Barton, Derek Harold Richard
BARTON, DEREK HAROLD RICHARD
(b. Gravesend, Kent, England, 8 September 1918; d. College Station, Texas, 16 March 1998)
organic chemistry, conformational analysis, free radical synthetic chemistry.
Between 1940 and 1970 organic chemistry experienced a complete transformation, which affected what organic chemists did and how they did it. In a nutshell, organic chemistry in 1980 retained only its self-imposed limitation to carbon-based compounds and its commitment to organic synthesis. This revolution was characterized by the adoption of organic reaction mechanisms and theoretical chemistry to explain the course of reactions, the use of physical instrumentation to determine chemical structure, and more generally the employment of techniques derived from physical chemistry. In undergraduate teaching, the rote learning of chemical properties and preparations was replaced by a problem-solving approach based on mechanistic chemistry. On the negative side, the determination of structure using degradation reactions—hitherto a major branch of organic chemistry—was completely swept away. During the transition period, however, the traditional and new methods of structure determination interacted in a fruitful manner. Difficult structures that had tormented chemists for decades were solved in the space of a few years, and insights obtained from mechanistic chemistry as well as biosynthetic reasoning led to the development of new reactions.
An informal cadre of brilliant chemists was at the heart of this revolution. Derek Barton was one of its most active members and exemplified the transformation of the revolution in organic chemistry better than anyone else, not least because he moved right across the whole field, rather than choosing to specialize in one area. Barton had the gift of drawing out the general implications of work initiated by other more specialized chemists (a trait he shared with Robert Burns Woodward and Paul Flory) and the ability to bridge the boundaries of different fields of chemistry. He also had the ability (and confidence) to use his intuition to realize a hitherto incomplete chain of reasoning (in contrast to Woodward’s insistence on the use of deductive logic). Barton called this use of intuition “gap jumping,” which is also the title of his autobiography. This intellectual role was balanced by a strong interest in inventing new reactions—a surprisingly rare phenomenon among modern organic chemists—that were of great value to the rapidly expanding pharmaceutical and petrochemical industries.
Education and Early Research. Barton was born on 8 September 1918, in Gravesend, Kent, England, the son of William Thomas Barton, a carpenter and timber merchant, and Maude Henrietta (née Lukes) Barton. The timber business prospered, and Barton became a boarder at Tonbridge, a leading public school in Kent, in 1932. When his father died in 1935, Barton left school and prepared to take on the family business. Within a couple of years, however, he decided to study chemistry. After a year’s preparation at the local technical college, he enrolled at Imperial College, and completed his BSc in two years.
For his PhD, Barton took up a research fellowship sponsored by the Distillers’ Company, investigating the pyrolysis (chemical decomposition or change brought about by heat) of the dichloroethanes. He was supervised by Martin Mugdan (1869–1949), who had been a leading industrial researcher in Munich before he was forced by the Nazis to leave Germany in 1939. As a result of his experiments, Barton was able to show that the thermal decomposition of 1,2-dichloroethane (ethylene dichlo-ride) could occur through two different pathways, the intramolecular elimination of hydrogen chloride or a more rapid free-radical chain reaction.
After he completed his PhD in 1942, Barton was recruited for military intelligence. World War II was at its height, and he had been declared unfit for military service because of a weak heart. He spent two years developing water-free invisible inks, which could not be detected with the iodine spray method. Barton married Jeanne Kate Wilkins, a clerk, on 20 December 1944. Their only child, William Godfrey Lukes Barton, was born on 8 March 1947, and they were divorced in the early 1960s. Toward the end of the war, Barton went into industry and worked on organophosphorus chemistry for Albright & Wilson, a major phosphorus producer, at its Oldbury factory in the English Midlands.
Imperial College and Harvard. After a year at Albright & Wilson, Barton returned to Imperial College as a teaching assistant. The teaching itself was mundane, but the move back to academia enabled Barton to devote himself to steroid chemistry. Steroids were a rapidly growing field of interest to the pharmaceutical industry and had already attracted the attention of many leading academic and industrial chemists. Having already annoyed Sir Ian Heilbron, the professor of organic chemistry at Imperial College, Barton was fortunate that Tim Jones (later Sir Ewart Jones) took him under his wing. A young upcoming lecturer at Imperial with an interest in steroid chemistry, Jones suggested that Barton investigate the relationship between optical rotation and the structure of the triterpenoids. This was a period when chemists tried to use the optical properties of complex molecules, in particular the steroids and terpenoids, to determine their absolute chemical structure without the need for lengthy and tedious chemical studies. Woodward had introduced his empirical rules for the ultraviolet spectra of ketones with a conjugated double bond in 1941. When a relationship between a given optical property and a structural feature had been established, the existing literature could then be trawled for other examples. Barton was able to correlate the structures of several triterpenoids using differences in molecular rotation. He then extended this approach to steroids, for which there was more data.
A shared interest in the chemistry of the steroids brought Barton to the attention of Louis Fieser at Harvard University. When Woodward took a sabbatical in 1949–1950, Fieser—as head of the chemistry
department—offered Barton a temporary position for a year. This was a turning point in Barton’s career because it introduced him into Woodward’s circle and to his rigorous mechanistic analysis of chemical problems. Even in 1986, Barton wrote with awe of Woodward’s legendary seminars, in which, following a talk from a visitor, Woodward would lead a thorough discussion and then present, and usually solve, a chemical problem.
During his stay at Harvard, Barton developed conformational analysis. After Henry van’t Hoff and Achille Le Bel had independently explained the optical activity of certain organic compounds in terms of a tetrahedral carbon atom in 1874, chemists had begun to visualize chemistry in three dimensions rather than two. Taking up the tetrahedral carbon hypothesis, Hermann Sachse showed in 1890 that, contra Adolf von Baeyer, strainless sixmembered rings (cyclohexane rings) were possible if they were not planar. Sachse identified two potentially stable forms, or conformers—what are now called the chair and the boat. Sachse’s mathematics were beyond any contemporary organic chemists, so his proposal lay fallow until 1918, when Ernst Mohr showed by x-ray crystallography that diamond consisted of an unbounded network of chair cyclohexanes. This finding revived Sachse’s hypothesis but left open the question of which, if any, conformation would predominate in the gas and liquid phases. In occupied Norway, in 1943, the physical chemist Odd Hassel had shown that cyclohexane itself preferred the chair conformation. Furthermore he had shown that decalin (two fused cyclohexane rings) favored the chair-chair conformation. This was an important finding, as two heavily researched groups of natural products— steroids and triterpenoids—contained fused cyclohexane rings. Although Barton had already used Hassel’s conformations in his research on abietic acid (a major constituent of rosin) at Imperial in 1948, it was only when Fieser presented a seminar on steric effects in the chemistry of the steroids at Harvard that Barton realized the immense value of the conformational approach for steroid chemistry. Drawing on the findings of Hassel and others, Barton showed that there were two different positions for substituents attached to a cyclohexane ring: polar (now called axial) and equatorial. Barton used this “conformational analysis” to explain the sometimes unexpected behavior of different substituents in ring compounds and to predict the relative stability of one conformation over another. He thus arrived at different conclusions from Fieser, and the older chemist generously suggested they both publish papers on the subject in Experientia. The subsequent short paper established Barton as the founder of conformational analysis, for which he received the Nobel Prize in 1969. During his sabbatical at Harvard, Barton also met Ernest Eliel at Notre Dame University in Indiana, and converted him to the cause of conformational analysis. As a leading stereo-chemist, Eliel became one of the major proponents of this new approach in the United States. Subsequently, molecular models played an important role in conformational analysis, especially the type introduced by the Swiss chemist André Dreiding in 1958.
Birkbeck College and Glasgow. On his return to Britain in 1950, Barton became a reader (equivalent to associate professor) at Birkbeck College. Part of the University of London, Birkbeck catered to part-time students; the teaching was done in the evening, leaving the rest of the day free for research. Barton continued his development of conformational analysis, using it, for example, to establish the chemical structure of B-amyrin (a triterpenoid found in rubber latex) and “artostenone,” a supposed sterol obtained from the jackfruit. He showed that artostenone was a terpenoid with an unusual cyclo-propane ring, and it was subsequently given the more appropriate name of cycloartenone. Barton also synthesized the important steroid lanosterol with Woodward and Arthur Patchett (working in relay across the Atlantic), using Woodward’s cholesterol synthesis as a starting point. It was during the Birkbeck period that Barton became a member of the elite group of organic chemists, and his growing stature was confirmed by his election to the Royal Society in 1954.
Although Barton was now a professor at Birkbeck, he was clearly in the running (and believed himself to be destined) for one of the major chemistry chairs. Hoping for Oxford, Barton agreed to go to Glasgow if he was not appointed. With hindsight—as Tim Jones’s forthcoming appointment to the Oxford chair was an open secret—it is perhaps surprising that he did not plan to succeed Jones in Manchester, which had hitherto been a stepping-stone to a chair at Oxford or Cambridge. However, having committed himself to Glasgow, Barton missed out on Manchester and also Imperial, where Patrick Linstead had been unexpectedly appointed rector of the college in October 1954. Barton’s stay in Glasgow as the Regius Professor of Chemistry was brief (1955–1957), but it was productive and marked a shift in his research. He worked closely with Monteath Robertson, the famous x-ray crystallographer, using traditional degradation methods to study the structure of several phytochemicals, such as limonin, while Robertson’s group obtained the structure using x-ray crystallography. This overlap of techniques (which also occurred in the case of B-amyrin, where the structure had been determined by Harry Carlisle using x-ray crystallography) was fruitful but short-lived—the traditional chemical methods were abandoned, mainly because of the introduction of computers into x-ray crystallography and the growing use of nuclear magnetic resonance for structure determination. In this period, Barton also applied himself to the study of phenolic coupling, a free radical reaction that linked two phenol molecules. In collaboration with Theodore Cohen, he used the concept of phenolic coupling to predict the biosynthesis of the morphine alkaloids. Barton had already become interested in organic photochemistry as a way of carrying out chemical reactions—another example of boundary bridging—and in Glasgow he studied the photochemical rearrangement of α-santonin (a compound found in Levant wormwood).
Return to Imperial College. Despite his success in Glasgow—the university authorities always agreed to his requests for funds and he formed a strong partnership with Ian Scott—Barton was keen to go back to his alma mater, Imperial College, when the chair became vacant again after the sudden death of Ernest Braude. Soon after his return to Imperial, Barton was invited to collaborate with the newly established Research Institute for Medicine and Chemistry in Cambridge, Massachusetts, funded by the Schering Corporation. The director, Maurice Pechet, a steroid chemist who had taken his PhD with Fieser, asked Barton to synthesize aldosterone acetate, a hormone that controls the electrolyte balance in the body. Drawing on his prior knowledge of free radical pyrolysis, Barton proposed a simple but hitherto unknown reaction. An alkyl nitrite could be photolyzed to establish an oxime group on a neighboring carbon. Fortunately Schering had hired an excellent Glasgow-trained chemist, John Beaton, who was able to carry out the proposed reaction (now known as the Barton reaction or the Barton nitrite photolysis) and thereby produced a large amount (60g) of hitherto scarce aldosterone acetate in 1960. Inspired by this successful industry-academia collaboration, the Ciba pharmaceutical company set up the Woodward Research Institute in Basel, Switzerland.
In the late 1950s and 1960s Barton continued to develop his ideas on the biosynthesis of morphine and related alkaloids involving phenolic coupling. He made extensive use of the radioactive tracers tritium (3 H) and carbon-14, which had just become commercially available from the Radiochemical Centre at Amersham, England. Barton was able to show the basic soundness of his ideas, sometimes forming an unexpected intermediate along the way. This work was then extended to the biosynthesis of other phenolic alkaloids, notably the alkaloids derived from the coral tree.
After 1970 Barton concentrated on the development of new reactions for use in organic synthesis. His first major success in this period arose from his collaboration with Schering, which was looking for a good way of removing hydroxyl groups from aminoglycoside antibiotics (such as gentamicin, discovered by Schering in 1963)
to increase their resistance to bacterial degradation. On the basis of another reaction, which involved the elimination of a thiocarbonyl group from a steroid, Barton suggested the free radical deoxygenation of a thiocarbonyl derivative of the aminoglycoside using tributyltin hydride as the hydrogen donor. The experimental work was carried out by Stuart McCombie in 1975, and this very useful reaction is usually known as the Barton-McCombie deoxygenation reaction. Subsequently, Barton’s group developed a whole series of free radical reactions based on thiohydroxamic esters.
The ideal intermediate in free radical synthetic chemistry is the “well-behaved” radical, one that follows the desired pathway and does not attack the solvent or produce excess by-products through side-reactions. In the mid-1980s, Barton developed the concept of the “disciplined radical,” which would be held in check by the “disciplinary group,” for example, the thiocarbonyl group. This approach arose from his attempt to create an effective free radical decarboxylation reaction. Free radical decarboxylation had been known since Hermann Kolbe electrolyzed the salts of carboxylic acids in 1846, but the reaction had hitherto been unsuitable for complex compounds. By reacting the mixed anhydride of a thiohydroxamic acid and a carboxylic acid with tributyltin hydride, the corresponding decarboxylated hydrocarbon was formed. This reaction, first carried out with William Motherwell and David Crich in 1983, is now known as the Barton decarboxylation.
In the early 1960s Barton suffered from nervous exhaustion after his divorce from Kate and threw himself into the reading of French classics. His reading made him wish to improve his French and he took French lessons at the Institut Français in South Kensington. Barton’s teacher, Christiane Cognet, soon realized she had a star pupil in her class and they were married in 1969. In the same year Barton was awarded the Nobel Prize jointly with Odd Hassel “for their contributions to the development of the concept of conformation and its application in chemistry.” The Hofmann Chair of Organic Chemistry was created for him by Imperial College in 1970, and two years later, he was knighted in Britain and enrolled into the Legion d’Honneur as a chevalier (he became an officer in 1985). He was president of the Royal Institute of Chemistry (now the Royal Society of Chemistry) in 1973–1974.
Barton was invited to join the editorial board of Tetrahedron soon after it was founded by Robert Maxwell in 1957. The board was initially chaired by Sir Robert Robinson and R. B. Woodward. Barton became co-chairman of the editorial board on Robinson’s death in February 1975 and the sole chairman when Woodward died in July 1979. Just before Robinson’s death, Maxwell also appointed Barton as the editor-in-chief of Comprehensive Organic Chemistry. He published this impressive and useful six-volume work in collaboration with David Ollis of Sheffield University (another member of the Woodward circle) in 1979. Nearly two decades later, Barton was joint editor in chief of Comprehensive Natural Products Chemistry with Koji Nakanishi of Columbia University, supported by Otto Meth-Cohn of Sunderland University. This impressive nine-volume work was published shortly after Barton’s death in 1998. Meanwhile Tetrahedron had expanded under Barton’s leadership from 3,137 pages in 1975 to 16,003 pages in 1998 and had spawned another journal, Tetrahedron: Asymmetry, in 1990.
France and Texas. In 1977, in a characteristic change of direction, Barton became one of the codirectors of the Institut de Chimie des Substances Naturelles (ICSN) at Gif-sur-Yvette, in the southwestern suburbs of Paris. He took early retirement (at sixty) from Imperial College a year later to become sole director of the institute following the amalgamation of its two departments with the agreement of the other codirector Pierre Potier. This was partly in the expectation that he would retire at seventy, but also because Christiane was keen to return home. During his time at Gif-sur-Yvette, Barton insisted that all meetings be held in French even if there were no French chemists present; this led to the introduction of neologisms such as “obvieusement,” “éléphant-blanc,” and “hareng rouge.”
Soon after Barton arrived at Gif-sur-Yvette, in 1980, John Cadogan, the new director of research at British Petroleum (BP) and a leading free radical chemist, offered him funds for a blue-skies project. Barton decided to examine the oxidation of hydrocarbons using iron chemistry, a field of obvious interest to BP. This research stemmed from his earlier work on biosynthetic pathways and perhaps from the Barton reaction, which led to the oxidation of previously unfunctionalized carbon atoms. His starting point was the oxidation of adamantane by Iwao Tabushi (a student of Paul von Ragué Schleyer) using an iron complex, B-mercaptoethanol, and oxygen. The initial experiments were failures, but Barton had the idea of adding metallic iron and acetic acid to the reaction, which had a positive effect on the yield of the reaction. His group eventually developed “Gif systems” for the oxidation of hydrocarbons with oxygen, which contained iron, acetic acid, and pyridine.
Barton had originally gone to France with the expectation of retiring at seventy, but the incoming Socialist government introduced a uniform retirement age of sixty-five in 1984. Hearing that Barton would have to retire soon, and knowing that he would want to continue his research, Scott, his friend from Glasgow days, and Albert Cotton—who knew Barton through Geoffrey Wilkinson, another Nobel laureate at Imperial College—decided to create a post for him at Texas A&M University. In 1986 they offered him a full professorship, and at the age of sixty-eight Barton moved to College Station, Texas, as the Dow Professor of Chemical Invention. At Texas A&M, Barton continued to develop “Gif chemistry,” and the Gif systems were followed by the GoAgg systems—which employed potassium or organic peroxides instead of oxygen. (“Go Aggies!” is the war cry of the supporters of the A&M football team, but it has been claimed that GoAgg is short for “Gif Oxidation in Aggie Land.”)
Christiane died of ovarian cancer in 1992, despite being one of the first patients to be given taxotere, and Barton lost the great love of his life. In the following year he married Judith Cobb, a neighbor in College Station who had been a great support to Barton in his bereavement. His colleagues and former students were determined to make the most of Barton’s forthcoming eightieth birthday, and in early 1998, celebratory conferences were held in the Maldives and at the Scripps Research Institute in La Jolla, California. Back home in College Station, Barton died suddenly of a heart attack on 16 March 1998.
Barton’s Place in History. Barton was one of the leaders in the revolution that took place in organic chemistry in the 1950s and 1960s. This was not because he was a pioneer in the use of physical instrumentation or even, despite his work on conformational analysis, in the discovery of organic reaction mechanisms, but because he introduced—with others such as Robinson, Woodward, and Elias James Corey—a new way of thinking about organic chemistry, which converted it from a practical—if also intellectual—exercise into a series of problems that had to be assessed and solved using organic reaction mechanistic theory and conformational analysis. He gained the ability to generate new insights by deliberately working at the boundaries between different fields, something that occurred accidentally early in his career, and by constantly moving to emerging areas of research. Late in his career, Barton became one of the few modern academic chemists to be a single-minded creator of new reactions, which perhaps harked back to his family craft traditions. His influence was strengthened by his social connections with other leading chemists, including Woodward, Sir Robert Robinson, Carl Djerassi, Vladimir Prelog, and Gilbert Stork, partly through frequent meetings at international conferences and partly through his editorial work for Tetrahedron. Whereas Woodward failed to produce many leading organic chemists to succeed him, Barton saw himself as the “kingmaker” of organic chemistry and he put considerable effort into making arrangements for the future of his best students. By 2005 these included the professors of organic chemistry at Cambridge (Steven Ley), University College London (Motherwell), Imperial College, London (Anthony Barrett), and Oxford (Sir Jack Baldwin).
The chemist Tony Barrett has noted (probably tongue-in-cheek) that many chemists considered Barton to be “aloof, demanding and taking pleasure in overwhelming any scientist he disagreed with,” but that he personally found him to be “kind, considerate, supportive and generous.” Certainly Barton’s perceived aloofness was mainly shyness. Barton kept a close watch on his students and liked to push them, but he was kind and generous in many different ways to those students who responded well to this pressure. As one of the “high priests” of organic chemistry (to use Stork’s revealing phrase), Barton felt a moral obligation to maintain rigorous standards, and to prevent any possible sloppiness or fraud. He habitually asked any student claiming they had made a new compound to show him the crystals. There was always a robust discussion of the latest results in his group’s weekly meetings, and his researchers sometimes held back a piece of good news, to be used when there was nothing else positive to report. Barton’s personality also mellowed as he grew older, partly as result of Christiane’s influence.
The most striking aspect of Barton’s character was his boundless passion for doing chemistry; he had published more than a thousand papers by the time of his death. He had an incredible work ethic and in his autobiography he remarked that he preferred chemistry to spare time. Even at Texas A&M University, when he was in his seventies, Barton worked long hours. Judy Barton recalls that: “Derek would get up around 4 a.m., read his journal while he drank a pot of tea, and be at work by 7 a.m. His only real meal of the day was a leisurely lunch at 11:30 a.m. for at least 90 minutes at home. He returned to the laboratory until at least 7 p.m. when he came home to tie up professional loose ends. He and I shared a social conversation every night when his work was completed” (Barton, personal communication). Like Woodward, he often worked on Christmas Day. The sources of his enthusiasm for chemistry and his work ethic are not clear. Barton considered becoming a priest in his early teens, with his father’s encouragement, and he remarked in his autobiography that he felt the need from an early age to devote himself “to some noble cause.” Barton never gave any explanation for his passion for chemistry beyond the fact he enjoyed reading science books when he was home on sick leave from Tonbridge School. Perhaps his work ethic arose partly from his need to justify his premature departure from the family business. It certainly stemmed from his strong sense of competition with his chemical peers and his desire to leave his imprint on organic chemistry. Although Barton realized that this could often be best achieved by collaborating with other chemists and supporting the careers of his students, he also “wished to be remembered for all time” for his contribution to organic chemistry (William Motherwell in Scott and Potier, 2000, p. 61).
There was another side to Barton’s nature that few outside his close circle ever saw. He claimed that he could have become a concert pianist instead of a chemist. He saw a similarity between chemical and musical notation, saying, “if I had not been a great chemist, I would have chosen to be a great composer,” for both music and chemistry were a matter of “orchestrating your own signature of creativity” (Motherwell, personal communication). Barton was certainly fond of music, especially the work of Gustav Mahler.
Barton was one of the great organic chemists of the twentieth century, yielding in significance only to Woodward and H. Emil Fischer. It is a measure of his greatness—as Motherwell has pointed out—that he was one of only two organic chemists in that century to give his name to an adjective: Bartonian (the other of course was Woodward).
WORKS BY BARTON
With David Ollis, eds. Comprehensive Organic Chemistry. 6 vols. Oxford: Pergamon Press, 1979.
Some Recollections of Gap Jumping. Washington, DC: American Chemical Society, 1991. This autobiography is by far the best source about Barton. The main text is short (the series editor, Jeffrey Seeman, had to coax three codas from him to flesh it out), and the amount of detail about his personal life is minimal. Like any other autobiography, Gap Jumping has to be treated with caution. Nonetheless, it is an useful source of information, not least because it shows what Barton himself considered to be important in his extensive body of research, and in one of his codas he sketches his personal philosophy.
With Shyamal I. Parekh. Half a Century of Free Radical Chemistry. Cambridge, U.K.: Cambridge University Press, 1993. This slim survey of his work on free radical chemistry provides a good introduction to the development of the “disciplined free radical.”
Reason and Imagination: Reflections on Research in Organic Chemistry; Selected Papers of Derek H. R. Barton. Singapore and River Edge, NJ: World Scientific/Imperial College Press, 1996. A collection of his most important papers (137 out of 1,041). The subtitle reflects Barton’s willingness to use his intuition as opposed to Woodward’s insistence on the rigorous employment of logic.
With Koji Nakanishi and Otto Meth-Cohn, eds. ComprehensiveNatural Products Chemistry. 9 vols. New York: Elsevier, 1999.
Coley, Noel G. “Barton, Sir Derek Harold Richard (1918–1998).”Oxford Dictionary of National Biography. Oxford: Oxford University Press, 2004. A good summary of his life, based largely on Gap Jumping.
Cotton, F. Albert. “Derek H. R. Barton, 8 September 1918–16 March 1998.” Proceedings of the American Philosophical Society 144 (2000): 292–296. Provides the only detailed account of Barton’s American period.
Ley, Steven V., and Rebecca M. Myers. “Barton, Sir Derek Harold Richard.” Biographical Memoirs of the Royal Society ofLondon 48 (2002): 1–23. Useful for the personal details lacking in Gap Jumping.
Scott, A. Ian, and Pierre Potier, eds. The Bartonian Legacy. London: Imperial College Press, 2000. A posthumous volume of recollections by his coworkers that nicely complements Gap Jumping.
Peter J. T. Morris