Professor Athel Beckwith is an organic chemist whose work has covered a number of areas ranging from theoretical calculations to the synthesis of complex molecules. He is best known for his research into the structure and behaviour of organic free radicals. He is a Fellow of the Royal Society and of the Australian Academy of Science and is also a Fellow and Past President of the Royal Australian Chemical Institute. In the course of his research career he has been the recipient of many prestigious awards and honours.
Interviewed by Professor Bob Crompton in 2003.
Contents
Being Australian and multicultural
Athel, may we begin with your family background?
My parents were both born in Western Australia. My father, Laurence Beckwith, grew up in Katanning, a small town about 200 kilometres from Perth, where his father was a builder and carpenter. My mother (Doris Johnson) grew up in Perth; her father was a joiner and cabinet-maker. At the age of 12 my father, having gained an entrance into Perth Modern School, moved to Perth to stay with his aunt. He never lived in Katanning again.
I guess I'm both Australian and very multicultural – all of my grandparents were born in Australia, but of my eight great-grandparents three were Scotch, one German, one Swiss, one Scandinavian, and two English. They seem to have come to Australia in the 1840s or '50s, the German group moving to the Barossa Valley and the rest to Victoria. My maternal great-grandfather's Scandinavian family owned a trading ship. As they happened to arrive in Melbourne at the time of the gold rush my great grandfather promptly left the family and went to Ballarat. He was never successful as a miner and he became involved with the ringleaders of the Eureka Stockade. He later became a successful professional musician.
I believe that when you went to Europe you delved into your family's history.
We know most about the Beckwiths – I have a detailed history of them back to the 1600s. They lived mainly in Leeds. In Yorkshire there are still many Beckwiths, apparently all descended from one lady, Catherine Beckwith. She had Anglo-Saxon aristocratic roots while the Norman next door had money and land but was not distinguished, so when they married (in Knaresborough, in about the 12th or 13th century) he took her name. The bells in York Minster are the 'Beckwith bells', down in the Minster crypt there are pieces of silver made by a John Beckwith in the 13th century, and there is a village of Beckwithshaw nearby.
Coming to the present Beckwiths, where were you born and when?
I can tell you precisely – on 20th February 1930, in Nurse Stockley's Nursing Home, Havelock Street, Perth. It is so deeply imprinted on my memory because whenever my mother took me, as a child, into Perth by tram down Havelock Street she would say 'That is where you were born'.
What sort of early childhood memories do you have?
I had a very happy childhood. Both my parents were gifted. My mother won a scholarship to go to university in Paris but because of the depression she didn't take it up. My father was awarded one of the few entrance scholarships to the University of Western Australia but he didn't take that up either, because he preferred to study pharmacy. They were good linguists and were very interested in reading and music. Both were excellent musicians. My father performed frequently on the ABC and with various choirs. As a child I was exposed to lots of music, including singing around the piano. My parents read to me in bed, and as I attended a good kindergarten I could already read when I entered primary school.
My maternal grandparents lived with us because of the Depression – both grandfathers had lost their businesses. My maternal grandfather had a great influence on me. He taught me how to use my hands, to do carpentry, to build models, to fish. When I was very young I spent many happy days fishing at Fremantle Wharf.
Where we lived is nowadays part of an inner Perth suburb, but at that time it was at the edge of nowhere. Between our house and the sea there was nothing but bush, where we could wander for hours on end. I came to know the Western Australian flora well and could name all the wildflowers. I fell in love with the Australian bush, and have remained so ever since.
So I spent my childhood building model aeroplanes, swimming, exploring the bush and doing all the things that kids do. It was a very good time, a very easy time.
Was all your primary schooling in Perth?
No. In 1942 families who lived close to the sea were evacuated because of the danger of invasion, so my mother, my grandmother, my two brothers and I went to live in the Porongurups, a beautiful part of Western Australia. I attended Mount Barker School, where a remarkable teacher, Mr Best, taught 6th, 7th, 8th and 9th standards, all in the one classroom. That was very good for us students. We were continually exposed to what was happening elsewhere, and although I was in 6th standard I picked up a lot of algebra, geometry and other subjects taught to higher classes.
Mr Best was the first person to show me a science experiment. He placed a four-gallon kerosene tin with some water in it over a Bunsen. When the water boiled, he quickly put the top on the tin and turned off the Bunsen. As we watched, the tin collapsed – an astonishing event! Air pressure. That first experiment left a lasting impression.
The tiny Mount Barker School had remarkable success in the Scholarship Examination taken by most Western Australian children in their 12th year. I was one of a number of pupils awarded a scholarship to go to Modern School.
As you entered secondary school you suffered a severe illness that could have cost you your life. It had a profound effect on you physically – it left you with persistent lameness – and on your philosophy of life.
That's right. It happened very suddenly. I went to school feeling well, intending to captain the basketball team, but by lunchtime I felt ill. By the afternoon I was virtually delirious and by evening I was unconscious. Because of the pain in my leg it was assumed I had poliomyelitis – infantile paralysis, as it was called – of which there was a serious epidemic at that time, and I was placed in quarantine in the infectious diseases hospital. That was something of a tragedy because by the time my doctors discovered it wasn't poliomyelitis but osteomyelitis, a staphylococcal disease in the bone, they couldn't get me out again. I lay in the infectious diseases hospital for about four weeks before treatment for the osteomyelitis could start, and during those weeks a great deal of damage occurred. I was then taken to the Mount Hospital and had a number of operations. I fell ill on April Fools' Day, 1943, and I did not get out of bed until Christmas Day, 1944.
What drugs were available for your treatment?
When I became ill all that was available in Australia for the treatment of osteomyelitis were sulfa drugs, and although they were partially effective, they were dreadful things to take. Meanwhile penicillin had been developed; if it was taken immediately osteomyelitis could be cured within a fortnight. But it was too late for me, because enormous damage had already occurred and a great deal of bone had to re-grow. Nevertheless, an American serviceman who was billeted with us was able to obtain some US Navy penicillin. It was used at home, under great secrecy because, of course, it was highly illegal (I suspect I may have been the first civilian in Australia to have penicillin – courtesy of the US Navy). It helped, but the disease kept recurring. It was about seven years before it was completely eliminated.
In the end it taught me two things. Having found out how close to death I was I have come to value every day that is available to me. I might not be here, so I should make the most of it. And going through such a great deal of pain has made me very careful about causing pain to any person or any creature. To endure that much pain at age 13 for something like two months leaves its mark.
Secondary school years: appreciating science by doing it
When you were able to return to Perth Modern School, you did very well, I believe.
The headmaster wanted to put me back a year because I had lost so much time, but he didn't realise that whilst in bed I had busily been doing correspondence classes and reading a splendid book called Wonders of Modern Science, and hence had kept relatively up to date. My mother, who was usually a very mild person, could be rather aggressive regarding the rights of her children. After she had firmly told the headmaster I should stay in the correct class for my year they came to a deal that if I went into that class and succeeded in first term, I could remain there. Because of the schooling I had while in bed, I did remarkably well – apart from Latin. I stayed in the correct class for my age.
Modern School was a marvellous school. When it was called 'Modern' at the time of its creation in the early part of the century it must have seemed extraordinarily modern and it was still modern in the '40s. There was no corporal punishment, it was completely co-educational, a lot of the study was done individually as independent study, and all science was taught in a laboratory. That was really wonderful; I came to realise that the best way to appreciate science is to do it, or to see it being done, rather than simply to hear about it. At that stage I started doing my own science at home, because having a father who was a pharmacist gave me ready access to all the things one needs for the sorts of experiments that young chaps like doing – thermite mixture and explosions, smells, and bangs.
You had an outstanding final year result, didn't you – except for Latin, I suppose!
I dropped Latin as soon as possible, and concentrated on science and mathematics. In those days it was necessary to study English and Art, and I also took music for Matriculation. I obtained Distinction in all seven subjects – the only person to do so in that year. It was a rare event.
You formed many friendships at secondary school, some of your friends later becoming very well known in business and many other fields. And during those years your love of music turned toward jazz, didn't it, Athel?
Yes. I had studied music from about the age of six, and had become quite proficient as a classical pianist. Indeed, I could play Mozart's sonatas much better at age 12 than I can now! It was when I was about 14 or 15 that I became interested in jazz. I studied composition for a while, being taught by a friend of my parents. Knowledge of harmony is a splendid aid to improvisation. I might say that jazz was of great assistance at parties and occasions of that sort. That's the age when one is beginning to be interested in young ladies, and young ladies become interested in pianists who can play jazz!
Later you moved on from the piano to the clarinet.
Yes. Not much later on, probably about the time that I matriculated, I saw a film version of the life of George Gershwin, and I heard the marvellous opening glissando of the Rhapsody in Blue. I thought it was wonderful, and so I took up the clarinet. I was very fortunate in studying privately with Alan Rule, the principal clarinettist in the Western Australian Symphony Orchestra.
Later I joined the ABC Training Orchestra. It had been set up by the Australian Broadcasting Commission to give young people practice in orchestral playing, with the expectation that some of them would later become professional musicians. There were two second clarinets and two firsts, of whom all but myself did indeed become professional musicians.
I loved playing the clarinet, but strangely enough, although it is a jazz instrument, I was never as good at jazz on clarinet as I am on the piano. I often played in dance bands on the piano, but only once on the clarinet. When I left Adelaide, the Chemistry Department gave me a big farewell party, including a jazz band with which I played during the evening.
If only I'd known that, Athel, I would have brought a piano in here and you could have performed for us!
In the orchestra we played with top-class conductors. With Henri Krips we played the standards of classical music: Beethoven, Mozart, Dvorák, and so on. Another well-known conductor, Rudolf Pekarek, introduced us to light music such as operetta, and I came to realise that sometimes music which is regarded as 'light' is often very difficult to play well. I learnt a great deal about music through playing in that orchestra. I continued to play the clarinet in small groups or bands until a few years ago but I never played with a symphony orchestra again.
An excellent place and time for a chemical education
From secondary school you went on to the University of Western Australia. Can you tell us something about the people there who influenced your interests and career?
The staff of the University of Western Australia included a number of outstanding people. The Chemistry Department was particularly fortunate in having as its head Noel Bayliss, a physical chemist of high international reputation. Doug White, an organic chemist, was an extremely good lecturer who inspired us all by bringing into the lecture theatre samples of natural products, particularly those with interesting odours. He showed how high and low concentrations of compounds can sometimes have completely different odours and how the detection of odours varies from one individual to another. I loved his lectures. Doug White had grown up in the traditional mould and taught us a lot of classical chemistry, but Joe Miller, who had worked at University College with Sir Christopher Ingold, was well versed in the more modern electronic theory of organic chemistry. Robin Stokes, who became a Fellow of the Academy, was also in the Department. So we were very fortunate. It would have been difficult to find a better place in Australia for a chemical education.
It was in fact a particularly good time to be in that Department. During my Honours year Andy Cole came back from Canada, where they were developing the very new technique of infrared spectroscopy, and Doug White had recently been on sabbatical in Zürich where he mastered the new technique of chromatography. So we learnt both classical chemistry and modern theoretical chemistry, we were introduced to new techniques, and we did a lot of practical chemistry. I really liked experimental work – it was a joy to make compounds that had not previously been described. One wondered whether those atoms had ever before been assembled in precisely that way. Watching crystals form in a flask added a very aesthetically pleasing aspect.
You mentioned the electronic approach to organic chemistry. What is that?
The traditional approach to chemistry was to conduct experiments, to determine the nature of the products, and then to try to deduce what had happened. But very little was known of why it happened. Various typical types of reactions could be recognised; treatment of a compound of a known class according to an established recipe would be expected to give a certain type of product. What wasn't known was why one expected it. What were the underlying rules that govern the chemical behaviour of molecules?
Then Robinson and Ingold in the UK developed the notion that chemical behaviour is linked to electronic factors. Since most organic molecules are held together by chemical bonds comprising electron pairs, they suggested that the way in which an organic reaction proceeds is determined by where the charge lies and the way the electrons move. That is, when a new bond is formed electrons move in to form the new bond and away from bonds undergoing fission. Once one understands the electronic approach to chemistry, one can develop predictive rules for molecular behaviour. Instead of just remembering what happens in chemistry, one can predict what will happen and why it happens. That was a very important andvance in the development of modern organic chemistry.
I believe that another important approach you met at university was White's First Rule. What was that?
Doug White was very interested in practical chemistry, and I must say he made us work hard at the bench. We learnt lots of techniques students don't learn nowadays, like glassblowing, and of course all our experiments were done with gas heating and ordinary water baths (fires in chemistry laboratories were quite frequent!). Doug's First Rule was: 'All the best chemistry goes down the sink.' What he meant was that the most interesting chemistry occurs when there is an unexpected outcome. There is a tendency among young students to set up an experiment and then, if the expected outcome isn't obtained, to regard the experiment as a failure and to dispose of the reaction mixture.
Doug said, 'If something has happened that is not what you expect, that is what is really interesting. It may indicate something new. This is how new chemistry is found.' So he would come around and ask, 'Have you had an unexpected result?' If we said the experiment was a failure, he'd say, 'No, it wasn't a failure. There was an unexpected outcome. Tell me exactly what you did. What did you see? What do you think it meant?' He taught us to be curious, to look for the unexpected. I now tell all my students: 'An experiment that you think is a failure may indeed reward you with the greatest find of your life – if you look.'
After those interesting experiences it was on to Honours. Did you do that in WA?
Yes. My Honours project was in two parts. First I worked with Doug White on natural product chemistry, a traditional area of chemistry that was very popular and interesting. One learnt how to handle very small quantities of material, and to purify them by chromatography. This experience was very important for me later on.
One of the great attractions of natural product chemistry was the collection of samples; plants that grow in attractive places were usually carefully chosen. I worked on Pittosporum phillyraeoides, for which the best source near to Perth was Rottnest Island. That necessitated a trip to Rottnest every second weekend to collect more of the plant material.
I enjoyed working with Doug White very much indeed. We made some useful advances – a few papers came out of this work – and it was exciting. But after a couple of months Doug went back to Switzerland and I shifted to a new project with Joe Miller involving research on reaction mechanisms.
The new project fascinated me – I discovered this was really what I wanted to do. Because Joe was mainly interested in the theoretical and electronic aspects of organic chemistry, working with him involved trying to discover why and how reactions occur; to identify God's rules, so to speak, for molecules and atoms. What are the laws that govern their behaviour? How can one use them predictively? These are essentially the type of questions I have pursued for most of my working life.
You got your First Class Honours at the end of 1951 and then became a graduate assistant in your old department. Why didn't you do a PhD instead?
In those days the PhD degree was unavailable in many Australian universities including the University of Western Australia; one could do a Masters degree but not a PhD. I had decided I would probably take a Masters degree anyway. One of the easy ways to do this was to take a graduate assistantship – an academic position, but lowly paid. We did some teaching, including quite a lot of laboratory supervision, but we were also allowed to conduct independent research. It was very good experience.
I decided to keep on working on the mechanisms of reactions. I explored a reaction of some commercial importance, one of the ways by which dyes are manufactured; namely, reactions of substances called diazonium salts with various reagents. Although it was quite successful, there was a serious problem when a particular reagent was used. When one is studying reaction mechanisms, the reproducibility of the experiment is very important. When one measures how fast reactions occur one expects that there should be little variability. But in this case I repeated the experiment many times with completely different results on each occasion – it was utterly irreproducible. I couldn't understand what was going on. Later I returned to this problem.
Among the great joys of being in that university and in that department at that time was the interaction with interesting colleagues. In the university at large there were many returned servicemen from the Second World War. They were mature and gave the university a completely different feeling. My colleagues in our department included Lloyd Zampatti, Geoff Watkins, who then went to work in Great Britain and is now a Fellow of the Royal Society, Don Watts, who is well known in Australia as an academic administrator, Jim Parker, who became a professor at the Australian National University, and Brian Bolto, who became a leading figure in CSIRO. They provided a very a stimulating atmosphere in which to work.
While you were still a graduate assistant, you got a scholarship offer to go overseas. Was that a University of Western Australia scholarship?
Yes. Winthrop Hackett had left a vast bequest to the university, which his executor had thoughtfully tripled before it was used, so the university was relatively rich. It charged no fees and was able to offer overseas scholarships, called Hackett Scholarships. I won one of these to study natural product chemistry for the PhD with Derek Barton at Birkbeck College in London.
But towards the end of that year, before I took up the scholarship, Professor Bayliss told me that he had received a letter from Professor Macbeth saying that he would like me to come to Adelaide as a junior lecturer. Bayliss strongly recommended that I accept this offer. So I did. I wrote to Barton to say I wouldn't be coming to London after all, turned down the scholarship, and prepared to go to Adelaide.
By the time you went to Adelaide you had a wife to accompany you. And you have just recently celebrated your golden wedding anniversary. Tell us about your wife.
Kaye's maiden name was Marshall. She is even more Australian than I. Not only were all of her grandparents born in Australia but also many of her great-grandparents. In fact, one of her ancestors was born in Sydney in 1802, and her family goes back to Captain Cook. At the celebrations of the first centenary of Australia her great aunt was a guest of honour.
Kaye was a secretary and then an accountant. We had very similar interests. We both loved swimming and spent as much time as we could on the beach – hence my skin these days is not as good as it should be. We loved music. At that time I was still playing a lot, as well as singing in various choirs. We both liked books, we enjoyed walking in the bush and we were very keen on the environment. I think one of the reasons we have been very happy together is that we share so many mutual interests.
Kaye later became professionally involved with the environment, being employed as a field officer by the Nature Conservation Society in Adelaide. Then she became interested in local government and was elected as the first woman councillor in the city of Mitcham, and later as the first woman alderman. Those elections provided all of us with interesting times. As well as electioneering, I used to act as a scrutineer and was able from time to time to point out that a bundle of votes had been put on the wrong pile. You've got to watch these council elections! Kaye was very successful as a local councillor and later on it was difficult for us to decide to come to Canberra, because she had to leave all her community work behind.
Did you go by train to Adelaide to take up your new position?
No, we went on the MV Westralia. I don't know why I came later to enjoy sea travel, because that was really not a very good voyage. At that time, however, it was the easiest way as any of getting across the Bight to Adelaide.
The sea was extraordinarily rough. Every meal was served on wet tablecloths and the seats were tied down. Even when one lay on the deck there was a danger of rolling overboard. One passenger, like us, was on his honeymoon but without his wife, because she had become so ill en route from Adelaide to Perth that she had to return by train!
The transition to university teaching
You had a very gracious introduction to academic and social life in Adelaide, I think.
Oh yes, much more gracious than it would be nowadays. On the first day I went in to the Chemistry Department to meet my new Professor, Killen Macbeth, who said, 'Well, before we get down to mundane matters like teaching and so on, I have some important things for you to do. I have an appointment for you with the Vice-Chancellor, who would like to meet his new member of staff, and then you should go to Government House to sign the Visitors' Book, because the Governor always likes to invite people from the University to come to dinner. And then you should take tea with Hedley Marston.'
So I did all of those things. It was very nice to meet the Vice-Chancellor, we were invited to receptions at Government House, and I was very pleased to meet Hedley Marston, one of this country's most colourful scientists. Perhaps I had an introduction to him because his division of CSIRO was next door to the Chemistry Department, and there was a good deal of collaboration between them.
What was it like to teach at Adelaide in those days, Athel?
My teaching load wasn't particularly heavy but it was a shock, because I came as an organic chemist but Professor Macbeth asked me to teach third-year inorganic chemistry and third-year spectroscopy. The spectroscopy was not too much trouble – I had received good training in that – but inorganic chemistry was probably the weakest branch of chemistry in Western Australia, and I knew little about it. So I kept one lecture ahead, leafing through Emeléus and Anderson, the textbook of the time. Also, I was so relatively young that many of the people in the class were older than me and it was pretty daunting. Not only were there ex-servicemen but also a number of refugees who had come to Australia to avoid the turmoil in Europe. One of them, Tom Kurucshev, who was certainly older than I, later became my best friend, and quite a distinguished physical chemist in Adelaide.
Round about this time you realised that you really ought to have a PhD.
Yes. During that time in Adelaide, almost two years, my own research went quite well. I continued to do natural product chemistry and some mechanistic work involving completely new systems. We found new ways of making some important compounds related to thyroxin, the natural hormone that occurs in the thyroid gland. That work was very interesting and also quite significant. But towards the end of the first year I decided that if I intended to continue with academic work, I really should go overseas to take a PhD.
I successfully applied for a CSIRO overseas scholarship (the expectation by CSIRO was that, in return, I would come back to work with them). Part of the deal was that I should discuss with the appropriate authorities in CSIRO what I wanted to do, so I went to Melbourne to see Ian Wark, Chief of the Division of Industrial Chemistry. He gave me some extraordinarily valuable advice.
First he asked just what I intended to do during my scholarship. I told him that I thought I should work with Derek Barton. I had already turned him down once. He was one of the great chemists of this century. Ian asked, 'And what will be your research area?' to which I replied that I would study natural product chemistry.
But Wark went on, 'Is there anything else you're interested in?' 'Yes' I said, 'I conducted some experiments during my Honours year that gave completely irreproducible results, and I am beginning to think they might involve free radicals. I wouldn't mind learning more about them at Oxford, with Professor Waters.' Wark said, 'Take my advice. Go to Oxford. In science you should always choose the new, the more adventurous area. Natural product chemistry is a well-ploughed field where many people have gone before. If you work on free radicals, you will be at the beginning of something new. It's dangerous, because nothing may ever come out of it. But if you want to do something really useful in science, always choose the field that is innovative and at the birth of a new area rather than at its middle age.' So I decided to follow his advice – it was a wise choice.
Perhaps this is the time to ask you to explain what is meant by free radical chemistry.
Free radicals, in solution, were first described in 1900, by an amazing pioneer called Moses Gomberg. Chemists had tried for years beforehand to make free radicals without success and had concluded that they didn't exist. Then Gomberg announced that he had successfully generated them, and indeed we now know that he had. He is also famous for a memorable footnote to the first paper, which was published in 1900 in the American Chemical Society Journal. Having described these new species, these free radicals, he notes, 'This work will be continued and I reserve the field for myself.'
In fact, he needn't have worried, because nobody else was very interested. Most scientists didn't believe he had actually generated organic free radicals in solution. And even at the time that I was entering the field, there were still many chemists who had similar doubts. There were a great many polemical articles in the scientific literature, with some chemists maintaining that organic radicals can't exist in solution. Others were convinced that they could. There were very few people seriously working in the field of organic radicals in solution – a couple in Great Britain, a couple in America – I suppose six people, in all, in the world.
Free radicals are very reactive molecules. All the more familiar organic compounds, such as sugar, alcohol and acetone, are stable; they can be stored for long periods without change. They are stable because they possess an even number of electrons arranged in pairs. The bonds between the atoms consist of pairs of electrons; a pair of electrons is a stable arrangement. Furthermore, around most of the atoms in such molecules there are eight electrons in four pairs. This is a very stable configuration.
However, if one of the two-electron bonds in such a molecule is broken by irradiation of a sample with light or by otherwise applying energy then one of the ways a bond may break is by each half taking one electron. There will then be two new molecules each of which has an odd number of electrons. Inevitably one of those electrons must be unpaired and that is a very unstable state. These newly formed highly unstable, and hence highly reactive, molecules are free radicals.
Are there now two free radicals, or one?
If a bond in an ordinary stable molecule is broken symmetrically, two free radicals are generated. Each new molecule has an unpaired electron, and the formal description of a free radical is 'any atom or molecule that contains an unpaired electron'. Hence any species that has an uneven number of electrons must be a free radical. Indeed any species that has an even number of electrons but has, for some reason or another, has two of the electrons unpaired is also a free radical (a diradical).
Because free radicals have an unpaired electron, they are inherently extremely reactive. To return to a stable state the unpaired electron must couple with another electron to form an electron-pair. One of the great virtues of free radicals is that they will often react with organic molecules at positions that are normally resistant to attack.
Oxford years: What happens when free radicals attack aromatic compounds?
So your task in Oxford was to find out more about free radical chemistry?
Yes. The electronic theory that I have already mentioned was initially based on studies of ionic substitution reactions of aromatic compounds such as benzene. My obvious goal was to determine what happens when free radicals attack aromatic compounds. It was known that the reaction mixtures would be very complex but nobody knew exactly why, and there was great confusion about the precise reaction mechanism. That was my problem, and I think I solved it in the course of my DPhil work. The mechanism of radical aromatic substitution was more or less clarified.
You did extraordinarily well, getting your DPhil after two years.
This is where my background training became so important. Doug White had taught me all about chromatography during my Honours year. It was, however, still a fairly new technique when I went to Oxford and I found that I knew far more about it than any of the other members of the group. Without that technical expertise I think we would not have made the progress that we did. It is the method par excellence for separating the types of aromatic compounds we were dealing with. As they fluoresce under ultraviolet light they were easily detected on a chromatographic column.
Did you say you went to work with Professor Waters?
Yes. At that time there were two chemists in the UK working mainly on organic free radical chemistry. Waters had published a book in 1946 and a little later a review with Donald Hey. Both generated considerable controversy because they claimed that many well-known reactions in common use were actually free radical reactions. Many chemists didn't believe them, and there was a vigorous argument about it in the literature. Even in the department in Oxford there were some people who thought we were way out on the left field. Sir Robert Robinson, Nobel Laureate, one of the great men of organic chemistry said when he first met me, 'You're another one of these idiots who believe in free radicals.' What an introduction!
Waters was very knowledgeable and a wonderful supervisor to work with. By and large he left one alone as long as things were going well. He encouraged you to think for yourself. We would meet only once a week because he was busy with his college duties and his teaching. Every Saturday morning he would wander round and talk to each of the students separately about his research. The group that worked with Waters in an area that was regarded as rather dubious by some in the department was tight-knit, with a very good collegiate spirit. Many of them later became well-known chemists.
What were your impressions of Oxford?
It was wonderful. There were many interesting activities available, and many interesting people. Bob Hawke was there – I've known Bob since the age of nine when we were close friends at primary school. He was a year ahead of me at Perth Modern School, and was also at the University of Western Australia while I was there. In Oxford we went to many social events together.
My wife and I loved college life. Kaye became a 'licensed boarding-house keeper' so that we could keep one or two students there as boarders. They helped out financially, as the scholarship didn't go very far, and they were built-in sitters for our baby daughter, which meant we were able attend a variety of interesting cultural events in Oxford. We became very fond of Oxford City and the Oxfordshire countryside.
Down and out and freezing in London
Was that the time when you gave your first talk to a fairly prestigious gathering?
Yes, that was at the Chemical Society and occurred straight after my time at Oxford. I finished my DPhil work and the degree was conferred somewhere about October 1956. We had arranged to come back on the Strathaird, leaving London in about November. We left Oxford with clothes for two weeks, having sent all the rest on ahead as we intended to have a final holiday in London before we sailed to Australia.
We had been in London for about three days when the Suez War broke out. The P&O Company wrote to me to say that the Strathaird was stranded in the Red Sea and that we couldn't expect to leave London for a considerable time. The CSIRO was very good and kept my scholarship going while we waited in a London flat. I started to work again. I used to commute to Oxford to work with Dick Norman and with Prof Waters, and I also worked at home in London.
During that period the Chemical Society wrote informing me that a special meeting was to be held in London and inviting me to attend to describe my DPhil work and related chemistry. That was the first time I addressed an important audience.
We didn't leave London until some time in February, so in many ways we were 'down and out in London'– it was an expensive place even then. We lived in a little flat in Chiswick. Rolf Harris, who I had known at secondary school, used to visit us fairly frequently and we would sit in the kitchen, all with our feet in the oven to keep warm! It became rather essential for us to get to know every free, warm place in London; the hothouses at Kew Gardens, the Butterfly House at the Zoo, and of course all the art galleries. My small daughter became very well trained in art appreciation.
At that time many students had volunteered to help the Hungarian Revolution. We joined the cause by raising money. We did quite a deal of doorknocking around London and through this became friends with many interesting people, including some politicians. We were invited to the House of Commons.
Eventually the Strathaird did take you to Australia?
Yes, but very slowly. We broke down on the way and had to spend a week in Cape Town when the Apartheid era was at its height. It was an interesting but depressing experience. We saw the flora of South Africa, which is very colourful, and visited the coast.
Free radicals as hydrogen removalists
When you returned to Australia and got to CSIRO, what research did you do?
I worked in a team headed by Dr H H Hatt. My task was to find commercial uses for wool wax. He suspected, quite rightly, that wool wax would be very useful if one could find a way of functionalising it (ie, replace some of the hydrogen atoms with oxygen atoms, or other non-carbon atoms) at positions in the wax molecule remote from the normal reactive group. Typically a wax molecule is a long chain, comprised mainly of carbon atoms and hydrogen atoms with an acid or an ester group (the reactive group) at one end. Hatt wanted me to devise a method to replace a hydrogen atom at the remote end of the molecule with an oxygen substituent.
Now, that's a really difficult problem, because a wax molecule contains a large number of hydrogen atoms. Why should any reactant selectively displace only one hydrogen atom at the end far from the existing reactive group? We tried all sorts of ways of doing this, and were quite unsuccessful. But I did make one interesting discovery, which later turned out to be rather significant.
There are many components in wool wax, but perhaps the best known of them is lanosterol a compound rather similar to cholesterol, a large molecule consisting of carbon and hydrogen atoms with only one oxygen atom at one end. Browsing through the literature I found the surprising report that cholesterol, after prolonged storage, often contains 25-hydroxycholesterol, a compound that contains two oxygen atoms, one at each end of the molecule. The question was why should cholesterol on ageing be converted selectively into such an unexpected product. This was an unprecedented and quite astonishing transformation. Was the report accurate?
So I wrote to friends around Australia saying, 'Please have a look in your store. If you have any cholesterol in a sealed bottle please send me some, with the date when it was purchased.' I analysed all these samples of cholesterol by means of spot tests and paper chromatography and found that indeed most of them did indeed contain 25-hydroxycholesterol. Furthermore, the amount of 25-hydroxycholesterol increased with age.
I conducted experiments to see how this unexpected product could be formed. Since I considered that the reaction must occur on the surface of the cholesterol, we treated crystalline cholesterol with pure oxygen and radical precursors under forcing conditions, using UV light. I had some absolutely spectacular explosions while doing this. It was quite dangerous work. I found that 25-hydroxycholesterol was formed. We had, as it were, accelerated an oxidation process involving attack of oxygen at an unexpected position remote from the existing oxygen. When conducted under normal conditions, reactions of cholesterol in solution proceed at positions adjacent to the existing substituent – never at the remote end. Why should this reaction of crystalline cholesterol be so different?
The structure of crystalline cholesterol provided a clue. The crystals are long, very flat, and very thin and the surface layers comprise cholesterol molecules with their unsubstituted tails sticking out. You can imagine the surface as closely packed molecules, side by side, each with the normally reactive end within the bulk of the crystal, and the other end exposed. It then occurred to me that reactions of crystalline cholesterol with oxygen occur at the normally unreactive end (the 25-position) because that is the only part of the molecule that the gaseous reagent can approach.
This work led to two important conclusions. One that I pursued later is that reactions on solid surfaces can often be quite different from reactions in solutions. This has important implications. The second was that oxygen-centred free radicals (formed by UV irradiation) are capable of removing a hydrogen atom from an unactivated carbon-hydrogen bond, that is one remote from an activating substituent. This is a most useful feature of free radicals that distinguishes them from other reagents. The big problem with most radical reactions is to persuade them to selectively attack the chosen hydrogen. The experiments with crystalline cholesterol showed one of the ways in which it can be done, that is by having each molecule closely packed on a crystal surface with each sheltered, as it were, by its neighbours.
Despite that success you didn't stay very long in CSIRO, did you?
No. I'm not too sure why I moved, except that CSIRO had rather restrictive rules about lab work and when one could come and go. I was used to the academic approach – when one had a bright idea, even if it was at 7 o'clock at night, one could hop in the car, go to work and do an experiment. So when it was made clear to me that I would have a strong chance of getting a good job at Adelaide, I applied, and was appointed. I moved back to Adelaide in early 1958, this time as a lecturer, a fully tenured staff member.
This second sojourn in Adelaide, from 1958 to 1981, was longer than the first. Your research interests at this time, I gather, were in the general area of the properties and behaviour of reactive intermediates. What are reactive intermediates?
A reactive intermediate is a molecule that is much more reactive than normal, and will usually occur only as an intermediate in a chemical reaction. It is halfway between two stable molecules, the starting material and the product. A free radical is a typical intermediate. Organic free radicals typically have lifetimes in solution of something like 10-4 to 10-9 seconds. That's an extremely short time when compared with ordinary stable molecules.
Many reactive intermediates are electron deficient. A free radical is electron deficient by having one electron missing. Other reactive intermediates such as carbenes and nitrenes lack two electrons – they have only six electrons in the outer shell of the reactive atom. The electrons can be arranged in three pairs, in which case there are two missing from the outer shell, or in two pairs and two single electrons. In each case the intermediate is electron deficient. They are still highly reactive because essentially they seek to attain a stable configuration with eight electrons in four pairs.
Not every reactive intermediate is a free radical. Only those intermediates in which the electrons are unpaired are free radicals. For example, if a carbene has six electrons as three pairs, with one empty orbital, it is not a free radical – it doesn't have an unpaired electron. Alternatively, if a carbene has two orbitals, each with a pair of electrons, and two more orbitals each containing one electron it is a radical. In fact, it is a diradical. It has two unpaired electrons and hence exhibits radical behaviour.
Free radicals and carcinogenicity
I have a special interest in your early years in Adelaide, as we were contemporaries and I knew the people in your department, Badger and Jordan. How did your research progress?
It went pretty well. I had come back from Oxford imbued with the idea of free radical research. We studied new types of radicals, and were particularly interested in radicals containing sulfur. One reason was that they are of great theoretical interest. Another was their possible implication in the induction of cancer. Geoffrey Badger was very interested in carcinogenesis – the process by which some aromatic hydrocarbons, particularly the larger ones like benzpyrene, have the property of inducing cancer in the skin of an experimental animal (or, for that matter, of humans). The question was how does this come about.
Our first experiments showed that sulfur radicals have the capability of binding very quickly to such polycyclic hydrocarbons, and we began to wonder whether this was the basis of their carcinogenicity. So we carried out quite an extensive study. We found that aromatic hydrocarbons do indeed react very rapidly with thiols (sulfur-containing compounds) in the presence of oxygen by a radical mechanism, and that this reaction is not limited to simple chemicals but extends to naturally occurring compounds that contain thiol groups, like glutathione, cysteine (one of the amino acids), and proteins such as bovine serum albumin. Perhaps carcinogenicity arose somehow because of such bonding to sulfur in components of the skin. Our subsequent experiments showed that carcinogenic aromatic compounds do indeed react very well with naturally occurring thiols.
Eventually we found that such reactions are not involved with carcinogenesis. However, when we returned to this work later these reactions proved to be very useful synthetically. Also they were related to important biological processes.
Were you working closely with Badger in those days?
Not particularly closely but we did have similar interests. At that stage he was very interested in pyrolysis, and how carcinogenic compounds are formed at high temperatures possibly via radical intermediates, because it was known by then that tars and smokes have the capacity to cause cancer. For this reason chimney sweeps were very prone to cancer.
A somewhat lighter episode occurred at the University of Adelaide, concerning Vice-Chancellor Rowe. Would you like to tell us about that incident?
I was a fairly lowly member of staff so I don't suppose Mr Rowe affected me very much, but I do know that his ideas for changing the way in which the university operated aroused considerable resentment among many staff and students. I think he had managed to put the students off side by being quite rude to them at a meeting.
At that time there were scare stories in the media about the Abominable Snowman, a strange animal that supposedly lived in the Himalayas and left footprints in the snow. So the students called Mr Rowe the Abominable Roweman. One morning when I came to work, there was a great kerfuffle – people standing around everywhere, the Registrar looking very upset – because leading from the Vice-Chancellor's house (which in those days was on campus) were some large white footprints. They went from his house through the campus, dropped in at the ladies' lavatory, came out again, followed one of the paths and then went right up the side of the Bonython Hall. And, on the top of the little tower above the Hall, there was the Jolly Roger flying!
The Registrar said, 'Ah! We've got 'em!' and there was a great hue and cry up the stairs, but nobody was found in the tower. There was just an ingenious mechanism for hoisting the Jolly Roger, and some time later the ropes, ladders and other apparatus that had been used was found in the ceiling. It must have been a very dangerous exploit, painting the wall of the Bonython Hall in the middle of the night. I don't know to this day who actually did it, but at the time it was thought to be one of the better student japes.
Stereochemistry: reprogramming the way molecules are seen
Late in 1961 you felt it imperative to become acquainted at first hand with the work of Barton at Imperial College, London, so you applied for and were awarded a Nuffield Foundation grant. What was so exciting about his work?
Barton was a really outstanding scientist, one of the great chemists of his time. Only Woodward, from Harvard, could compare with him. Barton had a fresh way of looking at chemistry. He was a good theoretician and very intuitive. He had a comprehensive knowledge of chemistry, and great powers of deduction.
For example, after I joined his group I heard a visiting lecturer explain how he had been attempting for many years to deduce the structure of a certain natural product. He said he had not yet been successful but he would show us all his results to date. Barton said at the end of the lecture, 'I've considered all your results and I can now tell you what the structure is.' He then drew the correct structure on the board. The visitor had worked on this problem for many years without success, but Barton was able, in the course of a single lecture, to solve it.
Barton shared a Nobel Prize for introducing the concept of stereochemistry. We had all become accustomed to drawing chemical structures on paper and hence to seeing them in two dimensions. Similarly we would see a cyclic molecule such as cyclohexane (A) as a flat ring with the hydrogen atoms around it as being equivalent. Barton, together with a couple of other scientists, pointed out that this was wrong.
One has to envisage a molecule in three dimensions (structure B). When one does that, you observe that the hydrogen atoms are not all the same. Some are above the ring, some below, and some approximately in the plane – they are spatially different and hence they are chemically different.
Barton pointed out that this chemical difference really exists. He showed, using three-dimensional models, that the hydrogen atoms bonded orthogonally to the general plane of the molecule – called axial (Hax) – have reactivity different from that of the equatorial atoms (Heq) which are within the plane. This had profound implications. So I went to study with Barton to
learn more about stereochemistry and his approach to chemistry. His laboratory was a very exciting place in which to work.
Research questions and administrative developments
After your year in Imperial College you came back to Adelaide. Was that when you first met Ian Ross?
Yes, indeed. I was working with carbenes at that time. Although during my life I have worked mainly with free radicals, from time to time I have examined other reactive intermediates such as carbenes and nitrenes. I explained to you a few moments ago that these compounds can exist in two forms – the singlet, which is still very reactive but has all its electrons in pairs, or the diradical form, the triplet. I found that I could generate these intermediates in one form or the other, depending on the experimental conditions, and hence could study the difference in reactivity between them.
We soon noticed that one form changed relatively slowly into the other. I consulted with Ian Ross, a spectroscopist and expert theoretician who was in Canberra at that time, to help me decide what controlled the rate of change. We reached interesting conclusions about the energy relationship between one form and the other.
In Adelaide you received rapid promotion to Senior Lecturer and then Reader, and finally – aged only 35 – to full Professor and Head of the Department of Organic Chemistry, replacing Geoff Badger. You introduced quite revolutionary innovations in departmental governance. Did your changes coincide with a general move in the University of Adelaide toward more democracy, under the leadership of Badger when he returned from his brief period at CSIRO in Canberra to become Vice-Chancellor? Or did you lead the charge?
I wouldn't say that I led the charge – I am not sure that there was a charge; it was more a single-handed approach. But I thought, being new to the Chair, that it was time to do things differently, and in particular to involve the staff much more in decisions about how the department was organised, how we taught, what we bought and, and so on. I set up a departmental committee that met about once a month to discuss all matters concerning the running of the department. Some decisions were relatively important, such as the ordering of chemicals, the siting of laboratories, and the buying of large equipment, but others were quite minor – entertaining visitors for example.
I took the view, which I still hold, that these sorts of committees should be advisory. I believe that if you are the head of an organisation you accept the responsibility for it. You take the blame for what goes wrong, so the final decision must be yours. But, although these were advisory committees, there were very few occasions when I didn't agree with what the committee recommended.
The importance of electron spin resonance
In 1968 you had a year's study leave in York, where you were introduced to electron spin resonance – yet another technique that became very important to your work.
That's right. Electronic spin resonance spectroscopy was a wonderful technique that had been developed immediately after the war. Essentially, it enables one to see the positions of unpaired electrons in radicals and to determine the nature of their environment. An electron spin resonance (ESR) spectrometer contains a very large magnet and a klystron, a device for generating microwaves that are led down a waveguide into a 'cavity'. The cavity is the area within the magnetic field where the sample goes. The results are recorded on a computer and can be printed.
The basis of ESR is that an unpaired electron can be regarded as a minute spinning electric charge and hence has its own magnetic field. In accordance with quantum theory, once an electron is placed in an external magnetic field it can take up only two orientations, either parallel to the external field or antiparallel, which have different energies. If an electron is irradiated in a specific magnetic field with microwaves of exactly the right frequency, some of the electrons in the lower energy form absorb microwave energy and move to the higher energy form. The ESR spectrometer detects the resulting absorption of energy.
The important thing from our point of view, however, is not just detecting a single electron. That gives only one absorption. In typical radicals there are many types of atoms that are also magnetic. The proton, for example also has a magnetic field, and hence assumes two energetically different orientations in an external magnetic field. The magnetic field of the proton affect the magnetic felt by the single electron. It will be sensitive to all of the nearby magnetic nuclei. Typically, in an organic radical these will be protons, deuteriums, carbon-13, oxygen-17 and others. Hence the microwave absorption spectrum reveals the molecular environment of the unpaired electron. This is a wonderful technique. Not only did it resolve for all time the arguments about the existence of certain organic radicals in solution but it also revealed details of the structure, shape, configuration and electron distribution that had not previously been available. A typical ESR spectrum, which is a plot of absorption of energy against magnetic field, has a multitude of lines.
Not frequency?
No. The spectrometer contains a large main magnet, which is set at a predetermined field, and some small subsidiary magnets, which allow this field to be changed. Normally the field is slowly increased over time, while the sample is exposed to microwave radiation led down the waveguide. When the field strength is exactly that required for the microwave energy to match the energy difference between the two orientations of the free electron absorption occurs, is detected, and is displayed as a plot of absorption against field strength. For various technical reasons it appears as a first derivative curve. The plot might then show, for instance, just two absorption peaks indicating that the unpaired electron is adjacent to a single proton. In other cases the plot can be very complicated.
The ESR spectrum of the allyl radical provides an illustration of the utility of the technique. The structure of the allyl radical is often depicted as having a double bond at one end and the unpaired electron (depicted as a small black dot) confined to the other terminal carbon atom (Structure A). However, ESR spectrometry shows very clearly that the unpaired electron interacts with a single proton (Ha), with a pair of equivalent protons (Hb), and with a second pair of equivalent protons (Hc). Hence in agreement with theory the true structure of allyl radical is planar and the unpaired electron is delocalised, that is to say it is spread over three atoms but resides mainly on the two terminal atoms. The two C-C bonds are equivalent (Structure B).
ESR spectrometry led to some enormous advances in radical chemistry. Not only did it confirm that radicals can exist in solution, but it also revealed their lifetimes, their compositions, their shapes, on which atoms the unpaired electron resides, and what reactions they can undergo. In short it revolutionised research on the structure and reactions of organic free radicals
Just before you returned from York, you were awarded a Carnegie Fellowship and made a very extensive tour in the United States, going to about 30 universities and giving lectures at nearly all of them. It must have been an exhausting time. You went to Canada too. Was that when you met Ingold for the first time?
Yes. On that trip I met many people who became close colleagues. One was Cheves Walling, from Columbia, and another one was Keith Ingold of the National Research Council in Canada who I met at a meeting at Santa Barbara. I was already aware of his work – we found that we had very similar interests and have worked closely together ever since.
Then it was back to Adelaide in 1969. Your work took a new direction now, because you could bring knowledge of this new technique. You had to buy an ESR spectrometer, which I am sure didn't cost tuppence ha'penny. How did you do it?
In those days, I seem to remember, one could submit ARGC applications more frequently than one can now. I suppose it must have been about March when I put in an application for an electron spin resonance spectrometer. Only a few weeks later I had a meeting with Bob Robinson, the Chairman of the ARGC. He said, 'This seems to be an important project. It just so happens we have some money left over from last year, so how would you like to go and buy a spectrometer now? Have the deal finished by June.' And I did. With the availability of the spectrometer we were able to explore many new aspects of radical structure and reactivity. It was a very productive time.
Rearrangement chemistry meets student radicalism
Your work in Adelaide collided unexpectedly with radical student politics, didn't it?
Yes. Before I went to York, I had discovered a completely new reaction involving lead tetra-acetate. It was one of those cases where White's Rule applied, where something completely unexpected happened and it turned out to be extremely useful synthetically. This was rearrangement chemistry, not free radical chemistry. Anyway, I published some papers – in fact, they were sent off for publication while I was in York.
When I arrived back to Australia there was a letter from the Maumee Chemical Co., in America, saying essentially that they were very interested in this work. If I were agreeable, they would take out the patent in my name so that I wouldn't have to do all the hard work of preparing it, and then I would assign the patent to them. There would be a nominal fee by law to you of exactly US$1, but they would make appropriate payments to the Department and the University. I asked the university authorities what I should do, and they said that I should first of all explore the possibility of this discovery being used in Australia. I did that, but the market for these chemicals was really a world-scale market and a world-scale plant would be needed to make them. As this was simply not feasible in Australia the University agreed to proceed with the deal with Maumee. So we did. The patent was prepared and sent to the University to be signed off.
At just this time, however, in response to a great deal of activism by the Students for Democratic Action, and other left-wing radical student groups, the University had decided it would open its Council meetings for the first time – observers would be allowed to attend (I should add that when we were in England and America in 1968 we had noticed a lot of student radicalism) 'But,' the University told the students, 'You must understand that some matters will be commercial-in-confidence. We will place those items on the agenda but you will not hear the discussion or the full details.'
The students at this time were very upset about the 'industrial-military complex', the way in which universities were 'helping the forces of evil'. And when they attended their very first open Council meeting, expecting to find out the worst, the first thing they saw on the agenda which was labelled 'Confidential' was an item: 'Agreement between Professor Beckwith of the Organic Chemistry Department and an un-named American company.' There was no way I could escape!
The activists attacked me ferociously and they attacked the Organic Chemistry Department. We had to introduce special security measures. I was defamed in the student newspaper. No matter what I said, they just didn't believe me. Even some of our own students became involved. It is interesting that when I asked one of my students, 'Why are you being so rude about this?' he said, 'Oh, you know we don't really mean it. We like you very much indeed, Professor, but the fact is that you are a symbol of authority.' One couldn't win. I was often in court standing bail for students from my own department who had become involved, but that didn't make the slightest difference. Eventually it all settled down when they found better targets to attack.
Might oxidation by micro-organisms involve radical chemistry?
And so another five years went by. In 1974 you went on study leave again – back to Oxford, this time to Sir Ewart Jones. What drew you to him?
Well, by now a lot of advances had been made in our understanding of radical chemistry and we were able to carry out a variety of novel radical reactions. I have already mentioned the ability of radicals to attack unactivated carbon-hydrogen bonds, a reaction which is very difficult to do in any other way. We had now found out how to achieve this process with high selectively.
Meanwhile, in the wider world of chemistry, it had been found that many useful transformations could be carried out with microorganisms. By that time, for example, almost all the corticosteroids were made from simple steroids, by incubating them in a fermentation broth with microorganisms that have the capacity to selectively introduce oxygen into molecules in unexpected places. I thought such transformations looked rather like free-radical chemistry, and decided we should investigate them further.
Sir Ewart Jones was an expert in this sort of work. He had microbiologists working with him in Oxford who were examining such microbiological reactions. I decided to go there and learn all about them. I greatly enjoyed working with Sir Ewart. He was a magnificent man, a chemist of the old school – a scientist and a gentleman.
We studied a variety of molecules and found it was certainly true that micro-organisms have the capacity to bring about transformations such as we had previously observed with 25-hydroxycholesterol – the selective insertion of an hydroxyl group at an unexpected centre far away from the usual position of reactivity. This was very interesting in so far as it interacted with the work we had been doing on surfaces.
It was not in this instance an example of radical chemistry, was it?
No, I don't think so, although one can't be certain. If radicals are involved they must be linked to enzymes. Obviously, there are some very reactive intermediates involved.
The work was new and interesting, but I do not think it led to a major change in direction for your research interests.
No. I came back to Adelaide intending to continue similar work, but it was too difficult to conduct microbiological experiments without a trained microbiologist on hand. What it did encourage me to do, however, was return to the sort of early work I had done with cholesterol at CSIRO, involving reactions of molecules as close-packed films on surfaces. We found out that this worked very well and was quite useful synthetically – many such experiments gave results remarkably similar to those obtained with microbiological systems. This remains an area to be explored further.
Stereoelectronics: why rings could have five members instead of six
As you entered your last five or six years as head of Organic Chemistry at Adelaide, what was the main thrust of your work? Was it still free radicals?
Yes, there remained some important outstanding problems especially concerning selectivity. In chemistry there are three types of selectivity. One is chemoselectivity, the ability to attack a specific group in a molecule. That is very easy to achieve. Another is regioselectivity, the ability to carry out a reaction at a predetermined point in a molecule. That is much more difficult, particularly if one hopes to attack a specific carbon-hydrogen bond, when there are normally many of them. Finally, there is stereoselectivity, the ability to attack a molecule not only at the chosen centre but also from the chosen direction in three-dimensional space.
By this time, radical chemistry was becoming more popular and some unexpected new phenomena were being recorded. Most chemical reactions, other things being equal, afford the most stable possible product. For example, radical ring formation, which may occur when the radical contains a suitably placed double bond, would be expected on these grounds to favour the most stable possible ring. In fact many experiments with suitable radicals showed the reverse outcome. For example when there was a choice between the formation of a five-membered or a six-membered ring the five-membered products were usually formed even though they were clearly less stable than the six. Other examples of free radical reactions that gave the less stable possible product were found. Why should this be so?
We wondered whether it might reflect the way in which new chemical bonds are formed by creating a new electron pair. Electrons don't always occupy spherical orbitals – often the orbitals have directions in space. So one could imagine that these unexpected products might be favoured because of the actual direction, in three-dimensional space, by which one reactive centre approaches another.
Leo Radom, a theoretical chemist, provided assistance. He examined how a new bond is formed by attack of a radical on a double bond and found that the preferred structure of the intermediate – the transition state – requires maximum overlap of the orbitals involved in bond formation. These are the orbitals of the double bond and that containing the unpaired electron of the radical. As shown below the acceptor double bond orbitals are orthogonal to the plane of the molecular framework. The required overlap seen here in cross section is readily attained for five-membered ring formation but not for six.
Clearly, if the radical approaches in the wrong direction it can't form a bond. If it approaches in the right direction it is possible to form a transition structure for five-membered ring formation. It is also possible to envisage formation of a six-membered transition structure but the energy is greater because of the strain engendered. Transition structures are intermediate energy states in chemical reactions – they define the eventual outcome. A chemical reaction normally involves an increase in energy as the reactants approach each other followed by a decrease as bond formation is completed.
In a review in 1970 I had initially suggested that such five-membered ring formation was favoured over six because of stereo-electronic effects. It is stereo because it has to do with three-dimensional space; it is electronic because it involves the interaction of electrons in molecular orbitals. We then set about determining the validity of this hypothesis both for ring formation and for many other reactions. The more experiments we conducted, the more support we found.
In this period you did a fairly major survey of the field with Ingold, I believe.
Yes, we published a major review on rearrangements of excited states. We visited each other frequently, we had some wonderful times together, and we experienced the real joy of making new discoveries.
There was one occasion I shall never forget. We had conducted similar experiments in Ottawa and Adelaide that that gave quite unexpected selectivity. The reactions occurred on only one face of certain molecules containing oxygen. Why was this so? One night, at dinner with our wives at a fish restaurant in Adelaide – a dinner at which we probably drank rather a lot – we discussed whether the unexpected selectivity of these reactions had something to do with the interaction of the orbitals. When we arrived home, we thought about it some more, and by midnight we were sure this was the case. These reactions were under stereoelectronic control.
This is a really wonderful time in science, the moment when suddenly one sees the solution to a difficult problem! And it is usually so simple. Most important problems seem to have simple solutions, and you kick yourself because you haven't seen them years before. Ingold said, 'Let's write the paper now.' So we did. We wrote until 3.30 or so in the morning. When we arose next morning we wondered what sort of rubbish we had written. To our surprise it was just fine and went into the literature almost without change.
During your final years in Adelaide you went again to Oxford for some months, in 1979, and made some other visits while you were overseas. Why Oxford this time?
It was becoming increasingly clear that radicals are very important outside of the test tube as well as in it, and particularly in natural systems. One of the things I used to ask my students was, 'Why don't we go rancid?' It's a good question. Our bodies contain lots of fat. If one leaves a bit of fat lying out in the sun for a couple of days, it smells to high heaven. Why don't you and I go rancid? Well, we now know that fats go rancid because of free radical attack. Indeed, free radicals are everywhere. Whenever a chemical bond is broken by ultraviolet light, cosmic rays or beta radiation free radicals are formed. So radicals are ubiquitous. When they attack fats oxidative processes involving oxygen occur. The reason we don't go rancid is that we are protected while we are alive by natural anti-oxidants such as vitamin E and vitamin C. Because of this I became very interested in the mechanisms of metabolic reactions possibly involving the attack of radicals on the constituents of living organisms.
Jack Baldwin, the Professor of Organic Chemistry at Oxford, was interested in penicillin production. Even though it is so important, the way in which penicillin is formed in nature was completely unknown. The starting material, a simple dipeptide, had been identified but all attempts to identify the intermediates between it and penicillin had failed. What was going on? Baldwin asked me to set up some experiments to see whether radicals might be involved.
Those particular experiments gave ambiguous results, but we were so enthused with this work that with Jack's agreement I continued it when I came to Australia, and we did find evidence that radicals might be involved. The most recent biogenetic scheme now indicates that the formation of penicillin does indeed involve enzyme controlled radical reactions.
Stereoelectronic guidelines for organic chemists
In your last two years in Adelaide you wrote some very influential papers, one of which led to the recognition of 'Beckwith's Rules', as they are called. What are they?
They are about using stereoelectronic ideas to develop guidelines – we never called them rules – that explain how and why free radical reactions behave as they do, and that can be used to predict their outcomes. We said that virtually all free radical reactions involve the interaction of the unpaired electron with some acceptor molecular orbitals and that this occurs under stereoelectronic control. It must occur in such a way that the orbitals involved achieve maximum overlap.
We had already started to deal with this hypothesis theoretically, by using what are called force field calculations. They supported the original hypothesis of stereoelectronic control. We set down the guidelines for radical reactions in four simple papers which showed the expected course of such processes as ring formation, ring opening, the abstraction of hydrogen atoms from stable molecules, and regiospecific atom-transfer processes. As outlined above, they predicted that if cyclic products are formed the smaller ring will often form more easily than the larger even though it is not the thermodynamic product, or that if a reaction occurs next to an oxygen atom it will usually proceed selectively on one face of the molecule. The predictions agreed with experimental observations thus indicating the utility of the guidelines in designing selective syntheses. Later, after I had moved to the Australian National University (ANU), we set about showing what all these rules meant in an extensive series of different reactions.
Free radical reactions for synthetic chemists
In 1981, after 22 years in Adelaide, you felt it was time to look for fresh pastures. You were successful in your application for one of the two chairs of chemistry at the ANU, in the Research School of Chemistry, where you followed immediately on the retirement of Professor Birch. You remained there until you retired in 1995. Did you find that the facilities available to you in Canberra were different from in Adelaide?
The facilities were better, there was more up to date equipment including better gas chromatographs and a new ESR spectrometer that was much more powerful than the one in Adelaide, and there was a large number of highly proficient and extremely helpful technical staff.
We started a number of new projects and made great progress. During 1981, for the first time a well-known synthetic chemist, Gilbert Stork, used free radical chemistry in synthesis. I was pleased that our results were being noticed and used but I also recognised that there would now be much more competition – and there was. Our work immediately began to attract the attention of a large number of synthetic chemists and I spent a lot of time travelling and speaking. It also meant that our work now took the direction of discovering new radical reactions that would be useful in synthesis. We began to examine the application of our rules to the preparation of complex molecules.
Did you propose, from what you knew, the way to go about getting a particular reaction, and then prove it yourself? Or did you just suggest it for somebody else?
Oh no, we always tried to prove it, but we didn't always conduct a complete synthesis of complex molecules such as alkaloids. Sometimes we were satisfied if we could efficiently prepare the essential framework of the molecule by radical methods. Also we showed that radical chemistry could be very specific – we could achieve very high stereoselectivity, and we observed outcomes that were quite unexpected.
International conferences: spreading the free radical message
Your contributions to science have included attendance at many international conferences, including a series on the chemistry of organic free radicals. The first of those took place in the mid-1970s, and I think you have been to most of them.
Yes, I've been to almost all of them. The last one, the Gomberg centenary conference in 2000, was very important. I was due to give a plenary lecture there, but I was unable to do so because of ill health.
You have given plenty of plenary talks at those conferences!
Yes. It was really very important in the early days to escape from the isolation in Australia, where for a long time I was the only person doing organic free radical chemistry. Later, one of my Adelaide colleagues, Frank Hewgel, joined the field and we met frequently. I would go to those early conferences with a map of the world upside-down and I would say, 'Well, all of the other people at this conference represent the bottom half, the northern hemisphere, while I am the sole representative of the top.' And that was true – for many years I was the only Australian at those international conferences.
When was the first of the Gordon conferences you went to?
I was invited to my first Gordon conference in 1978. It was on free radical chemistry, and it was really wonderful. There was a conference every two years on free radical chemistry, alternating with conferences on radical ions. Because our ideas were becoming so popular I was invited to all of them. I was in America at least once a year giving a plenary lecture at one or the other of these conferences. They were very invigorating and stimulating, and I made lots of friends. And, of course, I was no longer scientifically isolated.
From Cinderella theory to profound implications for science
Since you entered the field of radical chemistry it has grown from about six people working on it in the whole world, to a great community of interested people. You have said that from the beginning of your research career the overall aim has been not only to show that radicals could be involved in some organic reactions but also to develop the use of radical chemistry in complex organic synthesis. Would you care to elaborate on that?
Well, I think we have done that. We have used radical chemistry as key synthetic steps in ways that we would earlier never have dreamed possible. For example, we have recently used radical methods for making new amino acids that are not only stereochemically pure but also enantiomerically pure. This means they can be specifically prepared in either the right-handed form or the left-handed form. Also we have found completely new reaction mechanisms that proceed through transition structures where the electron is delocalised over a five-membered ring. And we have played our part in making free radical chemistry well known to the whole community. Nowadays free radicals are commonly mentioned in the media – we know how important anti-oxidants are; we know that free radicals can induce cancer; we know that free radicals are absolutely essential for some metabolic processes such as the synthesis of prostaglandins; and we now know a great deal about the mechanisms of such processes.
I suppose not many people can set out at the beginning of their career wondering if anything will come of their chosen field and then watch it slowly develop into a whole new area of science – in this case from a small, neglected byway of science that was barely believed by the scientific majority, to a major area with profound implications for chemistry, biology, environmental science and medicine.
One very pleasant recognition of your scientific achievement and contribution was your election to this Academy in 1973.
That was a great honour, and quite unexpected. I had given a major lecture to the Chemical Institute some time previously. A senior Australian organic chemist who was there said afterwards, 'That was a great lecture. I didn't realise that radicals could be so important. Maybe there will be a place for you in the Academy.' I thought no more of it, but one day I came home from work to find on the outside of our house a large notice reading, 'Welcome home, FAA'. My wife had heard that I'd been elected! (In those days potential candidates were not advised that their names had been put forward for election.) I was thrilled.
A crowning recognition of your achievement surely was your election to the Royal Society in 1987.
It was indeed. On this occasion we had forewarning that I might be elected and so we planned a party on the appropriate day and I awaited the telex to confirm my election.
At that time the only telex machine was in the chancelry. At 9 o'clock in the morning I went to the front office to see if a telex had been delivered, but there was none. I went again at 10, and still there was none. At 11 there was none. I was getting a bit worried. At 1pm I rang up my wife and said, 'We might have to cancel this party. Something's gone wrong. It's now 3am in London, the election is over, and I haven't heard a thing.'
And then there was a phone call from my brother in Western Australia to offer congratulations as he had just heard on the ABC that I had been elected to the Royal Society. Eventually the telex did turn up – it had arrived overnight in the chancelry, it had been read, placed in an envelope addressed to the Research School of Chemistry, sent in the ordinary mail, and delivered at about half past 2 in the afternoon. The Royal Society had done their part but the chancelry of the ANU had been somewhat lethargic. Anyway, we had a good party.
A prodigiously interactive life
Throughout your career you have been prodigiously active in science and tertiary education, but you have also had many other interests. We have heard a bit about some of them – environment and local government, including electioneering, the radical student movement, to which I suspect you were probably a contributor as well as trying to deal with it, and your contribution to this Academy. You have also been heavily involved with other professional societies, particularly the Royal Australian Chemical Institute (RACI) and the Federation of Australian Scientific and Technological Societies (FASTS). We have also your interaction with industry, your involvement with the Wine Research Committee, your commitment to indigenous affairs, and your interests in music – which we've touched on – literature, opera, theatre, ballet and politics. Would you like to pick up on just a few of the things we have not yet discussed?
I will briefly mention the Royal Australian Chemical Institute, because I have been involved with it all my working life. I think I have occupied every position one can possibly hold, having been Assistant Secretary, Secretary, State President, Federal President and Vice-President and so on. I think the most important thing I did in the Chemical Institute was to democratise it. Elections for the presidency became real rather than just determined within the council. We tried to make all the statutes and bylaws gender neutral, and we introduced other reforms.
One thing I have been very proud of is my association with the Science Olympiad. It does a tremendously important job. It also coincides with my interests in indigenous affairs, because through the Science Olympiad I discovered how much one of our sponsors, Rio Tinto, does for Aboriginal communities.
My wife and I have been closely concerned with indigenous affairs since we became interested in Aboriginal art during our Adelaide days. I guess Kaye became one of Australia's major experts in Aboriginal art. Through her work we came to know many Aborigines in Adelaide and we found out a great deal about the troubles that they experience.
The Carrington Hotel, in central Adelaide, was virtually the only meeting place in Adelaide for indigenous people. One of the more interesting things I did in the early 1970s was to go down to the Carrington every Friday night with a friend to see what was happening. Usually we were the only whites in the place. The police would come in, walk up to an Aborigine in a very confrontational way until they were only six inches or so apart, and just stand and stare at him. When someone intrudes on your space like that, inevitably you push him or her away. This was regarded as an assault! The police would then arrest large numbers of Aborigines. It was very discriminatory. As my friend said, 'Good heavens, if the police tried to do that in a hotel in Port Adelaide, the lumpers would slaughter them!'
When the police realised that we were watching them, this behaviour stopped. We discussed the situation with the Minister for Justice in the Dunstan government. New laws were passed. That was the start, I think, of our interaction with indigenous people. We've been interested and involved in Aboriginal affairs ever since.
You have been given many talents and you have used them all to the maximum possible extent. An interview of this length cannot possibly do justice to all your achievements, both within science and outside it. Although we have dwelt mainly on your involvement with and contribution to science, and where that has taken you, I hope that this interview has revealed not only the scientist but the person as well. Thanks for spending the time with us, Athel.
© 2024 Australian Academy of Science
