MODERN STRUCTURAL CHEMISTRY
LINUS PAULING, Director, Gates and Crellin Laboratories, California Institute of Technology, Pasadena, Calif.
It is with a deep and sincere feeling of appreciation that I receive this great recognition of my work, the Willard Gibbs Medal of the Chicago Section of the American Chemical Society. The investigations which I have carried on, with the aid of many able collaborators during the past 24 years, have covered a broad field of science, including parts of physics, mineralogy, chemistry, and biology; but, though varied in nature, they have had a common feature -- an emphasis on structure -- and they may all be considered as being comprised in the general subject of modern structural chemistry.
Structural chemistry -- the determination of the structure of chemical substances and the explanation of their properties in terms of structure -- is an old science, as old as chemistry itself. We remember Lucretius, who 2,000 years ago wrote about "honey, with smooth, round molecules which roll easily over the tongue, whereas wormwood and biting centuary consist of molecules which are hooked and sharp"; and Lomonosov, whose explanations of the properties of solids, liquids, and gases in terms of moving molecules were boldly imaginative 200 years ago, and yet were, we now know, very close to the truth; and Dalton, who first pointed out that the weight relations of chemical reactions have a simple interpretation in terms of the combination of atoms; and Avogadro and Cannizzaro, who showed that even in an element two or more atoms may be bonded together to form a stable molecule; and Frankland, Couper, and Kekule, who developed the concept of valence -- the representation of the combining power of an atom by a small integer; and again Kekule, with his strikingly simplifying picture of the benzene molecule as a ring of six carbon atoms, each with its attached hydrogen atom; and van't Hoff and le Bel, with their explanation of the right- and left-handedness of some substances, first discovered by Pasteur in tartaric acid, as resulting from the tetrahedral arrangement of the four valence bonds of a carbon atom; and Werner, who showed that the spatial arrangement of bonds determines the properties of many substances other than the compounds of carbon, and that an atom such as platinum may, in its quadrivalent state hold six atoms or groups about it at the corners of an octahedron, or, in its bivalent state, hold four atoms or groups at the corners of a square, rather than a tetrahedron; and we remember, as the last of the great structural chemists of the past, Gilbert Newton Lewis, whose identification, in 1916, of the chemical bond between two atoms with a pair of electrons held jointly by the two atoms, vulcanizing them together, initiated the period of theoretical clarification and precise experimental investigation which has in a few decades changed the old, qualitative structural chemistry into modern structural chemistry.
Modern structural chemistry differs from the older science in being precise -- quantitative, instead of qualitative; lucid, instead of vague. It is not longer enough to say that the chloroform molecule is tetrahedral in structure -- we now say that the four bonds are directed almost, but not quite, toward the corners of a regular tetrahedron, three of the bond angles (Cl-C-Cl) having the value 111°, slightly larger than the regular tetrahedral angle 109= 28', and the other three (Cl-C-H) 108°, and that each of the three chlorine atoms is 1.76 Å. from the carbon atom, and the hydrogen atom is 1.09 Å. from the carbon atom, and that the molecule may oscillate with certain frequencies, and that the stretching of one carbon-chlorine bond has a certain effect on the other bonds; and so on: and we use this information in discussing not only the simply physical and chemical properties of the substance but also for the calculation of its entropy and free energy and hence of the equilibrium constants for its reactions.
Period of Development
We have seen, during our lives, the development of modern structural chemistry. I became deeply interested in molecular structure and the nature of the chemical bond in 1919, when I first read Lewis' 1916 paper and Irving Langmuir's papers on this subject, and I began experimental work in the field in 1922. At that time, only a quarter of a century ago, there was not known the distance between the atoms in the molecules of any gaseous substance, nor, indeed, of any organic substance whatever (except diamond); it was not known that the two atoms in the hydrogen molecule are 0.74 Å. apart, the two in the nitrogen molecule are 1.094 Å. apart, and in the chlorine molecule 1.98 Å. apart. These values were determined, by the methods of band spectroscopy, during the next few years. In 1922 the only precise interatomic metrical information at hand was that which had been obtained since 1913 by the x-ray investigation of crystals, all inorganic except diamond -- it was known that the carbon-carbon distance in diamond is 1.54 Å., but it was not known that the carbon-carbon single bond in other substances. The first organic molecule for which a structure determination was made was hexamethylene tetramine, crystals of which were studied by Dickinson and Raymond in 1923; but it was not until 1929, when the technique of electron diffraction by gas molecules was developed by Mark and Wierl, that it became possible to determine the interatomic distances in a large number of organic molecules.
Methods
The methods of modern structural chemistry are largely physical in nature: they include molecular spectroscopy, the determination of the structure of crystals by the diffraction of x-rays, the determination of the configuration of gas molecules by the diffraction of electrons, the measurement of the electric dipole moments of molecules, the measurement of magnetic moments and of diamagnetic susceptibilities, the interpretation of heat capacity, entropy, and other thermodynamic quantities, and the application of theory, especially quantum mechanics. Each of these methods, in addition to providing the specific detailed information characteristic of it, has let to significant additions to our body of general chemical knowledge. Molecular spectroscopy not only has given us a great mass of data about moments of inertia, oscillational frequencies, electronic energy levels, etc., but also has verified, for example, the surmise made by Langmuir that the oxygen atom of nitrous oxide is at one end of the molecule and not in the middle.
The x-ray method proved in 1925 that the azide ion has the linear structure of N N N- and not the cyclic structure [Drawing of cyclic structure of azide ion]; and a few years later a linear structure was verified also for the azide group in a covalent azide (methyl azide) by the electron diffraction method. It was the x-ray study of ergosterol and calciferol by Bernal which led to the assignment of the correct chemical structures to the sex hormones and vitamin D by Rosenheim and King and Wieland and Dane; and recently we have seen the great power of this method exemplified in a striking manner by its use by Dorothy Crowfoot and Barbara Rogers-Low in the discovery of the β-lactam configuration for penicillin, for which the methods of the organic chemist had indicated an azlactone structure. I believe that, with the increasing power of x-ray diffraction methods, this technique will become a more and more useful adjunct to chemical methods for the elucidation of the structure of natural products.
Formulas and Structures Revealed
Another use of x-rays is in the assignment of chemical formulas to substances so complex that the method of chemical analysis fails to yield an unambiguous answer -- for example, in this way the formula Al13Si5O20(OH,F)18Cl was determined for the mineral zunyite, and (NH4)6-Mo7O24·4H2O for ammonium paramolybdate. It has been reported that with only micrograms of the materials available Zachariasen was able to establish the composition of many compounds of plutonium by the x-ray diffraction method.
The study of the patterns obtained by the diffraction of electrons by gas molecules has led not only to the determination of interatomic distances in many molecules of known chemical structure but also in a number of cases to the discovery of the correct structure or the verification of a structure about which there was some doubt. Donohue, Humphrey, and Schomaker were able in this way to prove the spiropentane structure for the hydrocarbon C5H8 obtained by Murray and Stevenson by the debromination of pentaerythrityl bromide with zinc dust. The o-biphenylene structure suggested for Lothrop's hydrocarbon C12H10 by its method of synthesis was verified by its electron diffraction pattern and also by an x-ray crystal structure determination. The doubt which had long existed about the structure of pirylene, C5H6, was finally dispelled by the electron diffraction investigation which showed it to be 1-methyl-2-vinyl acetylene. Ethylene ozonide has been shown to have the oxide-peroxide ring structure. A number of similar studies of inorganic compounds have also been made.
New Techniques Adopted
From time to time new physical techniques are found to be so useful to the organic chemist that they are incorporated by him into his collection of standard procedures, and become a part of organic chemistry. This has occurred in recent years with absorption spectroscopy. The value of the absorption spectra of complex organic substances in the ultraviolet and visible regions for the purposes of characterization and of the identification of certain structural features, especially of conjugated systems, has been strikingly demonstrated during the past 20 years by the work on vitamin D and other sterols and on vitamin A and the carotenoids. A very interesting new application of spectroscopic methods has been made recently by Zechmeister and his collaborators in the study of the cis-trans isomerism of carotenoids. It has been shown that the intensity of the principal absorption band is greater for the all-trans isomer of a carotenoid than for the cis isomers, and this property has been used for the reliable identification of the all-trans isomer, which occurs in the near ultraviolet; by the consideration of details of the spectra, especially this "cis-peak", Zechmeister has made tentative assignments of configurations to many of the carotenoid isomers. An especially interesting isomer is prolycopene, which occurs in the "tangerine" tomato, giving it its bright orange color; this isomer is thought to have the cis configuration about six of its double bonds. A single gene in the tomato plant determines whether prolycopene will be formed in the fruit, or all-trans lycopene, which gives the red color to ordinary tomatoes.
Physiological Activity of Chemical Substances
The field of application of modern structural chemistry which seems to me to have the greatest promise for the future is that of the explanation of the physiological activity of chemical substances. Little success has resulted from the efforts of chemists and physiologists to correlate the physiological properties of substances and their ordinary chemical properties, the properties which depend upon breaking the chemical bonds within molecules and forming new chemical bonds. I believe that usually the specific physiological properties of substances are determined not by these strong intramolecular forces, but instead by the weak forces -- van der Waals forces, hydrogen bonds -- which operate between molecules, and that the understanding of physiological activity will be consequent to the detailed consideration of these forces in relation to the size, shape, and structure of the interacting molecules. Strong evidence for this point of view has already been obtained through the study of the behavior of systems of antibodies, antigens, and haptens; and I am confident that, as our knowledge of the structure not only of simple molecules but also of proteins and other complex constituents of organisms increases, we shall in time achieve an insight into physiological phenomena which will serve as an effective guide in biological and medical research, and will contribute to the solution of such great practical problems as those presented by cancer and cardiovascular disease.
June
14, 1946
