The Nobel Prize in Chemistry 1990
Elias James Corey
History of Organic Syntheses
Origin, Development, Organization, Operations
Prior to 1914, the industrial production of organic chemicals in the United States was very limited both in the number of compounds and quantities. Petroleum refining was primarily by distillation; there were no cracking processes and no petro-chemical plants. Replacement of beehive coke ovens by byproduct coking ovens recover aromatic chemicals had just started. Most organic compounds were imported from Europe; research chemical for use in universities and industrial laboratories were imported from Germany (Kahlbaum's Chemicals), Great Britain (Boots Ltd.), and France. There were only a few small scientific supply houses that distributed small amounts of imported chemicals. Indeed, organic research in universities and industry was limited to a few schools and very few companies (1). In 1914, the outbreak of the war in Europe led to embargoes, blockades, and destruction of shipping, which meant that chemical supplies in the United States were quickly exhausted. The escalation of World War I (2), with United States involvement in 1917, demanded immediate production of tremendous amounts of food, grains, meat, oils, coke, iron, steel, nonferrous metals, ships, trucks, guns, tanks, airplanes, gasoline, kerosene, lubricating oils, war gases, phenol, toluene, glycerol and nitric acid, protective agents, dyes, and drugs. Since all the industrial plants and laboratories were in use, the chemistry staff at the universities began to increase their "student preps" to make chemicals needed for research. Clarence G. Derick of the Chemistry Department at the University of Illinois in Urbana, actually initiated "Summer Preps" with about five students in 1914 before the war started. In the summer of 1915, Ernest H. Volwiler, a graduate student, joined Derick's prep group and was placed in charge during 1916 and 1917. Oliver Kamm, a member of the teaching staff after 1915, also helped in the prep work.
Carl S. Marvel, who started graduate study in 1915, began making compounds in June of 1916 and worked full time until August 1919. He was a most skillful operator and "speedily" (3) built a reputation for modifying poor procedures so that they would work. Roger Adams joined the chemistry staff in 1916, and enthusiastically took up the idea of synthesizing research chemicals in larger quantities: one-half to several kilos. The compounds made during 1917 - 1918 were those needed in the World War I effort. Dr. William A. Noyes, Head of the Chemistry Department of the University of Illinois, persuaded the Illinois administration to provide a revolving "Organic Chemical Manufactures" fund, which was used to purchase chemicals and to pay the summer prep chemists. These graduate students, numbering from 10 to 12, worked full time, 8-10 h/day for the 8-week summer session. Their pay started at 25cents/h in 1915 and gradually rose over the years, but the students received one unit of graduate credit for their work. Adams and Marvel put the operation on a sound cost basis by requiring all students making preps to keep careful notebook records of the cost of chemicals, apparatus, and the time needed for each preparation. The compounds made were then sold to anyone who needed them and the money returned to the fund. In 1917 Roger Adams (4) published a list of 43 organic chemicals available for purchase, and in 1918 a note listing 59 compounds as available at once, 37 to be made, and 29 more that would probably be available by the end of the summer. When the importation of dyes for sensitizing photographic film stopped in 1914, Hans T. Clarke, who had just joined the research division of the Eastman Kodak Co., was called on to synthesize the dyes. The lack of organic raw materials for this project and others led Clarke and C. E. K. Mees to recommend to George Eastman the formation of an Eastman Organic Chemicals Division. It would assist research chemists by repackaging commercial chemicals in small lots, purifying industrial chemicals, and synthesizing any needed but nonavailable chemicals. Clarke visited Adams and Marvel at the University of Illinois and spent several weeks observing how "Summer Preps" was operated. The Eastman Organic Chemicals Division began operations at the end of 1918 and contributed greatly to the advancement of organic chemical research. Its synthesis group worked out many good procedures and designed unique laboratory apparatus and techniques. After Clarke left in 1928, William H. Hartman took charge.
The production and distribution of Pyrex laboratory glassware by the Corning Glass Works, Corning, New York in 1915 was a very important factor in the preps work. Pyrex? lab ware was far superior to the old lime-soda glass against breakage by mechanical or thermal shock, and resistance to reagents. It surpassed even the Jena glass that had been imported from Germany prior to 1924. Pyrex? round bottomed reaction flasks became available in large 5, 12, and 22L and smaller sizes. Glass bowing with Pyrex was easily mastered; hence, special distilling flasks, fractionating columns, the now familiar three-necked flasks for use with a mechanical stirrer, and the reflux condenser and dropping funnel were made and used as standard items in the prep labs. Also in 1914, when shipments of laboratory porcelain ware from Germany ceased, the Coors Porcelain Company of Golden, Colorado, converted their ovenware and pottery plant to chemical porcelain ware. High-quality Coors U.S.A? glazed laboratory porcelain evaporating dishes, Buchner funnels, casseroles, mortars and pestles became available. The armistice of November 11, 1918 ended the war but did not end the shortage of research chemicals. Hence, the synthesis of special research compounds, not available commercially, was continued during the summers under the direction of Carl S. Marvel who became a member of the Organic faculty at Illinois after completing his graduate study. The expanding organic and biochemical research divisions of universities and commercial concerns requested the compounds to be made in the "preps" lab. About 1940, Harold R. Snyder took over operations from Carl S. Marvel and carried the synthetic work through the difficult World War II years (1941-1946). The prep group made unclassified starting compounds and intermediates needed to be any of the various wartime agencies. Leonard E. Miller of the Organic Chemistry Department at Illinois directed the Summer Prep work during 1948-1950. After 1950 the program was discontinued because by that time many organic and biochemical supply companies had been established for the synthesis of specialty chemicals. The Summer Prep operation had provided a superior education for over 500 graduate students (and some seniors) for 36 years. Other universities also incorporated advanced organic preparations in their graduate programs. These well-trained chemists contributed to the pool of expert synthetic organic chemists for the organic chemical industries that had established real research laboratories from about 1922 onward.
The foregoing account is incomplete, however. What were the sources of the procedures, operating directions, techniques for carrying out reactions, isolating, and purifying the products? Most of the compounds made were not new; they had been described in the various journals, both American and European; some were described in patents. Beilsein's "Handbuch" gave only a sentence or two summarizing the method. Houben-Weyl's "Methoden" were likewise limited. The previous literature procedures were so incomplete that frequently a synthesis, using what seemed to be a simple reaction, became a research problem of weeks or months. Four laboratory manuals available in 1915-1916 that proved helpful were Ludwig Gatterman's Die Praxis der organischen Chemie, 1st ed., 1894, later revised by H. Wieland (21st to 24th eds.). L. Vanino's Handbuch der preparativen Chemied, Part II, summarized the literature preparations of several hundred organic compounds. E. Fischer's Anleitung zur Darstellung Organische Preparative (1908) was useful as was J. B. Cohen's Practical Organic Chemistry, 2nd ed. (1908). These manuals, designed for the first course in organic chemistry, were very useful but limited in scope. It was common experience that many procedures in the chemical literature could not be duplicated; indeed, certain procedures were hazardous. Hence, from the very beginning of Summer Preps in 1914, and continuing through all the years, each student had to write out in detail the procedures they used, add precautionary notes, and references to the literature. The procedures were carefully filed and used in succeeding years; each prep person added their observations plus data on yield and purity. The first batch of directions culminated in the publication of four pamphlets; Organic Chemical Reagents, by Roger Adams, O. Kamm, and C. S. Marvel. These were bulletins published by the University of Illinois Press, Urbana, Illinois, from 1919 to 1922, containing directions for preparing a total of 111 compounds. Although not advertised, these bulletins were quickly sold out, as their availability became known at meetings of the Organic Division of the ACS and from citations in articles published in the journals.
The success of these little booklets, and the accumulation of several hundred additional good directions for the syntheses of organic compounds, led Roger Adams (6) to consider the publication of an annual volume of satisfactory methods. He discussed this project with James B. Conant of Harvard, Hans T. Clarke of Eastman Kodak, and Oliver Kamm of Parke Davis. The unique feature was the preparation of sets of directions which, if carefully followed, could be duplicated by an advanced student (senior or graduate). Moreover, before publication, each preparation must be checked in the laboratory of an editor and always in a laboratory other than that of the submitter. In addition, the fact that this original group represented both industrial and university laboratories constituted excellent support for the project. The first annual volume of Organic Syntheses was published in 1921. The procedures were collected, checked, and edited by the first Board of Editors; Roger Adams (University of Illinois), James B. Conant (Harvard), Hans T. Clarke (Eastman Kodak Co.), and Oliver Kamm (Parke Davis). Publication was made possible through the friendship of Mr. Edward P. Hamilton of John Wiley & Sons, Inc. This was a most unusual publication venture for those times; there was no assurance that the publisher could recover the costs of the printing, binding, and distribution of this slender little "pamphlet" of 84 pages.
Each of the first four members of the Editorial Board acted as Editor-in-Chief of one or two volumes. Then the Editorial Board was expanded during the next 10 years to include Carl S. Marvel (University of Illinois), Frank C. Whitmore (Northwestern University), and Carl R. Noller (Stanford). In 1929, C. F. H. Allen was appointed Secretary to the Board when the number of chemists contributing preparations rose from 8 to 24, thereby causing a great increase in correspondence and record keeping. Each of the new editors took turns in preparing volumes. The policy of changing membership on the editorial board by selecting additional organic chemists to serve on the active board and moving those who had already served a term and edited one or more volumes to an Advisory Board of Editors was adopted. A new secretary to the Board of Editors was appointed every 10 years. Beginning with Collective Volume 11 the retiring secretary became the Editor-in-Chief of the collective volume for the years in which he served. Thus, this project involved many different university and industrial research chemists so as to make it representative of as many institutions as possible. These policies continue today (6). In addition to the first 8 editors mentioned above, there are 51 other organic chemists who have served on the Boards of Editors. Their names are listed on the title page of this volume. They are an enthusiastic group of chemists working with their students in universities and coworkers in industry, dovetailing their regularly assigned work with writing up procedures, and editing and checking them in their "spare time." None of the contributors of procedures, editors, or checkers received any pay or any of the royalties from the sale of the volumes. The starting chemicals needed for checking procedures were contributed by the chemistry departments of the universities or the research departments of industrial companies, and the products of the syntheses then were added to the research stocks of the contributors or editors. The products were always more valuable than the crude commercial starting materials so this was an economical way of getting valuable intermediates for research.
From 1921 to 1939 the Organic Syntheses Editorial Boards operated in a very informal fashion. However, changes in the income tax laws led to the formal incorporation of Organic Syntheses as a "Membership Corporation" under the laws of the State of New York on December 11, 1939. The certificate specified: The purpose for which the corporation is to be formed are the following: To collaborate in the writing, editing, and causing to be published from time to time of books and articles dealing with the methods of preparation of organic chemicals and other subject matter connected with organic chemistry; the royalties or other proceeds received from them to be placed in a fund, the principal and income thereof to be used exclusively (apart from bona fide expenses of operation of the corporation) for the establishment of fellowships, scholarships and other benefits for students in organic chemistry in various colleges and universities; to acquire property both read and personal, for the conduct of its corporate purposes. The corporation is to be organized and operated exclusively for strictly scientific, educational and charitable purposes, and not for pecuniary profit, and no part of its net earnings will insure to the benefit of any member, director, or officer other than as reasonable compensation for services in effecting one or more of such purposes, or to any other individual except as a proper beneficiary of its strictly charitable purposes, and no part of its activities will be the carrying on of propaganda or otherwise attempting to influence legislation. The First Board of Directors consisted of Roger Adams (University of Illinois), President; William H. Hartman (Eastman Kodak Co.), Treasurer; A. Harold Blatt (Queens College), Secretary to the Editorial Board; Louis Fieser (Harvard), and John R. Johnson (Cornell). Royalties from the sale of the Annual Volumes and Collective Volumes were paid to the Organic Syntheses treasurer and used to pay postage and typing expenses in collecting preparations and editing the volumes. Periodically any balance in the fund was invested in stocks in the growing chemical industries. A set of By-Laws of the Corporation was adopted and filed with the State of New York. They were amended from time to time as conditions changed, but always conformed to the above-cited nonprofit purposes. The Board of Directors for 1992-1994 consists of the following officers and members:
My birth in July 1928 in Methuen, Massachusetts was followed just eighteen months later by the death of my father, Elias, a successful business man in that community 30 miles north of Boston. My mother, Fatina (n?e Hasham), changed my name from William to Elias shortly after my father's passing. I do not remember my father, but all his friends and associates made it clear that he was a remarkably gifted and much admired person. I have always been guided by a desire to be a worthy son to the father I cannot remember and to the loving, courageous mother who raised me, my brother, and two sisters through the trials of the Depression and World War II. My grandparents on both sides, who emigrated from Lebanon to the United States, also knew how to cope with adversity, as Christians in a tragically torn country, under the grip of the Ottoman empire.
In 1931, our family grew to include my mother's sister, Naciby, and her husband, John Saba, who had no children of their own. We all lived together in a spacious house in Methuen, still a gathering place for family reunions. My uncle and aunt were like second parents to us. As a youngster I was rather independent, preferring such sports as football, baseball and hiking to work. However, when my aunt, who was much stricter than my mother, assigned a household chore, it had to be taken seriously. From her I learned to be efficient and to take pleasure in a job well done, no matter how mundane. We were a very close, happy and hardworking family with everything that we needed, despite the loss of my father and the hard economic times. Uncle John died in 1957, and too soon afterwards, in 1960, my aunt passed away. My mother died in 1970 at the age of seventy. They all lived to see each of the four children attain a measure of success.
From the ages of five to twelve I attended the Saint Laurence O'Toole elementary school in Lawrence, a city next to Methuen, and was taught by sisters of the Catholic order of Notre Dame de Namour. I enjoyed all my subjects there. I do not remember ever learning any science, except for mathematics. I graduated from Lawrence Public High School at the age of sixteen and entered the Massachusetts Institute of Technology, just a few weeks later, in July, 1945, with excellent preparation, since most of my high school teachers had been dedicated and able. Although my favorite subject was mathematics, I had no plan for a career, except the notion that electronic engineering might be attractive, since it utilized mathematics at an interesting technological frontier. My first courses at M.I.T. were in the basic sciences: mathematics, physics and chemistry, all of which were wonderful. I became a convert to chemistry before even taking an engineering course because of the excellence and enthusiasm of my teachers, the central position of chemistry in the sciences and the joy of solving problems in the laboratory. Organic chemistry was especially fascinating with its intrinsic beauty and its great relevance to human health. I had many superb teachers at M.I.T., including Arthur C. Cope, John C. Sheehan, John D. Roberts and Charles Gardner Swain. I graduated from M.I.T. after three years and, at the suggestion of Professor Sheehan, continued there as a graduate member of his pioneering program on synthetic penicillins. My doctoral work was completed by the end of 1950 and, at the age of twenty-two, I joined the University of Illinois at Urbana-Champaign as an Instructor in Chemistry under the distinguished chemists Roger Adams and Carl S. Marvel. I am forever grateful to them for giving me such a splendid opportunity, as well as for their help and friendship over many years.
Because my interests in chemistry ranged from the theoretical and quantitative side to the biological end of the spectrum, I decided to maintain a broad program of teaching and research and to approach chemistry as a discipline without internal boundaries. My research in the first three years, which had to be done with my own hands and a few undergraduate students, was in physical organic chemistry. It had to do with the application of molecular orbital theory to the understanding of the transition states for various reactions in three dimensional (i.e. stereochemical) detail. The stereoelectronic ideas which emerged from this work are still widely used in chemistry and mechanistic enzymology. By 1954, as an Assistant Professor with a group of three graduate students, I was able to initiate more complex experimental projects, dealing with the structure, stereochemistry and synthesis of natural products. As a result of the success of this research, I was appointed in 1956, at age twenty-seven, as Professor of Chemistry. My research group grew and the scope of our work broadened to include other topics: enantioselective synthesis, metal complexes, new reactions for synthesis and enzyme chemistry. The pace of discovery accelerated.
In the fall of 1957, I received a Guggenheim fellowship and my first sabbatical leave. It was divided between Harvard, to which I had been invited by the late Prof. Robert B. Woodward, and Europe. The last four months of 1957 would prove eventful. In September, shortly after the beginning of my stay at Harvard, my uncle John passed away. At least I had been lucky enough to have seen him just two days before. I was deeply affected by the loss of this fine and generous man whom I loved as a real father. In solitude and sadness I returned to my work and a very deep immersion in studies which proved to be pivotal to my future research. In early October several of the key ideas for a logical and general way of thinking about chemical synthesis came to me. The application of these insights led to rapid and unusual solutions to several specific synthetic problems of interest to me at the time. I showed one such plan (for the molecule longifolene) to R. B. Woodward and was pleased by his enthusiastic response. Later in 1957 I visited Switzerland, London and Lund, the last as a guest of Prof. Karl Sune Bergstr?m. It was at Lund, in Bergstr?m's Department, that I became intrigued by the prostaglandins. Our research in the mid 1960's led to the first chemical syntheses of prostaglandins and to involvement in the burgeoning field of eicosanoids ever since.
In the spring of 1959 I received an offer of a Professorship at Harvard, which I accepted with alacrity since I wanted to be near my family and since the Chemistry Department at Harvard was unsurpassed. The Harvard faculty in 1959 included Paul D. Bartlett, Konrad Bloch, Louis F. Fieser, George B. Kistiakowski, E. G. Rochow, Frank H. Westheimer, E. B. Wilson and R. B. Woodward, all giants in the field of Chemistry. Roger Adams, who was always very kind and encouraging to me, gave his blessing even though years before he had declined a professorial appointment at Harvard. I have always regarded the offer of a Professorship at Harvard as the most gratifying of my professional honors.
At Harvard my research group grew in size and quality, and developed a spirit and dynamism which has been a continuing delight to me. I was able to start many new scientific projects and to teach an advanced graduate course on chemical synthesis. Using the concepts of retrosynthetic analysis under guidance of broad strategies, first-year graduate students could be taught in just three months to design sophisticated chemical syntheses. My research interests soon evolved to include the following areas: synthesis of complex, bioactive molecules; the logic of chemical synthesis; new methods of synthesis; molecular catalysts and robots; theoretical organic chemistry and reaction mechanisms; organometallic chemistry; bioorganic and enzyme chemistry; prostaglandins and other eicosanoids and their relevance to medicine; application of computers to organic chemical problems, especially to retrosynthetic analysis. My personal scientific aspirations can be similarly summarized: to be creative over a broad range of the chemical sciences; to sustain that creativity over many years; to raise the power of research in chemistry to a qualitatively higher level; and to develop new generations of outstanding chemists.
In September, 1961, I married Claire Higham, a graduate of the University of Illinois. We have three children. David Reid is a graduate of Harvard (A.B. 1985) and the University of California, Berkeley (Ph.D., 1990), who is currently a Postdoctoral Fellow in Chemistry/Molecular Biology at the University of California Medical School at San Francisco. Our second son, John, graduated from Harvard (A.B. 1987) and the Paris Conservatory of Music (1990) and is now carrying out advanced studies in classical music composition at the latter institution. Our daughter, Susan, graduated from Harvard with a major in anthropology (A.B. 1990) and plans graduate work in Education. Claire and I live near the Harvard Campus in Cambridge, as we have for nearly thirty years. My leisure interests include outdoor activities and music.
I am very proud of the many graduate students and postdoctoral fellows from all over the world who have worked in my research group. Their discoveries in my laboratory and their subsequent achievements in science have been a source of enormous satisfaction. The Corey research family now includes about one hundred fifty university professors and an even larger number of research scientists in the pharmaceutical and chemical industry. It has been my good fortune to have been involved in the education of scholars and leaders in every area of chemical research, and especially, to have contributed to the scientific development of many different countries. My research family has been an extraordinarily important part of my life. Much of the credit for what I have achieved belongs to that professional family, my wonderful teachers and faculty colleagues, and not least, to my own dear personal family.
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