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 interested 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.