The Story of “The Nature of the Chemical Bond”: Coordinating Research & Funding

[Ed. Note: This year marks the 75th anniversary of Linus Pauling’s publication of his landmark text, The Nature of the Chemical Bond.  For the next six weeks we will take a detailed look at the creation, release and impact of a book that changed the scientific world.]

Linus Pauling’s The Nature of the Chemical Bond, first published in 1939, was the product of over two decades of diligence, sacrifice, and collaboration among a broad range of actors that included Pauling’s family, research assistants, professional colleagues and a variety of institutions. Pauling’s prefatory remarks to the book – “For a long time I have been planning to write a book on the structure of molecules and crystals and the nature of the chemical bond” – give an indication of the extent to which this was a long-term objective for Pauling, despite his being only 38 years old.

Looking back at his process, Pauling’s application for a grant from the Carnegie Institute in February 1932 provides a more detailed affirmation of his ambitions. In it, Pauling relayed how his undergraduate research in crystal structures at Oregon Agricultural College between 1917 and 1922 had laid the foundation for his current work by bringing him into contact with contemporary questions in structural chemistry. As a graduate student at Caltech, Pauling began to search for answers to those questions in the newly developing field of quantum mechanics.

In pursuit of those answers, Pauling and his wife Ava Helen, with the support of a Guggenheim Fellowship, left their one-year-old son, Linus Jr., with Ava Helen’s mother in Portland and traveled to Europe in 1926 to study quantum mechanics at its source. There, Pauling deepened his understanding and immersed himself even more by beginning to apply the new physics directly to chemical bonding.

J. Holmes Sturdivant

Upon returning to Caltech in 1927, Pauling began to seek funding so he could continue what he had begun. Let down by the National Research Fund, Pauling supported his work with funding from Caltech and the National Research Council, money which allowed him to hire a full time assistant, J. Holmes Sturdivant, who focused on x-ray crystallography and continued to work with Pauling for many years. Pauling also brought aboard Boris Podolsky for nine months to assist him with the more detailed technical components of connecting quantum mechanics to chemical bonding.

In 1932 Pauling expressed a hope that, with help from the Carnegie Institute, he could expand his work by funding more assistants and purchasing equipment like an “electric calculating machine,” a “specialized ionization spectrometer,” and a microphotometer. The Carnegie Institute was not interested. Luckily for Pauling, the Rockefeller Foundation came through with a general grant of $20,000 per year over two years, to be split between the physics and chemistry departments at Caltech. This allowed Pauling to keep Sturdivant on staff while adding George Wheland, Jack Sherman, and E. Bright Wilson, Jr. to his research team.

This scramble to secure funding and bring new people into the lab came amidst the publication of Pauling’s first four “Nature of the Chemical Bond” articles for the Journal of the American Chemical Society, proof positive that Pauling’s work was bearing fruit. Once the funding was secured and Sherman and Wheland began producing results, Pauling wrote – with Sherman and Wheland as co-authors – three more “Nature of the Chemical Bond” articles the following year, published in the newly established Journal of Chemical Physics. Wheland also worked with Pauling on a monograph discussing the application of quantum mechanics to organic molecules. Wheland finished his part of the book by 1937, but Pauling never got around to his portion: his desire to write a book length treatment of chemical bonds began, more and more, to take center stage.

Warren Weaver

In order to keep the funding coming in through the lean years of the Great Depression, Pauling was compelled to follow the lead of his patrons, the Rockefeller Foundation. Warren Weaver, Director of Natural Sciences for the foundation, told Pauling in December 1933 that the organization was “operating under severe restrictions” and that funding would go to projects “concentrated upon certain fields of fundamental quantitative biology.” That Pauling’s work had “developed to the point where it promises applications to the study of chlorophyll, haemoglobin and other substances of basic biological importance” was key to his potential receipt of continued dollars.

The commitment of Caltech’s chemistry department to continue pursuing the line of research suggested by Weaver helped Pauling to secure funding for the following year. A three-year commitment came after that, providing the Caltech group with a reliable source of support into 1938. Pauling thanked Weaver in February of that year for his direction, writing,

I am of course aware of the fact that our plans for organic chemistry not only have been developed with the aid of your continued advice but also are based on your initial suggestion and encouragement; and I can forsee that I shall be indebted to you also for the opportunity of carrying out on my own scientific work in the future to as great an extent as I have been during the past six years.

Secure funding allowed Pauling to maintain a research group consisting of graduate students and post-doctoral fellows. In his preface to The Nature of the Chemical Bond, Pauling expressed his gratitude to several of these individuals, including Sherman and Sturdivant. Another, Sidney Weinbaum, earned his doctorate under Pauling and continued on afterwards, helping Pauling with quantum mechanical calculations and molecular structures.

Fred Stitt worked as research fellow with Pauling and assisted him in teaching his graduate course on the applications of quantum mechanics to chemistry – an exercise, no doubt, that helped to shape Pauling’s own thoughts on the subject, crystallizing them in preparation for the book.

Charles Coryell and Linus Pauling, 1935.

Charles Coryell and Linus Pauling, 1935.

Charles Coryell worked as a research fellow at the Caltech lab with Pauling on the topic of magnetic susceptibilities, which were central to investigating chemical bonds.  (Coryell also later helped Pauling to construct a magnet for the Caltech labs, based on one already in place at Cornell.)

Edwin H. Buchman, according to a 1985 oral history interview, was self-supporting due to royalties from his synthesis of vitamin B1. Buchman told Pauling in May 1937 that he would assist Pauling “on any problem in which an organic chemist could be useful and for which extra space could be had.”

Once assembled, Pauling’s team helped him to refine his understanding of chemical structures and bonding as the time approached when he could produce a book-length treatment on the subject.

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Pauling’s First Hemoglobin Publications: Understanding Oxygen Binding

Pastel drawing of the hemoglobin structure, by Roger Hayward. 1964.

“You know, hemoglobin is a wonderful substance. I like it. It’s a red substance that brings color into the cheeks of girls, and in the course of my hemoglobin investigation I look about a good bit to appreciate it.”

– Linus Pauling, March 30, 1966

Seventy-five years ago, in 1935, Linus Pauling began publishing his research on the protein hemoglobin with a set of papers titled “The oxygen equilibrium of hemoglobin and its structural interpretation” appearing in Science and the Proceedings of the National Academy of Science .

In the fall Pauling extended this work and began collaborating with newly minted Caltech Ph. D. Charles Coryell, on the problem of the binding of oxygen to hemoglobin in the formation of the compound oxyhemoglobin. In April 1936, the duo published a paper specifically devoted to the subject, “The magnetic properties and structure of hemoglobin, oxyhemoglobin, and carbonmonoxyhemoglobin,” an important article which appeared in PNAS.

In order to better understand this early hemoglobin work, it is important to first discuss some of the basics of the hemoglobin molecule. Hemoglobin is a major protein component in the cytoplasm of red blood cells, and is made up of two distinct parts – the heme and the globin. Its primary function is to facilitate gas exchange: it picks up oxygen in the lungs, carries it to the tissues, and returns to the lungs in order to expel the carbon dioxide produced in the tissues.

There are four hemes per hemoglobin molecule, and each is made up of a single iron atom surrounded by a porphyrin ring. Each heme has the ability to bind to a single oxygen dimer, therein giving hemoglobin the capacity to bond with four molecules of O2. The globin is the main protein component of the molecule. Carbon dioxide, rather than competing with oxygen for a binding site at the heme, instead binds to the globin.

Charles Coryell and Linus Pauling. 1935.

In their 1936 paper, Pauling and Coryell tackled the question of how oxygen binds to hemoglobin by looking at the molecule’s magnetic behavior, using an experiment involving bovine blood and magnets.  In a 1976 interview, Pauling provided this description of their experimental design.

It occurred to me that the same magnetic methods that we had been using to study simple compounds of iron, in order to determine the bond type, could be used to study the hemoglobin molecule. One of my students, Charles Coryell, and I, then got some blood, cattle blood, and put it into an apparatus. It consisted of a balance, which we had fitted out in such a way that a wire was suspended from one arm of the balance through a hole in the base of the cabinet, and held a tube. This tube was placed between the poles of an electromagnet. We filled it with blood, oxygenated blood, and balanced it to measure its weight. Then we passed an electric current through the coils of wire and the apparent weight changed.

From the experimental results, the pair found that oxyhemoglobin contains no unpaired electrons, although free oxygen molecules contain two, and each heme contains four. This was something of a surprise as, quoting from the paper,  “It might well have been expected, in view of the ease with which oxygen is attached to and detached from hemoglobin, that the oxygen molecule in oxyhemoglobin would retain these pair of electrons.”

In spite of this possibly more intuitive expectation, Pauling had earlier theorized that oxygen binds to hemoglobin covalently, a prediction which the experiment confirmed. Indeed, it was found that “the oxygen molecule undergoes a profound change in electronic structure on combination with hemoglobin,” and binds to the iron atom in the heme covalently.

Pastel drawing of Hemoglobin at 100 angstroms, 1964.

This was, however, only one of the striking discoveries that surfaced out of this research.  In a deoxygenated hemoglobin molecule, the bonds between iron and the four porphyrin nitrogen atoms surrounding it are ionic. Nonetheless, upon the binding of oxygen, these bonds become covalent, a rather dramatic change. Pauling and Coryell were keen to point this out:

It is interesting and surprising that the hemoglobin molecule undergoes such an extreme structural change on the addition of oxygen. Such a difference in bond type in very closely related substances has been observed so far only in hemoglobin derivatives.

Clearly something of consequence was being observed.  In their conclusion, the authors noted as much.

It is not yet possible to discuss the significance of these structural differences in detail, but they are without doubt closely related to and in a sense responsible for the characteristic properties of hemoglobin.

Linus Pauling’s work with hemoglobin continued on and off until his death in 1994, and led to a number of important discoveries – most prominent among them the molecular basis of sickle cell anemia. For more information on Linus Pauling’s hemoglobin research, please visit the website It’s in the Blood! A Documentary History of Linus Pauling, Hemoglobin, and Sickle Cell Anemia.