Chemistry: Molecular Structure and Stereochemistry

Introduction

A daunting hurdle for early chemists was the recognition that molecules have a three-dimensional shape, a concept known today as stereochemistry. This article will focus on the tetrahedral geometry of carbon and the crucial role played in its development by two young Europeans during the second half of the nineteenth century. At a time when some scientists still doubted the very existence of atoms, or whether molecular architecture could ever be known, French chemist Joseph-Achille Le Bel (1847–1930) and Dutch physical chemist Jacobus van't Hoff (1852–1911) independently introduced this novel idea. The rapid (and almost universal) adoption of the tetrahedron effected a quiet revolution as chemists tacitly employed such structures for the depiction of the spatial arrangement in carbon. The van't Hoff-Le Bel hypothesis has dominated stereochemistry and has thus provided scientists with a powerful tool for the prediction of molecular properties.

Historical Background and Scientific Foundations

One of the great systematizers of the first half of the nineteenth century was the Swedish chemist Jöns Berzelius (1779–1848). Not surprisingly, he was one of the early advocates of the atomic theory, a notion first proposed in 1808 by the British chemist and meteorologist John Dalton (1766–1844), which stated that elements consist of tiny particles that combine in specific ratios to form molecules. While the Scandinavian enthusiastically endorsed the central tenants of Dalton's hypothesis, however, he suspected that many of the latter's formulas were inaccurate.

From his conviction that the errors arose from insufficient data on the relative weights of the chemical elements, Berzelius carried out precise measurements of volume and mass changes during reactions. He compiled extensive tables of atomic weights that he published during the second decade of the nineteenth century (and revised throughout his career). Of equal importance, he introduced the convention of letters and numbers that chemists continue to use in their formulas. For example, Berzelius denoted water as H₂O (indicating two parts hydrogen for each oxygen) and ammonia as NH₃ (conveying a 3:1 ratio of hydrogen to nitrogen).

Chemists during this period became quite adept at the art of analysis. Among the most prolific in the characterization of substances from animals and plants was the German chemist Justus von Liebig (1803–1873), who created one of the first teaching laboratories in Europe. As the volume of analytical data expanded, many scientists were deeply puzzled by substances known as isomers, which shared the same chemical formula but exhibited different physical properties. In 1828, for example, another German chemist, Friedrich Wöhler (1800–1882) found the transformation of ammonium cyanate into urea (named for its presence in urine). Both had the same composition (two nitrogens, four hydrogens, and a carbon), but were obviously isomers: urea had a melt temperature of 271°F (133°C), but ammonium cyanate underwent decomposition on heating.

Two Frenchmen made important discoveries during the first half of the nineteenth century that had important implications for molecular structure. Physicist Jean-Baptiste Biot (1774–1862) devoted a large portion of his prolific career to the study of polarized light, a term that refers to the parallel orientation after a beam of light passes through a crystal. He carried out innovative measurements of its interaction with solids, liquids, and gases. In 1815 Biot found that several natural oils (including turpentine and lemon) had the ability to rotate light, and in 1828 reported that tartaric acid (from grapes) had the same property. He even developed improved devices (called polarimeters) to measure solutions and suggested that chemists could use the optical rotation as a proxy for the concentration of compounds in solution.

One chemist who took Biot's recommendation to heart was French chemist and microbiologist Louis Pasteur (1822–1895). Like many Europeans in wine-producing regions, he was intrigued by the physical and chemical changes that occurred during the fermentation process. For his research as a candidate for a doctoral degree, Pasteur focused on a chemical from wine sediments known as racemic acid. Curiously, this substance had the same elemental composition as Biot's tartaric acid, but did not affect polarized light. During the 1840s, most chemists regarded optical rotation as an exotic technique with no practical value, but Pasteur, with the help of his elder countryman, dramatically altered that perception.

Pasteur was able to draw from a rich tradition in the study of crystals that had existed for nearly seven decades. In 1781, the French mineralogist René-Just Haüy (1743–1822) first noticed how calcium carbonate (calcite) breaks when he accidentally dropped a specimen. He subsequently carried out extensive geometric analyses to learn how such minerals might form. Another French chemist, who sought to extend Haüy's methods to chemical compounds, was Auguste Laurent (1808–1853), who shared a laboratory with Pasteur at the Normal School in Paris. Laurent suggested that Pasteur focus his studies on the shape of the wine crystals, and also gave him important practical advice that ensured the experiment's success.

When Pasteur checked the solid under a microscope, he was shocked to find two types of crystals (in right- and left-handed forms). Fortunately, Pasteur was able to prove his own adage that “In the field of observation, chance favors the prepared mind.” Pasteur knew that Biot had reported a similar phenomenon in quartz. Working alone in the laboratory, he carefully separated the two materials and found (using Biot's own polarimeter) that each rotated light in opposite directions. Upon publishing this remarkable data in 1848, he proposed a mirror-image relationship at the molecular level, but the primitive state of structural chemistry prevented Pasteur from any more definitive conclusions.

An essential element in the structure of carbon-containing compounds is the number of linkages that each forms. The English chemist William Odling (1829–1921) was the first to recognize (in 1855) that carbon could form four bonds to other atoms. However, it was the German chemist August Kekulé (1829–1896) who first assigned the formula CH₄ to methane (a gas produced by microbes living in marshes) and assigned double and triple bonds to other molecular structures. In 1857 Kekulé introduced the term “valence” to describe the number of links that an atom formed. He played an especially prominent role in understanding molecular structures, and emphasized that chemical formulas could be a predictive tool.

One of Kekulé's champions was the Russian chemist Alexander Butlerov (1828–1886). He wrote more clearly than the German, who often buried important concepts in obscure footnotes. Many scientists thus learned about the Kekulé valences through Butlerov's publications. In an 1861 article, Butlerov also expressed a distinction between the chemical structures inferred from experiments and the absolute arrangement of atoms in the true molecule. One year later, he published a provocative discussion of ethane (C₂H₆), in

which he proposed a tetrahedral geometry for carbon. However, he made no effort to apply this insight to more complex compounds with other atoms in place of hydrogen.

The Science

In 1873 the German chemist Johannes Wislicenus (1835–1902) had just made the puzzling observation that lactic acid, a compound found in sour milk (C₃H₆O₃), did not rotate polarized light, whereas another form of lactic acid from meat did. Van't Hoff suggested that molecules with four different groups at the central carbon could exist as a pair of mirror-image structures (often called optical isomers). According to this hypothesis, sour milk contained a mixture of the two isomers, such that the effects would cancel and no rotation would be observed with polarized light. By contrast, meat should contain just one, although van't Hoff could not specify which. He also included a list of compounds that are not expected to rotate polarized light: CH₃(CH₂)_nCH₃, CH₃(CH₂)_nCO₂H, and CH₃(CH₂)_n CH₂OH (where n is any positive integer). He noted that none of these formulas possessed an asymmetric carbon, and thus would show no optical effect.

Le Bel and van't Hoff published their analyses almost simultaneously. While both discussed lactic acid, Le Bel adopted a more abstract (and therefore more general) treatment. For example, he was intrigued by the symmetry of methane (CH₄) and how the geometry contrasted with other derivatives. While van't Hoff focused entirely on the prediction of isomers (thus his model was therefore more likely to be used by chemists), Le Bel explained the same phenomena in the language of physics. He also concluded his article with some prescient observations on the stereochemistry of chemical reactions. Specifically, he made a bold prediction: if one started with a compound that lacked an asymmetric carbon, then the products would contain equal quantities of the mirror-image forms. Le Bel advanced an even bolder prediction when he suggested that a chemist could influence the stereochemical outcome of a reaction by employing substances with a known handedness or even by shining polarized light on the solution.

Both men also described the structures of compounds containing carbon-carbon (C=C) double bonds. They implicitly recognized that this unit was inherently rigid, which would give rise to distinct isomers, but the atoms with single bonds were free to rotate. Furthermore, van't Hoff suggested that some observations could be explained by the presence of two different geometries about the central double bond.

A noteworthy factor in Le Bel and van't Hoff's presentations is the striking difference in their use of illustrations. Le Bel employed a convention, borrowed from the British chemist Alexander Crum Brown (1838–1922), in which solid lines denoted the connections between atoms. While he referred repeatedly to carbon's tetrahedral geometry, nowhere did he provide a true perspective drawing. By contrast, van't Hoff dramatically illustrated his article with drawings of the mirror-image pair of isomers containing a true tetrahedron, as well as possible geometries for maleic and fumaric acids. Chemists were able to follow his arguments more easily than Le Bel's.

Influences on Science and Society

At first van't Hoff and Le Bel's publications were virtually ignored by the chemical community. Not surprisingly, such a chilly reception impelled each to pursue alternate projects. Le Bel turned to botany, while van't Hoff studied reaction rates and the properties of membranes (winning the first Nobel Prize for chemistry in 1901). Fortunately, the concept of a tetrahedral carbon atom gained a few patrons among the German chemists, especially Wiscilenus and Victor Meyer (1848–1897). Significantly, the former arranged for a German translation and promoted its discussion at scientific meetings. While van't Hoff became the public spokesman for the model, he always gave equal credit to the absent Le Bel. Meyer not only employed the tetrahedral carbon in his own textbook, he also introduced the term “stereo-chemistry” to refer to the three-dimensional molecular shapes. Finally, the British physicist John Strutt, Lord Rayleigh (1842–1919), coined the equally important word “chirality” from the Greek for right- and left-handedness.

Wiscilenus in particular played an often unrecognized role in the early dissemination of van't Hoff and Le Bel's hypothesis. As an administrator in the universities at Wurzburg and Leipzig, he could lend his professional prestige to the tetrahedral carbon. Just four years after van't Hoff and Le Bel's article appeared, Wiscilenus began teaching it to his students as part of the Wurzburg chemistry curriculum. A decade later he also published the first of a series of research articles in which he described ten independent lines of evidence to assign the structures of maleic acid and fumaric acid.

For example, maleic acid can be converted into its isomer (but not the reverse), suggesting that the oxygens are more stable when the atoms are further apart. This brilliant tour de force was replete with three-dimensional diagrams in which he relied extensively on the concept of tetrahedral carbon. Wiscilenus also coined the term geometric isomers, which chemists still use to refer to compounds that differ only in the arrangement of groups about a double bond.

Another German chemist who relied explicitly on the tetrahedral carbon was Emil Fischer (1852–1919). He is best known for his extensive studies of sugars, which began in 1884 and spanned two decades. He brought order to this complex subject by characterizing the numerous asymmetric carbons in these compounds. He also made significant contributions to biotechnology and the life sciences when he examined the behavior of different sugars in the presence of yeasts, demonstrating (among other findings) that the sugar mannose was digested by eleven varieties of yeast, but its stereoisomers were not affected at all. In related research, Fischer introduced his vivid lock-and-key analogy to describe the remarkable specificity of sugar-protein interactions.

Fischer and his contemporaries recognized that they could only hypothesize whether or not two compounds were similar in their structure. Chemists at the end of the nineteenth century lacked the technology to map the true arrangement of atoms in space, and so Fischer made an educated guess for an isomer of tartaric acid as a standard. However, an x-ray study in 1951 headed by Dutch physicist Johannes Bijvoet (1892–1980) finally proved Fischer correct.

Pasteur occupied a unique position in discussions of chirality, because of his pioneering studies of optical rotation and crystalline form. While he publicly stressed the connection between molecular asymmetry and living processes, he simultaneously pursued private experiments in search of a nonbiological basis for the selection. Among other factors, he explored magnetic fields and sunlight reflected through a mirror, without observing any effect on the stereochemistry. Late in his career, Pasteur speculated in 1883 that life on our planet might be governed by a cosmic asymmetry, which had previously eluded scientists. Some historians have even suggested that he may have deferred this research for fear of alienating his royal patron, Napoleon III.

Chemists would learn from spectroscopic studies and other physical properties that the hydrogens in methane really do conform to the geometry predicted by van't Hoff and Le Bel. In developing his model for bonding in methane, American chemist Linus Pauling (1901–1994) assumed that he could ignore the inner electrons of carbon. Furthermore, to get the right arrangement, he devised the notion of hybrid orbitals (functions that define the location and energy of an electron), which had spatial properties in between those of the pure atomic orbitals. Pauling showed in 1931 that the tetrahedral geometry for the bonds in methane was consistent with the rules of quantum mechanics, at a time when other scientists were focused on much simpler molecules.

Pauling also popularized a way of portraying certain molecules as a combination of different structures in order to predict bond angles, charge distribution, and other physical properties. He also established the convention of using a double-headed arrow to depict these molecules. By drawing three structures in this manner, he and other chemists sought to convey the concept that the real molecule was actually in between these resonance forms. In this case, it is known from other studies of BF₃ that it has a trigonal planar geometry with equivalent B-F bonds.

The concept of resonance had been used in molecular theory since the inception of quantum mechanics, especially in London and in Heitler's treatment of hydrogen. Pauling, however, did more than any other scientist to demonstrate the advantages of this depiction. While some chemists misinterpreted resonance as an oscillation, it nevertheless remains an important tool for representing molecules.

The first support for van't Hoff and Le Bel's postulate of rotation about single bonds came from several American chemists during the 1930's. Henry Eyring (1901–1981), who modeled the rates of reactions, tried to estimate how fast the carbon-carbon axis moved in ethane (C₂H₆). He calculated that the bond must be twisting at a very rapid rate: 7 × 10¹³ times per second at room temperature. While many scientists accepted this value, George Kistiakowsky (1900–1982) and his colleagues used more direct experimental measurements to determine a rotation that was 300 times slower. However, this revised estimate remains fast, justifying the assumptions of van't Hoff and Le Bel.

Modern Cultural Connections

The concept of stereochemistry had profound effects on biology. Beginning in the late 1930s, Pauling embarked on an extended study of proteins, which serve such diverse functions as building materials, catalysts (which speed up reactions), and transport vehicles. For 15 years he bombarded proteins with x rays to determine the relative atomic positions, and also built models to interpret the data. In 1951 he finally published the first of a

series of research articles in which he provided explicit evidence that parts of these proteins exhibit a helical twist (like a corkscrew), held in place through hydrogen bonds. Although he studied silk, muscles, tendons, gelatin, hair, feathers, and horn, he found that the same principles apply to all proteins. Importantly, the helix is also a direct consequence of asymmetric carbons, which all possess the same chirality in the backbone of the structure. For these (and many other) achievements, Pauling received the Nobel Prize for chemistry in 1954.

Nearly all molecules found in living systems exhibit chirality. One rancorous debate during recent decades has centered on the vexing question of how we ended up with one set of optical isomers. Of course, attempts to simulate the formation of such compounds on the early Earth have typically started with carbon in the form of CH₄, CO, or CO₂. Because these gases all lack an asymmetric center, the products of the reactions always contain equal amounts of the two isomers (what chemists now call a racemic mixture), just as Le Bel had predicted. For example, when the American chemist Stanley Miller (1930–2007) published his first such synthesis from CH₄, NH₃, H₂, and H₂O subjected to simulated lightning, he reported that the amino acids (the building blocks of proteins) did not rotate polarized light.

Some geologists, such as the American Robert Hazen (1948–) of the Carnegie Institution, have suggested that life might have begun on mineral surfaces. He has done experiments on Haüy's calcite, in which different faces have the ability to bind amino acids of one chirality, which (in principle) could join together to form small proteins. Once the first organisms appeared, evolution would undoubtedly have favored those with one type of handedness. However, Hazen's model is also deeply rooted in the assumption that the origin of life (and chirality) was a very local phenomenon, perhaps occurring on the edge of a mineral that happened to stick out of the primordial mud in a tidal lagoon.

Other scientists have suggested that a more fundamental cosmic asymmetry played a role. For example, American chemist William Bonner (1919–) of Stanford University has proposed that a spinning neutron star remnant from a supernova may have passed near our solar system early in its history and bathed our neighborhood in circularly polarized sunlight that could have induced the formation or destruction of specific stereoisomers. He and his collaborators even carried out laboratory simulations using racemic mixtures of amino acids, which can be transformed after irradiation into a product that has a preponderance of one structure.

Surprising support for this unearthly notion has come from the analysis of a meteorite that fell in Australia in 1969, but which represents debris from the earliest period of our solar system. Some meteorites are especially rich in carbon-containing compounds, in contrast to the stony meteorites—from which they are completely absent. Planetary geologists have suggested that the ingredients for life could have been brought to our planet via this process. In 1997, the American chemist John Cronin (1937–) of Arizona State University reported results on some especially hardy amino acids. Remarkably, these compounds are non-racemic, indicating an extraterrestrial selection in the distant past. In the intervening years, the suite of such amino acids

has grown substantially, and they consistently reveal a bias toward the same stereochemistry found in modern proteins. Cronin believes that the ubiquitous preference for one type of chirality is most consistent with a flux of polarized light, such as from a neutron star or through light scattering by magnetically aligned interstellar dust.

Chirality has been a compelling issue not only in the study of life's origins, but also in the design and efficacy of drugs. Because biological molecules have an inherent handedness, many pharmaceuticals have asymmetric carbons that cause them to bind to specific sites in your body. In general, only one isomer is effective, while its mirror image may even be toxic. A striking example is thalidomide, which was sold throughout Europe during the 1950s to treat depression and, later, nausea. The drug was withdrawn when physicians reported severe birth defects, which some scientists attributed to one of the mirror-image forms based on studies in rats. In 1998, however, the U.S. government approved its limited use to treat the side effects of leprosy, and other applications may be pending. This drug continues to be sold as racemic mixture, partly because of its lower cost, but also because the isomers are rapidly interconverted inside the human body.

In conclusion, the concept of molecular handedness has had a profound influence on numerous applications in science and medicine. From the shape of a protein to the possible extraterrestrial origins of chirality, the tetrahedral carbon has become an integral part of modern chemistry. The tentative hypothesis of van't Hoff and Le Bel that was introduced in 1874 now rests on an ever-expanding body of data. Chemists will undoubtedly build on this tradition with new advances in medicine and other materials.

See Also Chemistry: Biochemistry: The Chemistry of Life; Chemistry: Chemical Bonds; Chemistry: Fermentation; Chemistry: Organic Chemistry.

Books

Ramberg, P.J. Chemical Structure, Spatial Arrangement: The Early History of Stereochemistry, 1874–1914. Burlington, VT: Ashgate Publishing Company, 2003.

Periodicals

Chyba, C.F. “Origins of Life: A Left-Handed Solar System?” Nature 389, no. 6648 (1997): 234–235.

Farley, J., and G.L. Geison. “Science, Politics and Spontaneous Generation in Nineteenth-Century France: The Pasteur-Pouchet Debate.” Bulletin of the History of Medicine 48 (1974): 161–198.

Hazen, R.M. “Life's Rocky Start.” Scientific American. 284, no. 4 (2001): 76–85.

Palladino, P. “Stereochemistry and the Nature of Life: Mechanist, Vitalist, and Evolutionary Perspectives.” Isis 81 (1990): 44–67.

Snelders, H.A.M. “The Reception of J.H. van't Hoff's Theory of the Asymmetric Carbon Atom.” Journal of Chemical Education 51, no. 1 (January 1974): 2–7.

William J. Hagan