The History of Molecular Structure Determination ... - ACS Publications

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The History of Molecular Structure Determination Viewed through the Nobel Prizes William P. Jensen* Department of Chemistry, South Dakota State University, Brookings, SD 57007; *[email protected] Gus J. Palenik The Center for Molecular Structure, The University of Florida, Gainesville, FL 32611-7200 Il-Hwan Suh Department of Physics, Chungnam National University, Taejon, 305-764, Korea

At the turn of the 21st century scientists have grasped the importance of determining molecular structures, but the ground work began many years ago. The discoveries of the past one hundred years as viewed through the Nobel Prizes illustrate some of the consequences that these advances have had on society. The Nobel Prizes were made possible through the immense wealth created by Alfred Nobel’s discovery that the unstable, unpredictable tendency of nitroglycerine to explode could be tamed by absorption on diatomaceous earth. Nobel was so appalled by the destructive uses of dynamite that he established the award that bears his name. He bequeathed the equivalent of $9,000,000 and dictated that the “...interest on which shall be annually distributed in the form of prizes to those who, during the preceding year, shall have conferred the greatest benefit on mankind” (1). The first award was 150,800 Swedish Crowns and has grown over the years to the last award of 9,000,000 Swedish Crowns or about $1,000,000 (2). An interesting bit of irony in the Nobel story was that Nobel had heart trouble and his doctor prescribed nitroglycerin (3). Nobel refused because he did not believe that nitroglycerin was effective and was aware of the headaches that were associated with its use. In 1998 the Nobel Prize in Physiology or Medicine was awarded to R. F. Furchgott, L. J. Ignarro, and F. Murad for their discoveries concerning NO as a signal molecule, research that was started, in part, to understand the use of nitroglycerin in treating angina (4).

tight cardboard box. He observed that every time he pulsed cathode rays through the tube, a screen made of barium platinocyanide crystals would fluoresce. He postulated that the fluorescence was a result of the production of what he called X-rays, rays that were not yet understood. Subsequently, he produced the first “medical” X-ray when he immobilized his wife’s hand above a photographic plate in the path of the Xrays and obtained an image of the bones of her hand and a ring she was wearing (6). Most people are aware of the use of X-ray photography in dentistry and medicine; some may even remember being fitted for new shoes as children using X-rays to “see” our feet. That practice has been discontinued since exposure to X-rays should be minimized, even to the relatively insensitive areas of the human body such as the feet. Röntgen’s discovery eventually gave crystallographers a powerful tool to probe crystals, using X-rays as the light to “see” atoms. 1904 Nobel Prize in Physics Awarded to Max Theoder Felix von Laue

William Conrad Röntgen (Figure 1; ref 5) was awarded the first Nobel Prize in Physics in 1901 for his discovery of the remarkable electromagnetic rays called X-rays. In 1895 Röntgen, professor of physics at the University of Wurzburg, constructed a cathode ray tube and enclosed it in a light-

Max Theoder Felix von Laue of Germany (Figure 2) received the Nobel Prize in Physics in 1904 for the discovery that X-rays are diffracted from crystals. Five years prior to the award, von Laue had joined the research group headed by Röntgen, who was then at Munich University. von Laue’s important discovery allowed scientists to apply X-ray diffraction to simple compounds. A “Laue” photograph of a copper sulfate pentahydrate crystal in random orientation, taken by Friedrich and Knipping at the suggestion of von Laue, was one of the photographs shown at the Nobel presentation ceremony (Figure 3; ref 7 ). The chairman of the Nobel Committee for Physics of the Royal Swedish Academy of Sciences, G. Granqvist, stated in his Nobel presentation speech, “As a result of von Laue’s discovery of the diffraction of Xrays in crystals, proof was thus established that these light

Figure 1. William C. Röntgen.

Figure 2. Max T. F. von Laue.

1901 Nobel Prize in Physics Awarded to Conrad Röntgen

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Figure 3. Laue photographs of copper sulfate pentahydrate. Random orientation (left) and an aligned crystal photograph (right).

Figure 4. W. H. Bragg (left) and W. L. Bragg (right).

waves are of very small wavelengths. However, this discovery also resulted in the most important discoveries in the field of crystallography. It is now possible to determine the position of atoms in crystals and much important knowledge has been gained in this connection” (8). Max von Laue was a man of high moral character. He defended, even at the risk of reprimand or even personal injury, scientific views that were not approved by Hitler and the ruling National Socialist Party. When Albert Einstein resigned from the Berlin Academy and the vice-president of the Academy stated that this was no loss, von Laue was the only member of the Academy who protested (9).

Laboratories on the campus and the equipment he designed is on display in the nearby physics building. A drawback of Bragg’s diffractometer was that the diffraction data were measured point-by-point by hand, which was very time consuming. Eventually, instrument improvements produced the modern computer-controlled diffractometer where several thousand measurements can be made in a few hours. However, before these developments, most of the X-ray structural data were collected by film methods using instruments developed by K. Weissenberg (11), the Weissenberg camera, and M. Buerger (12), the precession camera. The Weissenberg and Buerger precession single-crystal cameras are still in use many years after their development. Using these film instruments, X-ray intensity data for a typical small molecule, 10–20 atoms, could be collected in 1–2 months. Although Weissenberg and Buerger never received Nobel Prizes, data collected with their instruments led to several prizes. Another serious limitation in X-ray crystallography was the so-called “phase problem” (13). While the intensity of an X-ray beam diffracted from a crystal at some angle to the direct X-ray beam can be measured, the phase of the wave is lost during the experiment. In order to determine the structure of a crystal, knowledge of the phase of the diffracted beam must be determined. For simple compounds such as NaCl, the correct structure is easily obtained. The data for crystalline NaCl (Table 1; ref 14 ) can be used to illustrate a number of points about X-ray diffraction. The hkl values are the Miller indices of the plane in the crystal. The strength of the interaction of an atom with X-rays depends on the scattering factor, fNa and fCl in Table 1, which is related to the number of electrons and therefore the atomic number. The contributions of Na and Cl to the structure amplitude, F(hkl), also depend on the positions of the atoms and can reinforce or reduce the amplitude. F(hkl) is proportional to the square root of the observed intensity. Usually the F(hkl) is calculated from the measured intensity and a scale factor, listed in Table 1 as k|Fobs|, and is compared with a calculated F(hkl), assuming a specific arrangement of atoms in the unit cell, Fcalc in Table 1. The case of NaCl is relatively simple since the positions of the ions are known and Fcalc is easily calculated and compared to k|Fobs|. In general the positions of the atoms or ions are not known and the determination of the structure would require computations far beyond the capabilities of even modern high speed supercomputers unless phase information were available. Many scientists sought ways to circumvent the phase problem or to solve structures directly. A. L. Patterson de-

1915 Nobel Prize in Physics Awarded to William Henry Bragg and William Lawrence Bragg William Henry Bragg and William Lawrence Bragg (Figure 4), a rare father and son team, won the Nobel Prize in Physics in 1915 for their analysis of crystal structures of simple compounds by means of X-ray diffraction. W. H. Bragg designed and built the first X-ray diffractometer that allowed the intensity of X-rays diffracted from a single crystal to be measured at various angles relative to the incident beam. The crystal structures of a number of simple salts were determined using this instrument. Bragg also derived the important relationship nλ = 2dsinθ, known as the Bragg equation where n is a positive integer, λ is the wavelength of the X-ray, d is the spacing between planes in the crystalline material, and θ is the angle of incidence of the X-ray beam. W. L. Bragg said “Because I was able to use my father’s spectrometer, which was so much more effective than the Laue photograph, I was able to establish the structure of a number of simple crystals (CaF2, ZnS, FeS2, CaCO3). Even these simple crystals had a profound influence on chemical ideas at that time because they showed that inorganic compounds were composed of a regular pattern of atoms (or ions as we would now term them) and not of molecules. I well remember how startlingly novel this conception appeared to current chemical thought; we were begged to discover that there was some association, however small, between pairs of atoms in sodium chloride” (10). The Braggs were unable to attend the 1915 Nobel Award ceremonies in Stockholm, Sweden because of travel restrictions as result of World War I (remember that the Lusitania was sunk in 1915 and 1916 saw the battle of Jutland). W. H. Bragg held a professorship at the University of Adelaide in Australia. Travelers to Adelaide can view the Bragg 754

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P (UVW ) =

1 V

2

∑ ∑ ∑ Fhkl2 cos 2π(hU h

k

+ kV + lW )

l

Figure 5. The Patterson function.

vised a possible solution when a chemical compound contained only one or two atoms (or ions) of much larger atomic number than all the other atoms in the compound (15). Patterson showed that the position of the “heavy atom” could be deduced using a special function that could be calculated directly from the intensities and would become known as a Patterson function or map (Figure 5). The position of the heavy atom could be used to calculate approximate phases and an electron density map that could be used to locate the positions of the “light atoms” in the structure. The so-called heavy atom derivatives would play an important part in determining the structure of organic molecules and lead to several Nobel Prizes. Although A. L. Patterson never received the Nobel Prize for his work, a yearly “Patterson Award” was established by the American Crystallographic Association and today is a highly coveted award. A Nobel Prize winner in science must have outstanding accomplishments, but unfortunately outstanding accomplishments do not necessarily insure this ultimate recognition. In the early days of crystallography the research was done by just a handful of scientists. In 1942, these scientists formed the American Society for X-ray and Electron Diffraction. Eight years later the organization was renamed The American Crystallographic Association (ACA) with 133 charter members. Membership had grown to 600 by the end of World War II, and by 2000 the ACA had about 2,200 members worldwide.

The Nobel Prize in Chemistry was awarded to Petrus (Peter) J. Debye (Figure 6) in 1936 “for his contributions to our knowledge of molecular structure through his investigations on dipole moments and the diffraction of X-rays and electrons in gases” (5). Dipole moments are now measured in Debye units, 3.34 × 1030 coulomb–meter, named in his honor. Debye believed that X-rays would be diffracted by gases, liquids, and noncrystalline solids. Debye, and his assistant Paul Sherrer, studied powdered lithium fluoride, composed of randomly oriented microcrystals. The results were spectacular. The diffraction pattern of sharp lines revealed the symmetry arrangement of the individual atoms in lithium fluoride. The Debye–Scherrer powder diffraction method proved to be general for all crystals. Use of the Debye– Scherrer camera became the standard method to record a diffraction pattern on film from a powder sample. The camera was used for many years until counters replaced traditional film methods. A review of the development of the powder diffraction technique was published recently and provides more details (16). These tools, together with refinements to the diffractometer first built by W. H. Bragg, have dramatically improved our understanding of materials at the molecular or nanometer level. 1937 Nobel Prize in Physics Awarded to Clinton J. Davisson and George P. Thomson In April 1927 C. J. Davisson and L. H. Germer published a preliminary report of low voltage electron scattering from the surface of a nickel crystal (17). This report was followed in June by a letter from G. P. Thomson and A. Reid

1936 Nobel Prize in Chemistry Awarded to Petrus (Peter) J. Debye A fascinating aspect of science is the number of times theory and experiment coalesce in two or more research groups to provide almost identical breakthroughs. The Nobel Prizes that were awarded in 1936 to Debye and in 1937 to Davisson and Thomson illustrate this point.

Figure 6. Peter J. Debye.

Table 1. Obser ved and Calculated Structure Factors for NaCl ∆F

hkl

fNa

fCl

Fcalc

k|Fobs|

200

8.69

12.76

78.81

76.93

1.88

400

6.09

8.68

42.06

42.55

-0.49

600

4.14

7.08

20.90

19.58

1.32

800

2.71

5.86

8.81

9.83

-1.02

220

7.64

10.56

61.43

59.96

1.46

440

4.27

7.29

23.44

22.64

0.80

660

2.52

5.56

7.01

9.02

᎑1.99

111

8.98

13.60

᎑17.34

18.30

᎑0.96

222

6.79

9.41

50.22

47.01

3.21

333

4.72

7.61

᎑6.52

7.22

0.70

444

3.30

6.51

14.16

15.35

᎑1.19

555

2.45

5.46

-2.45

1.80

0.65


755


Figure 7. Clinton Joseph Davisson (left) and George Paget Thomson (right).

Figure 8. Francis H. C. Crick (left), James D. Watson (center), and Maurice H. F. Wilkins (right).

(18) and another in December by G. P. Thomson (19) describing experiments with 4–60 kV electrons transmitted through thin foils. This was a remarkable coincidence of almost simultaneous discoveries of electron diffraction effects. Clinton J. Davisson and George P. Thomson (Figure 7) jointly received the Nobel Prize in Physics in 1937 for their experimental discovery of the electron diffraction by crystals. These two scientists came from very different backgrounds. Davisson was born in Bloomington, IL, attended Bloomington public schools, and required scholarship and other university assistance to complete his studies. He was employed at the precursor of the Bell Telephone Laboratories. In this industrial setting he devoted himself to the study of the theory of electron optics and applications of this theory to engineering problems. Davisson’s approach was to investigate the interaction of electron beams with the surfaces of metal crystals. Thomson was the son of the physicist J. J. Thomson, a Nobel laureate famous for determining the charge-to-mass ratio of the electron. G. P. Thomson went to school in Cambridge and eventually was appointed Professor of Natural Science at the University of Aberdeen (Scotland). Unlike Davisson, Thomson studied electron optics by investigating the results of passing electron beams through thin films and metal foils. In his acceptance speech at the 1937 Nobel ceremonies Davisson said, “Troubles, it is said, never come singly, and the trials of the physicists in the early years of this century give grounds for credence in the pessimistic saying. Not only had light, the perfect child of physics, been changed into a gnome with two heads—there was trouble with electrons” (20). Thomson was unable to attend the Nobel ceremonies because of ill health. In a later speech he said “I should be sorry to leave you with the impression that electron diffraction was of interest only to those concerned with the fundamentals of physics. It has important practical applications to the study of surface effects. You know how X-ray diffraction has made it possible to determine the arrangement of the atoms in a great variety of solids and even liquids. X-rays are very penetrating, and any structure peculiar to the surface of a body will be likely to be overlooked, for its effect is swamped in that of the mass of underlying material. Electrons only affect layers of a few atoms, or at most, tens of atoms in thickness, and so are eminently suited for the purpose” (21). These discoveries provided important tools to investigate surfaces of materials and hence the behavior of catalysts. Heterogeneous catalysis, a very important branch of science, has today spawned many advances, including the automobile

catalytic converter, without which many urbanized parts of the United States would be uninhabitable.

756

1962 Nobel Prize in Physiology or Medicine Awarded to Francis H. C. Crick, James D. Watson, and Maurice H. F. Wilkins Francis Harry Compton Crick, James Dewey Watson, and Maurice Hugh Frederick Wilkins (Figure 8) received the Nobel Prize in Physiology or Medicine in 1962 for their discoveries concerning the molecular structure of nucleic acids (Figure 9) and their significance for information transfer in living material. The not-always-nice struggles for this award are described in the book The Double Helix by James Watson (22). Watson gives credit to “Rosy” Franklin, the crystallographer who took the X-ray photographs of a new strand of DNA. The data from these photographs were ultimately used to prove the postulate of base pairing and the double helix structure that is so commonly accepted today (Figure 10; ref 23). Anne Sayre (24) in her book, Rosalind Franklin and DNA, highlights a vexing problem with Watson’s book in which he uses the “affectionate term” Rosy. This was a term Rosalind Franklin’s friends would never use to refer to her and no one would ever dare use in her presence. Anne Sayre argues that Franklin was equally deserving of the Nobel Prize. The situation was resolved, to some extent, by the untimely death of Franklin in 1958 and provisions in Nobel’s will that specify that the prize cannot be shared by more than three people and that the winner or winners of the prize must be living.

Figure 9. The double helix.



Figure 10. Rosalind Franklin’s photograph of DNA B. Figure 11. Max F. Perutz (left) and John Kendrew (right).

1962 Nobel Prize in Chemistry Awarded to John Kendrew and Max Ferdinand Perutz

1964 Nobel Prize in Chemistry Awarded to Dorothy Crowfoot Hodgkin

John Kendrew and Max Ferdinand Perutz (Figure 11) won the Nobel Prize in Chemistry in 1962 for their work on the X-ray structures of globular proteins. Kendrew was recognized for his efforts in unraveling the structure of myoglobin, a protein responsible for transporting oxygen in muscle tissue. Perutz won his portion of the award for unraveling the structure of hemoglobin, a protein responsible for transporting oxygen in the blood. Perutz, an Austrian by birth, came from a family whose wealth derived from the textile industry. His parents wanted him to seek a law degree and continue the family businesses. However, because of the teaching of an outstanding chemistry teacher, Perutz wished to pursue a career in chemistry. His parents sent him to England and financed his education there. As World War II developed, his parents lost their fortune and Perutz lost his financial support. In fact, he also suffered a six-month setback by being interned as a foreigner in Canada during the war. His future as a scholar was rescued by Nobelist W. Lawrence Bragg, who secured a Rockefeller Foundation grant for Perutz. The hemoglobin and myoglobin structures were solved using a crystallographic technique called isomorphous replacement, which was first applied to proteins by Perutz. He used sodium p-chloromercuribenzoate to attach two mercury atoms to the sulfur atoms in the two cysteine groups. A second heavy atom derivative was then prepared using silver ions. Data from these two crystals, along with additional data from a crystal of hemoglobin containing no heavy atom, were used to overcome the phase problem mentioned earlier (25). The classic papers describing this work were published in Nature (26, 27). Kendrew was three years junior to Perutz and had spent time serving in World War II with the British Air Ministry Research Establishment. He came to the Cambridge lab with Perutz as his graduate mentor and was assigned to work on the structure of myoglobin. This molecule was one-fourth the size of the hemoglobin molecule and was somewhat simpler to solve. Using the isomorphous replacement methods and pioneering computer-aided procedures, Kendrew was able to solve the structure of myoglobin two years before the solution of hemoglobin was obtained. Hemoglobin has approximately 4,800 atoms, excluding hydrogen, and, at that time, could only be solved by an exceptionally persistent scientist with a cadre of assistants.

Dorothy Crowfoot Hodgkin (Figure 12) received the Nobel Prize in Chemistry in 1962 for unraveling the structures of important biochemical substances, including penicillin (Figure 13) and vitamin B12 (28–30). Her passion for science and her extraordinary ability to recognize the need to solve certain structural problems set her above her contemporaries. The incredible efforts she contributed to the eventual structure solution of penicillin along with the technological advances she was able to utilize in the successful completion of the task are documented in the series Great Events from History II, Science and Technology (31). In addition a recent biography Dorothy Hodgkin: A Life has appeared (32). Her efforts led to the commercial synthesis of penicillin, freeing society from obtaining the compound from natural substances and reducing the price of penicillin to an affordable level. Sometimes the importance of a great discovery is not realized quickly: the solution of the penicillin structure was accomplished in the early 1940s but the first total synthesis would not be reported until 1964. The structure determination of penicillin was accomplished with the collaboration of many researchers in England and in the United States. The work was begun in 1942 and completed four years

Figure 12. Dorothy C. Hodgkins.

O C

NH

S

CH2

CH3 CH3

N O C

O

HO Figure 13. Structure of penicillin G.


757


Figure 14. William N. Lipscomb.

later and credit was given in large measure to the persistence and gifted intuition Hodgkin brought to the problem. The solution was accomplished by the use of electron density calculations employing an old IBM punch card machine located in an evacuated building. This was a novel approach and pioneered the wedding of crystallography and the computer. The structure of vitamin B12 was also accomplished in Hodgkin’s laboratory, but it required different skills and insight. By this time electronic computers had been developed and ultimately the structure of vitamin B12 was deduced with the help of the Mark I computer at Manchester, the Deuce computer at the National Physics Laboratory, and SWAC (National Bureau of Standards Western Automatic Computer) at UCLA in Los Angeles. Kenneth Trueblood at UCLA played a significant role in the refinement of the B12 structure process using SWAC, a computer having 256 words of high speed memory, each 36 bits long, and 8192 words of drum storage. A calculation of structure factors took about 2 hours of card punching and 6 hours of computing time, while a cycle of least-squares calculations took about 25 hours, which is very long by today’s standards. Vitamin B12 was the largest and most complex organic molecule to have its structure determined in complete detail at that time. Hodgkin, an extraordinarily gifted person, would go on to determine the structure of insulin. A postscript remains. There were Nobel Laureates on both sides of the family. Her husband’s cousin, Alan Hodgkin, shared the Nobel Prize in Physiology or Medicine in 1963 for work in the basic processes underlying the nervous mechanisms of control and the communication between nerve cells. 1976 Nobel Prize in Chemistry Awarded to William N. Lipscomb William N. Lipscomb (Figure 14) won the Nobel Prize in Chemistry in 1976 for his studies on the structure of boranes, providing new insight to chemical bonding. A representation of a B10H102⫺ ion taken from Lipscomb’s book, Boron Hydrides (35), is shown in Figure 15. The concept of a chemical bond requiring two electrons shared between two atoms was at that time deeply rooted in the minds of most chemists. By combining his abilities in crystallography, theoretical chemistry, and an uncanny ability to embrace new concepts, he proposed and made sense of three atom–two electron bonding. A quote from one of his papers indicates the extent to which he laid his reputation on the line, “We have even ventured a few predictions, knowing that if we must join the ranks of boron hydride predictors later proved wrong, we shall be in the best of company” (33). It is interesting to note that at the time of the award The Washington Post quoted 758

Figure 15. The B10H102⫺ ion.

Roald Hoffmann (a future Nobel Prize winner) as saying that he was surprised that Lipscomb was recognized for his work on boranes rather than for his important X-ray studies on the structures of proteins that he had been performing for the previous nine years (34). One of this paper’s authors (WPJ) had the privilege of being a student in a physical chemistry class taught by Professor Lipscomb. It was abundantly clear that this instructor was a uniquely gifted person and that I had better rise to the occasion and learn thermodynamics to an extent to which I had not previously expected or perhaps even wanted to do. Lipscomb was also an accomplished clarinetist and inspired me to attend my one and only clarinet performance. 1982 Nobel Prize in Chemistry Awarded to Aaron Klug Aaron Klug (Figure 16) was awarded the Nobel Prize in Chemistry in 1982 for his development of crystallographic electron microscopy and his structural elucidation of biologically important nucleic acid–protein complexes. However, his career started inauspiciously when one of his first structure determinations (36), carried out at the University of Cape Town, was suggested to be (37) and was later shown to be incorrect (38). Klug had moved from Cape Town to the Cavendish Laboratory in England where his career flourished despite his poor start. Notable structures he solved include transfer-RNA and the tobacco mosaic virus; in addition he also made significant contributions to the determination of the structure of chromatin. “Over a period of a decade or more, Klug and his associates, using as a basis, techniques originating in X-ray diffraction, developed optical and computer methods for processing the two-dimensional images

Figure 16. Aaron Klug.



Figure 17. Herbert A. Hauptman (left) and Jerome Karle (right).

Figure 18. Johann Deisenhofer (left), Robert Huber (center), and Hartmut Michel (right).

produced in the electron microscope, so that it became possible for them to reconstruct the three-dimensional images of biological samples” (39). Colleagues have described Aaron Klug as a man who would be difficult to point out in a crowd, but if you were to criticize his scientific work, he would become a formidable adversary. “His success has come, in every case, by bringing together results using a variety of techniques and, above all, through his ability to match results of experimental work with insight revealing the crucial core of a problem and developing the theoretical basis essential for its resolution” (40).

puter program to use direct methods, MULTAN, variants of which are in use today. Today crystal structures, whether they contain a heavy atom or not, are often routinely solved by direct methods. It has been estimated that approximately 4000 structures had been determined by various methods prior to 1970. By the mid-1980s structures of some 40,000 substances had been determined through direct methods using data from computer-controlled diffractometers. By the turn of the century, the crystal structures of over 200,000 compounds have been determined, many of them by direct methods.

1985 Nobel Prize in Chemistry Awarded to Herbert A. Hauptman and Jerome Karle

1988 Nobel Prize in Chemistry Awarded to Johann Deisenhofer, Robert Huber, and Hartmut Michel

In 1985 Herbert A. Hauptman and Jerome Karle (Figure 17) received the Nobel Prize in Chemistry for outstanding achievements in the development of direct methods for the determination of crystal structures. The solution, sought by many crystallographers, was delivered clearly in the publication Solution of the Phase Problem 1 (41). The method was based on probabilities and can be applied to crystals that contain a center of symmetry. Development of probability methods for crystals without a center of symmetry would take longer (42–44). At present most published crystal structures use some form of the Karle–Hauptman approach to crystal structure solution. It should be noted that Hauptman was the first mathematician to win a Nobel Prize. Alfred Nobel did not include the field of mathematics in his list of disciplines to receive recognition and the Nobel committee has not extended the prize to this field. Again there were contributors whose work helped pave the way to a Nobel Prize but were not awarded a similar honor. The British crystallographer, Michael M. Woolfson, University of York, was in hot pursuit of the key that would unlock the secrets of the previously mentioned phase problem. This effort was acknowledged in the summary of his address as a 1997 Dorothy Hodgkin Prize winner “....and his own thesis work in which he derived an equation which later led to the Karle and Hauptman S1[sic] relationship” (45). The irony increases as Woolfson’s external examiner was Dorothy Hodgkin. She was “unusual because not only did she ask searching questions, but she carefully wrote the answers down in a note book” (45). Woolfson found out later that these notes were not criticisms of his thesis but were intended to be applied to the vitamin B12 structure solution. Michael Woolfson would collaborate with Gabriel Germain and later with Peter Main to produce the first fully automatic com-

Johann Deisenhofer, Robert Huber, and Hartmut Michel (Figure 18) received the Nobel Prize in Chemistry in 1988 for the determination of the three-dimensional structure of a photosynthetic reaction center. The positions of approximately 10,000 atoms in the protein complex were determined. “In addition to its importance in the understanding of photosynthesis, the work had other applications since membrane-bound proteins are also important in many disease states” (46). An interesting discussion of the significance of this work has been published. “The energy necessary for the sustenance of life on earth comes from the sun and is trapped by plants, algae, and certain bacteria in the process of photosynthesis.... The mechanism of the primary photochemical events of photosynthesis cannot be determined without a picture of the three-dimensional disposition of the electron donors and acceptors embedded in the protein milieu” (47). Deisenhofer, Huber, and Michel were awarded the Nobel Prize for revealing the details of this process. There was some controversy over their selection, but the Nobel laureate committee has the final decision regarding a particular award and these individuals clearly made outstanding contributions. 1994 Nobel Prize in Physics Awarded to Bertram N. Brockhouse and Clifford G. Shull Bertram N. Brockhouse and Clifford G. Shull (Figure 19) shared the Nobel Prize in Physics in 1994 for their pioneering contributions to the development of the neutron scattering techniques for studies of condensed matter. Neutron scattering is a nuclear phenomenon and, unlike X-ray diffraction, is independent of the atomic number of the atom


759


involved in the scattering. Consequently, neutron diffraction is more effective in locating hydrogen atom positions than is X-ray diffraction, even in the presence of atoms with large atomic numbers. This technique provided a new and powerful tool for molecular structure determination. Another important use of neutron scattering is in the study of magnetic material; in fact, Shull and Ernest O. Wollan provided the first experimental evidence for antiferromagnetism (48). One of the limitations to neutron scattering is the need for a nuclear reactor as a neutron source. In the 1940s and 1950s, and to some extent today, reactors were mainly located in government laboratories. The graphite reactor at Clinton Laboratory (now Oak Ridge National Laboratory) was completed in 1943. E. O. Wollan had constructed a neutron spectrometer and had carried out some scattering experiments when Shull arrived in 1946. Wollan died in 1984 and Shull ended his Nobel lecture by saying “I regret that he did not live long enough to share in the honors that have come to me” (49). Once again, the conditions of Nobel’s bequest had an influence on the recipients of the Prize. When Brockhouse was completing his Ph.D. work at the University of Toronto, he had heard of the experiments of Shull and Wollan, which apparently prompted him to accept a position to do work at the nuclear reactor located at the Chalk River Laboratories in Canada. The instruments used today have changed very little from the one that Brockhouse designed and built at Chalk River in the 1950s. The studies of Shull, Wollan, and Brockhouse provided a powerful new tool to study condensed phases that was an excellent complement to X-ray diffraction. According to an article in Physics Today, “Shull laid the path for studying the structure of materials while Brockhouse developed tools for exploring their dynamics” (48). Summary As a direct result of the many advances discussed in this paper, increasingly complex molecular structures are being solved. Molecules containing many hundreds or thousands of atoms are open to crystal structure solution today thanks to the advances of the past century. As an example, one possibly highly significant advance is the structure and mechanism elucidation of a class of compounds capable of attacking and neutralizing a number of viruses that include common cold rhinoviruses. The molecule, with the trade name Pleconaril (50), contains the key that may render ineffective many different species of these viruses and holds the potential to cure the common cold. The structure of Pleconaril contains 6820 atoms and incorporates 852 amino acid residues. In the early days of the 20th century, the tools and methods of crystallography were in their infancy. As the century progressed these tools and methods progressed. Crystal structure determinations advanced from those of simple inorganic structures to include compounds that are the basic building blocks of life. In place of the simple sealed X-ray tube source we now have rotating anode sources, much brighter than sealed tube sources, and synchrotron facilities where different and even multiple wavelength sources can be used on very tiny crystalline materials. New methods now being used to overcome the “phase problem” offer solutions to problems never thought possible by the pioneers of crystallography. 760

Figure 19. Bertram N. Brockhouse (left) and Clifford G. Shull (right).

The quality of life has clearly been improved by the scientific advances in crystallography and molecular structure determination in the past century and advances in the near future may dwarf those advances of the past. A search of the Protein Data Bank (51) reveals a total of 6663 structure factor files, 12,960 X-ray diffraction structures for peptides and viruses, 618 protein–nucleic acid complexes, 600 nucleic acids, and 14 carbohydrate structures (as of January 2002). This list will continue to grow. What we have learned about matter at the molecular level in the past 100 years using diffraction techniques is amazing and what is yet to come will be even more amazing. Editor’s Note Readers who are interested in tracing the development of chemical dynamics through the Nobel Prizes should consult the series of articles by Van Houten (52). Literature Cited 1. Nobel Channel Home Page. http://www.nobelchannel.com/ (accessed Mar 2003). 2. Prize Amounts. http://www.nobel.se/nobel/amounts.html (accessed Mar 2003). 3. http://www.nobel.se/medicine/laureates/1998/press.html 4. Travis, John. Science News 1998, 154 (16), 246. 5. All laureate pictures were obtained from the Nobel e-Museum. http://www.nobel.se/index.html (accessed Mar 2003); Additional biographical information can be found at the root Web site of the Nobel e-Museum. http://www.nobel.se/(accessed Mar 2003). 6. Nobel Lectures Including Presentation Speeches and Laureates’ Biographies, Physics 1901–1921; Elsevier Publishing Company: Amsterdam, 1967; p 7. 7. Nobel Lectures Including Presentation Speeches and Laureates’ Biographies, Physics 1901–1921; Elsevier Publishing Company: Amsterdam, 1967; p 353. 8. Nobel Lectures Including Presentation Speeches and Laureates’ Biographies, Physics 1901–1921; Elsevier Publishing Company: Amsterdam, 1967; p 345. 9. Nobel Lectures Including Presentation Speeches and Laureates’ Biographies, Physics 1901–1921; Elsevier Publishing Company: Amsterdam, 1967; p 359. 10. Bragg, W. L. In Trends in Atomic Physics; Frisch, O. R., Paneth, F. A., Laves, F., Rosbaud, P., Eds.; Interscience Publishers, Inc.: New York, 1959; p 149. 11. Weissenberg, K. Z. Physik 1934, 23, 229. 12. Buerger, M. J. The Precession Method; John Wiley & Sons, Inc.: New York, 1964.


Chemistry for Everyone 13. Stout, G. H.; Jensen, L. H. X-Ray Structure Determination A Practical Guide, 2nd ed.; John Wiley & Sons: New York, 1989; p 245. 14. Ladd, M. F. C.; Palmer, R. A. Structure Determination by XRay Crystallography; Plenum Press: New York, 1985; p 203. 15. Patterson, A. L. Z. Krist. 1935, A90, 517. 16. Jenkins, R. J. Chem. Educ. 2001, 78, 601. 17. Davisson, C. J.; Germer, L. H. Nature 1927, 119, 558. 18. Thomson, G. P.; Reid, A. Nature 1927, 119, 890. 19. Thomson, G. P. Nature 1927, 120, 802. 20. Nobel Lectures Including Presentation Speeches and Laureates’ Biographies, Physics 1922 –1941; Elsevier Publishing Company: Amsterdam, 1967; p 388. 21. Nobel Lectures Including Presentation Speeches and Laureates’ Biographies, Physics 1922 –1941; Elsevier Publishing Company: Amsterdam, 1967; p 402. 22. Watson, J. D. The Double Helix; A Personal Account of the Discovery of the Structure of DNA; Atheneum Publishers: New York, 1968. 23. Watson, J. D. The Double Helix; A Personal Account of the Discovery of the Structure of DNA; Atheneum Publishers: New York, 1968; p 168. 24. Sayre, A. Rosalind Franklin and DNA; Norton: New York, 1975. 25. McPherson, A. Preparation and Analysis of Protein Crystals; Robert E. Krieger Publishing Company: Malabar, FL, 1989. This is an example, as well as many other textbooks on X-ray crystallography, such as ref 12 and 13. 26. Perutz, M. F.; Rossmann, M. C.; Cullis, A. C.; Murihead, H.; Will, G.; North, A. C. T. Nature 1960, 185, 416. 27. Kendrew, J. C.; Dickerson, R. E.; Strandberg, B. E.; Hart, R. G.; Davies, D. R.; Phillips, D. C.; Shore, V. C. Nature 1960, 185, 422. 28. McGrayne, S. B. Nobel Prize Women in Science, 2nd ed.; A Birch Lane Press Book: Toronto, ON, Canada, 1998; p 225. 29. Julian, M. M. J. Chem. Educ. 1982, 59, 124. 30. Farago, P. J. Chem. Educ. 1977, 54, 214. 31. Great Events from History, 1931–1952; Magill, Frank N. Ed.; 1991; Vol. 3, p 1240. 32. Ferry, G. Dorothy Hodgkin, A Life; Granta Publications, Granta Books: London, 1998.

33. Lipscomb, W. N. Boron Hydrides; W. A. Benjamin, Inc.: New York, 1963; p 17. 34. Eberhardt, W. H.; Crawford, B., Jr.; Lipscomb, W. N. J. Chem. Phys. 1954, 22, 989. 35. The Nobel Prize Winners, Chemistry, 1969–1989; Magill, F. N., Ed.; Salem Press: Pasadena, CA, 1990; Vol. 3, p 972. 36. Klug, A. Acta Cryst. 1950, 3, 165. 37. Vand, V.; Pepinsky, R. Acta Cryst. 1954, 7, 595. 38. Pinnock, P. R.; Taylor, C. A.; Lipson, H. Acta Cryst. 1956, 9, 173. 39. The Nobel Prize Winners, Chemistry, 1969–1989; Magill, F. N., Ed.; Salem Press: Pasadena, CA, 1990; Vol. 3, p 1084. 40. Nobel Laureates in Chemistry, 1901–1992; James, Laylin K., Ed.; American Chemical Society and The Chemical Heritage Foundation: Washington DC, 1993; p 658. 41. Hauptman, H.; Karle, J. Solution of the Phase Problem 1. The Centrosymmetric Crystal; American Crystallographic Association; ACA Monograph Number 3, 1953. 42. Cochran, W. Acta Crystallogr. 1955, 8, 473. 43. Karle, J.; Hauptman, H. Acta Crystallogr. 1956, 9, 635. 44. Hauptman, H.; Karle, J. Acta Crystallogr. 1956, 9, 45. 45. History of Named Lectures. http://img.cryst.bbk.ac.uk/BCA/ Cnews/1997/Sep97/namel.html#DMCH (accessed Mar 2003). 46. Schlessinger, Bernard S.; Schlessinger, June H. The Who’s Who of Nobel Prize Winners, 1901–1995, 3rd ed.; Oryx Press: Phoenix, AZ, 1996, 39. 47. Nobel Laureates in Chemistry, 1901–1992; James, Laylin K. Ed.; American Chemical Society and the Chemical Heritage Foundation: Washington DC, 1993; p 730. 48. Levi, B. G. Physics Today 1994, 47 (Dec), 17. 49. http://www.nobel.se/physics/laureates/1994/shull-lecture.html 50. Product Pipeline Pleconaril. http://www.viropharma.com/Pipeline/Pleconaril.htm (accessed Mar 2003). 51. Protein Data Bank. http://www.rcsb.org/pdb (accessed Mar 2003). 52. a. Van Houten, J. J. Chem. Educ. 2001, 78, 1572–1573; b. 2002, 79, 21–22; c. 2002, 79, 146–148; d. 2002, 79, 301– 304; e. 2002, 79, 414–416; f. 2002, 79, 548–550; g. 2002, 79, 667–669; h. 2002, 79, 788–790; i. 2002, 79, 926–933; j. 2002, 79, 1055–1059; k. 2002, 79, 1182–1188; l. 2002, 79, 1297–1306; m. 2002, 79, 1396–1402.


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