WOODWARD, ROBERT BURNS

(b. Boston, Massachusetts, 10 April 1917;

d. Cambridge, Massachusetts, 8 July 1979), organic chemistry—synthetic organic, reaction mechanisms.

Woodward was one of the preeminent organic chemists of the twentieth century. Spending most of his career at Harvard University in Cambridge, Massachusetts, he won the 1965 Nobel Prize in Chemistry for his contributions to the science and art of organic chemistry. Woodward was acclaimed for his syntheses of complex organic molecules, including cholesterol and cortisone (1951), strychnine (1954), reserpine (1956), and vitamin B₁₂ (1972).

Woodward elegantly reproduced in the laboratory many chemical products of nature. A master at designing these complex syntheses, he was also known for determining the chemical structures of natural products, for his innovative thinking on the theory of organic chemistry, and for his aggressive use of the latest in analytical equipment. He believed instruments could routinely assist the chemist in the characterization of compounds and suggest new generalizations about the relationship of chemical structure to physical properties. Given Woodward’s diverse professional attachments and eye for the latest trends in chemistry, his career was emblematic of the growth of synthetic organic chemistry in the middle decades of the twentieth century. Though employed at Harvard from 1937 until his death in 1979, Woodward had extensive ties to commercial firms, especially in the pharmaceutical industry. Woodward was married in 1938 to Irja Pullman, with whom he had two daughters, Siiri and Jean; in 1946, he married Eudoxia Muller, with whom he had a daughter and a son, Crystal and Eric. This second marriage, though longer than the first, also ended in divorce.

Early Life and Career. Woodward’s father, Arthur, died in the influenza pandemic of 1918, when Robert was an infant. An only child raised by his mother, Margaret (née Burns), in often tight financial circumstances, Woodward attended public schools in Quincy, Massachusetts, but much of his education did not take place in the classroom. He was an autodidact whose interest in chemistry dated from his early years. At the age of fourteen, Woodward bought a copy of Ludwig Gattermann’s Practical Methods of Organic Chemistry(1896). In later life he did not discourage persistent rumors that he had performed all the experiments in Gattermann’s book. The youthful Woodward also received a number of catalogs and manuals from various chemical supply and laboratory equipment companies, and he requested issues of Liebigs Annalen der Chemie [Liebig’s Annals of Chemistry] and Berichte der Deutschen Chemischen Gesellschaft [Reports of the German Chemical Society] from Verlag Chemie of Berlin. Woodward’s interest in organic chemistry remained at the center of his being throughout his life.

Entering the Massachusetts Institute of Technology in 1933 at the age of sixteen, Woodward gained fame in the Boston newspapers as a prodigious youth. However, his narrow focus on chemical pursuits led to some difficulty at MIT. Only the personal intervention of James Flack Norris, Woodward’s organic chemistry professor, saved him from dropping out. Norris provided Woodward and MIT with a solution wherein Woodward satisfied his course requirements by examination without having to attend lectures. At MIT he earned his bachelor’s degree in 1936 and his doctorate in 1937. His thesis dealt with the female steroid hormone, estrone. Woodward’s estrone research resulted in the publication of several papers in the Journal of the American Chemical Society in 1940. By this time Woodward had already formed bonds with industry—industrial collaborators had provided intermediates for his estrone synthesis, free of charge.

After Woodward’s MIT graduation, he accepted a position at the University of Illinois, where he had significant difficulties finding his niche. Following an abortive summer there, he was able to return to Harvard when E. P. Kohler hired him as a private research assistant in the fall of 1937. Although the Harvard Society of Fellows turned him down in 1937, Woodward had better luck the next year, becoming a member of the society the following fall. Though he enjoyed the freedom this position allowed, he wanted to pursue a more aggressive research program, and this required collaborators, especially graduate students. In a country headed to war, a responsible teaching position may also have provided greater refuge from the draft. In the fall of 1941, he accepted the position of instructor in chemistry at Harvard, yet 1942 saw him entertaining an offer of a research fellowship at the California Institute of Technology in Pasadena from Linus Pauling and looking at the Chemistry Department at the University of California in Berkeley. The reason was that although he was happy at Harvard, it remained unclear whether there would be a long-term position for him there.

At this juncture, Woodward’s industrial connections proved their worth. Edwin Land, founder and head of the Polaroid Corporation, stepped in and offered Woodward some research opportunities. During World War II, Japanese advances in the Pacific in 1942 had cut off Polaroid from its sources of quinine, a key ingredient in the production of its light polarizing sheets and films. In that year, Woodward and his Polaroid collaborators produced a chemically simple, light-polarizing replacement for quinine. He had been interested in quinine itself since he was a child, using approaches to the synthesis of quinine as exercises while teaching himself chemistry. Now he asked Land to support an attempt at quinine’s synthesis. After Woodward failed to secure federal support, Polaroid agreed to fund his synthesis. In February 1943, Woodward and coworker William E. Doering began a synthesis of quinine, building on the work of German chemist Paul Rabe, who had determined quinine’s structure in 1908. They completed the synthesis of their key intermediate, quinotoxine, on 10 April 1944, Woodward’s twenty-seventh birthday. While some have since questioned whether their quinotoxine work constituted a total synthesis of quinine, there is no doubt that the wartime attention that quinine attracted gave Woodward national and even international recognition, including a large photo-news story in Life magazine. The excitement generated in the lay press by his approaches to quinine illustrated his keen ability to identify critical and high-profile targets for his chemical research. Also, Land’s bridging support for a team effort on quinine boosted Woodward’s career at a crucial moment. In 1944, he was appointed assistant professor and began his climb through the ranks of the Harvard faculty.

Synthesis. After World War II, Woodward worked on syntheses of patulin (an antibiotic), morphine, protein, and other materials with industrial potentials. He was promoted to associate professor in 1946, full professor in 1950, and Morris Loeb Professor of Chemistry in 1953. Much as he had before the war, Woodward continued to foster connections within both academe and industry, exchanging materials and findings with a large number of chemists. In 1948, with interest in cortical compounds growing, he again turned his attention to steroids. In the following years, he undertook and completed some of the first total syntheses of the steroids cholesterol and cortisone (1951) and then the related terpene lanosterol (1954). Woodward’s steroid work illustrated various strategies of competition or cooperation that he employed for academic as well as industrial research. His work on cortisone was in an intensely competitive field with a number of international groups vying to be the first to create this new “miracle” drug in the laboratory, with Woodward’s close industrial collaborations supporting his Harvard-based research efforts. Cortisone work brought Woodward into conflict with such eminent competitors as Oxford University’s Robert Robinson, much as Woodward’s work on the structure of strychnine did later. One can contrast the cortisone competition with the international cooperation that existed in the synthesis of the steroid lanosterol, on which Woodward and British chemist Derek H. R. Barton cooperated, or the collaboration of Barton and Woodward with the Swiss group of Vladimir Prelog and Oskar Jeger on the structure of cevine. In 1954, Woodward announced syntheses of strychnine and lysergic acid, followed in 1956 by a synthesis of reserpine that became a model of elegant technique and was employed commercially for reserpine production. Subsequent synthetic achievements included chlorophyll (1960), tetracycline (1962), colchicine (1963), and cephalosporin C (1965). With Konrad Bloch, he also first proposed the correct biosynthetic pathway to the steroidal hormones in living organisms. At the time of his death, Woodward was working on the synthesis of erythromycin.

Perhaps Woodward’s most highly regarded synthetic efforts were those he directed to reserpine in the mid-1950s. In 1953, the medical application of this natural product as a sedative contributed to a radical change in the treatment of mental illness. Urgency was added to reserpine research in the spring of 1955, when the Indian government, in response to increased western demand, placed an embargo on the export of Rauwolfia root, the natural source of the drug. While pharmaceutical firms successfully searched Africa and the Americas for alternative sources of the roots, Woodward completed the synthesis of this antihypertensive and antipsychotic drug in the spring of 1956, less than one year after its structural elucidation. Reserpine was one of his quickest major syntheses, a model of chemical efficiency and one of his most rapid publications of a total synthesis, appearing as a fifty-seven-page paper, “The Total Synthesis of Reserpine,” in Tetrahedron in 1958. In general, Woodward’s syntheses appeared quickly as brief published communications, but the full papers, complete with experimental and spectroscopic details, often appeared years later or not at all, because of his desire for the papers to be flawless. The resperine synthesis, with its highly effective transformations, readily lent itself to rapid publication without a great deal of experimental tinkering to maximize yields. The synthesis of this alkaloid was creative both because it produced a valuable commodity and because of its imaginative design.

In many ways reserpine was a model for the Woodward method of synthesis: coherent, concise, efficient. Woodward exercised precise control over the stereochemical outcome of the reserpine synthesis. Its initial structural solution was a two-dimensional picture, but the molecule existed in three dimensions. Reserpine, with six chiral (asymmetric) carbons, each of which could exist in two distinct configurations, might have sixty-four distinct isomers, all of them subsumed in the flat, two-dimensional drawing. Only one of these isomers was the natural product. To assemble such a complex natural product, one had to think and make representations in three dimensions. Beyond conception and design, Woodward’s coworkers had to perform a great deal of chemical manipulation in the laboratory. His synthetic route became the basis for the industrial production of reserpine. As with all of his best work, he was supported by students and collaborators of the highest quality. He also operated in a cooperative community that supported his work: He received authentic samples of reserpine and instrumental assistance from Pfizer; reserpine, reserpine intermediates, and compounds for resolving reserpine from Eli Lilly; compounds related to reserpine, such as yohimbines, from the French group of Maurice-Marie Janot; and advice and encouragement from the Squibb Institute and Merck.

Woodward patented his reserpine work and assigned the patent to a nonprofit foundation, the Research Corporation. Woodward gave the Swiss pharmaceutical firm Sandoz unpublished procedures and details of his synthesis as early as January 1957. In the next two years, Sandoz developed methods for scaling up and simplifying Woodward’s procedures. Sandoz’s method paralleled Woodward’s in its main points, but the Sandoz workers resolved their material at an earlier stage, thus saving expensive reagents in later steps. Through licensing agreements, commercial exploitation of Woodward’s synthesis continued on several fronts, though with less success on Woodward’s side of the Atlantic. As with quinine, reserpine brought Woodward to the attention of the general public through popular press reports.

While reserpine was a molecule of great practical importance, Woodward also pursued targets that were much more purely chemists’ challenges. In this vein, Woodward’s total synthesis of strychnine capped his earlier work on the structure of this deadly alkaloid. The publication in 1963 of this synthesis provided the final confirmation of his structure determination. Woodward was fascinated by this poison, with its exotic origins in the forests of Southeast Asia and its use in “extermination of rodents and other undesirables” (1963a, p. 247). Woodward’s strychnine work recalled the traditional relationship between structure determination and synthesis—in which the synthesis is the ultimate and necessary confirmation of structure—at a time when that relationship was changing in the face of new, powerful, analytical instruments. Later in his career Woodward synthesized other high visibility, complex molecules with little direct practical outcome. Vitamin B₁₂ and chlorophyll were the two giants in this category. While both were compounds considered vital to life, both were also readily available, cheaply, by means other than long, multistep chemical syntheses. Both chlorophyll and vitamin B₁₂ are large molecules with many rings containing heteroatoms (atoms other than the basic carbons fundamental to organic chemistry), particularly nitrogen.

Woodward’s synthesis of chlorophyll was begun on the heels of the reserpine work and completed in 1960, in just four years, by the efforts of more than a dozen postdoctoral students. As with other molecules, Woodward immersed himself in the existing literature, much of it in German, going back for decades. And as before, Woodward did not deploy much in the way of new chemistry, but he always used his encyclopedic knowledge of the synthetic chemistry literature and was able to utilize even rather obscure reactions to great and novel effect. In addition, he did bring to bear his structural insights to

assemble the molecule convergently in two pieces and bring it all together with stereochemical control. This synthesis showed Woodward’s ability to plan meticulously and still cope brilliantly with unforeseen chemical contingencies. Though he gave lectures on the subject, Woodward never published a full-length article on the chlorophyll synthesis, and therefore much of the technical detail remains unknown.

Following chlorophyll, Woodward approached the B₁₂ synthesis that would bring together the best aspects of his reserpine and his chlorophyll work. The coenzyme vitamin B₁₂ (cyanocobalamin) was large and complicated enough to merit the collaboration of Woodward’s group with that of another world leader in organic chemistry, Albert Eschenmoser of the Swiss Federal Institute of Technology (ETH) in Zürich. While the two men had independently begun work on this structure in the late 1950s and early 1960s, an exchange of information between them evolved into a full-scale collaboration by about 1965. Eschenmoser did the final assembly of the two halves—Woodward’s “western” half and his own “eastern” half—in 1972, after some twelve years of work. In 1976, after further refinements, Woodward’s group celebrated the completion of totally synthetic B₁₂ by a sequence of more than one hundred reactions. As with chlorophyll, controlling the relative positions of numerous substituents during construction was essential to a successful outcome.

Instruments and Structure Determination. Woodward garnered fame and recognition not just from syntheses but also from determining the precise chemical structures of complex natural products. His achievements in the field of structure determination were milestones: penicillin (1945), patulin (1948), strychnine (1947), ferrocene (1952), terramycin (1952), cevine (1954), gliotoxin (1958), ellipticine (1959), calycanthine (1960), oleandomycin (1960), streptonigrin (1963), and tetrodotoxin (1964). He never hesitated in adopting the latest analytical instrumentation, which—during the postwar decades—removed much that was chemically difficult from the process of structure determination. In Woodward’s view, instruments gave rapid access to chemical structure and also fostered new ways of thinking about chemistry. Woodward was an early adopter of ultraviolet and infrared spectroscopy. These instrumental techniques altered the traditional, complementary relationship between synthesis and structural determination and reduced the latter to a relatively commonplace procedure. Instruments increased the productivity of organic chemists by removing some of the painstaking work of isolating every intermediate in a synthesis, and they also provided insight into the reaction mechanisms by revealing by-products. Woodward believed that organic chemists should make use of instruments and interpret spectra as part of their daily practice. With this, Woodward claimed for synthetic organic chemists territory that once had belonged to their physical collaborators. At the same time, he labeled those synthetic organic chemists who disagreed with him inefficient and old-fashioned.

Beyond ultraviolet and infrared spectrometry, Woodward was an early promoter of another instrumental technology that would further the transformation of organic chemical practice, namely nuclear magnetic resonance spectroscopy (NMR). First developed in the late 1940s to investigate the properties of nuclei, NMR moved into mainstream organic chemistry a decade later for quite different purposes. NMR was set to take its place alongside infrared spectrometry as a probe of reaction mixtures and isolated products. Woodward was pleased with the results he obtained from the new method, and he believed NMR to be a method well suited to hands-on, regular, practical use by organic chemists.

For Woodward, the 1940s and 1950s were marked by new concepts of molecular shape and interaction and by instruments that gave new access to the molecular realm. Woodward believed that a revolution was underway in chemistry and actively sought to change the way other chemists thought about their subject. The revolution was embodied in both chemical theory and new physical methods. In the first instance, there was an understanding of how functional groups and molecular structures even within the same molecule interacted, what Woodward called nearest-neighbor relationships. This knowledge gave chemists the ability to predict the outcome, or possible outcomes, of reactions based on chemical mechanisms. He promoted mechanistic thinking, a way of conceptualizing chemistry as the interaction between reactants; as the making and breaking of bonds; and as a dynamic, spatially dependent process. In particular, early work on ultraviolet spectra and Arnold Beckman’s introduction in 1941 of a commercial ultraviolet instrument, pushed organic chemists to take note of advances in physical chemistry and instrumentation. Woodward’s innovations proved successful both for himself and for organic chemistry as a discipline.

With regard to structural elucidation, Woodward had two early, high-profile successes in competitive arenas: penicillin and strychnine. Both brought him into conflict with one of the twentieth century’s other great chemists, Oxford University’s Robert Robinson (the 1947 Nobel Prize winner in chemistry). During World War II, Woodward and Robinson had disagreed about the structure of penicillin. By 1945, work on penicillin was well advanced. Based on the data then available, Woodward proposed a structure for penicillin. His position, supporting a B-lactam structure for this antibiotic over Robinson’s oxazolone structure, proved correct.

Key to Woodward’s correct prediction were new spectroscopic data on the drug, made possible by new instruments. In 1948, Woodward published the structure of strychnine, again beating Robinson in the competition to solve this difficult chemical, again with the help of instrumental data. Indeed, Robinson’s relative lack of faith in spectroscopic data marked a generational difference in the chemical community. Though Woodward had correctly deduced the final structure of strychnine, by the time he came to the problem it had been nearly solved, much as in the case of penicillin. In both cases, two serious possibilities remained for the correct structure. Woodward’s task was to distinguish between those for strychnine, as he had for the B-lactam and oxazolone structures of penicillin. Woodward was able to absorb and assimilate an enormous amount of information and, through a mixture of deduction and chemical intuition, identify a solution that fit all the data. Conflicts over penicillin and strychnine—as well as competition over steroid syntheses—personally alienated these two men. Furthermore, Woodward’s avid adoption of instrumentation separated him from Robinson’s generation of chemists.

Woodward’s work in the area of structural elucidation did not end with strychnine. During the 1950s, he collaborated with Pfizer on the structural analysis of a new series of antibiotics: terramycin, aureomycin, and magnamycin. He also solved other prominent puzzles, including the structure of tetrodotoxin, a neurotoxin chemically interesting primarily for its structural complexity. Tetrodotoxin was infamously known as the poison found in the puffer fish, or fugu. While the puffer fish is considered a delicacy, its liver, gonads, and skin contain lethal amounts of tetrodotoxin. This dangerous profile, alongside its structural challenge, made it an appealing target to Woodward. Terramycin, on the other hand, was a medically and commercially important antibiotic whose structure was of great interest for the light it could shed on related compounds; in this regard terramycin was like penicillin. In contrast to penicillin, terramycin research was not sponsored and coordinated by the federal government, but by a pharmaceutical firm. Woodward consulted for Pfizer and worked closely with its team of chemists; the results of their collaboration were published in the Journal of the American Chemical Society. Sir Derek Barton described this work as the most brilliant analysis of a structural puzzle ever performed. Provocative structural puzzles such as tetracycline engaged Woodward, but he never wavered from simplifying them by instrumental insights.

Rules and Generalizations. Woodward’s use of theory— of generalizations—in organic chemistry underpinned his own success in synthesis and structure determination and revolutionized the entire field. Though often diffused through his practical work, these generalizations took shape as formal rules on at least three occasions during Woodward’s career: once in the 1940s with the Woodward rules and twice in the 1960s with the Octant rule and the Woodward-Hoffmann rules. In each instance, Woodward seamlessly mixed physical techniques and data with chemical intuition.

The same analytical instruments that routinely assisted the chemist in the characterization of unknown natural products and synthetic intermediates—compounds made along the way to the final target molecule— also suggested new generalizations about the relationship of structure to physical properties. Woodward’s early theoretical pursuits centered on the use of ultraviolet absorption spectra. In the early 1940s, Woodward published a series of papers correlating the ultraviolet spectra of a, B-unsaturated ketones with their structures. Professionally, these were his first major chemical achievements. These correlations of structure and spectra became known as the Woodward rules (or sometimes the Woodward-Fieser rules in acknowledgment of Louis and Mary Fieser’s contributions to them). Although the Woodward rules drew nothing like the public attention shown his quinine synthesis, they were well noted in the chemical community. Woodward relied heavily on spectroscopic data in

developing his rules for determining the structures of these compounds from their ultraviolet spectra. This was an application for organic chemists, not physicists. Although not unusual for this period, the Woodward rules were among the first of these types of generalizations, and they were quite numerically accurate and comprehensive in scope. They proved very useful in the structural determination of steroids, an important area of research at the time, a coincidence that contributed to the large volume of data already available to Woodward in the literature. Generalizations about chemical structures and physical properties could be expanded as new physical methods were brought into chemical laboratories. Woodward’s contributions lay in recognizing the power of these methods and in interpreting their output—he was not involved in developing the instruments themselves.

Woodward took a keen interest in promoting the method of optical rotatory dispersion (ORD). In 1961, Woodward and four coauthors published their work on the Octant rule, which correlated the ORD spectra of saturated ketones with their structures. (All the experimental data were provided by coauthor Carl Djerassi.)The Octant rule was of wide utility, as many biologically active molecules contained such structures. Thus, with a plot of wavelength—typically in the ultraviolet region of the spectrum—versus angle of rotation, an ORD curve could yield conformational and structural information about a compound that is of interest. Woodward and his collaborators took great pleasure in finding compounds and data that fulfilled all the possible predictions of the Octant rule. The rule proved valuable to the organic chemists in its simple qualitative form. Woodward’s network provided him with all the essentials for his work: moral support and appreciation; data and materials; and the most qualified collaborators. The Octant rule was the result of the highly productive crossroads of chemistry that was Harvard in the 1950s. Both the Woodward rule and the Octant rule were useful generalizations about the relationship between spectra and structure and created new uses for routine spectroscopic measurements. Both foreshadowed Woodward’s later work with Roald Hoffmann, though the earlier generalizations gave information about structures, while the latter was about the Woodward-Hoffmann rules,—work for which Hoffmann shared the Nobel Prize with Kenichi Fukui in 1981.

Woodward’s synthetic work on vitamin B₁₂ led to the recognition and formulation, with Hoffmann, of the concept of conservation of orbital symmetry, explicating a broad group of fundamental reactions. The resulting Woodward-Hoffmann rules were probably the most important theoretical advance of the 1960s in organic chemistry. They were first published serially as a number of papers and then in book form as The Conservation of Orbital Symmetry (1970). The rules were qualitative but firmly based on quantum mechanical arguments. Woodward and Hoffmann considered the absence of mathematical derivations in their work to be its great strength. By basing their rules on symmetry arguments rather than on the numerical approximations required for quantum mechanical calculations, Woodward and Hoffman believed the calculations to be more authoritative.

By employing these rules, chemists could predict the outcomes of a number of synthetically important reaction types. Notably, Hoffmann and Woodward made a crucial generalization that allowed chemists to distinguish the outcome of thermal as opposed to photochemical reactions. The same compound, when activated by heat, would yield a different product than if activated with light. The Woodward-Hoffmann rules predicted the product in each case. Although based on molecular orbital theory, the rules were readily usable by synthetic organic chemists. Representation and thinking in three dimensions were a defining aspect of theory in organic chemistry.

This conceptualization of the molecular realm in terms of shape and space—instead of equation and number—ran through much of Woodward’s work. In a real sense, the Woodward-Hoffmann rules contained much of what made the former’s contributions to synthesis transformative. Of course, they also contained a good deal of Hoffmann’s own special insight into molecular orbital theory and extended Hückel theory. Once again Woodward had provided himself with the best of collaborators.

Woodward’s synthetic work on vitamin B₁₂ led to the recognition and formulation, with Roald Hoffmann, of the concept of conservation of orbital symmetry, explicating a broad group of fundamental reactions. The instrumental techniques of structure determination, the readiness of journals to publish representations of three-dimensional chemical structures, and the availability of molecular model sets gave chemists a revolutionary new vision of what molecules looked like and a new conception of chemical reactions might or might not be possible.

Scientific Style. Woodward paid assiduous attention to detail in every publication and every public lecture. In his work as a teacher and promoter of organic chemistry, Woodward’s talks and lectures were fastidious and well prepared; they were exhibitions of his chemical prowess that often lasted for hours. Using his famous box of colored chalk, Woodward delivered to his audiences thorough chemical expositions that were carefully rehearsed to appear spontaneous and flawless. Precision marked his chemical work as well. Throughout his career, he demonstrated that understanding nearest-neighbor relationships made possible the planning and successful execution of extended sequences of reactions, building chemically complex compounds from the simplest starting materials. His publications were as perfect as he could make them, in both content and appearance. He took many editors, and even publishers, to task for not properly reproducing his diagrams, or worse, substituting other diagrams for his. Woodward’s precision and his successes drew attention from the press and from industry. His career was well documented in the media, and he was much sought after as a chemical consultant. Woodward moved expertly between the realms of academe and industry. During his career, he held consultancies with Lilly, Merck, Mallinckrodt, Monsanto, Polaroid, and Pfizer. In 1963, Ciba, a Swiss drug firm, established the Woodward Research Institute in Basel. Woodward then held dual appointments as Donner Professor of Science at Harvard and director of his institute. Counting both Cambridge and Basel, more than four hundred graduate and postdoctoral students trained in Woodward’s laboratories. Woodward promoted his methods through lectures, through the training of graduate and postdoctoral students, and through his publications.

Woodward possessed superb mental organization and a vast capacity for facts. Unlike some of his peers, he only rarely created new reagents for novel molecular transformations; rather, his genius lay in his ability to marshal all available data to solve even the most intricate of puzzles. He strove to out perform all others and to be the best organic chemist in the world. His competitive nature was a burden and a gift. It was a burden in connection with some of Woodward’s other passions, such as drinking and smoking, both of which may have contributed to his early death from heart disease. But in combination with his passion for chemistry, it was a marvelous gift. Given the set of data on a structure, or the planning of a synthesis, Woodward brought to bear a most remarkable ability to see the entire problem at once and to solve it systematically. His brilliance lay in the quality and depth of his thought, his painstaking preparations, and his chemical intuition. Woodward’s work was central to the chemical thought of the times, and his influence on other organic chemists was arguably greater than that of any of his professional colleagues. Woodward understood molecules as having shapes and reactivities governed by their nearest-neighbor relationships, which enabled chemists to understand the capability of a part of a molecule to undergo a transformation in terms of the properties and locations of the rest of the molecule. This structural understanding allowed the thoughtful practitioner to predict reliably the possible outcomes of chemical reactions. Nevertheless, Woodward’s ideal chemist had to be thoughtful without being fanciful. Logic and, whenever possible, physical data were Woodward’s tools for giving credence to his mechanistic thinking. Truth was paramount and deduction could reveal how chemical transformations took place. Woodward brought a special creativity to his work, as is suggested by the following words from his 1965 Nobel citation: “for his outstanding achievements in the art of organic chemistry.”

BIBLIOGRAPHY

Woodward’s extensive papers are held by the Harvard University Archives, Cambridge, Massachusetts. Both the Benfey and Morris collection and Todd and Cornforth article (cited below) contain a complete bibliography of Woodward’s published works.

WORKS BY WOODWARD

The Mechanism of the Diels-Alder Reaction.” Journal of the American Chemical Society 64 (1942): 3058–3059.

With Warren J. Brehm. “The Structure of Strychnine. Formulation of the Neo Bases.” Journal of the American Chemical Society 70 (1948): 2107–2115.

With Gurbakhsh Singh. “The Structure of Patulin.” Experientia 6 (1950): 238–240.

With Franz Sondheimer, David Taub, Karl Heusler, and W. M. >McLamore. “The Total Synthesis of Steroids.” Journal of the American Chemical Society 74 (1952): 4223–4251.

With F. A. Hochstein, C. R. Stephens, L. H. Conover, et al. “The Structure of Terramycin.” Journal of the American Chemical Society 75 (1953): 5455–5475.

“The Total Synthesis of Strychnine.” Experientia Supplementum Supplement 2 (1955): 213–228.

“Synthesis.” In Perspectives in Organic Chemistry, edited by A. R. Todd. New York: Interscience Publishers, 1956.

With F. E. Bader, H. Bickel, A. J. Frey, et al. “The Total Synthesis of Reserpine.” Tetrahedron 2 (1958):1–57.

“The Total Synthesis of Chlorophyll.” Pure and Applied Chemistry 2 (1961): 383–404.

With W. Moffitt, A. Moscowitz, W. Klyne, et al. “Structure and the Optical Rotary Dispersion of Saturated Ketones.” Journal of the American Chemical Society 83 (1961): 4013–4018.

With M. P. Cava, W. D. Ollis, A. Hunger, et al. “The Total Synthesis of Strychnine.” Tetrahedron 19 (1963a): 247–288.

“Art and Science in the Synthesis of Organic Compounds: Retrospect and Prospect.” In Pointers and Pathways in Research, edited by Maeve O’Connor. Bombay: CIBA of India, 1963b, 23–41.

“The Structure of Tetrodotoxin.” Pure and Applied Chemistry 9 (1964): 49–74.

“Recent Advances in the Chemistry of Natural Products.” [Cephalosporin C] Science 153 (1966): 487–493.

“Recent Advances in the Chemistry of Natural Products.” [Vitamin B₁₂] Pure and Applied Chemistry 17 (1968): 519–547.

With Roald Hoffmann. The Conservation of Orbital Symmetry. Weinheim, Germany: Verlag Chemie, 1970.

OTHER SOURCES

Benfey, Otto Theodor and Peter J. T. Morris, eds. Robert Burns Woodward: Architect and Artist of the World of Molecules. Philadelphia: Chemical Heritage Foundation, 2001. Contains Woodward’s major papers with historical annotations.

Blout, Elkan. “Robert Burns Woodward, April 10, 1917–July 8, 1979.” Biographical Memoirs of the National Academy of Sciences 80 (2001): 3–23.

Slater, Leo B. “Industry and Academy: The Synthesis of Steroids.” Historical Studies in the Physical and Biological Sciences 30 (2000): 443–480.

———. “Woodward, Robinson, and Strychnine: Chemical Structure and Chemists’ Challenge.” Ambix 48 (2001): 161–189.

———. “Instruments and Rules: R. B. Woodward and the Tools of Twentieth-Century Organic Chemistry.” Studies in History and Philosophy of Science 33 (2002): 1–33.

Todd, Alexander R., and John Cornforth. “Robert Burns Woodward.” Biographical Memoirs of the Fellows of the Royal Society 27 (1981): 628–695.

Leo B. Slater

WOODWARD, Robert Burns

(b. 10 April 1917 in Boston, Massachusetts; d. 8 July 1979 in Cambridge, Massachusetts), chemist and winner of the Nobel Prize in chemistry (1965), best known for his synthesis of complex organic substances, including quinine, cholesterol, cortisone, and vitamin B₁₂.

The only child of Arthur Chester Woodward, who died when Woodward was very young, and Margaret (Burns) Woodward, an accountant and realtor, Woodward entered the chemistry degree program at the Massachusetts Institute of Technology (MIT) in 1933 at age sixteen. By the spring of 1934 he had been suspended for a semester owing to his "inattention to formal studies." He spent one semester as an employee of MIT's biology department before being readmitted to study at the school in the fall of 1935. After this rocky start, Woodward went on to receive his B.S. degree in 1936 and his Ph.D. in 1937, both degrees in chemistry. By 1934 he had published his first paper, with W. J. Hall, on the precipitation of barium in a qualitative analysis scheme.

Woodward married Irja Pullman on 30 July 1938; they had two children and were divorced n 1946. On 14 September 1946 he married Eudoxia Muller; the couple had two children and divorced in 1972. After receiving his degree, Woodward taught summer chemistry at the University of Illinois. He joined Harvard University that same year and remained associated with that institution for the rest of his life. From 1937 to 1939 he held a postdoctoral fellow position under the direction of Elmer P. Kohler, from 1938 to 1940 he was a junior prize fellow of the Harvard Society of Fellows, and from 1941 to 1944 he held the title of instructor of chemistry. From 1944 to 1946 he was assistant professor, and from 1946 to 1950 he was associate professor. In 1950 he was promoted to professor, a title he held until 1953, when he was named Morris Loeb Professor of Chemistry. Finally, in 1960, he was named Donner Professor of Science, a title he held until his death. The Donner professorship allowed him to devote all his time to research.

In the early 1940s Woodward worked on correlating the ultraviolet spectra of steroid compounds with their molecular structure through a series of rules (Woodward's Rules) later presented in a series of four papers published from 1940 to 1942. One of his first synthetic achievements was the total synthesis of quinine in 1944, starting with simple materials, which he achieved in collaboration with William Doering. During World War II he participated in war-related research on quinine and penicillin, two drugs in short supply because of wartime conditions. Although his work did not produce synthesis that could be scaled up, this experience made his name known throughout the world.

For his research, Woodward chose problems that had practical applications—mainly the synthesis of natural products—but whose solutions were generally regarded as virtually impossible. He recognized that physical measurement had greater power than did chemical reactions in providing information on chemical structure. He was one of the major contributors to the instrumental revolution that extensively used instruments and techniques (including infrared spectroscopy, nuclear magnetic resonance, and mass spectroscopy) after World War II. The combination of instrumental techniques and classical chemical methods allowed the identification and characterization of organic substances that had been impossible or very difficult to analyze before.

Woodward chose to synthesize compound after compound of increasing complexity, becoming a legendary architect of molecules. By the time of his death he was generally regarded as the greatest figure in American organic chemistry and as the father of modern organic synthesis, as his achievements are unparalleled by those of any organic chemist of the twentieth century. Woodward did not limit his work to the area of organic synthesis. His achievements in the field of structure determination were demonstrations of new approaches and reasoning that have guided others in the field. He was the first to propose and show the fused-ring structure of the penicillins (1945), and he established the structures of the broad-spectrum antibiotics terramycin and aureomycin, as well as other compounds, such as strychnine (1947), calycanthine (1960), oleandomycin (1960), streptonigrin (1963), and tetrodotoxin (1964). Although his research work started in the 1930s, Woodward's contributions to the field of organic chemistry continued at a strong pace in the 1960s and even later on. In 1963 Woodward assumed the directorship of the Woodward Research Institute at Basel, Switzerland, named after him and founded by the Ciba Ltd. pharmaceutical company, a unique honor for a research scientist. From that point on he directed research activities in both Cambridge, Massachusetts, and Basel. The institute closed shortly after his death.

In 1965 he produced what the majority regard as his most significant contribution to organic chemistry. Together with Roald Hoffmann (Nobel Prize winner in 1981) he proposed the principle of conservation or orbital symmetry. The Woodward-Hoffman rule was used to predict and explain the course and stereochemistry of certain types of organic reactions, and profoundly changed the thinking of chemists. This has remained the most frequently cited of his publications.

Woodward demonstrated that the understanding of chemical reaction mechanisms made possible the planning and successful execution of extended sequences of reactions to build up complex compounds in the laboratory. He proposed the correct biosynthetic pathway to the steroidal hormones in living organisms and also synthesized cholesterol and cortisone (1951), chlorophyll (1960), tetracycline (1962), cephalosporin C (1965), and vitamin B₁₂ (1971). This last synthesis followed a sequence of more than one hundred intermediate reactions. Many of his syntheses have worked out so well that they have become the basis for the commercial manufacture of synthetic products that are less expensive and more accessible than the natural ones.

From 1966 to 1971 Woodward was a member of the Corporation of MIT, and from 1973 to 1974 he was Todd Professor of Chemistry and a fellow of Christ's College in Cambridge. He was also a member of the National Academy of Sciences and the Royal Society and an honorary member or fellow of several other scientific societies in various countries. He held more than twenty honorary degrees, including those from the University of Cambridge (1964), Brandeis University (1965), Israel Institute of Technology (1966), and Université de Louvain (1970). He received the Davy Medal of the Royal Society (1959), the National Medal of Science (1964), the Nobel Prize (1965), and Japan's Order of the Rising Sun (1970).

Woodward died of a heart attack in 1979. Keeping active in research, Woodward at the time of his death was working on the synthesis of erythromycin A. The synthesis was completed in 1980 by Yoshito Kishi, who had taken Woodward's place as principal investigator in the project.

Biographical works are Alexander Todd and John Cornforth, "Robert Burns Woodward," Biographical Memoirs of Fellows of the Royal Society 27 (1981); and Mary Ellen Bowden and Theodor Benfey, Robert Burns Woodward and the Art of Organic Synthesis (1992). An obituary is in the New York Times (10 July 1979).

Maria Pacheco

Woodward, Robert Burns

AMERICAN CHEMIST
1917–1979

Robert Burns Woodward is generally recognized as the leading organic chemist of the twentieth century. He and his coworkers determined the structures of biologically active natural products, developed theoretical rules for predicting the outcomes of organic reactions, and synthesized some of the most complex molecules known to humans. In 1965 Woodward received the Nobel Prize in chemistry for his "outstanding achievements in the art of organic synthesis."

Woodward was born on April 10, 1917, in Boston, Massachusetts. His father, Arthur Woodward, died of influenza eighteen months later. His mother, Margaret Burns Woodward, remarried, and the family eventually settled in Quincy, Massachusetts. Young Woodward fell in love with chemistry while doing experiments with his boyhood pals in Quincy: He ate, drank, and slept chemistry and dreamed up ways to synthesize the antimalarial drug quinine.

At age sixteen Woodward entered the Massachusetts Institute of Technology (MIT) and raced through their chemistry studies in record time: It took him three years to get his B.S. degree (in 1936), and only one to get his Ph.D. (in 1937). After a summer stint at the University of Illinois, Woodward joined the chemistry department at Harvard University, where, for the next forty-two years, he urged chemists worldwide to accept the creative challenges that organic synthesis had introduced.

Woodward was always attracted to molecules with novel structures or interesting biological activities. He attacked the synthesis of steroids during his years at MIT, and with American chemist Bill Doering in 1944, he published the paper that described the fulfillment of his boyhood dreams: the synthesis of quinine. What Woodward and Doering actually reported was the twenty-step synthesis of a quinotoxine, a molecule whose conversion into quinine had been reported by the German chemist Paul Rabe in 1918. Rabe's reported synthesis of quinine was later discredited, but that in no way diminished the impact of Woodward's beautifully planned synthesis of quinotoxine.

After quinine, Woodward and his coworkers synthesized a series of increasingly complex natural products, such as reserpine , lysergic acid , chlorophyll , cephalosporin C , vitamin B ₁₂, and erythromycin . Each synthesis had its own unique set of challenges, but Woodward's insistence on careful planning, great attention to detail, and observation shines through in all of them. He took full advantage of the latest advances in organic stereochemistry and reaction mechanisms and pushed for the use of spectroscopic and analytical tools to determine the structures of reaction products. Woodward used the same approach to determine the structures of natural (plant- or animal-derived) and synthetic products. During World War II he was asked to join the team of scientists that was investigating the miracle antibiotic penicillin. In characteristic Woodward fashion, he summarized all of the available chemical and spectroscopic data and was the first to propose the β -lactam structure for penicillin. After penicillin came strychnine, tetracycline, and, with its unprecedented iron-sandwich structure, ferrocene.

Woodward saw organic synthesis as a way to advance science and to solve practical problems. One need only look to his vitamin B₁₂ work to illustrate this. A reaction that Woodward had planned to use as part of the early stages of the synthesis of vitamin B₁₂ gave a product with unexpected stereochemistry, leading the perplexed Woodward to look for similar reactions in the organic literature. He found them, and with Roald Hoffmann, a theoretical chemist at Harvard, formulated what are now known as the Woodward-Hoffmann rules for the conservation of orbital symmetry. These rules explained the outcomes of a series of seemingly unrelated chemical reactions and correctly predicted the outcomes of many others. For his contributions to the orbital symmetry rules, Hoffmann shared the 1981 Nobel Prize in chemistry with Kenichi Fukui of Japan, who had reached similar conclusions independently. Woodward died before the 1981 Nobel Prize was awarded, and had he lived longer, he certainly would have received his second Nobel Prize.

Woodward also recognized in the drive of scientists to synthesize molecules something that spoke to the spirit of people. According to Woodward: "The structure known, but not yet accessible by synthesis, is to the chemist what the unclimbed mountain, the uncharted sea, the untilled field, the unreached planet, are to other men" (Woodward, p. 63).

Woodward died from a heart attack on July 8, 1979, but not before teaching generations of chemists the fine art of organic synthesis.

see also Chemical Reactions; Organic Chemistry; Penicillin; Synthesis, Chemical.

Thomas M. Zydowsky

Bibliography

Benfey, Otto Theodor, and Morris, Peter J. T., eds. (2001). Robert Burns Woodward: Architect and Artist in the World of Molecules. Philadelphia: Chemical Heritage Foundation.

James, Laylin K., ed. (1993). Nobel Laureates in Chemistry 1901–1992. Washington, DC: American Chemical Society; Chemical Heritage Foundation.

Woodward, Robert Burns (1963). "Art and Science in the Synthesis of Organic Compounds: Retrospect and Prospect." In Pointers and Pathways in Research, ed. Maeve O'Connor. Bombay: CIBA of India.