wrote to Liebig, there were severe experimental difficulties, including a multiplicity of small amounts of products that were hard to separate. In the meantime, he and his students were more successful (or so they initially thought) at further substantiating his claim of two isomeric series of aromatic com-
pounds. For example, Schmitt applied the idea to benzenesulfonic acids, and Lautemann prepared a variety of new iodo and hydroxy derivatives of salicylic acid and of phenol, all depicted as "phenyl" or "p" compounds.
Unfortunately, both lines of research soon reached dead ends. The chief difficulty was with salylic acid. Kolbe had thought he had more than sufficient evidence to identify this substance as an isomer of benzoic acid. The two solids were different in appearance and their crystal forms were distinct; salylic was only about a third as soluble in water as benzoic, it was more volatile, and it melted at 119ºC rather than 121ºC.[18] The existence of the acid was accepted by nearly everyone, including De La Rue, Müller, and Kekulé (although Kolbe later revealed that Lautemann himself, the actual discoverer, had always expressed doubt regarding the real existence of salylic acid).[19] But as early as the spring of 1861, Cannizzaro argued convincingly that decarboxylation of salylic and benzoic acids both produce a single substance, benzene, and that there is no other isomer of benzene. Later that year, Rudolf Fittig, an assistant of Limpricht and Wöhler at Göttingen, discovered that even tiny amounts of impurities in benzoic acid could dramatically alter its properties, such as crystal structure and solubility; he thought that salylic was simply impure benzoic acid. Two years later, Friedrich Beilstein established that whereas nitrodracylic was a true isomer of nitrobenzoic acid, "dracylic" and benzoic acids were identical. The following year he definitively confirmed Fittig's observations on "salylic acid."[20]
For some time, Kolbe attempted to defend the existence of salylic acid and its putative parent hydrocarbon. Forgetting the reasoning that had led him to abandon the ester hypothesis for the constitution of salicylic acid, he argued in 1863 that there must be four different isomers possessing the composition of salicylic acid. There are two parent hydrocarbons, hence there must be two different ester compounds (salicylic being one), as well as two true (hydr)oxybenzoic acids. After he had failed to crack the intractable aromatic reduction problem, Kolbe gave it to a student, Max Herrmann. In 1864 Herrmann published a paper claiming to have succeeded in adding four atoms of hydrogen to benzoic acid. The next year he thought he had accomplished an analogous transformation with hippuric acid, but an "unfortunate accident" prevented him from precisely characterizing the novel reduction product.[21]
But just about the time this last paper was published, Kolbe became convinced by Beilstein's work: salylic acid did not exist and benzoic acid had no known isomer. With the fall of salylic acid and the increasing evidence against a second isomer of benzene, Kolbe's isomerism
hypothesis appeared to be in trouble. When in 1865 Kolbe published a monograph reprinting his papers and those of his students since 1859, he omitted five aromatic papers, including the one announcing the synthesis of salicylic acid and the preliminary note that proclaimed the existence of intermediate links between aromatic and aliphatic compounds. When salylic acid was mentioned in another reprinted paper, Kolbe attached editorial notes denying its real existence and explaining the source of his error.[22]
"Kekulé Always Rides a Fiery Steed"
Although by 1862 Kolbe was encountering difficulties in substantiating his early aromatic conjectures and had partly repudiated them by 1865, he continued to work (and to assign his students projects) on aromatic compounds, and his laboratory produced many novel substances in the early 1860s. In the spring of 1863, two of his students in Marburg simultaneously and independently discovered the first case of triple isomerism in the aromatic series. Konstantin Zaitsev (in German transliteration, C. Saytseff), one of the first of numerous Russian students, never made a name for himself in chemistry, but he was the brother of the much more famous Aleksandr Mikhailovich Zaitsev, who arrived at Kolbe's lab a semester later. Early in 1863, Konstantin prepared from anisic acid (modern p -methoxybenzoic acid) a new hydroxybenzoic acid that was demonstrably distinct both from salicylic acid and also from Gerland's "Oxybenzoësäure." He named it "Paraoxybenzoësäure," the prefix simply indicating that it was an isomer.[23]
About the same time at a neighboring lab bench, Georg Fischer (who is even more obscure than K. Zaitsev) obtained the same compound starting from toluene through nitrodracylic (modern p -nitrobenzoic) and a novel para-aminobenzoic acid. The fact that there were now three hydroxybenzoic acids suggested to Fischer that, in addition to benzoic and salylic acids, there must be a yet undiscovered third isomer, "Parabenzoësäure."[24] Zaitsev's and Fischer's articles were published back to back in the Annalen . In that same issue, Beilstein argued that the aminobenzoic acids were now three in number. Shortly thereafter, H. Hlasiwetz and L. Barth revealed the existence of a third dihydroxybenzene, christened "resorcinol," and N. Sokolov concluded that three nitrobenzoic acids could be sharply distinguished. Finally, in a communication dated August 1864, Beilstein announced the discovery of a third distinct chlorobenzoic acid and concluded that there must also be three bromobenzoic and three iodobenzoic acids.[25]
What all this means is that within the space of about three years, the isomer problem in the aromatic series had suddenly and radically
changed. In 1861, it seemed highly probable that there were two of each species, in other words, two isomers of benzene itself, two isomers of each monoderivative such as benzoic acid, and two of each diderivative such as salicylic acid. By the end of 1864, it was becoming clear that there was only one benzene and only one of each mono-derivative of benzene, but that there were in general three of each diderivative such as hydroxy benzoic or nitrobenzoic acid. Kolbe's conjectures were no longer viable, and Fischer noted plaintively that the "very important question" of explaining aromatic isomerism was not presently answerable. In extenuation of his mistaken identification of salylic acid, Kolbe likewise commented in a note written in March 1865 that he had been led astray by his urgent desire to explain the genuine generic isomer problem for aromatic compounds.[26] But it would appear that Kolbe had given up on the problem as hopeless.
It was none other than Kolbe's nemesis Kekulé who first succeeded in finding a satisfactory solution to this problem, and this was precisely as Kolbe was writing the remark just cited. Kekulé hinted at double bonds in benzene in 1858, and he later implied that he had already formulated his benzene theory at that time. This claim, however, was probably disingenuous because, as we have seen, he accepted the existence of salylic acid and of two isomeric benzenes in 1861. But the new discoveries of 1861-1864 dramatically altered the requirements for a successful theory. If we can believe his famous dream anecdote (and circumstances suggest that we can), he had the idea for his benzene theory around early 1862, but this was still too early in the chronology to found a successful empirically based theory. By the end of 1864, it was time.
Early in 1865 Kekulé published a paper (in French, since he was then working in Francophone Belgium) that argued that a cyclohexatriene formula for benzene could probably account for all the known isomeric relationships in the aromatic series. The "Kekulé formula" would allow only one benzene and one benzoic acid, but would appear to predict three isomers (today referred to as ortho, meta, and para isomers) of every disubstituted benzene. Kekulé expressed himself cautiously in this article and spent most of his time discussing how the theory could explain isomer relationships of side-chains rather than positional (ortho/meta/para) isomers. But he was more definite and more confident on the crucial question of positional isomers in a long German-language article published in Liebig's Annalen in February 1866. A definitive treatment was published in the sixth fascicle of his textbook, which appeared that summer.[27]
Kolbe read Kekulé's Annalen paper with interest (he probably had not seen the earlier French papers, since he rarely read French jour-
nals). "What do you think about Kekulé's new philosophy in the February issue of the Annalen ?" he asked Erlenmeyer. "He always rides a fiery steed."[28] We do not possess Erlenmeyer's reply to this question, but there can be little doubt that it was favorable, for an article appeared in the very next issue by Erlenmeyer praising Kekulé's theory as the "most probable" representation of aromatic compounds (although Erlenmeyer also made a number of suggestions modifying and extending the theory). Kolbe must have been astounded at the overwhelmingly favorable response to Kekulé's theory. Not only did students and friends of Kekulé, such as Erlenmeyer, Williamson, Müller, Beilstein, Baeyer, Ladenburg, L. Meyer, Dewar, Hübner, and Körner, become advocates of the theory but also many who had no direct personal relationship to him, such as Wilbrand, Watts, Naquet, Fittig, and V. Meyer. In fact, three former members of Kolbe's own research group became strong advocates of the new theory, namely, Graebe, Crum Brown, and Claus, and Kolbe's good friend and theoretical comrade Frankland also joined the crowd.[29]
Some historians of chemistry have been misled by the lengthy but often minor disagreements over certain structural details into thinking that Kekulé's theory was poorly accepted until close to the end of the century. In fact, the proposers of principal "rivals" to Kekulé's structure thought of themselves essentially as advocates of the theory who were offering only reinterpretations of it. Ladenburg, the author of the "prism" formula, always stressed the similarities of his and Kekulé's formulas. In 1874 he conceded that Kekulé's formula was in most respects superior to his own; in 1876 he stated that virtually all chemists had accepted Kekulé's theory, at least to a certain degree, and that the cyclohexatriene formula was "at least as appropriate, if not more so, than the prism." Even Kolbe conceded in 1874 that Kekulé's theory was "accepted by the great majority of chemists."[30]
Kolbe's concession was by no means a surrender. Despite his repudiation of salylic acid in 1865, he did not immediately abandon his belief that there are isomeric "phenyl" and "benzyl" radicals corresponding to the formula C12 H5 , reaffirming this idea two years later.[31] Appalled by the growing popularity of Kekulé's "chaining" theory of structure and deeply concerned that Kekulé's cyclohexatriene interpretation of benzene was already then being viewed by many as the successful capstone of that theory, Kolbe was desperate to produce a coup in the aromatic realm. His interest in aromatics was of even longer standing than Kekulé's, and he shared Kekulé's identification of the central desideratum, namely, a general theoretical explanation for isomerism. He found it particularly galling that Kekulé, who had
been a thorn in his side on many occasions and whom he considered an upstart and a "superficial chatterer," had now become his chief rival. Even many of his own advanced students and junior associates during the years 1866-1870, such as Ernst Carstanjen, Carl Graebe, Hermann Ost, and Henry Armstrong, disagreed with his views on aromatics, and some of them preferred Kekulé's.
It was in response to the arguments and urgings of Markovnikov in 1866-1867 and possibly also Graebe in the summer of 1868 that Kolbe finally accepted the larger atomic weights for carbon, oxygen, and sulfur, which by that time had been adopted by virtually all German chemists. The first occasion when Kolbe employed the new weights was in his dedicatory lecture for his new institute on the Waisenhaus-strasse, on 16 November 1868. The topic of this printed academic dissertation was his conception of the constitution of hydrocarbons; its centerpiece was a novel theory of aromatic compounds. Both were offered explicitly as alternatives to Kekulé's ideas. Indeed, Kolbe's second sentence averred that his ideas were "essentially different from the views of the chemists of so-called modern chemistry, and especially from those based on Kekulé's chain theory." He continued,
I do not intend here to subject the latter to a thorough criticism; I merely state clearly and succinctly, in order at once to remove any doubt concerning my estimation of its significance, that I consider the chain theory, just like the earlier type theory, to be an ephemera among recent chemical hypotheses, and its principles to be untenable and erroneous, without denying that it is ingeniously devised, and, as experience confirms, is well suited to blind younger chemists.[32]
The next few pages of Kolbe's lecture recounted his views on aliphatic hydrocarbons, in their current state of evolution. Kolbe's readers (as well as the readers of this book) had seen this material before.
Trimethine-Trimethane
What they had not seen was Kolbe's new benzene theory. Just as three diatomic methylene radicals, he wrote, might substitute for three hydrogen atoms in each of two methyl radicals:
so might benzene be considered to be constituted from three trivalent methine (CH) radicals, which substitute for three hydrogen atoms in each of three methyl radicals:
Kolbe considered this to be the true constitution of benzene: a trimethine-trimethane.[33]
In structural terms, the first of the compounds just described would be considered to be a bicyclic cyclopentane in which two methines are symmetrically bridged by three methylene groups. The second would be a tricyclic cyclohexane in which each of three methines forms three bonds to three other methines. Thus, Kolbe's proposed benzene formula (interpreted structurally) was a species of the genus cyclohexamethine. Remarkably, nearly all nineteenth-century benzene theories, and all even modestly successful ones—Kekulé's, Ladenburg's, Dewar's, and so on—were cyclohexamethine theories.[34] More particularly, Kolbe's structural benzene formula was equivalent to Adolf Claus' "diagonal" structure, proposed two years earlier (cyclohexamethine with each carbon atom bonded not only to its immediate neighbors but also to a partner directly across the ring). Claus' structure did not prove to be popular, presumably because it appeared to predict only two isomers of every disubstituted benzene.[35]
Claus had been one of Kolbe's Marburg students (1858-1861), but he had then gone to Göttingen for his Ph.D. (1862), had become a structuralist, and in 1868 was ausserordentlicher Professor in Freiburg/Breisgau. Claus was much influenced by Kolbe and was one of the few who championed his and Frankland's priority claims to valence theory. Nonetheless, he was never intimidated by his former teacher. In 1871 he published a note in Kolbe's journal in which he claimed priority for Kolbe's recent formulation of diglycolic acid. In doing so, he also asserted in a strong and unambiguous way that Kolbe's formulas were essentially identical to those of the structuralists.[36] Given these circumstances, it is curious that Claus never claimed priority for Kolbe's benzene theory.[37] As for Kolbe, he admitted in response to Claus that he had been unaware of the existence of Claus' 1866 monograph in which both the diglycolic acid and the benzene formulas appeared; having received a copy from its author, he commented that Claus' benzene formula is "less improbable" than Kekulé's.[38]
Since Kolbe disagreed with all structuralist interpretations of his
constitutional notions, it is not surprising that he did not recognize Claus' structural formula as identical with his own. Indeed, there are some real distinctions between the two. Kolbe refused to speak or even think of bonds between atoms (only between radicals), and he asserted a chemical distinction for every notational difference in his formula. Consequently, he distinguished chemically between the three methine hydrogens (those within the parentheses) and the three methyl hydrogens (those at the bottom of his formula), and so he predicted isomeric relationships that were quite different from Kekulé's. Not only should there be two isomeric benzoic acids, two phenols, two toluenes, and two of every other monosubstituted benzene, but there should be no fewer than four of each disubstituted benzene when the two substituting atoms or groups are not identical—as in salicylic acid, for instance.
Kolbe thought that this view of benzene was far more beautiful, natural, and intrinsically probable than Kekulé's cyclohexatriene. The latter had been ingeniously "invented" (erfunden ), but certainly not "discovered" (gefunden ) in nature. It was highly artificial, he felt, exhibiting no analogies with inorganic chemistry or even with anything else in organic chemistry. No one had shown any reason to believe that there were both single and double carbon-carbon bonds in the molecule. There was no reason to believe that mere positional distinctions (ortho, meta, and para isomers) could produce the dramatic differences in chemical properties that were often observed. The formula was even misnamed: "It is called a benzene 'ring,' even though it is painted as a hexagon."[39]
Kolbe was sensitive to the question of the empirical adequacy of his own theory. In its favor, he cited the synthesis of benzene from three molecules of acetylene and of mesitylene from three molecules of acetone. He also pointed out that three of the six atoms of hydrogen seem to be more readily substitutable by other atoms or groups.[40] All of these arguments were also used by Kekulé and his allies—none could be said to clearly favor Kolbe's over Kekulé's theory. Even worse for Kolbe, known isomeric relationships strongly favored his opponent. For example, no second isomer of a monosubstituted benzene, nor an instance of four isomers of a disubstituted benzene, was yet known. Kolbe forthrightly recognized, even flaunted, these lacunae in his theory:
In contrast to the chain theory, and to the way that one effortlessly finds explanations for everything by using the so-called bonding of atoms alone, I am not now able to explain everything with the above hypothesis. But it seems to me to be not a weakness, rather to a certain degree
an advantage of a hypothesis, when it is capable of further expansion and so leaves something left over to explain.... Every attempt at explanation and every hypothesis which promises too much in this direction awakens initial mistrust. What matters is not that one explains everything, but how one interprets.[41]
Kolbe could have hoped for a more enthusiastic reception of his theory. He sent Hofmann and Liebig offprints and asked them for their reactions. His chief purpose, he told Hofmann, was to attack the structuralists and especially the benzene ring, "the show-horse of Kekulé's chain theory." He admitted to Liebig that he was thereby entering a "wasps' nest," but could no longer sit in silence. Apparently neither Hofmann nor Liebig satisfied Kolbe with an endorsement of his views.[42] The first published comment to appear was from Carl Glaser, perhaps Kekulé's most valued assistant in Ghent and Bonn during his critical "benzene years" of 1864-1869, who professed astonishment to find that Kolbe still relied on the Berzelian dicta that all organic compounds must be formulated to bear analogies to inorganic substances and be viewed as substitution products of the latter. Kolbe replied with deep scorn and contempt. He welcomed honest criticism from fledgling chemists, he said,
But when a young man with only a couple of chemical papers to his name undertakes to criticize an older experienced chemist who was publishing chemical papers when that young man was scarcely born... that testifies to an overabundance of confidence and a deficiency of caution and modesty.[43]
It is no exaggeration to say that virtually no one accepted Kolbe's theory, not even most of his own students and junior colleagues. As Armstrong, always a staunch defender of Kolbe, recollected sixty years after the events, Kolbe "held most peculiar views as to [benzene's] structure, which we [students] often disputed with him." A contemporary letter from Armstrong to his father supports this account.[44] Few textbook and review authors of the day even mentioned the theory, and when they did, it was usually to demonstrate its empirical inadequacy. Kekulé used Kolbe's words against him when he wrote sarcastically (but not for print) that the theory must have been very good indeed to leave so much left over to explain.[45]
Nonetheless, Kolbe never relinquished his theory. In fact, armed with what seemed to him to be the definitive interpretation, he was renewed in his conviction that there must exist, after all, a second undiscovered isomer of benzoic acid and of phenol and a fourth undiscovered isomer of salicylic acid. Mindful that a single such discovery
would weaken if not destroy Kekulé's brainchild, he spared no effort to produce one. This proved to be a hard row to hoe. He returned once more to salylic acid, his discredited isomer of benzoic acid, and to salicylic acid. In fiddling with these reactions, he encountered a new synthetic approach to the latter and thought for a time that he had promising results on the isomer issue.[46]
In 1873, he hit upon a crucial experiment to definitively confirm or refute Beilstein's argument for the nonexistence of salylic acid. Beilstein had shown that when salylic acid was distilled, pure benzoic acid was found in the receiver and a small residue of impurities remained in the distilling flask, from which he concluded that salylic was impure benzoic acid. Kolbe thought it possible that there had been an intramolecular rearrangement during the distillation from salylic to benzoic acid. Here was the possibility of a definitive test: recombine the distillate with the residue. If, as Kolbe thought, a rearrangement had occurred, then the recombined material should retain the properties of benzoic acid. If Beilstein were right that it was the impurities that produce the apparently distinct properties of "salylic acid," then those properties should reappear in the recombined material. Kolbe performed the experiment; the properties of salylic acid were regenerated, and even Kolbe regarded this as "unambiguous proof" that Beilstein had been right all along. Kolbe deserves credit for his honesty in forth-rightly publishing this result—even if he did delay the publication for two years.[47]
Kolbe had lost a battle, but not the war; even if salylic acid was a phantom, that did not mean that benzoic acid had no isomer. He had put his nephew, namesake, godson, and student (and eventual assistant and biographer) Hermann Ost on the problem, and Ost was coming up with interesting results.[48] But Kolbe suffered another personal setback in 1880. Having persuaded Heinrich Vieweg to hire Ost as editor of the organic portion of the sixth (posthumous) edition of E. F. Gorup-Besanez's popular textbook, Kolbe was dismayed to find that Ost discussed only Kekulé's benzene theory and failed to treat his own! When Kolbe asked him to include a discussion of the latter, Ost flatly refused, on the grounds that it would damage the reception of the book. Kolbe described these events in a letter to Ost's mother, his sister Bertha; the letter was written in a furious rage and is nearly illegible. He did not mind when students disagreed with him, in fact he encouraged it, but he thought it only common courtesy for Hermann to at least mention his uncle's theory. He told Bertha that he was "disinheriting" Hermann, chemically speaking. Fortunately, a second letter written on the same day reveals that shortly after the first was posted, Hermann came and apologized, promising to include the mate-
rial that Kolbe had requested.[49] Still, this must have been a bitter pill to swallow.
To the end of his life, Kolbe kept searching for the missing isomers. He never found them. However, the quest led him to one of his greatest scientific (and certainly his most lucrative technological) discoveries.
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]