Hundred Years of Structure Elucidation

Those natural products, the structures of which appear in the textbooks, are the basic representatives that form the core of organic chemistry. Most of these structures have been elucidated in the period that present-day chemists consider the "Stone Age" of organic chemistry. All the more, chemists should be willing to question the validity of these structure assignments. How solid are the facts that support the structure assignment? How cogent are the connections of these facts to the final conclusion? Surprisingly, very little knowledge on the structure elucidation of those natural products prevails at present; reason enough to bring these achievements of the previous generations of chemists to light again.

Figure 1

Hence, this treatise deals with exemplary structures elucidated in the hundred years from 1860 to 1960. While the facts presented are historic, this is not a history of the structure elucidations. This would be much too detailed, as the structure elucidations of most of the products covered here were highly ramified with many culs-de-sac.

Rather, one should justify the limits 1860 and 1960. The year 1960 approximately marks the change from classical structure elucidation by degradation to the era in which structure elucidation is mainly based on spectroscopic evidences and X-ray crystallography. Since it is the emphasis of this treatise to address classical structure elucidation, efforts made after 1960 are only considered in exceptional cases.

The other limit, 1860, has to do with the notion of structure. Prior to the advent of structural theory [1], there was no conceptual framework to address the "structure" of a compound. This framework was provided by Kekulé (1857) [2], Couper (1858) [3], and Butlerov (1859) [4, 5]. The insight that the C-atom has four valencies and that C─C bonds form the backbone of organic compounds constituted the basis of the structural theory; it is the distinct connectivity between the atoms that defines the structure of an organic compound [5]. This theory made it for the first time comprehensible why (and how many) isomeric substances could exist for a given elemental composition of a compound.

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Of similar importance was the foundation of stereochemistry by LeBel [6] (1874) and van't Hoff [7] (1875), making it comprehensible why (and how many) "stereoisomeric" substances could exist for a given constitution of a compound.

Subsequently, the determination of such connectivities, that is, the structure of any compound of interest, became the predominant task of organic chemistry. Yet, this task constituted a challenge of unprecedented dimensions for the chemists at the end of the nineteenth century, because the structure of a new compound had to be related to that of structurally known compounds in, what one could call, a self-consistent network of information. Obviously, at the beginning, there were only a rather small number of structurally characterized compounds, which fortunately expanded rapidly with every decade of dedicated work. Obviously, in the course of time, it was increasingly easier to reach a known compound upon degradation of an unknown compound.

Figure 2

The situation was aggravated by the fact that the tools to elucidate structures of a given compound, that is, to establish the relation to other known compounds, were deplorably limited. Indeed, all that chemists had at their disposal were next to simple glassware, a balance, a Bunsen burner, and a few thermometers. All the more, one has to admire and respect the achievements of the chemists of that period.

Figure 3 Source: (a) ref. [16] (b) With kind permission of Dr. Timo Mappes, www.musoptin.com; (c) ref. [17].

The concept of structure could be attributed only to a "uniform" compound, that is, the sample to be studied had to be homogeneous. In the absence of any chromatographic or spectroscopic means to establish homogeneity, there was only the criterion of the invariance of the melting point. This means that the melting point of the sample did not change upon repeated crystallization, preferably from different solvents.

As a next step in structure elucidation, the elemental composition was to be established, both qualitatively and quantitatively, to arrive at the molecular formula. Quantitative combustion analysis provided the ratio of the elements in the compound, that is, (CxHyNzOw)n. In those days, the methods to arrive at the molecular formula, that is, to determine n by vapor-density measurement, cryoscopy, or ebullioscopy, were known. Nevertheless, in most cases, n was assumed to be 1, and molecular weights were determined only when in doubt.

The next step in structure elucidation concerned the kind of functional groups present. The nature of the elements present in the compound provided a hint, as to which qualitative tests [8] for functional groups should be conducted.

The information reached at this level (melting point, molecular formula, and functional groups present) was sufficient to decide whether one deals with a known or a new compound, by consulting a compendium [9] of (common) known compounds, listed according to the melting point, and searching for a hit with the same characteristics.

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Figure 4 CRC Handbook of Chemistry and Physics.

When the compound at hand was not listed in the standard compendia, one would consult Beilsteins Handbuch der Organischen Chemie. There, compounds are listed in a systematic manner, according to which, for each compound with a given molecular formula and distinct functional groups, there is a unique place, where the compound should be listed. One could in this way check whether a compound with the same melting point was listed or which isomeric compounds of the proper composition were known, leaving the remaining isomers as possible candidates. For such a search, there was a limitation due to the closing date of a particular volume. To acquire information after such a closing date, one would have to search the formula registers of the annual volumes of the Chemisches Zentralblatt and later of Chemical Abstracts and, from these, the abstracts, and then the original papers to find out whether a compound with the same characteristics as that of the one at hand has already been described. A major hurdle in doing this was the fact that the nomenclature used for individual compounds has changed several times over the years.

Figure 5 Beilsteins Handbuch der Organischen Chemie.Source: With kind permission of Engelbert Zass, Zürich.

One aspect became immediately evident in doing such searches: the range of melting points, commonly between 20 and 320 °C, is with about 150 data points not sufficient to distinguish ten thousands of compounds. Hence, there was the requirement of preparing (crystalline) derivatives of the compound at hand and to compare their melting points as well with the published data. Actually, the compendia and Beilstein list the derivatives and their melting points right alongside the data of the parent compound. However, a single derivative may not be enough to differentiate between two known compounds, as seen in the case of the 3- and 4-isopropyl-cyclohexanones. Hence, it became customary to prepare at least two derivatives of a parent compound for definitive identification. When the melting points matched, identification was considered as accomplished.

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Beilsteins Handbuch der Organischen Chemie, 2. Supplementary work, 1948, 7, p.31.

At this point, the conclusion could as well be that the compound at hand is not known and that the structure had to be determined by chemical means. This endeavor would start with a degradation of the compound to smaller (hopefully known) compounds. Degradation relied on oxidative cleavage at or near the functional groups present in the molecule, such as ozonolysis of C═C bonds, oxidative cleavage at C═O groups effected with refluxing HNO3, alkaline KMnO4, or CrO3 in acetic acid. Admittedly, this approach is crude, very similar to the attempts to learn something about a Chinese porcelain figurine in a dark room by knocking it to pieces, collecting them, and to examine them later by light. But this approach was the only one chemists could apply at the end of the nineteenth century. Accordingly, Williams recommended [10]:

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Such degradation studies required large amounts of the material to be studied in order to obtain in the end not only something that crystallized but also the product in sufficient amounts to be characterized and to be - when necessary - degraded further. Experimental sections typically read as follows [11, 12]:

It is obvious that these experimental aspects restricted structure elucidation to those compounds that could be obtained - from nature or otherwise - in large quantities.

Degradation thus furnished a small number of fragments that reflect the position(s) of the functional groups in the parent molecule. Nevertheless, conclusions regarding the structure of the original molecule remained difficult.

Fortunately, the kind of transformation effected by a particular degradation reaction, for example, the ozonolysis of a C═C bond, may serve as a guideline in reconstructing the original structure.

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Even...