《天然药物化学》课程教学资源（文献资料）The History of Molecular Structure Determination Viewed through the Nobel Prizes

Chemistry for Everyone The History of Molecular Structure Determination Viewed through the Nobel Prizes William P.Jensen* Department of Chemistry,South Dakota State University,Brookings,SD 57007;*w.p.jensen@usa.net Gus J.Palenik The Center for Molecular Structure,The University of Florida,Gainesville,FL 32611-7200 ll-Hwan Suh Department of Physics,Chungnam National University,Taejon,305-764,Korea At the tu of the 21st century scientists have grasped ight cardboard box.He observed that every time he pulsed the im the e,a screen made of barium plati began many years ago.The discoveries of the past one hundred years as viewed through the Nobel Prizes luorescence was a result of the production of what he called illustrate some of the consequences that these advances have X-rays,rays that were not yet understood.Subsequently,he had on society.The Nobel Prizes were made possible through produced the first "medical"X-ray when he immobilized his the immense wealth created by Alfred Nobel's discovery that wife's hand above a photographic plate in the path of the X- the unstable,unpredictable tendency of nitroglycerine to ex- 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 uhedtheddictedhh .interest on which shall be annually distributed in the form since exposure to X-rays should be minimized,even to the of those who,during the pr nkin of the human body atest be y such as the for ward was 150.800 S on the using X- story was 1904 Nobel Prize in Physics Awarded to tor pres itroglyc. Max Theoder Felix von Laue refused because he did not glycerin was effective and was aware of the headaches Max Theoder Felix von Laue of Germany (Figure 2)re- vere associ with its use.In 1998 the Nobel Prize in Phys ology or Medicine wasawarded toR F.Furchgott,L eived the Nobel Prize in Physics in 1904 for the discovery hat X-rays are diffracted from crystals.Five years prior to Ignarro,and F.Murad for their discoveries concerning NO the award,von Laue had joined the research group headed as a signal molecule,research that was started,in part,to un- by Rontgen,who was then at Munich University.von Laue's derstand the use of nitroglycerin in treating angina(4). important discovery allowed scientists to apply X-ray diffrac- tion to simple compounds.A"Laue"photograph of a cop- 1901 Nobel Prize in Physics Awarded to per sulfate pentahydrate crystal in random orientation,taken Conrad Rontgen by Friedrich and Knipping at the suggestion of von Laue, was one of the photo aphs shown at the nobel prese William Conrad Rontgen (Figure 1;ref 5)was awarded tion ceremony (Figure 3:ref 7).The chairman of the Nobel the first Nobel Prize in Ph sics in 1901 for his disco the remarkable electrom nagnetic rays called-ryIn ttee for Physics of the Royal Swedish Academy of Sci- a cathod physi at the unive on Laue's disc fthe diffraction ray tube vist,stated in his Nobel presenatio Figure 1.William C.Rontgen Figure 2.Max T.F.von Laue. JChemEd.chem.wisc.edu.Vol.80 No.7 July 2003.Journal of Chemical Education 753

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; *w.p.jensen@usa.net 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 1. William C. Röntgen. Figure 2. Max T. F. von Laue

Chemistry for Everyone 9 Laue photographs of copper sulfate pentahy Ran Figure 4.W.H.Bragg (lefi])and W.L Bragg (right). on the campus ad ofhigh moral character.He oduced nal in tho urements can be made in ew hours.How erg camera,and awrence Bragg o产mB配出 Another serious limitation in X-r hyn15 e intens from a sing di伍 mporeantd using this instrument.Bragg also derived the compounds such as ion of n 金 at that time becau they showed that inor ional to the were composed o as w the (bkl) n the unit cell, case of NaCl is in sodium chloride().The Braggs were unabl to at hc191 Award ceremonies in Swede problem or to solve structures directly.A.de 754 Journal of Chemical Education.Vol.80 No.7 July 2003.JChemEd.chem.wisc.edu

Chemistry for Everyone 754 Journal of Chemical Education • Vol. 80 No. 7 July 2003 • JChemEd.chem.wisc.edu 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 posi￾tion 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 in￾jury, scientific views that were not approved by Hitler and the ruling National Socialist Party. When Albert Einstein re￾signed 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). 1915 Nobel Prize in Physics Awarded to William 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 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 crys￾tal 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 spec￾trometer, which was so much more effective than the Laue photograph, I was able to establish the structure of a num￾ber 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 remem￾ber how startlingly novel this conception appeared to cur￾rent 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 (re￾member 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 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 mea￾sured point-by-point by hand, which was very time consum￾ing. Eventually, instrument improvements produced the modern computer-controlled diffractometer where several thousand measurements can be made in a few hours. How￾ever, before these developments, most of the X-ray structural data were collected by film methods using instruments de￾veloped 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 at￾oms, 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 struc￾ture 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 crys￾tal. 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 am￾plitude, F(hkl), also depend on the positions of the atoms and can reinforce or reduce the amplitude. F(hkl) is propor￾tional 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 at￾oms 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 gen￾eral the positions of the atoms or ions are not known and the determination of the structure would require computa￾tions 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￾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)

Chemistry for Everyone PU网=7Σ2∑@2U+w+网 tions to Figure 5.The Patterson function. n dipole momens and hef 6 d he福a6 3.34 vised a possible solution when a chemical compound con The Debye-Sc use p of the the sucture.The cavyatonmdcni of the powde o rece have dramati gmpodorndersandiagofmaioilthcemolkau thisltinmarcreceognitioi 1937 Nobel Prize in Physics Awarded to Clinton J.Davisson and George P.Thomson American Socicry for X-ray and Electron handperiment coalesce in wo ormor Figure.Peter J.Debye 8 ups to prov to Davisson and Thomson illustrare this point. Table 1.Observed and Calculated Structure Factors for Nacl 、hM f k灯Fal 200 12.76 7R8 76.93 400 6.09 8.68 42.06 42.55 049 4.14 708 20.90 19.58 132 2 881 983 11切8 58 9.02 13.60 -17.34 18.30 -0.96 6.79 9.4 50.22 47.01 3.21 6.52 ChemEd.chem.wisc.edu Vol.80 No.7 July 2003.Journal of Chemical Education 755

Chemistry for Everyone JChemEd.chem.wisc.edu • Vol. 80 No. 7 July 2003 • Journal of Chemical Education 755 vised a possible solution when a chemical compound con￾tained 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 de￾termining the structure of organic molecules and lead to sev￾eral 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 sci￾ence must have outstanding accomplishments, but unfortu￾nately 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 Ameri￾can 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 mem￾bers worldwide. 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 No￾bel Prizes that were awarded in 1936 to Debye and in 1937 to 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 to our knowledge of molecular structure through his investiga￾tions 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 as￾sistant Paul Sherrer, studied powdered lithium fluoride, com￾posed 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 dif￾fraction 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 dramati￾cally improved our understanding of materials at the molecu￾lar 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 pub￾lished a preliminary report of low voltage electron scattering from the surface of a nickel crystal (17). This report was fol￾lowed in June by a letter from G. P. Thomson and A. Reid Figure 6. Peter J. Debye. Figure 5. The Patterson function. P UVW V F hU kV lW hkl h k l ( ) cos ( ) = ++ ∑ ∑∑ 1 2 2 2 π Table 1. Observed and Calculated Structure Factors for NaCl h f kl Na fCl Fcalc k|Fobs| ∆F 2 9 00 8 6 .6 1 1 2.7 7 3 8.8 7 8 6.9 1.8 4 9 00 6 8 .0 8 6 .6 4 5 2.0 4 9 2.5 -0.4 6 4 00 4 8 .1 7 0 .0 2 8 0.9 1 2 9.5 1.3 8 1 00 2 6 .7 5 1 .8 8 3 .8 9 2 .8 -1.0 2 4 20 7 6 .6 1 3 0.5 6 6 1.4 5 6 9.9 1.4 4 7 40 4 9 .2 7 4 .2 2 4 3.4 2 0 2.6 0.8 6 2 60 2 6 .5 5 1 .5 7 2 .0 9.0
1.99 1 8 11 8 0 .9 13.6
1 0 7.34 18.3
0.96 2 9 22 6 1 .7 9 2 .4 5 1 0.2 4 1 7.0 3.2 3 2 33 4 1 .7 7.6
6 2 .52 7 0 .2 0.7 4 0 44 3 1 .3 6 6 .5 1 5 4.1 15.3
1.19 5 5 55 2 6 .4 5 5 .4 - 0 2.4 1 5 .8 0.6

Chemistry for Everyone e.Clinon Joseph Davisson (f)and George (18)and another in December by G.B.Thomson (19)de- catalytic converter,without which many urbanized parts of the United States would be uninhabitable. most imultaneous discoveries of electron diffraction effects 1962 Nobel Prize in Ph ded to H.C.gyor Medicine and Maurice H.F.Wilkins s D.Watson Francis Harry Compton Crick.lames Dewey Watson his studic wa ture of nucleic acid dy Figure and the e theory of heor sctibed in the book ames Watson ().Watson gives credit n,the crystallog the Unive 23 Rosalind Frankl f passing ever use to he annot be shared 2otaemneiatpe and he winner o in with the funda has affect layers ofa few atoms.or tens of atoms (21) of materials and hence the behavior of catalysts.Heteroge Figure9.The double hel 756 Journal of Chemical Education.Vol.80 No.7 July 2003.JChemEd.chem.wisc.edu

Chemistry for Everyone 756 Journal of Chemical Education • Vol. 80 No. 7 July 2003 • JChemEd.chem.wisc.edu (18) and another in December by G. P. Thomson (19) de￾scribing experiments with 4–60 kV electrons transmitted through 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 their experimental discovery of the electron diffraction by crystals. These two scientists came from very different back￾grounds. 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 Laborato￾ries. 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 inves￾tigate 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 Profes￾sor of Natural Science at the University of Aberdeen (Scot￾land). 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 diffrac￾tion was of interest only to those concerned with the funda￾mentals 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 at￾oms 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 thick￾ness, 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. 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), and Maurice H. F. Wilkins (right). catalytic converter, without which many urbanized parts of the United States would be uninhabitable. 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 dis￾coveries 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 crystallog￾rapher 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

Chemistry for Everyone Figure 10.Rosalind Franklin's photograph of DNA B. Figure 11.Max F.Perutz()and John Kendrew (right 1964 Nobel Prize in Chemistry Awarded to Dorothy Crowfoot Hodgkin try in 1962 f 2 for unraveling the struc utz,an Aus rian by ventudstrnuctresolrionofpenicilinlongwithc tion of the task are documented in the from History l.Se igner in Ca ynthesis would not be reported until 196 voglobin structures were solved ue called States.The work was begun in 1942 and completed four years othe Data from these a crystal of he ogobinonwiningoha☒"are25. Figure 1.Dorothy C.Hodgkin (26 Hures.Ker excuding hydr en,and,at tha dbraneaopomiypenita JChemEd.chem.wisc.edu.Vol.80 No.7 July 2003.Journal of Chemical Education 757

Chemistry for Everyone JChemEd.chem.wisc.edu • Vol. 80 No. 7 July 2003 • Journal of Chemical Education 757 1962 Nobel Prize in Chemistry Awarded to John Kendrew and Max Ferdinand Perutz 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 myo￾globin, a protein responsible for transporting oxygen in muscle tissue. Perutz won his portion of the award for un￾raveling 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 tex￾tile 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 set￾back 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 re￾placement, 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 sec￾ond 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 sim￾pler 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 ap￾proximately 4,800 atoms, excluding hydrogen, and, at that time, 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 CH3 O C C 1964 Nobel Prize in Chemistry Awarded to Dorothy Crowfoot Hodgkin Dorothy Crowfoot Hodgkin (Figure 12) received the Nobel 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 for science and her extraordinary ability to recognize the need to solve certain structural problems set her above her con￾temporaries. The incredible efforts she contributed to the eventual structure solution of penicillin along with the tech￾nological 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 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 an affordable 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 total synthesis would not be reported until 1964. The structure determination of penicillin was accomplished with the col￾laboration of many researchers in England and in the United States. The work was begun in 1942 and completed four years