[Introductory remarks by Crellin Pauling]

William N. Lipscomb: The history of science is marked with milestone discoveries made by individuals whose genius and vision have transformed our understanding of nature. Linus Pauling was one such individual. His work spanned and stretched the frontiers between traditional disciplines -- chemistry and areas of physics, mineralogy and biology -- and opened up whole new areas of research for later generations of scientists.

Complex Ionic Crystals

An example of Pauling's work in bridging disciplines is the development of the rules for the stability of complex ionic crystals (Pauling 1928a). His early interest in minerals (1913), chemistry (1914), and metals and intermetallic compounds (1920) became focused on X-ray diffraction studies of mineral structures in 1922 under the tutelage of Roscoe Gilkey Dickinson (Pauling 1992a; Pauling 1992b; Dickenson and Pauling 1923). By 1928 the structures of many simple salts, most of the elements and a very few complex compounds were established by Pauling and others. However, progress on complex structures was very slow, and attempts by others to select among stable proposed structures by theoretical methods failed. There was need for a new idea. Pauling remarked in 1928, "complex crystals are of great interest, and it is desirable that structure determinations be carried out for them even at the sacrifice of rigor."¹ The method was to find a way to imagine and build models of plausible structures and to test the agreement between calculated and observed X-ray diffraction intensities. Essentially complete agreement was expected for the correct structure.²

Starting from the additivity of ionic radii in various compounds (Bragg 1920; Wasastjema 1923; Bragg 1937), and the consistent grouping of the larger anions around the smaller cations in simple, nearly regular polyhedra in many structures, Pauling proposed a set of five rules for structures of complex minerals and inorganic crystals. In order to formulate the most important of these rules, Pauling defined the strength of the electrostatic bond as the absolute value of the electrostatic charge divided by the number of close neighbors. This rule, the electrostatic valency principle, states that the valency of each anion is equal to the sum of the strengths of electrostatic bonds from these adjacent neighboring cations. One can visualize that the electrostatic lines of force which emanate from one ion end on the immediate neighbors. This is a kind of local electro- neutrality principle for structures in which the bonds are fairly ionic to largely ionic.

W.L. Bragg calls this rule the cardinal principle of mineral chemistry, and describes how it limits severely the number of plausible structures of crystals.³ For example, in a silicate where the Si⁺⁴ is tetrahedrally surrounded by four O^-2's the Si⁺⁴ contributes 1 (units of e) to each oxygen. For Al⁺³ in an octahedral AlO₆^-9 group each Al⁺³ contributes ½ to each oxygen, while Mg⁺² in an octahedral group contributes ⅓. Therefore, the oxygen at a vertex of an SiO₄^-4 will link to one silicon tetrahedron (to give Si₂O₇^-6), or to two Al octahedra or to three Mg octahedra. This rule, and the composition of the crystal, leave few alternative crystal structures. In structures in which the proportion of highly charged ions like Si⁺⁴ is less or absent in favor of less highly positive ions there is an increasing tendency for the polyhedra to share an edge or a face rather than a corner, as one might expect from electrostatic principles.

We used the electrostatic valency rules to check the correctness of the structure of a tetragonal basic iron phosphate (later to be named lipscombite). These rules were especially useful in proposing reasonable positions for the protons of the OH groups (Katz and Lipscomb 1951).

The Atomic Electroneutrality Principle

Pauling accepted my proposal to transfer from Physics to Chemistry in early 1941 and found a desk for me in the basement of Crellin Laboratories. I had been reading the 1940 edition of The Nature of the Chemical Bond, and was puzzled by the discussion of resonance contributors to bonding in CO. When Pauling stopped by, I told him that when I used the force constant for the :^-C=O⁺: and for the :⁺C-O^-: structures, the formal charges greatly shorten these bond contributions to the hybrid which also includes the :C=O: structure. He said, "Yes, Bill, that's why I didn't do it that way," and then he walked out! I had already noticed in Pauling's 1940 book (Pauling 1940a) that the formal charge corrections to the appropriate atomic radii were comparatively small, but I was still unprepared for this lesson in chemistry. Soon thereafter, in 1942, I realized that these full formal charges are not appropriate. Jurg Waser analyzes this problem as follows (Waser 1968). The electronegativity difference of 1.0 between C and O means an ionic contribution of only 22% per bond (Pauling 1960), so that the + charge in the :^-C=O⁺: structure is reduced to 0.34 units of e. Furthermore, the :C=O: structure, which leaves carbon electron poor, gives a formal charge of -0.44 (i.e., -2 x 0.22) for oxygen, and the approximately equal contribution of these two structures, neglecting the less probable third structure, leaves the C and O atoms approximately charge neutral in the hybrid, and is consistent with the very short bond distance of 1.13 Å.

In 1948 (Pauling 1948a) Pauling formulated the "postulate of the essential electroneutrality of atoms: namely, that the electronic structure of substances is such as to cause each atom to have essentially zero resultant electrical charge, the amount of leeway being not greater than about ±½. These resultant charges are possessed mainly by the most electropositive and electronegative atoms, and are distributed in such a way as to correspond to electrostatic stability." By that time I had left Caltech to teach at the University of Minnesota, but Eddie Hughes reported to me that the following exchange took place in Pauling's presentation of the electroneutrality principle:

Student: "Can you derive the principle?"
Pauling: "No. There is no derivation."
Student: "Then how did you arrive at this principle?"
Pauling: "I made it up."

Pauling's ideas were created from a detailed knowledge of vast amounts of the chemical (and physical) literature, from his mastery of areas of physics and chemistry especially relating to quantum mechanics and electrostatics, and from the rapidly expanding area of crystal and molecular structures. It is characteristic of Pauling's ideas that they correlated a large body of chemical structures and properties, as illustrated by the many examples in his paper of 1948 (Pauling 1948a).

Covalency

The empirical rules for the electron pair bond between atoms in molecules, formulated by Gilbert N. Lewis in 1916 (Lewis 1916; Lewis 1923) had to await discoveries in wave mechanics before they could be understood in physical terms. For H₂⁺, Burrau (Burrau 1927) gave an "exact" solution, and for the simplest molecule, H₂, Heitler and London (Heitler and London 1927) made a linear superposition of the 1s_A(l) 1s_B(2) + 1s_A(2) 1s_B(l) wave functions, called the valence bond approximation. The discovery of the molecular orbital method followed almost immediately (Hund 1928; Mulliken 1928). However, the solution of the equations for complex molecules, and their importance to chemistry was not readily accessible. Nevertheless, as early as 1928 Pauling (Pauling 1928b) introduced the concepts of hybrid bond orbitals which have directional character, based upon changes in the quantization within the L-shell of first raw elements caused by formation of chemical bonds. Thus, he showed how the hybridization phenomenon could explain the tetrahedral bonds about carbon, and interpret molecular geometries previously thought to be anomalous.

Pauling's own account of his early progress reveals a uniquely chemical approach. He writes in a statement dated August 6, 1979 as follows:

"During my early years as a scientist, beginning in 1919, I had a special interest in the problem of the nature of the chemical bond; that is, the nature of the forces that hold atoms together in molecules, crystals, and other substances. Much of my work during this early period was directed toward a solution of this problem, by application of both experimental and theoretical methods. As soon as quantum mechanics was discovered, in 1925, I began striving to apply this powerful theory to the problem. I published several theoretical papers in this field during the next few years, without, however, having been able to answer a number of important questions. Then one evening, in December, 1930, while I was sitting at my desk in my study at our home on Arden Road and California Street in Pasadena, California, I had an idea about a way to simplify the quantum-mechanical equations in such a manner as to permit their easy approximate solution. I was so excited about this idea that I stayed up most of the night, applying the idea to various problems."

The result was the remarkable and seminal paper which Pauling published in 1931 (Pauling 1931), in which he established for the first time the role of hybrid bond orbitals in determining the geometrical structures of simple and complex molecules. Thus, if one s eigenfunction (orbital) and three p eigenfunctions are available on an atom, the most stable bond configuration is tetrahedral. This result leads naturally to essentially free rotation about single bonds, and to no free rotation about a double bond. Similarly, if one d, one s and two p eigenfunctions are available, as in bivalent Ni, Pd or Pt, four bonds directed toward the corners of a square can be formed. Two d, one s and three d eigenfunctions form six bonds directed toward the vertices of an octahedron. Furthermore, the magnetic properties of many transition metal complexes allow the assignment of eigenfunctions directly involved in formation of chemical bonds. The concept of bond types intermediate between covalent and ionic was also established.

Pauling's paper of 1931 (Pauling 1931) changed chemistry. It was followed by several more publications and the three editions of The Nature of the Chemical Bond. A new focus was established: the relationship of geometrical and electronic structure to chemical and physical properties of molecules and their reactions. This first detailed paper, following a preliminary account in 1928 also by Pauling, made it clear that chemists had to assimilate and further develop the then new developments in quantum mechanics. The following papers, II-VII, of The Nature of the Chemical Bond series appeared in 1931-1933, and formed the basis of the three editions of his book which dominated this area of chemistry for many decades. Nevertheless, Pauling himself felt that the first paper of 1931 (Pauling 1931) "might well be considered the most important part of the work" for which he was awarded the Nobel Prize in 1954.

Hemoglobin

Shortly after Pauling's two-constant treatment of the oxygen uptake curve in hemoglobin (Pauling 1935), he and Charles Coryell showed that the uptake of oxygen changed the state of the iron from paramagnetic to diamagnetic (Pauling and Coryell 1936a; Pauling and Coryell 1936b). These and subsequent studies indicated a direct interaction between oxygen and the ferrous ions. Pauling's entrance into biochemistry was then followed by a study of methemoglobin (Coryell, Stitt, and Pauling 1937), in which the number of unpaired electrons was five for Fe⁺³ in the unligated, OH^- ligated or F^- ligated in methemoglobin, and one for the more strongly interacting CN^- and SH^- ions. The clear connection to the important 1931 paper (Pauling 1931) on relations of magnetic properties as an interaction of bond types is evident from these studies.

The α-helix and β-sheet Structures

Planarity (near-planarity) of the amide group was a logical consequence of the two resonance structures for amides proposed by Pauling in 1932 (Pauling 1932). Although helical configurations for a polypeptide chain were proposed by Huggins (Huggins 1943) and by Bragg, Kendrew and Perutz (Bragg, Kendrew and Perutz 1950), these proposed structures did not have planar peptide units, and they were based upon the assumption of an integral number of amino acid residues per turn. Besides assuming peptide planarity, Pauling relied on structural principles obtained from X-ray diffraction studies, mostly at Caltech, on amino acids, small peptides and related compounds, and in March 1948⁴ constructed a helical model in which there are 3.7 amino acids per turn, and hydrogen bonds N -- H^...O -- C along the direction of the axis of the helix.⁵ (See Figure 1.) Following a preliminary note (Pauling and Corey 1950), this structure and a more open one which has 5.1 amino acids per turn were published in 1951 in a remarkable series of eight papers (Pauling, Corey, and Branson 1951; Pauling and Corey 1951a-g). John Edsall has commented that "the formulation of the α-helix seems to me to be one of the great creative triumphs of thinking in the field of protein chemistry."

Experimental support (Perutz 1951) for the α-helix in several fibrous proteins was immediately forthcoming in the discovery of the 1.5 Å diffraction spacing. This diffraction arises from the amino acid repeat projected on the axis of the α-helix. Later studies show that the α-helix makes up some one-third of the secondary structure of globular proteins, although the variation is large, from 0% to about 85% in specific examples. In his Nobel Lecture of 1954, Pauling comments optimistically on the use of models based upon precise stereochemistry from small molecules, and the new ideas of structural chemistry:

"We may, I believe, anticipate that the chemist of the future who is interested in the structure of protein, nucleic acids, polysaccharide, and other complex substances with high molecular weight will come to rely upon a new structural chemistry, involving precise geometrical relationships among the atoms in the molecules and the rigorous application of the new structural principles, and that great progress will be made, through this technique, in the attack, by chemical methods, on the problems of biology and medicine."

Complementary Structures: Antibodies, Enzyme Catalysis

In 1940 Pauling asked (Pauling 1940b), "What is the simplest structure which can be suggested, on the basis of the extensive information now available about intramolecular and intermolecular forces, for a molecule with the properties observed for antibodies, and what is the simplest reasonable process of formation of such a molecule?" In that same year Pauling and Delbrück (Pauling and Delbrück 1940) expressed the idea of complementarity:

"It is our opinion that the process of synthesis and folding of highly complex molecules in the living cell involve, in addition to covalent bond formation, only the intermolecular interactions of the van der Waals attraction and repulsion, electrostatic interactions, hydrogen-bond formation, etc., which are now rather well understood. These interactions are such as to give stability to a system of two molecules with complementary structures in juxtaposition, rather than of two molecules with necessarily identical structures; we accordingly feel that complementariness should be given primary consideration in the discussion of the specific attraction between molecules and the enzymatic synthesis of molecules."

The many studies (including those of Dan H. Campbell and David Pressman) of hapten-antibody reactions, stimulated by these ideas and by conversations with Karl Landsteiner from 1936 to 1939 (Pauling 1948b), placed immunological specificity on a firm chemical basis. Pauling proposed that this specificity arose when folding of the polypeptide chain of an antibody precursor occurs in such a way that a region of the antibody was complementary to the antigen. However, the formation of antibodies in such a way as to be complementary to an antigen was shown many years later to be a complex clonal selection process, involving molecular recognition, somatic recombination of gene segments and somatic hypermutation during B cell differentiation (Tonegawa 1983; Tonegawa 1987). Nature evolved such a process in order to produce and refine the enormous diversity and specificity of the antigen-antibody response. Nevertheless, Foote and Milstein have very recently shown (Foote and Milstein 1994) that some antibodies show complex kinetics of hapten binding involving an equilibrium between at least two conformations such that certain ligands bind preferentially to one of these conformations.

The idea of complementarity of structures also was applied to the transition state of an enzyme-substrate reaction. Emil Fischer's 1894 lock (enzyme) and key (substrate) model (Fischer 1894) was modified by J. B. S. Haldane: "using Fischer's lock and key simile, the key does not fit the lock perfectly, but exercises a certain strain on it" (Haldane 1965). In 1948 Pauling (Pauling 1948b; Pauling 1948c) became much more precise in terms of transition state theory: "I think that enzymes are molecules that are complementary in structure to the activated complexes of the reactions that they catalyze" (Pauling 1948c). At that time Pauling and Carl Niemann began some quantitative studies using inhibitors that mimic the transition state (Pauling 1946). This area of design of such inhibitors became a very substantial field in later studies by R. Wolfenden (Wolfenden 1972; Wolfenden 1976), G.E. Lienhard (Lienhard 1973), and many others. The availability of three-dimensional structures of many enzymes has made this a very active field for rational design of inhibitors for enzymes and binding proteins.⁶

Francis Crick (Crick 1992) writes of the remarkable influence Pauling had on the elucidation of the Watson-Crick DNA structure. "It was because of Linus Pauling that our approach to the structural side of things had the character that it had, and it was successful because he had the right set of ideas."

Molecular Biology

Francis Crick continues, "So we should salute Linus Pauling not only for the wonderful things that he has done for chemistry, and in particular his realizing the importance of quantum mechanics for chemistry and applying it as a chemist (as opposed to just a theorist), but also for his absolute seminal role in getting molecular biology started."

A major early contribution to molecular biology was Pauling's identification of sickle-cell anemia as a molecular disease. He became interested in this problem during a lecture in 1945 by William B. Castle of the Harvard Medical School. This anemia is caused when abnormal hemoglobin molecules within the erythrocyte aggregate at low oxygen pressures. Pauling, Itano, Singer and Wells (Pauling, Itano, Singer, and Wells 1949) showed in 1949 that the hemoglobins from normal cells and sickle-cells had different mobilities. They further suggested that the numbers of acidic or basic groups were different in these two types of hemoglobin molecules, and that these differences favored the aggregation of the abnormal hemoglobin. The specific chemical difference was a mutation (Ingram 1956) of Glu 6 of the β-chains to Val in the sickle-cell hemoglobin. This mutation enlarged a hydrophobic patch, which developed intermolecular contacts in the aggregation process.

The "evolutionary clock" was an important contribution to molecular biology in which Zuckerkandl and Pauling (Zuckerkandl and Pauling 1962; Zuckerkandl and Pauling 1965a; Zuckerkandl and Pauling 1965b) suggested that mutations accumulate at an approximately constant rate for each protein during evolution. Comparison of protein sequences or DNA sequences for different species provides a way of establishing times of divergence among species. Surely the enormous amount of molecular data produced in subsequent years and therefore not available to Darwin and Wallace reinforces evolutionary relationships (Dickerson and Geis 1983) beyond any reasonable doubt.

Linus and Me

Pauling's influence was crucial to my own development as a scientist. In order to provide a background let me make a few autobiographical remarks. From an early age I was fascinated by astronomy and minerals, and after receiving a chemistry set as a gift at age eleven, I maintained a home laboratory through my high school years. At the University of Kentucky which I attended on a music scholarship, I read Dushman's Quantum Mechanics in my spare time and completed requirements for majors in both Chemistry and Physics. An appointment to graduate study in Physics at Caltech, at $20/month, allowed me to refuse Northwestern's offer of $150 as research assistant, and also allowed me to come to terms with a nice letter from H. C. Urey rejecting my application to Columbia University. I planned to study Quantum Mechanics with William V. Houston, but the influence of Linus Pauling led me to switch to Chemistry; and then World War II intervened in December 1941. For just over three years I worked full time on war projects: the analysis of smokes according to particle size, with J. H. Sturdivant, and on burning rates of nitroglycerine-nitrocellulose propellants which I prepared while handling beakers containing pure nitroglycerine.

Because I expressed an interest in structural chemistry, Pauling outlined a Ph. D. program in electron diffraction of gas molecules, X-ray diffraction and magnetic anisotropy of aromatic molecules in crystals. I began this program in my spare time, mostly evenings; the electron diffraction studies were on VCl₄, chloroethylenes, dimethylketene dimer and diketene (with Verner Schomaker), and the X-ray diffraction studies on CH₃NH₃⁺Cl^- and on α-glycylglycine (which I did not finish) were done with Edward W. Hughes. Pauling would stop by for a half-hour chat about every three months, and would suggest many new ideas that had not occurred to me. I did find time to go every year to the lectures on the Chemical Bond course, because the lectures were new from year to year, and I attended his course in Quantum Mechanics ("I guess I'll give the course," he once said; "I can give the lectures in my sleep. Perhaps I have!"). His illness from nephritis and his frequent trips meant that we did not see him very often, but he and his family did occasionally attend the Caltech Chemists games of (intermediate⁷) baseball in the local league.

In addition to the subject matter, I learned many important things from Pauling. For example, it is much better to risk an occasional error in interesting and original research, than to be always right in less original or more prosaic studies. I also learned how to choose important research areas, how to bring different areas together, how to use the stochastic method, and the importance of extensive background knowledge ("It's what you know that counts") and imagination ("Have lots of ideas and throw away the bad ones").

Pauling was a wonderful lecturer. Occasionally he would sit or lie down on the lecture desk "to improve the circulation in my brain." The first third of a talk was easy for everyone, the second third was real substance and often original, and the last third challenged the audience. Most teachers tell you what is known. Pauling would frequently outline whole areas of new research, for example, developing valence and bonding principles for intermetallic compounds, a favorite topic for most of his life. I found the lectures on boron hydrides especially puzzling, because Pauling's resonance structures involving formally paired one electron bonds had no predictive value: they are compatible with a variety of structures for a given formula. Moreover, the geometrical structures on which he relied for B₂H₆, B₄H₁₀, B₅H₉, and B₅H₁₁ as determined by S. H. Bauer were incorrect, although this fact was not known in the mid-1940s. Based upon the B₆ octahedron in the crystal structure of CaB₆, Pauling actually suggested to Bauer that the B₅ arrangement in B₅H₉ would be a tetragonal pyramid. However, Bauer decided that this arrangement was incorrect.

In my application for an NRC fellowship in 1946, later withdrawn so that I could accept a position at the University of Minnesota, I proposed a series of low temperature structure determinations on several hydrogen-bonded crystals which showed residual entropy problems, and then a series of single crystal studies of the boron hydrides. I am sure that Pauling wrote a strong letter of support, although he told me privately that he did not think that my proposed research was very interesting.

Our single crystal studies of B₅H₉, and B₄H₁₀ and B₅H₁₁ established the structures unambiguously, consistent with independent electron diffraction studies by Hedberg, Jones and Schomaker who also deduced these structures, although not unambiguously (Lipscomb 1954). These molecules then formed the basis of a valence theory using three-center and two-center bonds (Eberhardt, Crawford, and Lipscomb 1954). Whereas the boron atoms showed tetrahedral bonds, especially as directed toward terminal BH or bridge BHB hydrogens, the bonds toward the framework of boron atoms were not consistently directed along the BB internuclear directions. This result, obtained from molecular orbital calculations, was inconsistent with Pauling's criteria for specifying bonds from hybrid orbitals which are directed along internuclear directions. Our later calculations using full molecular orbital methods in which the results were converted into objectively localized bonds lent support to our interpretation of framework three-center bonds. These studies allowed the prediction of a number of new boron species and an interpretation of much of the transformation chemistry of the boron hydrides. Moreover, the studies were a departure from Pauling's single-bond resonance descriptions toward a molecular-orbital based description. When I asked Pauling why he did not use molecular orbital and group theory, he replied that he felt that chemists would not understand either the results or the methods (Pauling 1980). If these remarks seem critical, the reader is reminded that Pauling clearly recognized the boron hydrides as an interesting research area at an early time, before our studies, and before the early molecular orbital studies of H. Christopher Longuet-Higgins and M. de V. Roberts on octahedral B₆H₆^-2 and icosahedral B₁₂H₁₂^-2.

When I came to Harvard University in 1959, I conceived of programming the molecular orbital method for all valence electrons in the hope of filling the gap between the curly arrows of the resonance description and the more exact methods then largely inapplicable to even moderately complex molecules. The method was, of course, to be approximate, but applicable to any molecule. I spoke to Roald Hoffmann in the spring of 1959, but he decided to do research with Martin Gouterman, and to spend a year in Russia studying with A. S. Davydov. So I gave the problem to L. L. Lohr, Jr., who was interested in transition metal compounds and who started to write a program involving s, p, and d orbitals. When Roald returned, he decided to join my research group. His version of the program involved only s and p orbitals. These programs, later called the extended Hückel method, were readily applicable to compounds throughout the periodic table. The immediate applications were to the boranes and carboranes where structure, charges, rearrangements and reactivity were studied (Hoffman and Lipscomb 1962a-c). Roald Hoffmann made extensive use of the method in his later studies of concerted reactions of organic compounds (Woodward-Hoffmann rules) and interacting fragments in inorganic and organometallic chemistry (Hoffman 1982). And so I moved away from Pauling's early valence bond descriptions to molecular orbitals and back to new kinds of localized bonds in boron chemistry. Roald moved, under the influence of E. J. Corey and R. B. Woodward from electron deficient molecules to organic and metalloorganic areas. Nevertheless, we both followed Pauling's original commitment to the relationships between the structure and function of molecules.

What Might Have Been

At his eighty-fifth birthday celebration at Caltech in 1986, Pauling asked the question, "What would have happened if I had remained at Caltech?" He had resigned in 1963 (effective June 30, 1964) shortly after receiving the 1962 Nobel Prize for Peace, awarded in December of 1963. The publication of his book No More War! (Pauling 1958), and subsequent activities related to perceived genetic damage resulting from testing of nuclear weapons, led to his departure from Caltech.

The answer to Pauling's question is, of course, that no one knows. In a reminiscence on X-ray crystallography and the chemical bond, Pauling in 1992 comments on newer developments in X-ray crystallography (Pauling 1992a):

"The time required to determine an only moderately complicated structure has been decreased from years to perhaps an hour. A tremendous amount of information bearing on the question of the nature of the chemical bond has been obtained. I have followed this development with much interest, but also with considerable disappointment. The disappointment is the result of the fact that, so far as I have been able to see, the more recent investigations have not led to the discovery of new structural principles."

It seems to me that this statement does not take into account the tremendous impact of X-ray crystallography on principles of bonding in transition metal complexes, and on the structural principles beyond secondary structure into the tertiary and quaternary structures of proteins. Perhaps Caltech was slow about its commitment to the determination of protein structures following Bijvoet's description of the multiple isomorphous replacement method (Bokhoven, Schoone and Bijovet 1949; Bokhoven, Schoone, and Bijovet 1951), and the isomorphism of a heavy atom derivative of hemoglobin with the unmodified protein (Green, Ingram, and Perutz 1954). Even as late as 1959, the year of the low resolution structure of myoglobin, Pauling remained of the opinion that the determination of any protein structure would be extremely difficult.

On the other hand, Pauling continues in that same 1992 paper (Pauling 1992a),

"There is one branch of structural chemistry that needs further development. We still do not have a good theory of structural chemistry of metals and inter- metallic compounds, even though structure determinations have been made for 24,000 intermetallic compounds, representing about 4,000 distinct structures. There is still the possibility that some surprising discoveries will be made in this field."

Influenced by Pauling, I also commented in my Nobel lecture,

"My original intention in the late 1940s was to spend a few years understanding the boranes, and then to discover a systematic valence description of the vast numbers of "electron deficient" intermetallic compounds. I have made little progress toward this latter objective. Instead, the field of boron chemistry has grown enormously, and a systematic understanding of some of its complexities has now begun."

If one needs evidence of the undiminished power of Pauling's imagination in his later years, there is no better example than his proposal (Pauling 1992c) that quasicrystals are icosahedral twins of cubic crystallites, although the details are still incomplete. The apparent icosahedral symmetry of quasicrystals shows an apparent five-fold axial symmetry which is inconsistent with the translational symmetry of true crystals. Throughout his life Pauling took particular pleasure in solving problems on his own.

He also began and sponsored more general programs of research such as the very early use of IBM computers for data processing in diffraction studies, and structure determinations of amino acids and related compounds in order to elucidate structural principles. However, the intractability of the problem of folding of proteins has made it impossible so far to propose structures for globular proteins even though the structural elements of α-helix, β-sheet and reverse turns form the basis of most of these structures. Here, Pauling was too optimistic.

These long-term programs were clearly oriented toward structure and function. Indeed, during Pauling's chairmanship, the group of tenured members favored structural chemistry. However, the department participated inadequately in the enormous changes in syntheses of large organic molecules during the post-World War II period, and was slow to go beyond physical inorganic chemistry.

One wonders whether Pauling would have gone so far in his theories of anaesthesia, significant structure in atomic nuclei, vitamins, orthomolecular medicine and cancer if he had remained among his critics at Caltech. It is not so much that these ideas are wrong as that they are perhaps exaggerated or slightly displaced, possessing nonetheless some validity. For example, the correlations of anaesthetics and hydrophobicity (Pauling 1961) might be due to interactions with a region of a protein (Schoenborn and Nobles 1966), possibly a membrane protein, rather than with a hydrophobic region of a clathrate structure. Furthermore, Vitamin C (Pauling 1976) may be more effective as an antioxidant for cholesterol to reduce atherosclerotic plaques (Lehr, Frei, and Arfors 1994) and for delaying emphysema (Lehr, Frei, and Arfors 1994), and less effective for established cancers, or the common cold. Nevertheless, at >1 gm/day vitamin C reduces the duration of a cold by about one day (Hemil„ and Herman 1995), and reduces its severity by some 20-25% (Hemil„ 1994).

Finally, one has to admire the very close relationship of his proposed questionably static pictures (Pauling 1965) of significant structure in nuclei to the striking stochastic prediction of the correct structures of intermetallic compounds, for example Mg₃₂ (Al, Zn)₄₉ (Bergman, Waugh and Pauling 1952; Bergman, Waugh and Pauling 1957).

But it is too easy to criticize a truly original thinker as he grapples with concepts and truly important problems that most of his contemporaries have not even imagined. Let us remember the magnificent ideas and their influence on science, and his commitment to peace and its influence on humanity.

Pauling's Contributions to Peace

In 1952, one year after the publication of the helix and sheet structural proposals for proteins, Pauling was invited to be the principal speaker at a Discussion on the Structure of Proteins arranged by the Royal Society. Unfortunately, he could not attend: the State Department withdrew his passport because of his opposition to nuclear weapons. In 1955, along with seven well-respected physicists and the geneticist Hermann Muller, Pauling signed the manifesto against nuclear weapons which was drawn up by Albert Einstein and Bertrand Russell:

"There lies before us if we choose, continual progress in happiness, knowledge and wisdom. Shall we, instead, choose death, because we cannot forget our quarrels? We appeal, as human beings, to human beings: remember your humanity and forget the rest. If you can do so, the way lies open to a new paradise; if you cannot there lies before you the risk of universal death."

These events led to the first Pugwash Conference involving Western and Soviet scientists who proposed measures that would reduce the likelihood of nuclear war.

In 1958 Pauling's book No More War! was published, and he handed a petition signed by 9,235 scientists to the Secretary General of the United Nations, Dag Hammarskjöld,

" ... urging that an international agreement to stop the testing of nuclear weapons be made ... inasmuch as it is the scientists who have some measure of the complex factors involved in the problem, such as the magnitude of the genetic and somatic effects of the released radioactive materials."

A Few Stories

Few people at Caltech could match Edward Hughes for remembering and telling stories. Most of those that follow come from him, as I remember them; the first comes directly from his own writings (Hughes 1968).

In 1939, I was working on the structure of melamine (Hughes, 1941).

I was trying to fit the expected planar ring into the cell so that it would be about perpendicular to the direction, reported in the literature, for the vibration direction in the crystal for the smallest refractive index for light. Each successive Fourier projection synthesis based on these attempts produced what appeared to be a very good projection of the chair form of a saturated ring....

One day Professor Pauling visited my office and looked carefully at these drawings. On the way out he paused long enough to remark that it was very interesting but that he hoped I would have better judgment than to present that structure to the local seminar. Much later, after having abandoned the work for some months (because the structures would not refine properly to any kind of ring), a reinspection of the X-ray data alone suggested another orientation for the ring. A quick optical experiment showed that the published position for the acute bisectrix of melamine was off by something like 50˚. The actual position was almost exactly at the place suggested by the X-ray data, and there was no more trouble in getting a good intensity chart. I need hardly add that it yielded a planar aromatic ring as expected.

One day Pauling had deduced the structure of a mineral, and wanted an X-ray diffraction test. Impatient with the slow and methodical development of the X-ray equipment, he went to the darkroom, wrapped a film in black paper, attached it to a ring stand, measured the crystal-to-film distance with a plastic ruler, and then, after X-ray exposure, developed the film. Much later, Pauling wrote (Pauling 1992a), "I miss the old days, when nearly every problem in X-ray crystallography was a puzzle that could be solved only by much thinking."

Pauling became Chairman of Chemistry and Chemical Engineering at Caltech in 1936. He looked so young that Ava Helen suggested that he grow a beard. One day Pauling was walking in Los Angeles when a distinguished elderly gentleman stopped him to ask, "Of what cult are you the Swami?" Linus and the man then discovered a mutual interest in polyhedra.

It was on a transcontinental train that Linus and Ava Helen were riding when he decided to visit the train's barber for a haircut and to have the beard shaved off. Ever conscious of his image as seen by others, he returned to his seat by Ava Helen and pretended to make advances which sprained the eyebrows of several other passengers who were saying "Just wait til the guy with the beard comes back."

At my request, Pauling visited the University of Minnesota in about 1952. In the middle of his lecture he stopped suddenly and began banging the doors of the lecture desk, asking, "Bill, don't you have any structure models here?" He found it: a model of the new α-helix that he had placed there earlier in the day so that he could put on this moment of performance.

Linus was driving Crellin to kindergarten and asked, to engage his attention, "Crellin, how many days are there in September?" Silence. Pauling asked, "Crellin, did you hear me?" "Yes," said Crellin, and, after a pause, "I'm finking." Finally the answer came, "Sixty." Pauling asked, "How did you know that?" "Oh," Crellin replied, "I remembered the poem, Firty days, half September.'"

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