Chemistry for Everyone JChemEd.chem.wisc.edu • Vol. 80 No. 7 July 2003 • Journal of Chemical Education 753 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 ex- plode 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 be- queathed 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 nitroglyc- erin (3). Nobel refused because he did not believe that nitro- glycerin was effective and was aware of the headaches that were associated with its use. In 1998 the Nobel Prize in Physi- ology 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 un- derstand the use of nitroglycerin in treating angina (4). 1901 Nobel Prize in Physics Awarded to Conrad Röntgen 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- tight cardboard box. He observed that every time he pulsed cathode rays through the tube, a screen made of barium plati- nocyanide 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 X- rays 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 pow- erful 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 Max Theoder Felix von Laue of Germany (Figure 2) re- ceived 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 diffrac- tion to simple compounds. A “Laue” photograph of a cop- per 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 presenta- tion ceremony (Figure 3; ref 7 ). The chairman of the Nobel Committee for Physics of the Royal Swedish Academy of Sci- ences, G. Granqvist, stated in his Nobel presentation speech, “As a result of von Laue’s discovery of the diffraction of X- rays in crystals, proof was thus established that these light 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 Figure 2. Max T. F. von Laue. Figure 1. William C. Röntgen.
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Chemistry for Everyone
JChemEd.chem.wisc.edu • Vol. 80 No. 7 July 2003 • Journal of Chemical Education 753
At the turn of the 21st century scientists have graspedthe importance of determining molecular structures, but theground work began many years ago. The discoveries of thepast one hundred years as viewed through the Nobel Prizesillustrate some of the consequences that these advances havehad on society. The Nobel Prizes were made possible throughthe immense wealth created by Alfred Nobel’s discovery thatthe unstable, unpredictable tendency of nitroglycerine to ex-plode could be tamed by absorption on diatomaceous earth.Nobel was so appalled by the destructive uses of dynamitethat he established the award that bears his name. He be-queathed the equivalent of $9,000,000 and dictated that the“...interest on which shall be annually distributed in the formof prizes to those who, during the preceding year, shall haveconferred the greatest benefit on mankind” (1). The firstaward was 150,800 Swedish Crowns and has grown over theyears 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 thatNobel had heart trouble and his doctor prescribed nitroglyc-erin (3). Nobel refused because he did not believe that nitro-glycerin was effective and was aware of the headaches thatwere associated with its use. In 1998 the Nobel Prize in Physi-ology or Medicine was awarded to R. F. Furchgott, L. J.Ignarro, and F. Murad for their discoveries concerning NOas a signal molecule, research that was started, in part, to un-derstand the use of nitroglycerin in treating angina (4).
1901 Nobel Prize in Physics Awarded toConrad Röntgen
William Conrad Röntgen (Figure 1; ref 5) was awardedthe first Nobel Prize in Physics in 1901 for his discovery ofthe remarkable electromagnetic rays called X-rays. In 1895Röntgen, professor of physics at the University of Wurzburg,constructed a cathode ray tube and enclosed it in a light-
tight cardboard box. He observed that every time he pulsedcathode rays through the tube, a screen made of barium plati-nocyanide crystals would fluoresce. He postulated that thefluorescence was a result of the production of what he calledX-rays, rays that were not yet understood. Subsequently, heproduced the first “medical” X-ray when he immobilized hiswife’s hand above a photographic plate in the path of the X-rays and obtained an image of the bones of her hand and aring she was wearing (6). Most people are aware of the useof X-ray photography in dentistry and medicine; some mayeven remember being fitted for new shoes as children usingX-rays to “see” our feet. That practice has been discontinuedsince exposure to X-rays should be minimized, even to therelatively insensitive areas of the human body such as the feet.Röntgen’s discovery eventually gave crystallographers a pow-erful tool to probe crystals, using X-rays as the light to “see”atoms.
1904 Nobel Prize in Physics Awarded toMax Theoder Felix von Laue
Max Theoder Felix von Laue of Germany (Figure 2) re-ceived the Nobel Prize in Physics in 1904 for the discoverythat X-rays are diffracted from crystals. Five years prior tothe award, von Laue had joined the research group headedby Röntgen, who was then at Munich University. von Laue’simportant discovery allowed scientists to apply X-ray diffrac-tion to simple compounds. A “Laue” photograph of a cop-per sulfate pentahydrate crystal in random orientation, takenby Friedrich and Knipping at the suggestion of von Laue,was one of the photographs shown at the Nobel presenta-tion ceremony (Figure 3; ref 7 ). The chairman of the NobelCommittee for Physics of the Royal Swedish Academy of Sci-ences, G. Granqvist, stated in his Nobel presentation speech,“As a result of von Laue’s discovery of the diffraction of X-rays in crystals, proof was thus established that these light
The History of Molecular Structure DeterminationViewed through the Nobel PrizesWilliam P. Jensen*Department of Chemistry, South Dakota State University, Brookings, SD 57007; *[email protected]
Gus J. PalenikThe Center for Molecular Structure, The University of Florida, Gainesville, FL 32611-7200
Il-Hwan SuhDepartment of Physics, Chungnam National University, Taejon, 305-764, Korea
Figure 2. Max T. F. von Laue.Figure 1. William C. Röntgen.
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waves are of very small wavelengths. However, this discoveryalso resulted in the most important discoveries in the fieldof crystallography. It is now possible to determine the posi-tion of atoms in crystals and much important knowledge hasbeen gained in this connection” (8).
Max von Laue was a man of high moral character. Hedefended, even at the risk of reprimand or even personal in-jury, scientific views that were not approved by Hitler andthe ruling National Socialist Party. When Albert Einstein re-signed from the Berlin Academy and the vice-president ofthe Academy stated that this was no loss, von Laue was theonly member of the Academy who protested (9).
1915 Nobel Prize in Physics Awarded toWilliam Henry Bragg and William Lawrence Bragg
William Henry Bragg and William Lawrence Bragg (Fig-ure 4), a rare father and son team, won the Nobel Prize inPhysics in 1915 for their analysis of crystal structures ofsimple compounds by means of X-ray diffraction. W. H.Bragg designed and built the first X-ray diffractometer thatallowed the intensity of X-rays diffracted from a single crys-tal to be measured at various angles relative to the incidentbeam. The crystal structures of a number of simple salts weredetermined using this instrument. Bragg also derived theimportant relationship nλ = 2dsinθ, known as the Braggequation where n is a positive integer, λ is the wavelength ofthe X-ray, d is the spacing between planes in the crystallinematerial, 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 spec-trometer, which was so much more effective than the Lauephotograph, I was able to establish the structure of a num-ber of simple crystals (CaF2, ZnS, FeS2, CaCO3). Even thesesimple crystals had a profound influence on chemical ideasat that time because they showed that inorganic compoundswere composed of a regular pattern of atoms (or ions as wewould now term them) and not of molecules. I well remem-ber how startlingly novel this conception appeared to cur-rent chemical thought; we were begged to discover that therewas some association, however small, between pairs of atomsin sodium chloride” (10). The Braggs were unable to attendthe 1915 Nobel Award ceremonies in Stockholm, Swedenbecause of travel restrictions as result of World War I (re-member that the Lusitania was sunk in 1915 and 1916 sawthe battle of Jutland).
W. H. Bragg held a professorship at the University ofAdelaide in Australia. Travelers to Adelaide can view the Bragg
Laboratories on the campus and the equipment he designedis on display in the nearby physics building. A drawback ofBragg’s diffractometer was that the diffraction data were mea-sured point-by-point by hand, which was very time consum-ing. Eventually, instrument improvements produced themodern computer-controlled diffractometer where severalthousand measurements can be made in a few hours. How-ever, before these developments, most of the X-ray structuraldata were collected by film methods using instruments de-veloped by K. Weissenberg (11), the Weissenberg camera, andM. Buerger (12), the precession camera. The Weissenberg andBuerger precession single-crystal cameras are still in use manyyears after their development. Using these film instruments,X-ray intensity data for a typical small molecule, 10–20 at-oms, could be collected in 1–2 months. AlthoughWeissenberg and Buerger never received Nobel Prizes, datacollected with their instruments led to several prizes.
Another serious limitation in X-ray crystallography wasthe so-called “phase problem” (13). While the intensity ofan X-ray beam diffracted from a crystal at some angle to thedirect X-ray beam can be measured, the phase of the wave islost during the experiment. In order to determine the struc-ture of a crystal, knowledge of the phase of the diffractedbeam must be determined. For simple compounds such asNaCl, the correct structure is easily obtained.
The data for crystalline NaCl (Table 1; ref 14 ) can beused to illustrate a number of points about X-ray diffraction.The hkl values are the Miller indices of the plane in the crys-tal. The strength of the interaction of an atom with X-raysdepends on the scattering factor, fNa and fCl in Table 1, whichis related to the number of electrons and therefore the atomicnumber. The contributions of Na and Cl to the structure am-plitude, F(hkl), also depend on the positions of the atomsand can reinforce or reduce the amplitude. F(hkl) is propor-tional to the square root of the observed intensity. Usuallythe F(hkl) is calculated from the measured intensity and ascale factor, listed in Table 1 as k|Fobs|, and is compared witha calculated F(hkl), assuming a specific arrangement of at-oms in the unit cell, Fcalc in Table 1. The case of NaCl isrelatively simple since the positions of the ions are knownand Fcalc is easily calculated and compared to k|Fobs|. In gen-eral the positions of the atoms or ions are not known andthe determination of the structure would require computa-tions far beyond the capabilities of even modern high speedsupercomputers unless phase information were available.
Many scientists sought ways to circumvent the phaseproblem or to solve structures directly. A. L. Patterson de-
Figure 3. Laue photographs of copper sulfate pentahydrate. Ran-dom orientation (left) and an aligned crystal photograph (right).
Figure 4. W. H. Bragg (left) and W. L. Bragg (right).
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vised a possible solution when a chemical compound con-tained only one or two atoms (or ions) of much larger atomicnumber than all the other atoms in the compound (15).Patterson showed that the position of the “heavy atom” couldbe deduced using a special function that could be calculateddirectly from the intensities and would become known as aPatterson function or map (Figure 5). The position of theheavy atom could be used to calculate approximate phasesand an electron density map that could be used to locate thepositions of the “light atoms” in the structure. The so-calledheavy atom derivatives would play an important part in de-termining the structure of organic molecules and lead to sev-eral Nobel Prizes. Although A. L. Patterson never receivedthe Nobel Prize for his work, a yearly “Patterson Award” wasestablished by the American Crystallographic Association andtoday is a highly coveted award. A Nobel Prize winner in sci-ence must have outstanding accomplishments, but unfortu-nately outstanding accomplishments do not necessarily insurethis ultimate recognition.
In the early days of crystallography the research was doneby just a handful of scientists. In 1942, these scientists formedthe American Society for X-ray and Electron Diffraction.Eight years later the organization was renamed The Ameri-can Crystallographic Association (ACA) with 133 chartermembers. Membership had grown to 600 by the end ofWorld War II, and by 2000 the ACA had about 2,200 mem-bers worldwide.
1936 Nobel Prize in Chemistry Awarded toPetrus (Peter) J. Debye
A fascinating aspect of science is the number of timestheory and experiment coalesce in two or more researchgroups to provide almost identical breakthroughs. The No-bel Prizes that were awarded in 1936 to Debye and in 1937to Davisson and Thomson illustrate this point.
The Nobel Prize in Chemistry was awarded to Petrus(Peter) J. Debye (Figure 6) in 1936 “for his contributions toour knowledge of molecular structure through his investiga-tions on dipole moments and the diffraction of X-rays andelectrons in gases” (5). Dipole moments are now measuredin Debye units, 3.34 × 1030 coulomb–meter, named in hishonor. Debye believed that X-rays would be diffracted bygases, liquids, and noncrystalline solids. Debye, and his as-sistant Paul Sherrer, studied powdered lithium fluoride, com-posed of randomly oriented microcrystals. The results werespectacular. The diffraction pattern of sharp lines revealedthe symmetry arrangement of the individual atoms in lithiumfluoride. The Debye–Scherrer powder diffraction methodproved to be general for all crystals. Use of the Debye–Scherrer camera became the standard method to record a dif-fraction pattern on film from a powder sample. The camerawas used for many years until counters replaced traditionalfilm methods. A review of the development of the powderdiffraction technique was published recently and providesmore details (16). These tools, together with refinements tothe diffractometer first built by W. H. Bragg, have dramati-cally improved our understanding of materials at the molecu-lar or nanometer level.
1937 Nobel Prize in Physics Awarded toClinton J. Davisson and George P. Thomson
In April 1927 C. J. Davisson and L. H. Germer pub-lished a preliminary report of low voltage electron scatteringfrom the surface of a nickel crystal (17). This report was fol-lowed in June by a letter from G. P. Thomson and A. Reid
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(18) and another in December by G. P. Thomson (19) de-scribing experiments with 4–60 kV electrons transmittedthrough thin foils. This was a remarkable coincidence of al-most 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 theirexperimental discovery of the electron diffraction by crystals.
These two scientists came from very different back-grounds. Davisson was born in Bloomington, IL, attendedBloomington public schools, and required scholarship andother university assistance to complete his studies. He wasemployed at the precursor of the Bell Telephone Laborato-ries. In this industrial setting he devoted himself to the studyof the theory of electron optics and applications of this theoryto engineering problems. Davisson’s approach was to inves-tigate the interaction of electron beams with the surfaces ofmetal crystals. Thomson was the son of the physicist J. J.Thomson, a Nobel laureate famous for determining thecharge-to-mass ratio of the electron. G. P. Thomson went toschool in Cambridge and eventually was appointed Profes-sor of Natural Science at the University of Aberdeen (Scot-land). Unlike Davisson, Thomson studied electron optics byinvestigating the results of passing electron beams throughthin films and metal foils.
In his acceptance speech at the 1937 Nobel ceremoniesDavisson said, “Troubles, it is said, never come singly, andthe trials of the physicists in the early years of this centurygive grounds for credence in the pessimistic saying. Not onlyhad light, the perfect child of physics, been changed into agnome with two heads—there was trouble with electrons”(20). Thomson was unable to attend the Nobel ceremoniesbecause of ill health. In a later speech he said “I should besorry to leave you with the impression that electron diffrac-tion was of interest only to those concerned with the funda-mentals of physics. It has important practical applications tothe study of surface effects. You know how X-ray diffractionhas made it possible to determine the arrangement of the at-oms in a great variety of solids and even liquids. X-rays arevery penetrating, and any structure peculiar to the surface ofa body will be likely to be overlooked, for its effect is swampedin that of the mass of underlying material. Electrons onlyaffect layers of a few atoms, or at most, tens of atoms in thick-ness, and so are eminently suited for the purpose” (21). Thesediscoveries provided important tools to investigate surfacesof materials and hence the behavior of catalysts. Heteroge-neous catalysis, a very important branch of science, has to-day spawned many advances, including the automobile
Figure 7. Clinton Joseph Davisson (left) and George Paget Thomson(right).
Figure 8. Francis H. C. Crick (left), James D. Watson (center), andMaurice H. F. Wilkins (right).
catalytic converter, without which many urbanized parts ofthe United States would be uninhabitable.
1962 Nobel Prize in Physiology or MedicineAwarded 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 theNobel Prize in Physiology or Medicine in 1962 for their dis-coveries concerning the molecular structure of nucleic acids(Figure 9) and their significance for information transfer inliving material. The not-always-nice struggles for this awardare described in the book The Double Helix by James Watson(22). Watson gives credit to “Rosy” Franklin, the crystallog-rapher who took the X-ray photographs of a new strand ofDNA. The data from these photographs were ultimately usedto prove the postulate of base pairing and the double helixstructure that is so commonly accepted today (Figure 10; ref23).
Anne Sayre (24) in her book, Rosalind Franklin andDNA, highlights a vexing problem with Watson’s book inwhich he uses the “affectionate term” Rosy. This was a termRosalind Franklin’s friends would never use to refer to herand no one would ever dare use in her presence. Anne Sayreargues that Franklin was equally deserving of the Nobel Prize.The situation was resolved, to some extent, by the untimelydeath of Franklin in 1958 and provisions in Nobel’s will thatspecify that the prize cannot be shared by more than threepeople and that the winner or winners of the prize must beliving.
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1962 Nobel Prize in Chemistry Awarded toJohn Kendrew and Max Ferdinand Perutz
John Kendrew and Max Ferdinand Perutz (Figure 11)won the Nobel Prize in Chemistry in 1962 for their workon the X-ray structures of globular proteins. Kendrew wasrecognized for his efforts in unraveling the structure of myo-globin, a protein responsible for transporting oxygen inmuscle tissue. Perutz won his portion of the award for un-raveling the structure of hemoglobin, a protein responsiblefor transporting oxygen in the blood. Perutz, an Austrian bybirth, came from a family whose wealth derived from the tex-tile industry. His parents wanted him to seek a law degreeand continue the family businesses. However, because of theteaching of an outstanding chemistry teacher, Perutz wishedto pursue a career in chemistry. His parents sent him toEngland and financed his education there. As World War IIdeveloped, his parents lost their fortune and Perutz lost hisfinancial support. In fact, he also suffered a six-month set-back by being interned as a foreigner in Canada during thewar. His future as a scholar was rescued by Nobelist W.Lawrence Bragg, who secured a Rockefeller Foundation grantfor Perutz.
The hemoglobin and myoglobin structures were solvedusing a crystallographic technique called isomorphous re-placement, which was first applied to proteins by Perutz. Heused sodium p-chloromercuribenzoate to attach two mercuryatoms to the sulfur atoms in the two cysteine groups. A sec-ond heavy atom derivative was then prepared using silver ions.Data from these two crystals, along with additional data froma crystal of hemoglobin containing no heavy atom, were usedto overcome the phase problem mentioned earlier (25). Theclassic papers describing this work were published in Nature(26, 27).
Kendrew was three years junior to Perutz and had spenttime serving in World War II with the British Air MinistryResearch Establishment. He came to the Cambridge lab withPerutz as his graduate mentor and was assigned to work onthe structure of myoglobin. This molecule was one-fourththe size of the hemoglobin molecule and was somewhat sim-pler to solve. Using the isomorphous replacement methodsand pioneering computer-aided procedures, Kendrew wasable to solve the structure of myoglobin two years before thesolution of hemoglobin was obtained. Hemoglobin has ap-proximately 4,800 atoms, excluding hydrogen, and, at thattime, could only be solved by an exceptionally persistent sci-entist with a cadre of assistants.
Figure 10. Rosalind Franklin’s photograph of DNA B.Figure 11. Max F. Perutz (left) and John Kendrew (right).
Figure 12. Dorothy C. Hodgkins.
Figure 13. Structure of penicillin G.
CH2
O
NH
N
S
O
HO
CH3
CH3O
C
C
1964 Nobel Prize in Chemistry Awarded toDorothy Crowfoot Hodgkin
Dorothy Crowfoot Hodgkin (Figure 12) received theNobel Prize in Chemistry in 1962 for unraveling the struc-tures of important biochemical substances, including peni-cillin (Figure 13) and vitamin B12 (28–30). Her passion forscience and her extraordinary ability to recognize the needto solve certain structural problems set her above her con-temporaries. The incredible efforts she contributed to theeventual structure solution of penicillin along with the tech-nological advances she was able to utilize in the successfulcompletion of the task are documented in the series GreatEvents from History II, Science and Technology (31). In addi-tion a recent biography Dorothy Hodgkin: A Life has appeared(32). Her efforts led to the commercial synthesis of penicil-lin, freeing society from obtaining the compound from natu-ral substances and reducing the price of penicillin to anaffordable level. Sometimes the importance of a great discov-ery is not realized quickly: the solution of the penicillin struc-ture was accomplished in the early 1940s but the first totalsynthesis would not be reported until 1964. The structuredetermination of penicillin was accomplished with the col-laboration of many researchers in England and in the UnitedStates. The work was begun in 1942 and completed four years
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later and credit was given in large measure to the persistenceand gifted intuition Hodgkin brought to the problem. Thesolution was accomplished by the use of electron density cal-culations employing an old IBM punch card machine locatedin an evacuated building. This was a novel approach and pio-neered the wedding of crystallography and the computer.
The structure of vitamin B12 was also accomplished inHodgkin’s laboratory, but it required different skills and in-sight. By this time electronic computers had been developedand ultimately the structure of vitamin B12 was deduced withthe help of the Mark I computer at Manchester, the Deucecomputer at the National Physics Laboratory, and SWAC(National Bureau of Standards Western Automatic Com-puter) at UCLA in Los Angeles. Kenneth Trueblood at UCLAplayed a significant role in the refinement of the B12 struc-ture process using SWAC, a computer having 256 words ofhigh speed memory, each 36 bits long, and 8192 words ofdrum storage. A calculation of structure factors took about2 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 thelargest and most complex organic molecule to have its struc-ture determined in complete detail at that time. Hodgkin,an extraordinarily gifted person, would go on to determinethe structure of insulin. A postscript remains. There wereNobel Laureates on both sides of the family. Her husband’scousin, Alan Hodgkin, shared the Nobel Prize in Physiologyor Medicine in 1963 for work in the basic processes under-lying the nervous mechanisms of control and the communi-cation between nerve cells.
1976 Nobel Prize in Chemistry Awarded toWilliam N. Lipscomb
William N. Lipscomb (Figure 14) won the Nobel Prizein Chemistry in 1976 for his studies on the structure of bo-ranes, providing new insight to chemical bonding. A repre-sentation of a B10H10
2� ion taken from Lipscomb’s book,Boron Hydrides (35), is shown in Figure 15. The concept ofa chemical bond requiring two electrons shared between twoatoms was at that time deeply rooted in the minds of mostchemists. By combining his abilities in crystallography, theo-retical chemistry, and an uncanny ability to embrace new con-cepts, he proposed and made sense of three atom–twoelectron bonding. A quote from one of his papers indicatesthe extent to which he laid his reputation on the line, “Wehave even ventured a few predictions, knowing that if we mustjoin the ranks of boron hydride predictors later proved wrong,we shall be in the best of company” (33). It is interesting tonote that at the time of the award The Washington Post quoted
Roald Hoffmann (a future Nobel Prize winner) as saying thathe was surprised that Lipscomb was recognized for his workon boranes rather than for his important X-ray studies onthe structures of proteins that he had been performing forthe previous nine years (34). One of this paper’s authors(WPJ) had the privilege of being a student in a physical chem-istry class taught by Professor Lipscomb. It was abundantlyclear that this instructor was a uniquely gifted person andthat I had better rise to the occasion and learn thermody-namics to an extent to which I had not previously expectedor perhaps even wanted to do. Lipscomb was also an accom-plished clarinetist and inspired me to attend my one and onlyclarinet performance.
1982 Nobel Prize in Chemistry Awarded toAaron Klug
Aaron Klug (Figure 16) was awarded the Nobel Prize inChemistry in 1982 for his development of crystallographicelectron microscopy and his structural elucidation of biologi-cally important nucleic acid–protein complexes. However, hiscareer started inauspiciously when one of his first structuredeterminations (36), carried out at the University of CapeTown, was suggested to be (37) and was later shown to beincorrect (38). Klug had moved from Cape Town to theCavendish Laboratory in England where his career flourisheddespite his poor start. Notable structures he solved includetransfer-RNA and the tobacco mosaic virus; in addition healso made significant contributions to the determination ofthe structure of chromatin. “Over a period of a decade ormore, Klug and his associates, using as a basis, techniquesoriginating in X-ray diffraction, developed optical and com-puter methods for processing the two-dimensional images
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produced in the electron microscope, so that it became pos-sible for them to reconstruct the three-dimensional imagesof biological samples” (39). Colleagues have described AaronKlug as a man who would be difficult to point out in a crowd,but if you were to criticize his scientific work, he would be-come a formidable adversary. “His success has come, in ev-ery case, by bringing together results using a variety oftechniques and, above all, through his ability to match re-sults of experimental work with insight revealing the crucialcore of a problem and developing the theoretical basis essen-tial for its resolution” (40).
1985 Nobel Prize in Chemistry Awarded toHerbert A. Hauptman and Jerome Karle
In 1985 Herbert A. Hauptman and Jerome Karle (Fig-ure 17) received the Nobel Prize in Chemistry for outstand-ing achievements in the development of direct methods forthe determination of crystal structures. The solution, soughtby many crystallographers, was delivered clearly in the pub-lication Solution of the Phase Problem 1 (41). The methodwas based on probabilities and can be applied to crystals thatcontain a center of symmetry. Development of probabilitymethods for crystals without a center of symmetry would takelonger (42–44). At present most published crystal structuresuse some form of the Karle–Hauptman approach to crystalstructure solution. It should be noted that Hauptman wasthe first mathematician to win a Nobel Prize. Alfred Nobeldid not include the field of mathematics in his list of disci-plines to receive recognition and the Nobel committee hasnot extended the prize to this field.
Again there were contributors whose work helped pavethe way to a Nobel Prize but were not awarded a similarhonor. The British crystallographer, Michael M. Woolfson,University of York, was in hot pursuit of the key that wouldunlock the secrets of the previously mentioned phase prob-lem. This effort was acknowledged in the summary of hisaddress as a 1997 Dorothy Hodgkin Prize winner “....andhis own thesis work in which he derived an equation whichlater led to the Karle and Hauptman S1[sic] relationship” (45).The irony increases as Woolfson’s external examiner was Dor-othy Hodgkin. She was “unusual because not only did sheask searching questions, but she carefully wrote the answersdown in a note book” (45). Woolfson found out later thatthese notes were not criticisms of his thesis but were intendedto be applied to the vitamin B12 structure solution. MichaelWoolfson would collaborate with Gabriel Germain and laterwith Peter Main to produce the first fully automatic com-
puter program to use direct methods, MULTAN, variants ofwhich are in use today.
Today crystal structures, whether they contain a heavyatom or not, are often routinely solved by direct methods. Ithas been estimated that approximately 4000 structures hadbeen determined by various methods prior to 1970. By themid-1980s structures of some 40,000 substances had beendetermined through direct methods using data from com-puter-controlled diffractometers. By the turn of the century,the crystal structures of over 200,000 compounds have beendetermined, many of them by direct methods.
1988 Nobel Prize in Chemistry Awarded toJohann Deisenhofer, Robert Huber, andHartmut Michel
Johann Deisenhofer, Robert Huber, and Hartmut Michel(Figure 18) received the Nobel Prize in Chemistry in 1988for the determination of the three-dimensional structure ofa photosynthetic reaction center. The positions of approxi-mately 10,000 atoms in the protein complex were deter-mined. “In addition to its importance in the understandingof photosynthesis, the work had other applications sincemembrane-bound proteins are also important in many dis-ease states” (46).
An interesting discussion of the significance of this workhas been published. “The energy necessary for the sustenanceof 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 pho-tosynthesis cannot be determined without a picture of thethree-dimensional disposition of the electron donors and ac-ceptors embedded in the protein milieu” (47). Deisenhofer,Huber, and Michel were awarded the Nobel Prize for reveal-ing the details of this process. There was some controversyover their selection, but the Nobel laureate committee hasthe final decision regarding a particular award and these in-dividuals clearly made outstanding contributions.
1994 Nobel Prize in Physics Awarded toBertram N. Brockhouse and Clifford G. Shull
Bertram N. Brockhouse and Clifford G. Shull (Figure19) shared the Nobel Prize in Physics in 1994 for their pio-neering contributions to the development of the neutron scat-tering techniques for studies of condensed matter. Neutronscattering is a nuclear phenomenon and, unlike X-ray dif-fraction, is independent of the atomic number of the atom
Figure 18. Johann Deisenhofer (left), Robert Huber (center), andHartmut Michel (right).
Figure 17. Herbert A. Hauptman (left) and Jerome Karle (right).
760 Journal of Chemical Education • Vol. 80 No. 7 July 2003 • JChemEd.chem.wisc.edu
involved in the scattering. Consequently, neutron diffractionis more effective in locating hydrogen atom positions than isX-ray diffraction, even in the presence of atoms with largeatomic numbers. This technique provided a new and power-ful tool for molecular structure determination. Another im-portant use of neutron scattering is in the study of magneticmaterial; in fact, Shull and Ernest O. Wollan provided thefirst experimental evidence for antiferromagnetism (48).
One of the limitations to neutron scattering is the needfor a nuclear reactor as a neutron source. In the 1940s and1950s, and to some extent today, reactors were mainly lo-cated in government laboratories. The graphite reactor atClinton Laboratory (now Oak Ridge National Laboratory)was completed in 1943. E. O. Wollan had constructed a neu-tron spectrometer and had carried out some scattering ex-periments when Shull arrived in 1946. Wollan died in 1984and Shull ended his Nobel lecture by saying “I regret that hedid not live long enough to share in the honors that havecome to me” (49). Once again, the conditions of Nobel’s be-quest had an influence on the recipients of the Prize.
When Brockhouse was completing his Ph.D. work atthe University of Toronto, he had heard of the experimentsof Shull and Wollan, which apparently prompted him to ac-cept a position to do work at the nuclear reactor located atthe Chalk River Laboratories in Canada. The instrumentsused today have changed very little from the one thatBrockhouse designed and built at Chalk River in the 1950s.
The studies of Shull, Wollan, and Brockhouse provideda powerful new tool to study condensed phases that was anexcellent complement to X-ray diffraction. According to anarticle in Physics Today, “Shull laid the path for studying thestructure of materials while Brockhouse developed tools forexploring their dynamics” (48).
SummaryAs a direct result of the many advances discussed in this
paper, increasingly complex molecular structures are beingsolved. Molecules containing many hundreds or thousandsof atoms are open to crystal structure solution today thanksto the advances of the past century. As an example, one pos-sibly highly significant advance is the structure and mecha-nism elucidation of a class of compounds capable of attackingand neutralizing a number of viruses that include commoncold rhinoviruses. The molecule, with the trade namePleconaril (50), contains the key that may render ineffectivemany different species of these viruses and holds the poten-tial to cure the common cold. The structure of Pleconarilcontains 6820 atoms and incorporates 852 amino acid resi-dues.
In the early days of the 20th century, the tools and meth-ods of crystallography were in their infancy. As the centuryprogressed these tools and methods progressed. Crystal struc-ture determinations advanced from those of simple inorganicstructures to include compounds that are the basic buildingblocks of life. In place of the simple sealed X-ray tube sourcewe now have rotating anode sources, much brighter thansealed tube sources, and synchrotron facilities where differ-ent and even multiple wavelength sources can be used on verytiny crystalline materials. New methods now being used toovercome the “phase problem” offer solutions to problemsnever thought possible by the pioneers of crystallography.
The quality of life has clearly been improved by the sci-entific advances in crystallography and molecular structuredetermination in the past century and advances in the nearfuture may dwarf those advances of the past. A search of theProtein Data Bank (51) reveals a total of 6663 structure fac-tor files, 12,960 X-ray diffraction structures for peptides andviruses, 618 protein–nucleic acid complexes, 600 nucleic ac-ids, and 14 carbohydrate structures (as of January 2002). Thislist will continue to grow. What we have learned about mat-ter at the molecular level in the past 100 years using diffrac-tion techniques is amazing and what is yet to come will beeven more amazing.
Editor’s Note
Readers who are interested in tracing the developmentof chemical dynamics through the Nobel Prizes should con-sult the series of articles by Van Houten (52).
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