A Time to Remember

by Alexander Todd

  Compared to the Frankfurt Chemical Institute the Dyson Perrins Laboratory in Oxford was rather primitive when I joined it in 1931. No micro-analysis facilities were available, and analyses were carried out down in the semi-basement by the laboratory steward, Fred Hall, using the classical macro-procedures. Fred had been Perkin's chief assistant and in my time ruled the Dyson Perrins - and its professor - with a rod of iron; many stories are told about him but I always got on well with him and found him very helpful. [I did hear, years later, that he told someone that the only two real gentlemen who ever worked in the Dyson Perrins were Alex Todd and Donald Somerville (who later went into the law and politics and became Attorney General).] Blount and I used to send our materials to Schoeller in Berlin for micro-analysis and it was not until 1933 when Drs Weiler and Strauss came as refugees from Nazi Germany that routine micro-analysis was developed in the Dyson Perrins. Blount and I also introduced catalytic hydrogenation and ground glass joints to Oxford but, during my time, the other equipment available amounted to a very indifferent polarimeter, a visible absorption spectrometer and an American pressure hydrogenator which didn't work. Robinson was like his teacher and predecessor Perkin in having little interest in gadgets - he was firmly attached to the degradative and synthetic methods of classical organic chemistry and was slow to adopt such things as ultra-violet and, later, infra-red spectroscopy as aids in structural work.

  In those days Robinson was at the height of his powers and he was the most inspiring director of research with whom I have ever come in contact. Certainly one had to be reasonably tough and independent to appreciate him fully, and many a budding chemist who came to Oxford from another school where 'spoon-feeding' of Ph.D. students was the rule, found it difficult to settle into the rather haphazard Oxford scheme of things. Robinson had a razor-sharp mind, but he was interested in many topics and his interest would flit from one to the other with great frequency. He was liable to concentrate all his attention on the topic interesting him at any given moment, to the exclusion of everything else. This made many people regard him as frequently tactiturn if not downright rude, and his collaborators had to get accustomed to being alternately badgered about their progress several times a day, and being almost totally ignored for weeks on end. Perhaps because of the proximity of my laboratory to his, I only observed but did not suffer much from his behaviour. Robinson did not pursue solid experimental work, and differed in this way from his predecessor Perkin. Generally he confined himself to a few preliminary experiments, usually in glass boiling-tubes, and left the follow-up to a junior collaborator. He was very emotional in his reaction to events and impatient with those holding views contrary to his own. This perhaps helps to explain the enormous range of his contributions and the reason for his name being associated with the discovery of a prodigious number of reactions used in synthesis, but with relatively few completed syntheses of complex molecules like steroids. His instinct when confronted with a difficulty in experimental work was at once to seek an alternative route to his objective, or even to change the objective itself; this practice led frequently to the discovery of new reactions, but also, at times, to the premature abandonment of synthetic routes which were later shown by others to be practical.

  My sojourn in Oxford was a very important period in my career. Quite apart from establishing a permanent bond with Robert Robinson I learned to know and made lifelong friends among the host of young chemists who, like me, came to the Dyson Perrins to work with him, or followed him there from elsewhere - Gulland, R. D. Haworth, Baker, King, Erdtman (Sweden), Sugasawa (Japan), Walker, Schlitter (Switzerland), Morf (Switzerland), Ramage, J. D. Rose, Briggs (New Zealand), Watt (Australia) and many others. We also had two refugee professors from Germany during the latter part of my stay -Arnold Weissberger and Fritz Arndt, whose chain-smoking of cigars ensured that his presence in the laboratories was always well advertised!

  In 1932 I completed the synthesis of the flower colouring matters hirsutin, pelargonin, malvin, and cyanin, chlorides, and so effectively rounded off the anthocyanin field leaving, as far as synthesis was concerned, only some mopping up operations. Accordingly I was looking around for some new subject when Harold Raistrick asked Robinson if he would like to look at the chemistry of some red pigments in certain plant pathogenic moulds of the Helminthosporium group; the problem was turned over to me and much of my time was devoted to it during my last two years in Oxford. Before getting immersed in that problem I had prepared a quantity of gossypol from cottonseed, but never got around to studying it; indeed, I rather think I still have the material in a bottle in my specimen collection in Cambridge. I dropped it in favour of a very brief foray into the steroids following the first (erroneous) structure advanced by Rosenheim and King in 1932. I began to check certain degradations of cholesterol but abandoned them when the correct structure was put forward shortly afterwards by Wieland and Dane. Thereafter, it is true, I devoted a few weeks to a rather hare-brained scheme whereby I sought to generate a tetracyclic nucleus of the steroid type by a very short route beginning with a somewhat unlikely reaction between hexatriene and methyl cyclohexenone. The first problem was to prepare hexatriene; the literature route via divinylethylene glycol was rather unattractive. While I was doing some preliminary work on possible modifications, Robinson travelled with Professor J. F. Thorpe to Manchester on a consulting visit to the Dyestuffs Group of Imperial Chemical Industries and mentioned my problem to him. Thorpe immediately said there was no need to synthesise hexatriene since it was readily available as a major constituent of the so-called 'railway hydrocarbon', the low-boiling residue left behind in the gas cylinders still used for lighting railway carriages in those days. All that you needed to do was to warm it slightly and pass the gas evolved into bromine whereupon you would obtain a copious supply of hexatriene hexabromide. It was characteristic of Robinson that, before returning to Oxford, he ordered a quantity of railway hydrocarbon from the London Midland and Scottish Railway Company. The stuff was duly delivered in a thirty-gallon metal drum which was dumped in the laboratory yard where, it being high summer, it lay gently hissing and smelling to high heaven. It was closed by a large hexagonal nut which appeared to be immovable. However, aided by the laboratory handyman, a monkey wrench and a hammer, I forced an entry. With difficulty we capped the resulting gusher and managed to collect some of the contents. Following Thorpe's instructions I then used up every particle of bromine in Oxford but obtained only a mixture of ethylene dibromide and butadiene tetrabromide contaminated by - at most - a trace of the hexatriene compound. I returned to the preparation of divinylethylene glycol and the railway hydrocarbon - at the urgent request of the local inhabitants - was returned to the railway company.

  3. Edinburgh, London and Pasadena

  My 1851 Senior Studentship was extended for a third year and was due to expire on 30 September 1934. By the early part of that year I had therefore to begin casting around for something with which to support myself. It was not an easy time for finding an academic position, which I would have preferred to one in industry, although I did not rule out an industrial career; but industrial jobs were about as scarce as academic ones. I remember being approached about taking charge of a laboratory at the Courtauld Institute of Art which was of no interest to me, and also about an assistant lectureship at Bangor which I did not find at all attractive. However, in May 1934 George Barger, then Professor of Medical Chemistry in the University of Edinburgh, visited Oxford to seek Robinson's advice. Barger, who himself was half Dutch, was a friend of B. C. P. Jansen of Amsterdam who had in 1926 first isolated the anti-beriberi vitamin B1 from rice hulls in Batavia. Jansen, who did not consider himself a chemist, had heard that both the IG-Farbenindustrie in Germany and Merck & Co. in the United States had embarked on the structural investigation of vitamin B1, with a view to its commercial synthesis, and he felt that he really ought to do something himself. He therefore wrote to Barger and asked if he would take up the problem. Barger was naturally intere
sted but felt he was not really qualified for the job since it would involve working with very small amounts of material - all that was available from Jansen was about five milligrams of crystalline vitamin and a description of the isolation procedure from rice (which contains a few milligrams per ton). So he came to Oxford to ask Robinson what he should do. Robinson suggested he should ask me since I was a natural product chemist and I had acquired micro-techniques in Germany. I jumped at the offer, since it gave me the chance of doing exactly the kind of work I wanted to do; vitamins were just becoming accessible to organic chemists and I was fascinated by the possibility of finding out why they were so important, i.e. what function they performed in living creatures. So I went to Edinburgh in the summer of 1934 on the basis of a Medical Research Council grant eked out by the promise of some part-time demonstrating in medical chemistry; this meant, overall, a cut of around twenty-five per cent in my income but I reckoned it would be worth it.

  Barger was a close friend of Marcus Guggenheim, the Research Director of Hoffman La Roche & Co. of Basle, and through him was in close contact with that firm. As a result the firm agreed to do the preliminary concentration of vitamin B1 for me and send to Edinburgh bottles of the concentrate which, corresponding in weight to less than 0.1 per cent of the original rice hulls, made it possible for me to isolate small amounts of vitamin for study; without that help the scale of operations needed would have been impossible for an academic laboratory. Perhaps this would have been even more true in Edinburgh than in some other places, for the Medical Chemistry Department was not only inconveniently housed in the massive Victorian pile of the medical school but, when I arrived, the general level of equipment was deplorable. To aid the vitamin B1 work Barger got a substantial grant from the Rockefeller Foundation and with it I was able at least to ensure that we got adequate glassware and some minor instruments. But I was not able to spend more because of Barger's extraordinary attitude to the grant; for some obscure reason of his own, he felt it was up to him to show how economical he could be, and he was determined to return as much as possible to the Rockefeller Foundation. In this he was successful, and, indeed, when I finished the work on vitamin B1 he spoke with pride of how it had been done with so little Rockefeller money!

  I admit that when I first saw the Medical Chemistry Department my heart sank and I was exceedingly depressed. But there was one bright spot which helped to restore my optimism. This was the presence of Dr Franz Bergel. An Austrian by birth, he had been a young Privat-Dozent in Freiburg when, following Hitler's accession to power, he came to Edinburgh as a refugee supported by a grant from Hoffmann La Roche obtained through the efforts of Guggenheim and Barger. We quickly struck up a friendship which has lasted to this day, and he decided to join me in the vitamin B1 work. We did in fact work together for four years, first in Edinburgh and then in the Lister Institute, before we parted in 1938 - I to Manchester University and he to the new research department of Roche Products Ltd at Welwyn Garden City. I soon gathered round me a rather motley group of people - Barger's laboratory was much frequented by foreign students, perhaps because of his wide international contacts. At any rate, I soon had working in the B1 field not only Franz Bergel but Anni Jacob from Frankfurt (she remained with me until 1944), Juan Madinaveitia from Madrid (who later married Anni), Karimullah from Lahore, Keller from Basle and Fraenkel-Conrat, a German refugee who is now in Berkeley, California.

  I need not detail here all the hectic and at times frenzied work during these two years in Edinburgh. Details of the work can be found in the literature. We were beaten to final synthesis, although only by a short head, by the Germans and Americans but our synthesis was not only quite different in concept from the others but proved to be sufficiently superior for it to be used by Hoffmann La Roche to take a major share of the world B1 market. I should add that, since my work was partly supported by the Medical Research Council, I was not allowed to patent anything. This attitude, I fear, cost the country - and probably me also - very large sums of money and this may have been, in part, responsible for a later change of heart by the Research Councils. It incidentally played a role in the creation, much later on, of the National Research Development Corporation. Through advance knowledge of our results, which we naturally supplied to them in gratitude for their assistance, Hoffmann La Roche were in a position to establish themselves in the field and to take advantage of the opportunity thus presented to them. I have never grudged them their success, and remain ever grateful for the help they gave me on vitamin B1 and on vitamin E where I had an exactly similar relationship with the firm. Hoffmann La Roche ever since those days have always been ready and willing to help me with grants or materials required for my research and always without commitment on my part. In my experience their behaviour has been a model for industry/university collaboration in general.

  One or two recollections of the B1 work may be worthy of mention here. The first reveals another trait of George Barger. The first breakthrough in the structural work on vitamin B1 was made by R. R. Williams and the Merck group, who effected what has come to be known as the 'sulphite cleavage' and which yields a thiazole derivative together with a pyrimidine sulphonic acid. The result first appeared (I think in December 1934) as a paragraph in the New York Times in such a form that it was not wholly clear just what had been established. I can't remember now exactly how I got hold of this information, but I told Barger of its existence and he said I should draft a telegram to Max Bergmann at the Rockefeller Institute in New York and ask him to ascertain the facts and let us have some more detailed information. I accordingly drafted a telegram and showed it to Barger who almost exploded.' Todd,' he said, 'you are an unmitigated spendthrift; that telegram would cost us several pounds! Let me redraft it for you.' This he did, reducing it to about a dozen words and told me to despatch it. The following morning we received in return a telegram from Bergmann which read 'Cannot understand your communication. Please explain.' I then sent off my original version and got the required information much to Barger's chagrin! The delay between then and 1936 in establishing the true structure of the vitamin was due to an error made initially by all three groups working on it. The 'sulphite cleavage' was clearly fission of a quaternary ammonium salt. This was so unexpected that we all jumped to the entirely erroneous conclusion that the pyrimidine ring was directly linked to the quaternary nitrogen and that an ethyl group was attached to the pyrimidine ring system. It took nearly eighteen months for the German group to establish that in the pyrimidine sulphonic acid from the cleavage the sulphonic acid residue was attached through a CH2-group to position 5 of the pyrimidine ring system. It followed that there must indeed be a CH2-group between the pyrimidine ring system and the quaternary thiazole in the intact vitamin. Bergel and I, meanwhile, went directly for the erroneous formula by total synthesis, a difficult task in which we succeeded; as the product was not identical with the vitamin we could easily deduce the correct structure (which was one we had always regarded as a possible alternative) and we proceeded to synthesise it. The fact that we first had to synthesise the correct pyrimidine intermediate delayed us as compared with the others and left us a month or two behind the Germans and somewhat less behind the Americans; but on the other hand our prior work on the wrong B1 structure gave us a much more elegant vitamin synthesis. So, in the end, not a great deal was lost and we certainly could congratulate ourselves on our performance against two large and powerfully equipped organisations. The final clearing up was done after I moved to the Lister Institute in London in the autumn of 1936.

  Towards the end of my Edinburgh period I also began preliminary work on vitamin E, although I only developed that work seriously after moving to London. However, my stay in Edinburgh had another, and indeed vital, consequence for my career. It was there that I first met a young lady, Alison Dale, who was doing postdoctoral research in the department of pharmacology under A. J. Clark. Pharmacology was next door to medical chemistry and I fear I spent quite a lot of time there.
Suffice to say that by the time I left Edinburgh we were engaged to be married and did indeed marry in January 1937 after I had moved to London. That was perhaps the best thing I ever did, for my wife has always been a vital part of my career; to her I am forever grateful. Her father was Sir Henry Dale, the famous physiologist, and through her and her family I also met many people in the biomedical field, and these contacts have undoubtedly affected many of my scientific interests.

  (As a good Scotsman I can record that my fiancee consented to become formally engaged while we were attending a meeting of the Biochemical Society in Aberdeen. I at once bought her an engagement ring at Woolworths in that city. Hardly were we back in Edinburgh when one of the 'diamonds' fell out of its setting. Ever free with cash, I told her to throw away the ring and then bought her another - in the Edinburgh branch of Woolworths!)