FIESER, LOUIS FREDERICK

(b. Columbus, Ohio, 7 April 1899; d. Cambridge, Massachusetts, 25 July 1977)

organic chemistry.

Fieser, son of Louis Frederick Fieser and Martha Victoria Kershaw, attended Columbus schools and then enrolled at Williams College, where he received a B. A. in 1920. He won letters in varsity football, basketball, and track. Harvard University awarded him a doctorate in 1924. After a year of postdoctoral research in Germany and England, he taught at Bryn Mawr from 1925 to 1930. Among his students was Mary Peters, a premedical student who became a chemist under his influence; they married on 21 June 1932. In 1930 Fieser accepted a Harvard appointment as assistant professor, becoming full professor in 1937 and Sheldon Emery Professor of Organic Chemistry in 1939. He retired in 1968.

Famous as a preparative chemist, Fieser served on the editorial boards of Organic Syntheses and Organic Reactions and was one of the most prolific contributors to the former. Among his many honors was election to the National Academy of Sciences in 1940. Because of his work with chemical carcinogens, the surgeon general in 1963 appointed Fieser to his committee to investigate the relation between smoking and health. Its 1964 report concluded that smoking is a major cause of lung cancer, chronic bronchitis, pulmonary emphysema, and coronary artery disease. Ironically, Fieser was a heavy smoker and in 1965 underwent surgery for removal of a lung tumor; he also suffered from emphysema and bronchitis. Following his surgery he became a campaigner against smoking.

At Harvard, Fieser studied under James B. Conant, several of whose students became leaders in physical organic chemistry. Fieser, however, loved the active life of the experimenter and became primarily a chemist of natural products and their synthesis. His work with Conant resulted in six joint publications (1922–1925). His dissertation, on the reduction-oxidation potentials of quinones, set new standards of accurate experimentation and is a classic in its field. It had an addendum, the result of independent work in Gregory Baxter’s gas analysis course. Fieser used his knowledge of quinones to invent “Fieser’s solution,” a quinone-containing reagent used to absorb oxygen from other gases and the subject of his first solo publication (1924).

Under Conant’s direction Fieser prepared many known and unknown quinones; measured the reduction potentials as a means to uncover relationships between structures and energy of reactions; and determined the effect of ortho-, meta-, and para-directing substituents on the potentials. This work quickly gave him a reputation as an expert in quinone chemistry.

While at Bryn Mawr, Fieser extended his studies, becoming increasingly interested in problems of synthesis, as he prepared more and more quinones. During his five years there, he wrote outstanding papers that placed him in the top rank of American organic chemists. He studied quinones in relation to aromatic systems, the nature of aromaticity, tautomeric forms, and reduction potentials as a measure of the stability of quinonoid structures. In 1927 he achieved the first synthesis of the yellow pigment lapachol, a naphthoquinone with an isoprenoid side chain that was significant for his later work on vitamin K and antimalarials.

The lapachol work stemmed from Fieser’s association with Samuel Hooker, an English-born chemist employed at a sugar refinery in Philadelphia. Between 1889 and 1896 Hooker had isolated and elaborated the structures of many natural quinones, including lapachol, and possessed many unique samples. Fieser needed types of quinones that only Hooker had, and he collaborated with Hooker from 1926 until the latter’s death in 1935. Hooker bequeathed his samples to Fieser, who wrote or experimentally completed eleven of Hooker’s posthumous papers and used the samples in his own researches.

Mary Fieser was a member of her husband’s research group at Harvard. She began graduate study there, but the negative attitude of some members of the chemistry department toward women chemists dissuaded her from continuing. Her position in her husband’s research group was secure, however, and she engaged in much of the quinone and steroid research, including the development of a new synthetic route to the anthraquinones (1935). Her name appears as coauthor of thirty-six papers.

The best-known synthesis associated with Fieser was achieved in 1939. In that year Henrik Dam, P. Karrer, Edward Doisy, and others had isolated vitamin K₁ as a water-insoluble yellow oil. Fieser thought that it might be a naphthoquinone related to lapachol. Using absorption spectra, composition, and degree of unsaturation, he inferred a structure of 2-methyl-3-phytyl-1, 4-naphthoquinone, the phytyl being a large hydrocarbon side chain of four fivecarbon isoprenoid units and identical to the hydrocarbon part of the alcohol phytol (a constituent of alfalfa and green leaf pigment). Fieser then developed a simple synthesis by directly combining the methylhydroquinone with phytol and oxidizing the product to the quinone. Although the reaction produced a considerable amount of by-product, he easily isolated the vitamin K₁ in every way, including biological activity. Fieser protected the synthesis with a patent assigned to the Research Corporation, which in turn licensed Merck to manufacture the vitamin.

His studies of phenanthrene quinones in the 1920’s led Fieser to polycyclic systems and the steroids. He developed a new route to polynuclear aromatic types containing the phenanthrene ring system. Soon after moving to Harvard in 1930, he learned that the Royal Cancer Institute in London had found that one of the compounds synthesized by him in 1929, 1, 2, 5, 6-dibenzanthracene, induced cancerous growth in mice; the compound thus became the first known pure carcinogen. Fieser moved quickly into research on polycyclic hydrocarbons and was soon a leader in this area, making several substances available for medical study. His syntheses involved many steps and set such high standards of experimentation that his work laid the foundation for Harvard’s preeminence in organic synthesis.

The group at the Royal Cancer Institute also tested methylcholanthrene, first isolated in Germany in 1933 as a bile acid derivative. It proved to be the most potent carcinogen yet known. In 1935 Fieser synthesized it, using the then little-used Elbs reaction, a pyrolytic cyclodehydration of diaryl ketones. He had first used this reaction in the 1920’s and thereafter used it to prepare cholanthrenes and various carcinogenic hydrocarbons, finding it to be the best means to obtain important polycyclic hydrocarbons. The awareness that polynuclear hydrocarbons can evoke tumors in animals opened a promising new field of investigation in cancer research. Fieser synthesized carcinogens in the benzpyrene, phenanthrene, and benzanthracene series, and in 1941 received the Katherine Berkan Judd Prize for cancer research.

His researches on condensed ring systems made Fieser the most qualified person to compile a major reference work for the American Chemical Society’s Scientific and Technologic Monographs, The Chemistry of Natural Products Related to Phenanthrene (1936), of which the confused and undeveloped field of steroid chemistry constituted a large part. He elucidated and critically reviewed the field, along with sections on alkaloids and resin acids. Thesecond and third editions followed in 1937 and 1949. By the 1950’s, research in steroid chemistry had become so extensive—with many important studies on hormones, vitamins, and animal and plant sterols—that the field completely took over the fourth edition, titled Steroids (1959). Like the third edition it was written with Mary Fieser and became an indispensable reference work.

The Fiesers had an intimate knowledge of steroids and contributed to steroid chemistry in terms of its stereochemistry, its reaction mechanisms, the partial synthesis of steroid derivatives, the isolation of sterols associated with cholesterol, the synthesis of the first i-steroids in the ergosterol series, and the nomenclature used to designate the conformation of substituents in the steroid nucleus.

During World War II, Fieser suspended his teaching and research program to engage in the war effort. Working under contract with the National Defense Research Committee, he led a large group in research on explosives, incendiaries, and antimalarials. The Harvard group was intact for four years and produced a number of key weapons.

Fieser first synthesized a number of nitro compounds and evaluated them as explosives. He then turned his attention to divinylacetylene, a Du Pont substance used as a drying oil that often exploded during its manufacture. Divinylacetylene changed from a liquid to a gel on standing and retained its sticky consistency on burning. Fieser thought it might be useful as an explosive or as a spontaneously flammable substance. He soon found, however, that rubber dissolved in hydrocarbons made a superior incendiary. He prepared rubber-gasoline gels and tested them behind Harvard Stadium.

When Japan gained control of the Pacific sources of rubber, America had to find an alternative source. The need was for a gel stable over a wide temperature range and tough enough to withstand the blast of an explosive that would scatter burning globs of gel over an area. An empirical search led Fieser to naphthenic acid, a commercial mixture of cycloparaffin acids from petroleum refining. The aluminum soap made a good gel with gasoline. Napalm, a jellied gasoline made from aluminum na phthenate and aluminum palm itate, quickly became a component of incendiary bombs and was used in flamethrowers during World War II and in Vietnam. In 1967, in the face of student criticism, Fieser declared that he felt no guilt for having developed the chemical and would do it again if called upon.

The Fieser group developed napalm for a variety of applications, including use in incendiary bombs employed in both the European and Pacific war theaters by the millions, in flamethrowers, in gelfilled grensdes, and as small incendiaries carried by saboteurs to light fires and ignite oil slicks.

Fieser’s war research was the subject of The Scientific Method (1964), his only book written from a personal viewpoint. It consists of twenty-three chapters on napalm, weapons, relations with military officers, trips to manufacturing and testing facilities, and his medical-related projects.

Fieser also headed a large group engaged in a program to develop an antimalarial drug. Since the cinchona tree plantations were in Japanese hands and troops were fighting in malarial regions, the need for alternatives to quinine seemed likely. The Office of Scientific Research and Development’s Committee on Medical Research funded about forty programs at universities and drug firms. Fieser worked on sulfa drugs, which the Rockefeller Foundation had shown combated parasites in some cases of malaria.

Various university groups prepared different types of substances, including all possible isomers, derivatives, and analogues of both known and potential drugs, and sent them to Abbott Laboratories for screening. The results changed the course of Fieser’s research. Three derivatives of lapachol selected from his Hooker samples had definite antimalarial activity. Fieser switched the work of his group from sulfas to quinones and prepared naphthoquinones with various straight, branched, and cyclic side chains that were numbered and tested.

In 1943 the Rockefeller Foundation reported that the naphthoquinones both suppressed and cured malaria in chickens, and a review panel concluded that they were the most promising of all antimalarials. With top priority the Harvard group worked day and night in a crash program. Some of the substances tested proved to be more potent than quinine, and Fieser felt certain that a superior drug would be developed. At war’s end, however, his samples still had not undergone the lengthy and difficult testing needed to provide information on their biological activity in the body.

The best of Fieser’s antimalarials was lapinone—potent, effective, and resistant to metabolic deactivation. Its practical value remained unrealized, and Fieser’s new drugs never received full evaluation. Theresearch, however, was not wasted, for twentytwo papers appeared on the drugs, beginning in 1948, with details of their preparation, chemistry, and metabolic activity. The government resumed interest in them at the time of the Vietnam war.

Another wartime project with medical aspects was Fieser’s work on cortisone, first isolated by Edward Kendall in 1936. The therapeutic value of the hormone was unknown because of inadequate supply. The Committee on Medical Research sought a synthesis in order to explore its medical applications. A major difficulty lay in the fact that cortisone has an oxygen atom at the 11 position in the third ring. No natural steroid served as a starting material. A practical synthesis did not emerge during the war, only complex ones with many steps and small yields, including a method developed at Harvard.

The first batch of synthetic cortisone became available for clinical testing in 1948, and Robert Woodward at Harvard achieved its total synthesis in 1951. That synthesis depended on Fieser’s use of compounds prepared by Adolf Windaus in Germany with double bonds that might be used to add oxygen to the 11 position. Fieser synthesized an 11-keto steroid in a four-step sequence. With those steps established, Woodward synthesized the hormone, starting with a common coal tar product.

Fieser’s greatest impact lay less in his research than in his writing of important scientific textbooks and reference works. He regarded his success as a teacher to be his greatest achievement. His introductory organic chemistry course, tough and demanding, was taught to large numbers of premedical students. They regarded Fieser as a dynamic, inspirational teacher and were captivated by his enthusiasm for the subject.

Fieser’s concern for effective teaching manifested itself in several innovative projects. The earliest was a laboratory manual. Experiments in OrganicChemistry (1935). It and its successor edition, retitled Organic Experiments (1964), were possibly the best available manuals for three decades. He continually revised them, always looking for new methods, equipment, and reagents to test and modify for student use. In its successive editions the manual incorporated new methods of separation and isolation, such as chromatography, and new syntheses, such as Fieser’s own of vitamin K₁. It differed from other manuals in its diversity of reactions and preparations involving natural products and in being written by a man versed in research who used methods and reactions taken from actual laboratory work, often that of his own group.

A second project aimed at more effective teaching was the film Techniques of Organic Chemistry, produced in the 1950’s as an aid to laboratory work. Fieser often used novel setups in class demonstrations. His large classes led him to seek a more effective method, and he thought of making a film. He developed the script, obtained a grant from the Ford Foundation, and had the film made by a professional company in his laboratory with himself demonstrating the techniques. He also created and found a manufacturer for a set of inexpensive plastic molecular models of the Dreiding design that students could use to study the spatial relationships in organic chemistry. The American Chemical Society recognized his colorful and innovative teaching with several awards, the last being its Award in Chemical Education (1967), for his contributions as a teacher and writer.

The first of the Fieser’s textbooks, Organic Chemistry (1944), was so widely adopted that it and its succeeding editions and translations into fifteen languages dominated the market for over a decade. The project began with the time Fieser spent on his travels from coast to coast on his war-related projects: many hours on trains, in hotels, and at airports while delayed by weather. He hated to be idle. Mary Fieser thought writing a book might help to keep her husband’s mind on his eventual return to teaching and offered him her notes on her reading, hoping he would write a text on organic chemistry. He wrote while on his journeys, keeping a record of where and when he wrote each page.

Mary Fieser collected material faster than her husband could process it, and at his suggestion she began to write some chapters. Thereafter she wrote part of every textbook and reference work he published: Textbook of Organic Chemistry (1950); Introduction to Organic Chemistry (1957); Basic Organic Chemistry (1959); Advanced Organic Chemistry (1961), an expansion of the textbook for both beginning and advanced students, with historical and biographical material: and Topics in Organic Chemistry (1963) and Current Topics in Organic Chemistry (1964), both of which include material omitted from the 1961 book in order to keep the latter to a reasonable size.

The dominance of Organic Chemistry is owing to its excellence. Well written, sound, and authoritative, it uses information and examples of organic reactions that are experimentally real and incorporates historical and biographical material that provide a personal dimension for the reader. The succeeding editions included new developments in antibiotics, vitamins, enzymes, chemotherapy, reaction mechanisms, orbital theory, and aspects of organic chemistry related to technology. These were departures from current texts, and teachers welcomed such innovations.

After Steroids (1959) the Fiesers published Style Guide for Chemists (1960), devoted to effective communication. Originally based on notes prepared by Mary Fieser on grammar, rhetoric, and style, and incorporated into a pamphlet for contributors to Organic Reactions, the Guide expanded the notes into a small book; it was still in print and selling well in the 1980’s.

Fieser was able to continue his writing following his surgery in 1965. He was by then on his final major project, the Reagents for Organic Synthesis series. Six large volumes appeared between 1967 and 1977, as well as several more after his death (under the direction of Mary Fieser). Essential to the practicing chemist, the reagents series provided a source of information on new reagents, which was especially vital as synthesis became increasingly sophisticated and new reagents appeared in the literature at a rapid rate.

By 1967 the Fiesers’ textbooks no longer dominated the market; newer ones, reflecting advances in theoretical and physical organic chemistry, were in demand as teachers stressed the intricate details of reactions and structures in terms of reaction intermediates, and mechanisms at the expense of more descriptive synthetic and natural products chemistry. The Fiesers transferred their zeal for preparative chemistry into a new channel: an exhaustive account of substances used in organic synthesis. Each succeeding volume covered the literature up to the date of publication. Listing reagents alphabetically, each volume gave the structure, composition, physical constants, method of preparation purification, uses, flow sheets, reaction conditions, yields problems, and references for each, thereby freeing chemists from making lengthy literatuResearches. The volumes were reliable and thorough, representing an extraordinary effort to search the world’s chemical literature, no matter how obscure the journal. The Fiesers were at their best here, utilizing their devotion and skill in finding, collecting, and conveying essential material for the practicing chemist. Thereby, they may be said to have influenced the course of future research through their legacy of indispensable reference works.

BIBLIOGRAPHY

1. Original Works. A list of Fieser’s books and papers is in Poggendorff, VIIb (1968), 1389–1395. Among the more significant papers are the following: “Reduction Potentials of Quinones, I. The Effect of the Solvent on the Potentials of Certain Benzoquinones,” in Journal of the American Chemical Society, 45 (1923), 2194–2218, written with James B. Conant; “Reduction Potentials of Quinones, II, The Potentials of Certain Derivatives of Benzoquinone, Naphthoquinone and Anthraquinone,” ibid., 46 (1924), 1858–1881, written with James B. Conant; “The Alkylation of Hydroxynaphthoquinone, III, A Synthesis of Lapachol,” ibid., 49 (1927), 857–864; “The Tautomerism of Hydroxy Quinones,” ibid., 50 (1928), 439–465; “The Synthesis of Methylcholanthrene,” ibid., 57 (1935), 228–229, 942–946, written with Arnold M. Seligman; “A New Diene Synthesis of Anthraquinones,” ibid., 1679–1681, written with Mary Fieser; “Syntheses in the 1.2Benzanthracene and Chrysene Series,” ibid., 61 (1939), 1647–1654, written with William S. Johnson; “Synthesis of Vitamin K₁,” ibid., 3467–3475; “Napalm,” in Industrial and Engineering Chemistry, 38 (1946), 768–773; and “A New Route to 11-Keto Steroids by Fission of a Δ^{9 (11)}Ethylene Oxide,” in Journal of the American Chemical Society, 73 (1951), 5252–5265, written with Hans Heymann.

Fieser’s account of his work on napalm, vitamin K, cortisone, antimalarials, and the writing of his textbook is in The Scientific Method: A Personal Account of Unusual Projects in War and Peace (New York, 1964). His reflections on the surgeon general’s report are in “More on Smoking and Health,” in Chemistry, 37 (March 1964), 18–19. He provided an autobiographical sketch for McGraw-Hill Modern Scientists and Engineers, 1 (New York, 1980), 372–374.

II. Secondary Literature. On Fieser’s life and work, see C. J. W. Brooks, in Nature, 270 (1977), 768–769; Hans Heymann, in Journal of Organic Chemistry, 30 (1965), insert before 1693; and William S.Johnson, in Organic Syntheses, 58 (1978), xiii-xvi. An article based on interviews with Mary Fieser is Stacey Pramer, “Mary Fieser: A Transitional Figure in the History of Women,” in Journal of Chemical Education, 62 (1985), 186–191.

Albert B. Costa