Todd, Alexander Robertus (Baron Todd)

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TODD, ALEXANDER ROBERTUS (BARON TODD)

(b. Glasgow, United Kingdom, 2 October 1907;

d. Cambridge, United Kingdom, 10 January 1997), chemistry, natural products, vitamins, plant pigments, synthesis, structure.

Todd was an outstanding organic chemist of the twentieth century. He worked chiefly on the synthesis and structure of natural products, including plant pigments, penicillin, and vitamins. His studies on nucleosides and nucleotides led to a Nobel Prize in 1957.

Early Years. Alexander Robertus Todd was born at Cath-cart, Glasgow, the elder son of Alexander Todd, a clerk with the Glasgow Subway Railway Company, later to become its cashier and secretary. His mother was Jane Lowrie. The parents were born within a mile of each other in Glasgow and were hardworking people with no education beyond elementary schooling. Yet they passionately believed in the value of education and sent Alexander to local schools until, having passed the Scottish “eleven-plus” examination, he entered Allan Glen’s School in Glasgow, otherwise known as the Glasgow High School of Science.

A few years earlier Todd had received a gift of a home chemistry set, and it may have been this gift that started his interest in the subject. He did well at most subjects except art (which prompted the teacher of that subject to remark on his parents’ sense of humor in giving him the initials A.R.T.). At Allan Glen’s he much enjoyed chemical lessons, while the proximity of Baird and Tatlock, laboratory suppliers, enabled him to purchase chemicals and apparatus for further experiments at home.

In 1924 Todd entered Glasgow University to read chemistry. Here he enjoyed lectures from the two professors, G. G. Henderson and T. S. Patterson, though he greatly disliked the routine of inorganic quantitative analysis, at which he fared badly. In 1928, his final undergraduate year, he carried out a research project on the action of phosphorus pentachloride on ethyl tartrate, which led to his first publication. After graduating with first-class honors, Todd worked for a year with Patterson on optical rotatory dispersion, then a technique in its infancy and requiring formidable mathematical skills. Having been attracted to organic chemistry, and with Patterson’s approval, he sought a move to Germany, where natural product studies flourished. In 1929 he migrated to Frankfurt, joining the school of Walther Borsche, a former pupil of Adolf Windaus in Göttingen.

The Frankfurt laboratories were very well equipped, and Todd was set to work in the field of bile acids. These are members of the steroid family that had been studied for about thirty years by Windaus and Heinrich Wieland, but Todd’s results suggested that their accepted structure for the steroid nucleus was wrong. In this respect he was correct, though his own alternative of a 7-membered ring was also wrong. He was awarded his doctorate on the grounds chiefly of his experimental results. Todd’s stay at Frankfurt had been pleasant and gave him a fluency in German that would later serve him well. He was there in the dying years of the Weimar Republic and saw street fighting between students on the extreme left or right of the political spectrum. He formed the view that disillusionment with parliamentary government opens the way for extremists. Many of the student body had right-wing political leanings that would later lead them to support the Nazi regime. Todd was horrified by the leadership vacuum that Adolf Hitler would eventually fill. His experience inclined him, years later, to say that if he had been a really good demagogue he could have had left-wing students in Cambridge goose-stepping in jackboots down King’s Parade in six months!

Oxford. Seeking to further his experience of natural products, but in Britain, Todd applied to join the team at Oxford headed by Robert Robinson. He was successful and in 1931 entered the Dyson Perrins Laboratory and also Oriel College where (unlike Robinson) he found the collegiate system much to his liking. Robinson was then absorbed in work on anthocyanins (red and blue flower pigments). These are glucosides of anthocyanidins, which Robinson had already synthesized; the problem was to make the pigments themselves, especially where they were 3,5-diglucosides. For this they needed the 2-glucoside of phloroglucinaldehyde, and Todd came up with a strategy of treating the aldehyde with β-bromoacetyl glucose. All his efforts proved unavailing, but an accidental spillage into hot water of a gummy product caused the crystalline product to appear the next day on the walls of the discarded glass flask—a classic example of serendipity in chemical discovery. By 1932 he and Robinson had synthesized the pigments hirsutin, pelargonin, malvin, and cyanin. Further work at Oxford included some less successful forays into steroid chemistry and the synthesis of hexatriene. A picnic beside Lake Bala in North Wales led to an unexpected chemical inquiry. Noting the aphid infestation on some nearby foxgloves, and the deep coloration of the aphids, Todd began to investigate the constituents. However, the onset of war before the next aphid season meant that this topic had to be postponed for many years.

Todd had been funded for these Oxford years by an 1851 Senior Studentship (an award derived from the Great Exhibition in London), but this expired in 1934. At Robinson’s suggestion he went to the Medical Chemistry Department at Edinburgh to work under George Barger on the recently isolated vitamin B1 (thiamine), a substance necessary for avoidance of the disease beriberi, and present in rice hulls. Together with Franz Bergel (a refugee from Austria), Todd effected a synthesis of an isomer of thiamine on the basis of a formula generally agreed on but now shown to be wrong. Synthesis of an isomer of this product led to the true vitamin and thus to its correct structure, with a pyrimidine nucleus linked to a thiazole nucleus by a methylene group (see Fig. 1). The delay caused by the first synthesis meant that they lost the priority to a German and an American group. This piece of classical organic chemistry inevitably brought contacts with people in the medical and biochemical fields. Pharmacology was another allied subject, and because its laboratories were next door to those of medical chemistry, Todd found himself frequently there. Among the postdoctoral students he met was Alison Dale, daughter of the physiologist Sir Henry Dale. By the time Todd left Edinburgh they were engaged, and in January 1937 they married.

Lister Institute, London. Todd’s next move came by invitation from the Lister Institute of Preventive Medicine in London. This followed John Masson Gulland’s appointment to a chair in Nottingham in 1936. Robinson had supported Todd’s appointment to the vacant readership,

but in view of his youth (he was then 28) he had been in the post several months before this was granted.

Todd’s experience in vitamin research was appropriate for the Lister, which had for years worked in this area (the name vitamine was invented there). He immediately began work on vitamin E, a component of wheat germ oil and necessary for the reproductive processes in rats. This vitamin is a mixture of tocopherols, substituted benzopyrans. Todd and his colleagues isolated and also synthesised α-and β-tocopherols and established their biochemical importance. He also started work on several other natural products, including cannabis. He had not been long at the Lister before he became aware of further possible career moves, notably in North America. In the end these came to nothing because he was offered, and accepted, the position of Sir Samuel Hall Professor of Chemistry at the University of Manchester.

Manchester. Todd brought with him from London two outstanding women research chemists, Anni Jacob and Marguerite Steiger. His first work at Manchester was a continuation of topics begun elsewhere. The studies on cannabis had to stop when it became clear that existing techniques of separation as column chromatography were inadequate for the task. Another twenty years elapsed before Israeli workers were able to isolate the active principle. The work on vitamin E was brought to a successful conclusion. By now Todd’s interest in vitamins was so great that he embarked on an ambitious program to investigate how vitamins worked. By this time it was clear that they participate with coenzymes, several of which contain nucleotides in which bases such as purines and pyrimidines are associated with sugars and phosphoric acid. Accordingly, he started on the synthesis of purines and pyrimidines and then of their glycosides. To complete the syntheses, a satisfactory technique for phosphorylation had to be devised. This was a highly ambitious enterprise and, given the demands of war work, it is hardly surprising that it was not completed in Todd’s six years at Manchester.

Just after the declaration of World War II, the Todds’ first child, Alexander Henry (Sandy), was born. They had a daughter, Helen, in 1941. Fear of inner-city bombing led them to move home from Withington to Wilmslow. Meanwhile, Todd had joined the Dyestuffs Division Research Panel, which (despite its name) was an Imperial Chemical Industries (ICI) organization promoting all kinds of chemical research, including synthetic drugs. He also found himself chairman of the Chemical Committee of the Ministry of Supply, responsible for the development and production of agents for chemical warfare. With two research students and an industrial chemist, he discovered a vastly improved method for the manufacture of diphenyl chlorarsine (a potential war gas).

Other activity associated with the war effort included participation in an Anglo-American project on penicillin. On his own admission, Todd was not very good at such cooperative efforts, especially those in which he did not have a strong personal interest. His chief success was to form a sulphoxide from penicillin, which demonstrated the lactam structure for the molecule and also paved the way for later syntheses of β-lactam antibiotics. Other topics “of national importance” included a study of the “hatching factor” of the potato eelworm, a parasite whose larvae hatch into worms that attach themselves to the roots of potatoes, causing “potato sickness.” Their hatching is triggered by substances secreted by potato roots and also by tomatoes, which proved to be a more convenient source. Isolation proved to be impossible with the equipment available, and a further blow was the destruction of their tomato supply (in Cheshunt) by a flying bomb. Yet another abortive enterprise was a search for blood anticoagulants.

Despite such setbacks as these, the equipment in the Manchester laboratories was developed so fast that they became probably the best-equipped laboratories in Britain. Under Todd’s guidance new items were developed by Ralph Gilson, the laboratory steward, and in some cases later became widely available. They included items such as evaporators, drying pistols, and electromagnetically stirred autoclaves.

Todd’s Manchester days were much enjoyed, not least for the friendships formed. Some of these derived from communal efforts at nighttime fire-watching (locating fires started by incendiary bombs), which involved students and staff; he considered that this experience made the Manchester chemical school of those days into a tightly knit group and set up relationships of mutual trust and respect that endured for many years. One of those friendships was with Gilson and another was with Frank Stuart Spring. He stuck up a lively friendship with Arthur Lapworth, recently retired. James Kenner, from the Manchester College of Technology, and Patrick Maynard Stuart Blackett were abrasive individuals whose encounters he nevertheless enjoyed, though he distanced himself from Blackett’s left-wing politics. However, the strongest links seem to have been with Michael Polanyi, the Hungarian-born chemist, sociologist, and philosopher.

These loyalties, combined with a supportive vice-chancellor in Sir John Stopford and a flourishing research school of about thirty chemists, made him reluctant to leave Manchester. An invitation in 1943 to take the chair of biochemistry at Cambridge was refused, partly for these considerations, partly because the Cambridge department was fragmented and ill-organized, and partly because Todd regarded himself as an organic chemist rather than a biochemist (later in life he saw the boundaries much less sharply). However, moves continued in Cambridge to recruit him, and he was shortly invited to take the chair of organic chemistry that had, in fact, been founded as a chair of chemistry in 1702. Again he showed considerable resistance. Chemistry at Cambridge, like biochemistry, was in a fragmented condition. There were essentially two departments. The one he was invited to inherit, the Department of Organic and Theoretical Chemistry, was in a sadly run-down condition after years of neglect by the ailing professor Sir William J. Pope, whose death had triggered the new appointment. The other was the Department of Physical Chemistry, run by Ronald Norrish and likely to go its own way. A visit to the laboratories, then in Pembroke Street, showed them to be thoroughly unsatisfactory, with few facilities, in old buildings and with only gas lighting. Todd’s reluctance was understandable.

Cambridge and Afterward. Todd eventually agreed to move to Cambridge, but stipulated many conditions. These included the removal from their wartime quarters of chemists from Queen Mary’s College and St. Bartholomew’s Hospital, and of the government’s uranium research team; replacement of gas by electric lighting; appointment of Gilson, his own laboratory steward, and of B. Lythgoe (a Manchester lecturer working with Todd on nucleotides); and priority for a new university chemical laboratory on a different site. Perhaps surprisingly, all these conditions were accepted and, with many misgivings, Todd agreed to go to Cambridge, starting in October 1944. He chose a fellowship in Christ’s College. The family quickly settled in, for it was familiar territory for Alison, who had studied at Newnham College, while her father and brother had been to Trinity. In 1946 a second daughter, Hilary, was born.

Many of his Manchester colleagues accompanied Todd to Cambridge, and at first they were the largest group in his department. These included Basil Lythgoe and James Baddiley. Years later, his Manchester research group formed the basis of a dining club formed in Cambridge (1971), named (at his suggestion) the Toddlers. John Edward Lennard-Jones was professor of theoretical chemistry. Seeing the dearth of modern inorganic chemistry at Cambridge, Todd was instrumental in recruiting Harry J. Eméleus in 1946, first as reader and soon afterward as professor of inorganic chemistry. Senior colleagues included the Cambridge chemists Frederick George Mann and Bernard Charles Saunders (authors of a best-selling textbook on practical organic chemistry), and Frederick Stanley Kipping and Peter “Pete” Maitland, following their demobilization from the armed forces.

With the end of the war, Todd was sent, with his friend and former colleague Bertie Kennedy Blount, to Germany in an attempt to revive science in the British Zone of Occupation. Using Göttingen as a base, they visited Hamburg, Kiel, and Cologne. They also called at Frankfurt, though in the American Zone, and renewed old acquaintances in a town devastated by Allied bombing. In 1947 he was invited by Sir Henry Tizard to join his Advisory Council on Scientific Policy. Five years later he was invited by the lord president of the council, Lord Woolton, to succeed Tizard as chairman and to become Woolton’s advisor in science. Under pressure, he agreed and remained until 1964, just before the Labour Party came to power. He regretted the council’s restricted role under Labour, being mainly limited to advice on grants to research councils. He considered that the policy issues previously discussed were of greater value to the country, and under his chairmanship the money received by science increased tenfold.

In Cambridge the old laboratory had been greatly improved and library facilities much increased. The first major research effort was a resumption of the studies begun in Manchester on nucleosides and nucleotides (their phosphate esters). Contrary to popular wisdom, Todd proceeded to synthesize nucleotide coenzymes by traditional techniques of organic chemistry. By 1949 Todd and Baddiley had synthesised the nucleoside adenosine. With others he established the β-glycosidic nature of the linkage between sugar and the base. A new technique for phosphorylation using dibenzyl phosphorochloridate gave three nucleotide coenzymes based on adenine, AMP, ADP, and ATP (adenosine mono-, di- and triphosphates) (see Fig. 2). Their identity with the natural products was confirmed by their effects on muscle preparations. Reagents known as phosphoroamidates were found to react cleanly with other phosphates and so to convert (for example) AMP to ADP.

From this it was a natural step to examine further the mysterious molecules ribonucleic acid (RNA) and deoxyribonucleic acid (DNA). Again, classical methods were employed to work out the structures. Colleagues working on these topics included Daniel M. Brown and Roy Markham. In 1952 the 250th anniversary of the chair was celebrated; to mark it, the first papers about the general chemistry and structures of RNA and DNA were published.

It turned out that the work in Todd’s laboratory was of much value to James D. Watson, Francis Crick, and others in their formulation of the double-helical structure. By this time Todd’s reputation was truly international. In 1954 he received a knighthood, and three years later was awarded the Nobel Prize for Chemistry for his work on nucleotides and nucleotide coenzymes.

Much other work was performed at Cambridge. The research begun on aphids before the war was resumed and the complicated structure of several pigments established. Vitamin B12, known to combat pernicious anemia, had been isolated in 1948, but its structure was unknown and complex. Together with Alan Woodworth Johnson and others, Todd isolated a number of degradation products, which, in conjunction with the x-ray crystallographic analysis by Dorothy Hodgkin at Oxford, led to a complete solution of the problem (1955).

The promised new laboratory was not started until 1950, on its present site in Lensfield Road. The long delay was partly because it was to be a steel-framed structure, and steel was in short supply in the late 1940s. The organic laboratories were finished some six years later, and the building was officially opened on 6 November 1958 by Princess Margaret. The finest chemical laboratory in Britain, it was very much Todd’s creation, in terms of both modern equipment and of structure. A small wing was first built and then tested (almost to destruction) by his staff, with lessons learned then passed on to the architects. Refurbishment was not needed until the mid-1990s.

Todd was becoming increasingly involved in academic politics and foreign travel, his first visit to Southeast Asia being in 1958. In the late 1950s he attended meetings at the home of Winston Churchill about the foundation of a new college where science and technology were respected. This became Churchill College, with Todd as a trustee. From 1955 he served on the council of the International Union of Pure and Applied Chemistry, and from 1963 to 1965 was its president. By now he was a close friend of the American chemist Robert Burns Woodward, and together they would often attend conferences overseas. He was frequently invited abroad to receive honorary degrees. India, the United States, and (especially) Australia were among his favorite destinations.

In 1962 he was awarded a life peerage, with the title of Baron Todd of Trumpington, and took his seat on the cross-benches of the House of Lords. The next year he was appointed master of Christ’s College, Cambridge. In 1965 he became the first chancellor of the University of Strath-clyde and also chairman of the Royal Commission on Medical Education. Further demanding trips abroad, and extensive cigarette smoking, were beginning to take their toll, and in 1970 Todd suffered a massive heart attack. During his convalescence he attempted to teach himself Chinese. Taking warning from the episode, he resigned his chair the next year. He managed, however, to preside at the British Association in September 1970.

Other tasks however followed. Todd became chairman of the syndics of Cambridge University Press, then in the doldrums and in need of fresh ideas. These he supplied, and saw the press begin its rise to prosperity and success. He was also prevailed upon to become chairman of the managing trustees of the Nuffield Foundation in 1973. Then, in 1975, came an honor that he seems to have appreciated most: he became president of the Royal Society in 1942. His aims were to increase the influence of the society on government, to support research by funding further research posts, to relate more closely to technology, and to strengthen the society’s international relations. In setting future trends in all these areas, he seems to have had considerable success during his five-year tenure. He received the Order of Merit in 1977. A few other appointments followed, but gradually he let go of committee work while maintaining former friendships and an interest in the progress of science in Britain. In 1987 his wife died; he survived for another ten years, in the care of his former secretary, Barbara Mann. His own death came on 10 January 1997 at a nursing home near Cambridge, from heart disease and pneumonia. He died a millionaire.

Alexander Todd was of striking appearance, over six feet six inches tall, with a strong Glaswegian accent. Even in the laboratory he dressed as a patrician, immaculate in a pin-striped suit, reflecting an awareness of how far he had traveled from his working-class origins. He did not like party politics, especially of the left, a tendency inherited from his father. Conservative by nature, he objected to student protests, and reacted strongly against the proposals of the Robbins Report of 1963 for extensive expansion of the universities. He believed this would lead to a diminution of standards and that the small number of very talented students would suffer. This was elitism, but in an academic rather than a social sense. Deemed arrogant by many, he possessed insatiable ambition and great tenacity. He had a fine sense of humor, which frequently surfaces in his well-written autobiography. He has been said to have had a “huge presence” in Cambridge, and his massive contribution to science policy, coupled with his immense achievements in organic chemistry and in biochemistry, make him one of the great men of twentieth-century science.

BIBLIOGRAPHY

Cambridge University Library maintains an archive of Todd’s papers. The article by Brown and Kornberg cited below includes a bibliography of Todd’s publications.

WORKS BY TODD

“Chemistry of Life.” Interview. Chemistry in Britain 10, no. 6 (1974): 207–214.

A Time to Remember: The Autobiography of a Chemist. Cambridge, U.K.: Cambridge University Press, 1983.

OTHER SOURCES

Archer, Mary D., and Christopher D. Haley. The 1702 Chair of Chemistry at Cambridge: Transformation and Change. Cambridge, U.K.: Cambridge University Press, 2005.

Baddiley, James. “Lord Todd, 1907–1997.” Chemistry in Britain 33, no. 4 (1997): 70.

Brown, Daniel M., and Hans Kornberg. Biographical Memoirs of Fellows of the Royal Society 46 (2000): 515–532.

Freemantle, M. “Cambridge Marks 300 Years of History.” Chemical & Engineering News (12 August 2002): 39–43.

Colin Russell