THE SIGNIFICANCE OF STRUCTURAL CHEMISTRY

By Linus Pauling

Introductory lecture of the George Fisher Baker Lectureship in Chemistry, Cornell University. 8:15 P.M., Tuesday, October 12, 1937. Also used at Pomona, 8 P.M. March 10, 1938, under the title "THE STRUCTURAL CHEMISTRY OF BLOOD."

President Day, ladies and gentlemen: Before beginning the discussion of the topic for the evening, "The Significance of Structural Chemistry," I wish to thank the University and especially the members of the Department of chemistry for their kindness in extending to me an invitation to present the George Fisher Baker Lectures for the present academic year. It is indeed a great honor and privilege to speak and work in this wonderful laboratory, as well as a great pleasure to spend some months on this beautiful campus.

I have seen on looking over the books published by earlier Baker Lecturers that in most cases the Lecturer has chosen for the topic of his Introductory Address some philosophical, economic, or political question. After much thought I have abandoned the idea of doing this, in part because I have been unable to think of any such topic to which I feel I could make a significant contribution. Remembering, however, the statement of Aristotle, "Old men should be politicians, young men mathematicians," I have decided to speak about the subject of structural chemistry, to which I have devoted most of my professional attention for fifteen years.

In his "Mathematical Theory of Relativity," Eddington wrote "The investigation of the external world in physics is a quest for structure rather than substance." This is true in the main not only for physicists but for all scientific investigators. I am taking the risk of boring you with familiar ideas to make a survey of the dimension of the universe. On a logarithmic scale, there is shown plotted the dimensions with which humans deal. Scientists endeavor to discuss the objects in each region in terms of entities in the region below. Thus the astronomer discusses the universe as a whole in terms of island universes, these in terms of stars and solar systems; the earth is then discussed in terms of rocks and other objects of ordinary dimension, and these in terms of molecules; the chemist discusses the structure of molecules in terms of atoms, the physicist the structure of atoms in terms of nuclei and of nuclei, now, in terms of protons, neutrons, etc.

[Diagram illustrating a scale of distances denoting "The Astronomer's Region," "Region of ordinary perception," "The great unknown," "Molecular structure," and "Nuclear structure."]

We see that the large magnitudes, studied by the astronomer, are, while interesting, not of practical importance; whereas, contrary to cosmology, the researchers of physics and chemistry in the region of small magnitudes are of great practical significance, as they deal with the structure of our environs. Mention great unknown region.

It is with the region 10^-7 - 10^-8 cm that we are now concerned. This is now the region of structural chemistry, including in its scope relatively simple molecules.

The idea of accounting for the properties of substances in terms of the shapes of the particles of which they are composed is an old one. Just two thousand years ago the Roman poet Lucretius wrote "Wine flows easily because its particles are smooth and round and roll easily over one another, whereas the sluggish olive oil hangs back because it is composed of particles more hooked and entangled one with another." This is essentially the modern point of view. Lucretius went beyond us in interpreting the taste of substances also in terms of the shape of their molecules, writing "There is this, too, that the liquids of honey and milk give a pleasant sensation of the tongue, when rolled in the mouth; but on the other hand the loathsome nature of wormwood and biting centaury set the mouth awry by their noisome taste; so that you may easily know that those things which can touch the senses pleasantly are made of smooth and round bodies, but that on the other hand all things which seem to be bitter and harsh, these are held bound together with particles more hooked."

The structures of diamond and graphite form a good example of the significance of structural chemistry as developed during the last century and the present one. Each of these substances is made of carbon atoms only. IN diamond each atom is bonded to four neighbors which surround it tetrahedrally - this exemplifies the quadrivalence of carbon as suggested originally by Kekulé and Couper 100 years ago, and also the tetrahedral nature of the atom postulated by van't Hoff and le Bel 50 years ago. The great hardness of diamond is due not only to the strength of the C-C bond, but also to the arrangement of the bonds. The same bonds occur in soft graphite, which owes its softness to the ease with which the layers slip over one another; and also in linen fibers (and other such fibers), which show a tensile strength of several hundred pounds per square inch, as great as that of the strongest steel.

All hard substances, abrasives, such as corundum, carborundum, quartz, etc., are held together by bonds which connect all the atoms in a crystal into one giant molecule in the same way. Quartz, for example, is held together by Si-O-Si-O bonds according to the pattern (see model). We can see the effect of changing the structure - the arrangement of bonds - without changing the nature of the bonds by comparing quartz with mica and asbestos. All of these are essentially the same in composition, but quartz is hard and compact, mica splits into sheets, and asbestos into fibers, because of the difference in the way the bonds are arranged. [Diagram of quartz structure]

The fields of the structure of ordinary molecules and of crystals are now well understood, although much detailed work needs to be done. When we approach biochemical problems, especially those dealing with proteins, we begin to get into the region of the unknown. To illustrate the difficulties I shall discuss hemoglobin, about which as much is known as for any giant molecule.

Hemoglobin is the respiratory pigment of the blood, carrying oxygen from the lungs to the tissues. It serves this purpose for all vertebrates and for many other animals. There is a great deal of hemoglobin about - it comprises about 15% of blood, and since about 7% of the body is blood, hemoglobin makes up about 1% of the body weight; each of us carries around about a pound and a half of it. Hemoglobin is a perfectly good chemical substance - it can be purified, crystallized, put in a bottle and labeled just like anything else. But it is extremely complex - it has a molecular weight of 68000, each molecule containing about 10000 atoms! To attack the problem of the structure of this giant seems hopeless - but hemoglobin is such an interesting substance, because of its significance to life, that any attack is worth while. Of course to the chemist every chemical substance is interesting, just as to the mathematician every number is interesting. You probably know the story about Ramanujan, the great Indian mathematician, the first Indian to be elected to the Royal Society. While in a hospital in London he was visited by Hardy, who, to pass time, said "The cab in which I came had a most uninteresting number, 1729," to which Ramanujan replied "On the contrary, that is a most interesting number - it is the smallest number which can be expressed in more than one way as the sum of two cubes."

The hemoglobin molecule is about 50 Å in diameter - it is so large that a clump of about one million of them could be seen under a microscope. It consists of a globin molecule, which serves the main purpose of keeping the molecule in solution in the blood plasma, and four hemes, each consisting of one iron atom and about 75 other atoms. The structure of these hemes is known as the result of the studies of the great organic chemists, culminating in Hans Fischer, and of some magnetic studies. [Diagram of the hemoglobin molecule, annotated as follows: "It is a big round molecule - like a big orange - a California orange, or two Florida oranges."] The atoms in a porphyrin are arranged as shown. The iron atom can be assumed to be in the position indicated. We ask - what about the attachment to globin, and what about the bonding of oxygen? These questions were answered in an interesting way.

Over 90 years ago Faraday measured the magnetic susceptibility of dried blood. But only two years ago we found the susceptibilities of venous and arterial blood to differ by a large amount. Now ferrous iron atoms in molecules are of two kinds; those forming ionic bonds, which are paramagnetic, and those forming six octahedral covalent bonds, which are diamagnetic. Hence our result showed that in oxyhemoglobin there are bonds [diagram of bonds in oxyhemoglobin]. The iron forms a definite bond to oxygen and to globin as well as to the four porphyrin nitrogens.

The next question which arises is this - do the hemes bind oxygen independently, or is there an interaction between them? This is answered [by] the oxygen equilibrium curve, which is S-shaped. This shows that there is an interaction - each heme binds oxygen more readily after the others are oxygenated. The reason for this to have been developed is obvious - a bigger "payload" can then be carried to the tissues.

Next we ask - is there further interaction? There is - the oxygen binding power depends on the acid strength of the plasma, showing that there is interaction between the hemes and acid groups (8 perhaps), such that oxyhemoglobin is a stronger acid than hemoglobin. The only information we have about these groups, aside from their acid strength constants, is that they are "zwitterionic" groups - charged groups such as R-N⁺H₃; this, as yet unpublished, is shown by the salt effect.

The reason why this acid interaction has been developed is also clear. The blood also carries CO₂ back from the tissues to the lungs. This is done in the blood plasma, the CO₂ dissolving as HCO₃ ^-. Now in the tissues CO₂ goes into blood, making it acid, and thus helping expel oxygen. Then in the lungs O₂ adds to hb, increasing it acidity, and thus helping expel CO₂.

Before leaving heme and porphyrin, I might say a word about these substances as they occur in nature without globin. Heme occurs free only in one place, to my knowledge - in the blood of old males of the big red worm urechis. This worm, about 1" in diameter and 8 to 12" long, lives, like many other things, in California. It has many peculiar features other than the free heme in its old male blood. It lives in a U-tube, eats with a slime bag, etc.

Porphyrin, free of iron, occurs in many places. Thus the brown color of brown egg shells is due to a porphyrin, called oöporphyrin, which is the same as that in blood. Also the brown stripe down the middle of the back of an angleworm is due to a porphyrin. I suppose that the best source of porphyrin (next to blood) would be the giant angleworms in Australia - which are twelve feet long, live in burrows down which they flop with a slimy plop whenever visitors approach, and which lay eggs two inches in diameter - perhaps the eggs are brown, too.

Now we come to a real question - the way the remaining 9700 atoms, making up the globin of hemoglobin, are arranged. Unfortunately, we do not know yet. Globin, like other proteins, is composed of amino acid residues in a long polypeptide chain, [diagram of the chain], extending for 100 such 3-atom groups. We do not know, for any protein, the sequence of the amino acids, nor do we know the definite configuration the chain assumes by coiling back and forth, held together by hydrogen bonds between the side-chain amino and carboxyl groups from the basic and acid residues. You may ask - do we know that the protein has a definite structure? The answer to this is yes; we know because we can destroy the structure and obtain something different. This process is called denaturation. Just by heating the white of egg it is denatured; the same thing can be done with hemoglobin. Now hemoglobin from different species behave differently - show specific differences in oxygen affinity, color, solubility, crystalline form, etc., attributable to a difference in structure of the globin. but on denaturation all these specific differences are lost - they were due to structural differences which vanish with loss of structure. Moreover, there is proof that denaturation is the change from an ordered structure ot a random flapping about of the polypeptide chain. The physicist has a function, entropy, which measures degree of disorder. On denaturation there is a change in entropy of one hundred entropy units - a very great amount corresponding to just the process we have postulated.

And so, ladies and gentlemen, I come to the end of my story - to the end of present knowledge in this region around 10^-6 cm in dimensions. But I am confident that it will not be long before much more can be said. One hundred years ago the structural formula of not one organic substance was known - now these formulas can be written for a hundred thousand organic compounds. Twenty-five years ago the exact dimension of not one molecule was known - now, as the result of study by the diffraction of x-rays and electron waves, they are known for hundreds of molecules. At present we know the detailed structure of not one protein molecule; I am sure that, as a result of the attack from beneath that I have been describing, in ten or twenty or thirty years the protein problem will have been solved, that we shall be able to say (to mention an example that seems trivial to most people, though serious enough to the sufferer from hay-fever) how the ragweed protein finds its complementary pattern in the proteins of some people but not of others, how the protein antitoxin destroys the protein toxin that is endangering life, how the chromosome carries within its minuscule dimensions the factors of heredity, and even, we may hope, the secret of life itself - how a protein molecule is able to form, from an amorphous substrate, new protein molecules which are made after its own image.