Predictions Fulfilled:
Diacids and Novel Alcohols
In his major theoretical article, "On the Natural Connection of Organic and Inorganic Compounds," Kolbe made predictions that
were more successful. Having accepted the dibasic character of oxalic acid, he now proposed two "carbonic acid radicals" for other known diacids, such as succinic, malic, and tartaric acids. All three of these substances were known to have the same number of carbon atoms (four) and two carboxyl groups. Succinic acid has no other functional groups, whereas malic and tartaric acids have one and two additional atoms of oxygen (two and four equivalents), respectively. Kolbe suggested in his paper that malic and tartaric acids may have a similar relation to succinic acid as lactic and glyceric acids have to propionic acid, namely, that they may contain one and two (O2 H) groups, respectively, substituted for H. He named them Oxy- and Dioxybernsteinsäure .[45] When, late in 1859, Lautemann discovered that hydrogen iodide was capable of directly reducing the (O2 H) group of lactic acid to H, Kolbe reasoned that he could test his prediction by attempting to reduce malic and tartaric acids to succinic acid by using the same reagent. He assigned the task to his promising young assistant, Rudolf Schmitt.
The reduction occurred uneventfully, and Kolbe sent the paper to Liebig. Liebig rushed it into print, fitting it into the very next issue after the one that carried Kolbe's prediction.[46] Ironically, Liebig had recently published a different hypothesis regarding the constitutions of malic and tartaric acids.[47] He wrote Kolbe a very friendly letter:
. . . the real purpose of this letter is to express to you the great satisfaction which your paper on the natural connection of organic and inorganic compounds gave me; the preparation of succinic from malic and tartaric acids is the triumph of your theory; I am only sorry that I recently gave a different interpretation of the constitution of these two acids, but I willingly recognize that yours is better.[48]
To say that Kolbe was pleased by this letter is more than a small understatement. For the past six years, Liebig had been cool and sometimes even hostile toward him, at first apparently because of the one-sided and polemical character of parts of his book and then because in an article in the Handwörterbuch Kolbe had ignored Liebig's analytical method for mercury. Kolbe had been mystified by Liebig's unfriendliness. At first he supposed Liebig's residence in the Bavarian capital and association with King Maximilian II had made him an arrogant courtier; he then suspected that enemies were whispering in Liebig's ear.[49] He replied to Liebig, delighted to see, as he put it, that his enemies had failed to sway Liebig's good opinion of him. A more public expression of approval, he hinted, would hasten the end to the influence of those who view the goal of chemistry as the "decoration of Gerhardt's schemata." To Vieweg he declared his intention of using Liebig's letter to pry more money out of the Kurhessian ministry.[50]
Kolbe was still earning the same miserable salary he had accepted in 1851.
Feeling like the proverbial cat that swallowed the canary, he immediately wrote his closest friend, Vieweg, enclosing Liebig's letter. He added that he had long been convinced that his ideas would eventually triumph, and he now predicted that in a few years no one would even mention "the completely unscientific manner of treating chemistry of Gerhardt and his consorts, which unbelievably even Strecker has adopted . . ." Liebig's letter could make this happen all the faster; he asked Vieweg to return it as soon as possible so that he could make appropriate use of it with his Ministerium.[51]
From this time onward, Liebig strongly supported Kolbe's research. Kolbe's discoveries, Liebig wrote him in December 1860, had the effect on him like that "of a trumpet on an old war horse," and he invited Kolbe to continue sending him his "gems" for publication. The following year Liebig averred to Kolbe that "the important thing is always that one starts down the right path, and all your work demonstrates that you are on the right path." There is much good work being done now in organic chemistry, Liebig continued, but also much playing around with formulas, and in most work one cannot discern the "scientific idea" that one must have as a goal, to clarify the physiological origins of various compounds.[52] Liebig meant this praise sincerely; to Vieweg, to Fehling, and to Volhard he wrote in much the same terms about Kolbe.[53] In February 1862 Liebig satisfied Kolbe's request for a public statement of approval, and in December of that year he proposed Kolbe as foreign member of the Bavarian Academy of Sciences.[54]
Liebig's approval appears to have been founded on two general areas of agreement. First, like Kolbe, Liebig took conventional equivalents to be the chemical atoms themselves, and so for both of them such Gerhardtian types as HOOH (two molecules of water in equivalents but one molecule of water in atomic weights) were imaginary and therefore absurd.[55] Second, Liebig felt that organic chemistry only made sense when it is pursued in conjunction with physiology. Since carbonic acid plays such a central role in physiology—especially for biosynthesis in plant physiology, from which most organic compounds dealt with in mid-nineteenth century organic laboratories were derived—Kolbe's carbonic acid theory made sense to Liebig in a way that the more abstract and schematic Gerhardtian theory did not.[56]
Other predictions by Kolbe concerned novel alcohols. Kolbe, like the structuralists, formulated ethyl alcohol as a carbon atom (which for Kolbe was the double atom C2 , his "Grundradikal") combined with two hydrogens, a methyl group, and what became known as a hydroxyl
radical. In his major theoretical paper, Kolbe pointed out that if one or both of these two hydrogen atoms were replaced by one or two additional methyl radicals, two novel substances would be formed. They would retain the hydroxyl group, but they would not be oxidizable to an aldehyde or an acid since each of these oxidation reactions requires abstraction of two hydrogens from the same carbon. They would therefore fail the defining criterion for alcohols, but could be termed "pseudoalcohols."[57] These compounds are what modern chemists call isopropyl alcohol and tertiary butyl alcohol.
Of course, alcohols were familiar substances, long known to chemists chiefly as products of fermentation. The best known was ordinary (ethyl) alcohol, but it was also known that the so-called fusel oil, a higher boiling residue that remained after the redistillation of grain or potato alcohol, contained alcohol-like materials. The major constituent of fusel oil was found to be amyl alcohol (C5 H11 OH), but there was also a sizable amount of butyl alcohol (C4 H9 OH) and a much smaller amount of propyl alcohol (C3 H7 OH), along with a number of trace constituents. These three compounds were initially thought to be simple homologs of ethyl alcohol. The amyl and butyl alcohols were later found to possess branched-chain structures (for example, the latter is [CH3 ]2 CHCH2 OH), and so they were eventually given the names iso butyl and iso amyl alcohols, the prefix designed to distinguish them from the straight-chain (or "normal") primary alcohols such as ethyl alcohol, or propyl alcohol from fusel oil. In the same way that ethyl alcohol could be dehydrated to ethylene, so could propyl, butyl, and amyl alcohols be dehydrated to the homologous olefins propylene, butylene, and amylene. During the 1850s, Berthelot demonstrated how to convert these olefins back to the alcohols by aqueous distillation from dilute sulfuric acid solution.
In the summer of 1862, Wurtz' student Charles Friedel published a note in which he described the reduction of acetone to a three-carbon alcohol, using nascent hydrogen generated from sodium amalgam. He refused to identify his product with propyl alcohol from fusel oil, saying the matter needed study.[58] Four months later (12 November 1862) Kolbe learned of this paper by reading a German abstract. The next day he sent Emil Erlenmeyer, editor of the biweekly Zeitschrift für Chemie , a short article on Friedel's compound, asking that it appear in the next issue. "The subject interests me all the more," Kolbe wrote in his cover letter, "since I expect to find through Friedel's work a confirmation of my view (based on purely theoretical speculations) concerning the existence of such new alcohol-like compounds."[59] In this paper, Kolbe suggested that Friedel's new alcohol was the isomeric propyl alcohol he had predicted years earlier. The
test would be to oxidize the compound; a secondary alcohol must yield acetone, whereas the known (primary) propyl alcohol would give propionic acid. He also suggested, presumably by comparing boiling points, that Friedel's product was the same as that propyl alcohol produced by Berthelot years earlier by hydrating propylene. But he said he did not want to forestall Friedel and so was leaving it for him to complete the investigation.[60]
A few months later Friedel reported the oxidation experiment and confirmed Kolbe's prediction. But he added a mild protest. What other product than acetone could have been expected when the reduction product of acetone was oxidized?! Obviously, no one could imagine this was common propyl alcohol. He had been perfectly well aware of what he had when he published his first paper; he only wanted to be able to present clean results devoid of conjecture and had been having troubles over impurities, so he had temporized. In rebuttal, Kolbe conceded he could not prove that his idea had formed the basis for Friedel's reaction, but thought it curious that Friedel had not made the discovery until Kolbe's interpretation had appeared in print. His conclusion was that the episode clearly demonstrated the fruitfulness of his own theory and the barrenness of type theory.[61]
Six months after Kolbe's rebuttal, in the summer of 1864, A. M. Butlerov identified a "tertiary pseudobutyl alcohol," trimethyl methyl (modern tertiary butyl) alcohol. He had obtained this new compound the previous year from the reaction of phosgene with methyl zinc, but had not immediately been able to specify its constitution. Butlerov noted that once more a prediction by Kolbe had been fulfilled. By this time, predictions of new isomers based on structure-theoretical precepts were rapidly proliferating. Butlerov argued, for example, that in addition to the known normal butyl alcohol and his new tertiary compound, exactly two more butyl alcohols should exist: a branched-chain primary (isobutyl) alcohol and a secondary butyl alcohol. (Here Butlerov was repeating a statement published a few months earlier by Kolbe.) As for the next higher homolog, no fewer than eight amyl alcohols should exist: four primary, three secondary, and one tertiary —or, by another manner of accounting, three associated with a straight-chain carbon skeleton, four with a branched-chain, and one containing a quaternary carbon atom. As far as lower homologs were concerned, structure theory appeared to predict a single methyl and a single ethyl alcohol. A similar analysis applied to the higher alcohols as well, and Butlerov was not slow to use the reaction that had given him t -butyl alcohol for the synthesis of new hexyl and octyl alcohols.[62]
The secondary butyl alcohol predicted by Kolbe and Butlerov was first prepared by V. H. de Luynes about the time of Butlerov's paper. This appears to have been a fortuitous event, and de Luynes did not
attempt to determine the compound's constitution. Definitive identifications and structural assignments of all four isomers of butyl alcohol were first made in 1869 by Adolph Lieben, a student of Bunsen and Wurtz then working at the University of Turin.[63]
The formula for the butyl alcohol found in fusel oil by Wurtz was at first structurally indeterminate, but presumably the substance was assumed to be normal butyl alcohol.[64] Oxidation, however, did not yield normal butyric acid. In the meantime, Kolbe not only predicted the existence of an isobutyric acid (dimethyl acetic acid), but suggested no less than two different synthetic routes to it: isopropyl alcohol to isopropyl iodide to isopropyl cyanide, whose hydrolysis should yield isobutyric acid, or reduction of the hydroxyl group of acetonic acid (dimethylhydroxyacetic acid) using Lautemann's reducing reagent, hydrogen iodide.[65] Even while making corrections and exchanging proofs of the article containing these ideas with his editor Erlenmeyer, Erlenmeyer informed Kolbe of his current attempts to produce isobutyric acid by oxidizing the butyl alcohol from fusel oil. Erlenmeyer published this work shortly before V. V. Markovnikov independently published essentially the same reaction. Erlenmeyer and Markovnikov both concluded that their starting material contained a branched carbon chain, i.e., that it was isobutyl alcohol, because they found that Kolbe's suggested syntheses from isopropyl compounds yielded the same product.[66] In 1867 Frankland and Duppa removed any possible doubt about these structural assignments by ethylating and dimethylating ethyl acetate, yielding butyric and isobutyric acids, respectively.[67]
Of all these new alcohols, isoamyl proved perhaps the most interesting—and intractable. It had long been known (simply as amyl alcohol) as the major component of fusel oil, as had the associated olefin amylene. Wurtz published a series of articles in 1862-1864 on these compounds, and especially on rehydrated amylene, which he called amylene hydrate, an alcohol-like material differing in properties from the original natural alcohol.[68] Wurtz had the ill luck to have tackled a problem whose solution was beyond the capabilities of the science of his day. In fact, dehydration and rehydration of the natural alcohol had the effect of transferring the hydroxyl group two carbons down the chain, transforming a primary into a tertiary alcohol. The work was also hindered because fusel oils are complex mixtures from which it is difficult to isolate pure materials and because fusel oils from different sources often have quite different compositions (as Kolbe himself had discovered in his very first independent chemical research).
Erlenmeyer oxidized amyl alcohol from fusel oil; he obtained a valeric acid distinct from the normal variety. That this was isovaleric acid, i.e., a branched-chain structure, Erlenmeyer showed by produc-
ing the same compound by chain lengthening of isobutyl alcohol (converting to iodide, then to cyanide, and then hydrolyzing). Since isobutyl was by then known to be branched, the same had to be true for isovaleric acid.[69]
As for Wurtz' amylene hydrate, Erlenmeyer and Kolbe independently suggested that it was a secondary alcohol.[70] As early as December 1863, Kolbe was privately predicting that oxidation of amylene hydrate would yield diethyl ketone or, less likely, methyl propyl ketone. "Wurtz' most recent papers," he wrote Frankland, "are examples of how not to work, [they are] loose and sloppy." In February 1864 he claimed to have isolated what was "without question" the latter oxidation product and suggested that amylene hydrate was therefore methyl propyl carbinol (2-amyl alcohol); this was published in the Annalen later that year. However, the oxidation was not clean; from elemental analysis Kolbe concluded that he got only around fifty percent yield, the remainder being unreacted starting material. His formula assignment was based on an involved argument regarding boiling point regularities.[71] Wurtz' investigation of the same reaction, published in the meantime, was just as problematical, but not consistent with Kolbe's results; he found that the carbon chain was broken, with the chief products being acetic acid and acetone. Ever cautious, Wurtz refused to draw any conclusions regarding the constitution of amylene hydrate.[72] In fact, it was eventually established that amylene hydrate as prepared and identified by Wurtz does produce acetic acid and acetone upon oxidation. Straight-chain amyl alcohols are essentially absent in all fusel oils, and so Kolbe's published results are not easily explicable. He is vulnerable here to the suspicion of having found what he needed to find in order to verify his prediction.
At the same time that all of this was developing, Frankland and Baldwin F. Duppa published on the alkylation of oxalic ester, using zinc alkyls. A particularly interesting product was the diethyl compound, found to be isomeric with leucic acid (the latter was leucine, a six-carbon amino acid, converted by Strecker to a hydroxyacid by replacing its amino group by a hydroxyl group). Privately to Frankland and publicly in his paper on isomerism, Kolbe formulated it as diethyl glycolic acid. Although Kolbe did not realize it, this was consistent with Frankland's own formulation.[73]