SIR ROBERT ROBINSON Shell Centre London England
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Interview with PETER F A R A G O
Sir Robert Robinson
Editor
Chemistry in Britoin
by Peter Farago
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What do you consider your most significant contribution to science? In the first place, I ought to say, that more than 65 years 01 active research work is being considered, and it is impossible to select a particular topic as having had much greater significance than others which came to the fore at a later period. The first interest in reactions was what I caN the Heteroenoid Systems. Collie had treated ethyl Baminocrotonate with ethyl bromide in alcohol and had obtained a small amount of ethyl acetoacetic ester; he ethylated the acetoacetic ester, and afier I had done some work on this reaction I asked him what he thought was the mechanism. He sent me a letter in which he said that it was a very bad reaction; he thought that ihe aminocrotonate had condensed with various bases, that ammonia and certain pyridine bases were present and that it also led to the formation of ethyl acetoacetate, and these bases had formed the base salt of the ethyl acetoacetate which had been alkytated by ihe ethyl halide in the usual way. Of course that wasn't the proper exptanation at all, and what really happens is that the aminocrotonate contains an unsaturated amino-double bonds system which I called heteroenoid and which is now called enamic or one particular form of it, and this is alkylated in accordance with the tautomerisms of the enamic system; that is to say the methyl goes on to ihe carbon and the charge is neutralized by the nitrogen. I proved this, when I was in Australia for my first chair, by alkylating aminocrotonic ester with ethyl iodide so as to obtain an adduct of ethyl iodide to the enamic system and then this was hydrolyzed. The salt obtained was not analyzed or isolated, but was immediately hydrolyzed and gave the alkylacetoacetic ester. This was interpreted as showing the way in which sodioethylacetoacetate reacts. Nobody had done that before: it was quite new. When I had done this work, and lor example showed that you could dialkylate acetoacetic ester ( I used for that purpose the ethylenediamine condensation product with
ethyl acetopropionate, and from that substance made the adduct in the usual way, and then on hydrolysis the dimethylacetoacetic ester) this was a further indication of the correct mechanism of the process and another analogy with the sodioacetic ester reaction. As those substances all contained the carbethoxy group I thought it desirable to do another case where there was no carbelhoxy group. That was done also in Sydney . . using I-benzvlidene-2-methvltetrahydroisoquinoline. The unsaturated base is methylated in accordance with the enamic system and the methyl goes in the beta position to ihe nitrogen. A little later I applied the same ideas to the biogenesis of corydaline where you obviously get dihydroberberine which contains an enamic system as biosyntheticalty methylated in the beta-position and to physostigmine or etherine-a suggestion I made to Barger which was acknowledged by him. This was one of the first things I did,and this was further developed as an explanation of ihe reactions of phenols and amine, pyrroles and furan, all 01 them on the basis of the partial valency system which I had introduced. This was dinerent from the Thiele system because it was based on partial valencies instead of on residual valencies. With Thiele each carbon double bond was associated with residual valency and these coupled together to give you the conjugated system. Using the Thiele system Becker had already written what I would describe as an enamic conjugated system on the Thiele basis. He had applied it only to the conversion of salts from ihe exo-double bond, into the double bond 01 the aromatic nucleus. It was a question of hydrogen transfer. I made my system much more certain by using alkyl groups instead of hydrogen; but Becker had already used the Thiele system to explain the activation of a double bond by nitrogen-he didn't go any further. I think it is only right to mention that H. Becker was the first to see that there was a conjugated system when nitrogen is attached to a double bond. The whole
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theory 01 the heteroenoid systems and enamic reactions has been developed in obvious directions-acyiation as welt as aikyiation-and created a large amount of work which sometimes makes up for lack 01 novelty. Next, I became interested in the alkaloids owing to some conversations with Lapworth before I went to Sydney, and this was the reaction of pseudobases. These were interpreted by Lapworth in a very characteristic Lapworthian manner. He really helped me enormously to understand what was going on in reactions, with cotamhe and so on and which were developed quite a tot. This also was brought into the partial valency theory, and then about 1920-this I think is the major work I did-I founded the qualitative theory of electronic mechanisms in organic chemistry. This was opposed by Fluorsheim and tngold lor four years, but at the end 01 1925 1 wrote a paper lor ihe Chemicai Society which was a summary of work that I had done on the nitration of catechot and quinol ethers. I sent a copy of this to tngold and i have a letter in my possession which is his reply. He said that "I agree with you that your theory is a theory of organic chemistry and no1 just of benzene substitution." It was quite a nice reply, I want to tell you that I think that the work on the electronic theories was the most important to all this work--eartier on there was the synthesis of hopinone and the biogenesis of the alkaloids which was summarized in a book called "Structural Relations of Natural Products." 01 course very many suggestions that were made there were incorrect, especially about the indoie alkaloids: indoie atkatoids are known to have originated in terpenes as Thomas suggested and not from tryptophane as Woodard and I thought. Barge, was the first to suggest that-at Madrid in 1925. t n Oxford me continued the work on the anthocyanines, that had been started in Manchester. Todd made the main 3,Cdiglucosidic anthocyanines-the anthocyanines 01 the rose, the pelargonium, wild mailow, and peony: in other words some very important anthocyanines; he made ail these in a row having found out how to prepare the 2qtucoside of phloroglucinaMehyde-this was the essential thing. We had to giucosidate the ortho postlion there. There is a rather amusing story about that. Todd was a great crossword tan, and he had been trying to put this bromoacetylgiucose into the phiorogiucinatdehyde. Benzoyi chloride benzoyiates the ortho position quite ail right, so we thought that bromoaceloglucose should do the same. This didn't succeed at all under ordinary conditions. Finally he had an experiment going with acetonitrile as solvent and was doing his crossword puzzle, and the little flask containing this material responded to a bump on the steam bath and got immersed in the water. In an exclamation of disgust he put it on the draining rack to abandon it, but when he came to look at this thing alterwards he found that crystals had come out, and these crystals turned out to be the right substance, and ever alter the compound was Crystallized by dissolving it in acetonitrile and adding boiling water to it. With this intermediate in his hands he was able to make all these things, because the righl-hand component the glucoside of the other side of the molecule giving the 3-giucoside eventually in the anthocyanines-that was already known lrom the synthesis of crysanlhamine which had been accomptished in Manchester days, but this 2-giucoside of phtorogtucinot was really made, and he also synthesized the 84
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glucoside 01 apigenaine cMorMe which is gesmorine and which has no hydroxide in position 3. Well, he did that as welt. How did your interests develop? With Btount we made some tropinone analogs, and then I started in earnest on the synthesis 01 cholesterol, which was finally accomptished with the valuable help of J. W. Cornlorth about 20 years later. Alter that we began to use the alkyl dihydric phenols like methytresorcinol which you can get lrom a low temperature carbonization lrom Bosover-they provided this material in kilogram quantities-one ot the workers there was Herchel Smith. He worked with me later on this subject, but he combined the knowledge of the resources from the aikyt resorcinols with synthesis invenled by a Russian and made a substance that was a strong contraceptive which was very much better than anything else. He did that largely by replacing a methyl group with ethyi-this was possible using these alkyl polyhydric phenols as a starting point. t believe that Herchel Smith is one of the several students 01 mine who now simply watch the noughts come on at the end 01 his bank balance. In collaboration with E. C. Dodds, I made a highly active oestrogen, namely, stiiboestrol. Our collaborators were W. Lawson, who was with me in Liverpool and then went with me to British Dyes Ltd. in Huddersfield, and then direcl)y to Dodds' Laboratory; also I. Golberg, who came as a student to Oxford lrom South Africa. Rather extensive attempts to prepare androgens and analogs 01 pmgesterone and corticosterone in a similar manner failed, although the number ot synthetic oestrogens was quite large; none 01 them excels stilboestrol in praclice. Another activity which occupied many years 01 my work at Oxford, was that on the structure of strychnine. My main contribution was described in the Bakerian Lecture and was an explanation 01 the degradation series carried out by Leuchs. Earlier, the structure of morphine had been revised and one of my Presidenlial addresses to the Royal Society was an essay in which I explained the course 01 the reaction 01 phenylmagnesium bmmide on thebaine. It is an elegant reaction producing a 10 ring. K. W. Bentley and I later established the correctness of my proposal, by experiment. When you started your chemical career did you have any specific aim in mind? No, I had not consciously. I was very interested in organic chemistry. t was destined to go into my lather's works-a prosperous business manulacturing surgical dressings. He was very disappointed when I decided to take on chemistry instead. 1just did it because I was interested in organic chemistry, but very soon after entering Perkin's private laboratory I became extremely interested in the brazitin problem, and I contributed to that by suggesting the correct formulae tor brazilin, working on trimethyl brazitone and also carrying out some syntheses-the formula Perkin had at the time was proved to be incorrect by the synthesis of a pyrylium satt which should have been a trimethyibrazilium salt, and it wasn't. Anyway, I knew it was going to be different before i finished, because we had already synthesized some of the degradation products of brazilin, namely brazilinic acid and tactone 01 dihydrobrazilinic acid. Braziiin has been an interest ail my tife-in tact at the present moment I am doing some work on brazilin --getting some extremely interesting results too. Wite Fhursinght synthesized brazilin and haema-
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toxylin but publication (1970) was much delayed. What are your views on the mie of chemistry in industry-the role of the chemist not only as a developer 01 his particular discipline, but aiso as having some force within the economic or social context oiindustry? Organic chemistry is a key science because it is right in the middle of the sciences; it has contacts with physical chemistry on one hand and through that with physics and mathematics, and contact with biochemistry. Biochemistry is really organic chemistry, affecting physiology, pharmacology and aN medicine, and also the normal academic subjects of botany and zoology-in fact there is hardly any science which hasn't got some contact with organic chemistry. In that respect I think organic chemistry is rather unique. This means that organic chemists have a very general and balanced outlook, or shouid have, and has proved to be so in the past because some of the most successlut directors or managers in industry have been organic chemists-this is certainly true in the German chemical industry, and I believe it is true in America too. There is no doubt whatever that they do have a certain capacity for a broad view which some of the more specialized scientists do not have. Chemists as a whole have proved excellent managers and advisers in industry-more so than almost any other scientists, unless you come to a very specialized thing-like, say, oil, where of course the oil engineer and the geologist are supreme. You think that chemists should not stick to the laboratory bench but should seek wide opportunities in industry? I don't think they can all do that, but selected chemists from time to time show particular aptitude lor management and shouid be given the opportunity to develop it. If every chemist thought he was going to be a manager then of course we shouid have a very Gilbertian situation. Did YOU yourself take any active part in what one might call public affairs? Certainly I did. During the war I was a member 01 altogether about 30 diflerent committees-was Chairman of two of the Chemical Delence committees-the Chemical Committee, which was the one to examine the preparation of new substances and the Technological Committee which was to examine the way to make the preferred compounds. I was Chairman 01 both those committees. I made several visits to America in this connection; I was also a member of the Explosives Committee but never a very active one-Chemical Defence was my main activity; then later on on anti-malariab for the Medical Research Council-it was done for the coloniai Policy Research Council. i was also a member 01the substitute committee. Did you like your committees? Did you think they were effective? Were they able to generate the required recommendations, and were they accepted? They seemed very effective at the time. One felt that one had done some good work, then later on perhaps realized that it had been dissipated and that the work was still good but less notice had been taken of it than should have been. You can't generalize on that-some of these committees were doing extremely good work; i think the Research Councii of Ministry of Supply under Tizard did exceilent work and was listened to. Would you advocate that scienlists should try to get themselves more involved with this kind of activity?
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Not that they should push themselves into it if they don't feel suited to it, but I think that the people who choose these commfttees, especially the Chairmen 01 them, should be very careful to see that they get active members. They soon lind out whether a man is keen enough on the work to carry on with it-and you can weed the others out in that way. I don't think it is possible to lay down any general rules, it depends so much on individual personality and all kinds of things which you cannot possibly assess in a general way. What are your views on chemical education? it is extremely difficult to describe what a perfect chemical course should be. The one I took in ManChester struck me as being pretty well designed with excellent lectures by Dixon and Perkin, and of course some of these lectures, at times experimentally illustrated, were particularly good. Shuster, at physics, was an awfully good lecturer to the extent to which the students would allow him to be so, because they were very rowdy. What we had then, which I lind missing now, was some history of chemistry-/ believe you should pay attention to the history of chemistry-it's a kind of contact with the humanity side of the science and must be of very great interest-1 know it was 01 very great interest to me. I couldn't have known so much about subjects I have talked about if i had not had a course on the history of chemistry. Should we aim at educating a very large number of people with a superlicial knowledge of chemistry or a relatively few people to a detailed knowledge 01the subject? I think you do both-you have your honours school and your ordinary school. The ordinary people will just get more than a smattering; they wilt have a proper course of lectures, but it won't be lollowed up in detail later on. One great trouble about university education is that the lecturers tend to lecture enthusiastically about subjects that they are themselves personally enthusiastic about. They don't take a broad enough view of the subject to enable them to deal with it fairly in all its parts. I think that the specialized courses should not be compuhory. There should be some people avaitable in the university departments who are particularly good at lecturing and who are willing to take a broad view-and lecture with equal enthusiasm over the whole of the course. Do you conceive of chemistry as an educational process in the same way as one can conceive of Latin? Oh, yes, a better education. What are your views on the state of the art 01 chemistry when you started, and developments in the next lilty years? That's a very interesting question-it's one I have very definite views about. I'm extremely interested in the use of modern physical methods lor the determination of structure. Suppose Bayer had been able to put his indigo into a machine and grind out the structure, which is quite possible nowadayswhat do you gain? You gain a quick knowledge 01 the structure. And what does that mean? It means that you don't know ail the indoie chemistry-you don't know about isitin-you don't know about the propiolic acids, nitropropiolic acids-you don't know aN the things that Bayer did on the way to getting the structure of indigo. So the use of more and more sophisticated physical methods will make it more and more easy to obtain the structure; and this is a very good thing because it saves a very great deal of time which would othenvise Volume 51, Number 2, February 1974
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have been spent on other things; but it does not mean that the subject has been exhausted-you have still got to go back and work on the chemistryof that compound. In your starting days were you ever conscious that you only had primitive toots at your disposai? Of course one was conscious of the fact that I have a couple of combustions to do today, and that is going to take me at least four hours. You don't do that now-that is overcome by the process of sending for someone to do the analysis. But of course then you have the realization that you have no confidence realty in these results. Would you say that lack of sophisticated tools makes lor better chemists? No, certainty not-you get better chemists if you have sophisticated tools. Where do you think chemistry is going? I think chemistry is going on and on. The circumference of research is expanding and we get more and more chemistry every year-more and more organic chemistry every year, provided we don't get swallowed up by life science people. But do you think there are any particular areas in chemistry that are going to develop more actively than others? Yes, t think the areas associated with physiology, the transmission of impulses and nerves and all that kind of thing, and enzyme chemistry and enzyme mechanisms-though t think that is going to develop much more quickly. There are also indications that have been given by Charles Porter's recent work with antigenic compounds-for which he received the Nobel Prize. This biological work is going to be the main thing. ll's extremely difficult to find a new, really new thing in fundamental industrial chemistry-the last new achievements have been by Ziegler. There are certain to be new synthetic reactions like the Wittig reaction that has not been used enough. The other main discovery following the Ziegler reaction was the discovery of the Phillips metathesis-that is a reaction in which
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you use heavy-metal catalysis like molyMenum and tungsten-very often in association with atuminum, but what the aluminium does f am not quite clear-it may possibly reduce the tungsten to a lower state of valancy, but anyway you get the two ligands on the metal atom. These two tigands, two olefins, may react together to produce two new otelins, and by this method you can tailor the olefins-if you have got too much propylene-where you can convert it into ethylene and butytene and vice versa. This Is t think a new fundamental reaction-quite as important as the Ziegler reactionbut it is very difficult to see where the next one is coming from; these things are very few and far between, and the great discoveries are going to be made in the biotogical sphere where the field is wide open and there are enormous areas of unknown terrltory to explore. Farago: One of the debates of the last five or ten years has revolved around the topic of scientists' social responsibility. Robinson: In wartime I think that one's loyalty to the State is supreme. You make inventions in wartime which are to be applied by other people, and you feel no responsibility for that at all-the applications are going to be made in accordance with the rules and conventions of war. In peacetime I think the situation might be rather different. It is possible that scientists should consider how their discoveries can be apptied-but even so I think there is a grave danger of injustice being done to scientists in this respect. I don't think the scientist is actually responsible for the use that is made of his discoveries. Fancy trying to make Rutherford or J. J. Thompson responsible for the results of their discoveries-l mean you just can't do it. Their discoveries are discoveries of something that occurs in nature, and I think the scientist has always got a right and a duty to say what he sees in nature, and then if other persons, ill-disposed or unwise persons, choose to make bad applications of these things I don't think you can blame the scientist.
