Creativity in Organic Chemistry
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Lindau Nobel Laureate Meetings162 / 340
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00:00
NobeliumChemistryAcetateX-ray crystallographyMoleculeIsomerTitaniumBromineMultiprotein complexEntropyThermoformingHalideRacemizationOperonEthaneIonenbindungHydrogenPharmacyHydrocarbonHydrogen bondDoppelbindungEnzymeConformational isomerismReducing agentStereoselektive SyntheseChemical propertyChemical compoundMolecular modellingAzo couplingIronCyclohexanKohlenhydratchemieAromaticityTriterpeneSystemic therapyChlorideOrganische ChemieElectronic cigaretteGolgi apparatusHuman subject researchMethylgruppeDipol <1,3->1,1,2,2-TetrachloroethaneChemical plantElectronDeformation (mechanics)Fatty acid methyl esterSteroidKetoneBiosynthesisYield (engineering)ButylSubstituentHydroperoxideCrystallographyConstitutive equationWine tasting descriptorsGesundheitsstörungChemical structureDiketoneCell cycleEthylgruppeSpectroscopyCytochrom P-450NobeliumCalculus (medicine)Alpha particleProcess (computing)Optische AktivitätAtomic orbitalDiolTiermodellChemical reactionBoronWaterCarbon (fiber)Physical chemistryInorganic chemistryAcidAlcoholOrigin of replicationTheoretische ChemieChemistryPyridineWursthülleMetallorganische ChemieVitaminFood additiveOxideLactitolReactivity (chemistry)Resonance (chemistry)Medical historyBranch (computer science)AbiogenesisHydroborierungHydroxylAnaerobic exercisePolymerAageActivity (UML)AntigenTranslation <Genetik>NaturstoffAtomic numberColourantMolecularityStructural elucidationPorphyrineAnomeric effectCHARGE syndromeDecalinSetzen <Verfahrenstechnik>Octane ratingSunscreenAlkeneCarcinoma in situKernproteineEnzymkinetikDensityDerivative (chemistry)Chemische SyntheseZunderbeständigkeitStereochemistryCondensationSulfur
Transcript: English(auto-generated)
00:12
The title of my talk certainly included the key word of this meeting. The minister, I noticed, used the word creativity
00:24
at least 10 times in his talk. When a minister uses a word, it's always a good thing to pay attention to. In fact, Capa Cornforth, who is not only a brilliant chemist,
00:41
but also a very able poet, was so inspired by my title that he wrote a poem. And he has given me permission to read this poem to you. Now, I don't think that you should try to translate it. A poem is too sophisticated and subtle a thing
01:02
for easy translation. But here you are, here is Capa Cornforth's poem about creativity. You see that it is a limerick, and you can see how it is supposed to rhyme.
01:20
And here is the poem. Three kings who were at the nativity praised Joseph for his creativity. And credit is rarely allotted more fairly for all forms of ghosted activity. I think that's John.
01:42
Well, well for Capa Cornforth. Now, I was going to give you a nice talk about creativity with lots of chemical reactions, but the Count Bernadotte got at me
02:01
and told me that I had to tell you how to win a Nobel Prize when you are not yet 31. So I'm giving my talk for those people present who have less than 31 years. Organic chemistry is about organic molecules.
02:23
And there are a number of simple definitions that all students of organic chemistry know. I just remind them, we must take away these lights. Who is, where is the light expert?
02:40
These, oh no, not those, these. Who is in charge of lights? Voila. So, now we have to have a number of definitions. And in molecules, we recognize molecular structure.
03:01
First of all, we have to determine the molecular formula, which is the number of atoms and the kinds of atoms. Then we have to determine the constitution, a concept originally due to Kekulé, that is to say which atoms are bonded to which. We then have to define the configuration, which goes back to the time of Van't Hoff and Lebel
03:23
in the last century. And the configurations are the ways of arranging the molecule about the asymmetric centers. And I take the most simple definition. This point, say the asymmetric centers involving carbon atoms, where you have four different bonds to one carbon. And as Van't Hoff pointed out,
03:41
you have two to the n isomers, where n is the number of asymmetric centers. And that is a very fine formula, which has stood the test of time. And Emil Fisher, for example, spent a long time showing how true it was in sugar chemistry. Now we come to confirmation. And confirmation, the definition of confirmation
04:01
always leads to argument. I give you my definition, which is a very simple definition. My definition is that the confirmation of a molecule of defined constitution and configuration is the various arrangements of that molecule in space which are not superposable.
04:21
That is to say you allow for bond rotation, angle flexing, bond stretching. It gives you an infinity of confirmations for every molecule. You would think that that idea, that concept would be of no value, but it so happens that organic molecules usually like to have a preferred confirmation. One, usually one confirmation,
04:41
or several preferred confirmations. And the study of these confirmations is conformational analysis. That is how the molecule really is in three dimensions. And the correlation of that three-dimensional preference with chemical and physical properties. Well, to most people today, all that sounds very obvious and simple.
05:04
That is because conformational analysis, which was not known really, or not appreciated, in 1950, in the 1940s, has since become something which is taught in all universities, which is taught even to high school students.
05:25
Let us just take one or two little examples for simple nature. Here we have our old friend cyclohexane. And cyclohexane has always been used by people who studied confirmation because of its symmetry.
05:40
And you remember that we have two kinds of cyclohexane if we start putting substituents on. Here we're putting them in the one and four positions. And if they're on the same side of the molecule, imagining the cyclohexane to be flat, which is what we thought it was at one time, then this is cis. And if they're on the opposite sides, they are trans.
06:02
And we all know nowadays that it is the chair confirmation of cyclohexane which is preferred to the boat, or what is in reality the preferred form of the boat when we really do have a boat, that is the twist boat. And I have here some molecular models that I will talk about later.
06:20
And there you can see very clearly there is a perfectly respectable chair. And I just have to flip it and it becomes a boat. And then I twist it a little more and it becomes a twist boat. And we recognize two kinds of hydrogen bonds in the cyclohexane chair confirmation. And they are, of course, just geometrical.
06:42
Just a geometrical analysis of the molecule. Those bonds parallel to the threefold axis are axial and those which are not axial are equatorial. And to arrive at that nomenclature took us some time, but eventually everybody agreed about that. I know you know all this
07:00
and I'm going to go through it rather quickly. But there may be some people who don't. Now here is another little piece of conformational analysis where we're looking at what are the conformations of these two compounds, the cis-disubstituted compound and the trans-disubstituted compound.
07:22
And you see here is one chair. And if we pull up this end and push down the other end, we will turn it into another form of chair. And you notice that we have one equatorial bond there and one axial bond there, which have become one equatorial bond and one axial bond. So in fact, we have performed no operation whatsoever
07:42
in chemical terms. All we have done is to contribute to the entropy of the molecule. It's not true for the trans isomer because there we have two equatorial bonds. And when we flip the ring up and down, we end up with two axial bonds for X.
08:01
And so that's a real difference that you can, that molecules, the structures are not superposable and you can start to discuss why. Now I'm going to say something about Professor Hassell because I shared the 1969 Nobel Prize
08:21
with Professor Hassell. And the citation was for the concept of conformation. Now Professor Hassell was born in 1897 and he died two years ago. He spent nearly all his life at Oslo University, though he did his graduate studies in Germany.
08:42
He was at the university from 25 to 1964 and then later on as Professor Emeritus, he was professor from 34 to 64. And he went to Germany to learn about X-ray crystallography. But when he got back to Oslo, he found, of course, that he couldn't afford any X-ray crystallography apparatus.
09:01
So he had to make do with measuring dipole moments, which in those days was something you could do relatively inexpensively. And then he moved on to electron diffraction. But these two techniques had a rather bad reputation in the 1930s with organic chemists. Organic chemists at that time
09:20
didn't believe very much in the results because there were plenty of symmetrical molecules which were supposed to have dipole moments and which of course really didn't. And for electron diffraction, you had to compare the density on a photographic plate and that was done with the eye without an instrument
09:42
and so there was always room for interpretation. It was a subjective measurement. And I draw your attention to one little paper, which I thought was rather nice from Professor Hassell in 1939 in the JACS. This is a preliminary communication. And in this preliminary communication,
10:01
he describes the tetrabromide of cyclohexane-1,4-dien, cyclohexa-1,4-dien. It's a well-known compound, nicely crystalline substance. And he said, well, it has two bromines equatorial and two bromines axial. And he determined that by dipole moments,
10:21
by electron diffraction, and then he did some X-ray diffraction. And he writes in his paper, something which I think is typical about preliminary communications, he writes, although these investigations have not been brought as far as we would have wished in the case of the X-ray crystallographic part,
10:43
we should not like to delay publication much longer and are therefore publishing our results now in preliminary form. And it will not surprise you to learn that there was no subsequent publication in any other form. But of course, the war came along.
11:01
And that completely changed the nature of science. In 1943, Professor Hassell published a very important paper in a very obscure journal, and in Norwegian too.
11:21
And so nobody knew about this paper. Why he did this, well, of course, the country at that time was occupied. And probably it was, he didn't want to send it for publication in Germany, and he couldn't send it for publication in America or in the UK.
11:41
So he published it in Norwegian. And it was later translated and republished in this reference. So if you want to read it, there it is. And what he does is to summarize his results, dipole moments and electron diffraction results, principally, on halogenated cyclohexanes.
12:01
And he shows that this is the preferred conformation of cyclohexyl chloride. This is the preferred conformation for the 1,2-trans dihalides. This is the preferred conformation for the 1,4-trans dihalides. And this for the 1,3-cis dihalide. And he suggests that this one can't exist,
12:22
but as you will see later, natural product chemists are perfectly familiar with molecules of that kind. So what he does then is to say that, well, the conformation is preferred when the substituents, the majority of substituents are equatorial. And this is the less preferred conformation when the substituents are axial.
12:42
That, of course, is a very simple, simplistic way of presenting things, as we now know. But nevertheless, at the time, was a very stimulating and important observation. The only problem was, as I said, that we didn't know about it, because we couldn't read this journal, and nobody really knew about it until it was republished.
13:04
Now, to continue with this 1943 contribution of Professor Hassell, he didn't get all of it quite right. He was worried about cyclohexane 1,4-dione, because he said it ought to be in the chair. But it had a dipole moment.
13:21
So he didn't want to say there was any of the boat there to explain the dipole moment, which is the real explanation. He wanted to say everything was absolutely clear, it was chair or boat, couldn't have both, and that, therefore, cyclohexane dione had to exist partly enolized under the conditions of his experiment. Well, that, of course, is not true,
13:41
but it's just a little thing in passing. In 1943-44, he was arrested, and he spent two years in prison, so he didn't make any contributions to the literature during that time. After the war, in 44, I think, he came back to the University of Oslo and took up his work again with Professor Bastiansen.
14:02
Bastiansen, a very able assistant at that time, later became professor of physical chemistry in Oslo, like Hassell, and is now rector. And what they published in Nature in 1946 was this, and this is what first attracted me to the subject of conformational analysis.
14:21
Hassell found, Hassell and Bastiansen found, that trans-decalin existed in a two-chair form, as everybody thought it should, and that cis-decalin existed in another two-chair form. And that was completely contrary to what was written in all the textbooks at that time. If you look at the textbooks of the 1920s and 30s,
14:42
you will find that cis-decalin is supposed to exist in a two-boat conformation. Now, where did that strange idea come from? It came from a writings by Moore in 1918, who had said that cis and trans-decalin must be different compounds, must exist and must be different compounds.
15:02
Now, today, of course, it's quite obvious to us that they're two compounds, but at the time, many people believed that cyclohexane was flat, and if you put two flat cyclohexanes together, they said you will only get one decahydronaphthalene.
15:20
And in fact, of course, real correct theory teaches that you will get two. So, there we are, that changed the textbooks. Then, there was one more publication from Professor Hassell on sugars, where he correctly interpreted the conformations, and where he recognized, for the first time,
15:43
the existence of the anomeric effect. Now, in 1953, I had to review a field of conformational analysis, and I wrote about Professor Hassell as follows, I think I'll read it to you. The admirable researches of O. Hassell and his colleagues at the University of Oslo
16:01
on the electron diffraction of cyclohexane compounds in the vapor phase have contributed greatly to our knowledge of these more subtle aspects of stereochemistry. I have never been able to find any reference where Professor Hassell wrote anything about me. Now, conformational analysis is nowadays
16:23
one of the subjects which has a history book about it. And this book deals with the work of Hassell and myself, and it deals also with the work of Professor Prelog and Professor Cornforth. And it's published, it's written by Ramsey, and it was published in 1981.
16:42
And he gives the principal events in conformational analysis, apart from Hassell and myself, and he says, well, in 1890, Saxer wrote a paper about cyclohexane existing in chair and boat forms. That is quite true, that paper had absolutely no effect upon organic chemists, because they could never isolate the isomers
17:02
which would have been predicted by this postulate, and therefore they said it was wrong. In any case, Von Baier told us that cyclohexane was probably flat. Then 1918, the work of Moore, the publication that they're both theoretical papers to which I've already referred. In the 1920s, Hermans and Boeseken in Holland
17:23
did some very elegant work on the reaction of alpha diols with boric acid, and they showed that complexes were formed when the hydroxyls had the right to conformational relationship in space, and really, that was early conformational analysis. Nobody paid much attention to it, though.
17:41
And then in 1929, Hobbeth, a great organic sugar chemist who later got the Nobel Prize for vitamin C, he wrote a book on the sugars, and he defines the word conformation in the way that I have defined it, more or less, and that's the first reference in the literature, I think, to the word.
18:00
Then in 37, 38, Isbell, in another obscure publication, studied the bromine oxidation of sugars and corrected and interpreted the results correctly. And finally, I must make reference to Professor Prelog, who in 1950 published a paper in a British journal on the conformations of medium-sized rings.
18:24
I well remember Professor Prelog's lecture in London in 1949, when he told us about this very interesting work. I said that we could choose the preferred conformation of molecules. We've already said the chair is the preferred conformation.
18:42
This all comes about because of the existence of the ethane barrier. And the ethane barrier was something discovered by Kemp and Pitzer in 1936, who were studying entropy and were then calculating entropy, and were determining entropy calorimetrically,
19:02
and then calculating it by statistical mechanics, what it should be, and they didn't get the same result, unless they postulated a barrier to rotation of about three kilocals in ethane. And you see that there are two forms, two extreme forms of ethane, the eclipsed and the staggered. And these models, there we are,
19:20
have it, it's completely eclipsed there. You can only see the one hydrogen sits on top of the other, and then the alternative is the staggered, where they are at a maximum distance away from each other. And if the forces are attractive, then it is the eclipsed form which would be favored. And if the forces are repulsive, then it would be the staggered form
19:41
which would be favored. These are non-bonded interactions between hydrogens, of course. And if you transfer that down to cyclohexane, where all the bonds are completely staggered in the chair conformation, that would favor the chair conformation. Now, at this point, Professor Eyring came in and made a contribution,
20:03
which everybody thought was very important. Eyring, at that time, was the leading theoretical chemist in the world, certainly in the States, and everybody followed what he calculated with great attention. And he calculated, in a paper in the GACS in 1939, that the eclipsed was more stable than staggered.
20:21
And so, that was exactly the opposite to reality, but naturally, in the 1930s, people didn't know. And then, Langseth and Back, in 1940, in the Journal of Chemical Physics, published a paper on Raman spectra. And they said that they had showed
20:42
that cyclohexane was planar, which, of course, it's not. And they said they also showed that this tetrachloroethane was eclipsed for the preferred conformation. So, it wasn't really quite so clear as we now know it to be. It wasn't clear in the early 1940s.
21:01
And Professor Hassell, in 1943, when he wrote his famous paper, he went at great lengths to show that Langseth and Back were completely wrong. He didn't say anything about Eyring. Now, I am going to say a little about myself. And you will notice that my list of accomplishments
21:21
is much longer than Professor Hassell's. And that is because I know much more about myself than I do about him. And you see, I was born in 1918, and that I'm going to die in the next century.
21:49
And that's because I wished to attend the Nobel celebrations in 2001, which will be the centenary year, and there's bound to be some splendid celebrations in Stockholm.
22:02
And I'm sure that the king's famous Bordeaux will be flowing as it did before. Now, my, as I've said before, the Nobel Prize, I shared, because of my publication in the Expedian theory in 1950, this very short paper on the conformation of the steroid nucleus.
22:22
It was a very short paper because I had to type it myself, not having any secretarial facilities. Now, why you get, I was 31 at this time when it was published. How did you get, how did I get to that point? That is what I'm trying to teach the younger chemists here.
22:42
Well, first of all, I went to school. Everybody has to do that. Then my father died, and suddenly, and I left school. So I spent two years in industry doing routine work. And I convinced myself very quickly, this was such a horrible way to spend your life, there must be something better, and that better had to be at the university.
23:03
So, although I had no past, no formal examinations, I got to work, and in one year, I did three years exams, and I got to Imperial College. Imperial College is an excellent place to go to, because it's a very serious university where students still work.
23:25
The war came along, so we did wartime-related work, and a PhD was quickly obtained in 1942. 42 to 44, I was in military intelligence. I was inventing secret inks. And if you wish me to write you a letter on a piece of paper that you will never read,
23:41
I can still do it. Then a year in industry, that was a formative period, because in organophosphorus chemistry, where I didn't discover the Wittig reaction or anything important like that, but I did discover that I didn't like industry very much, because I wanted to do, I knew what I wanted to do, and it wasn't what other people
24:01
were going to tell me to do. So, I took half the salary that I was being paid, and I went back to Imperial College as a demonstrator, but as a demonstrator in practical inorganic chemistry to mechanical engineers. And there is no lower position
24:20
that you can have in a university than that. That's really the bottom. But after one year, I was promoted, and I was allowed to teach physical chemistry. So I had three years teaching physical chemistry, chemical kinetics, and then I had one year at Harvard where I wrote this paper,
24:41
where I replaced R.B. Woodward for a year in teaching, and then five years in Birkbeck where I could finally do organic chemistry. That was a night school, so it was a very good place to be, because you could work 14 or 15 hours a day, and the only thing was that it wasn't very good for your wife. The bad effect on wives.
25:01
Then the University of Glasgow for two years, then back to Imperial College for 21 years, and now I'm in Gif since 1977, in fact, and I find my life in the CNRS has completely rejuvenated me. It's a very stimulating organization. All Nobel Prizes, prize winners who get near to 59
25:20
should come and join us in the CNRS. Now, in 19, now I will tell you a little bit about my work at that time, because it's relevant. What have we established so far? We've established that I tried several things before I found out what I really liked,
25:42
and that I was prepared to pay the price. Now here, you see the first piece of work that I did, and your first published work is always interesting, and on the first published work, it was my own work that I did myself. P. Alexander is Professor Alexander now,
26:01
Professor of Cancerology in London, but at that time, he was just a student like me, and he was studying inert dust insecticides, and he noticed that when the insect died, some of them, particularly this one, tribolium, it gave off something which changed the color of the inert dust, and so there must be an excretion.
26:23
So I grew the insects, isolated the compound, and showed it was esselquinone, and that's in the Biochemical Journal in 1943, and it's the first identification of a volatile substance produced by an insect, I believe, but we never went any further in that field.
26:42
And then, but that was good, because that was done in my spare time. That was done after six o'clock in the evening, or on Sundays, because the rest of the time, I was with the secret inks. And here in 42 to 48, I did purely theoretical work on molecular rotation differences, that is, looking at the literature of steroids
27:01
and triterpenoids, and trying to correlate the structures proposed with their optical rotations. And this way, we could correct quite a number of structures. It's a principle which goes right back to van't Hoff, so nothing original in it, was just the application that was interesting. And then in 48, force field calculations. I was so impressed by Hassel's systecolin work
27:25
that I set out to calculate what should be the relative energies of these molecules. And this is the first force field calculations applied to cyclohexane and ethane, and things like that. The other work was done by Westheimer on hindered rotation, and Hughes and Ingold
27:43
on the SN2 process. And to do this, I designed these molecules, these models that you see here. These were designed, I did the calculations and gave the plans to a watchmaker who then made the models, and these were the models which you converted into steroids, get to be quite big,
28:01
which enabled me to really get a feeling for conformational analysis. So these force field calculations, of course, were very trivial things. They just required lots and lots of time, and with these models, I could measure instead of having to calculate all the distances.
28:22
But I got things in the right order, more or less than the right numbers, too. And then there was the 1950 paper on the conformational analysis of the steroid nucleus, into which I will not go in detail at this time. But I will say that to write this, one had to have a prepared mind.
28:42
And what I had was a background in physical chemistry, some knowledge of inorganic chemistry, because I taught that, too. But a love for organic chemistry, and a complete knowledge, more or less complete knowledge of old steroid and triterpenoid publications
29:00
of the time, because there weren't so many. And this part, I had all done in my spare time when I wasn't doing the work for which I was paid to do. And so I would say to you that if you want to do something when you're young, you have to be really motivated, you have to like it, you have to work very hard,
29:22
you have to read a lot of literature, you have to do a lot of thinking. And if you are multidisciplinary, you have a much better chance of finding something interesting than if you stick to just one discipline. Now, in 1951, Arthur Birch was able to write in the annual reports, and I read this to you
29:41
because it was only one year after the publication, confirmation analysis for the study of the stability and reactivity of saturated or partly saturated cyclic systems, promises to have the same degree of importance as the use of resonance in aromatic systems. I think he was right. Now, what did I do after 1950
30:03
in the world of confirmation analysis? We turned, first of all, to the pentacyclic triterpenoids. These are rather complicated molecules, as you see. They have eight or nine centers of asymmetry, depending on whether you look at the unsaturated or the saturated molecule. So there are 128 racemates there and 256 there.
30:24
We were able to get the problem down to one out of two racemates by just confirmation analysis, by looking at the molecule in this way. And then the X-ray crystallographers came along, and I've always worked in close collaboration with X-ray crystallographers. I've always believed in X-ray crystallography.
30:42
Very rarely do they get anything wrong. Just occasionally, they get something wrong, usually because their assistant has copied it down the wrong way around. Their technician, that seems to be the problem. Anyway, this was given to Carlisle, former collaborator of Dorothy Crowfoot, Dorothy Hodgkin, and he got the right result very nicely.
31:02
And then 53 was lanosterol, and lanosterol was a molecule which, as soon as you had the structure, the constitution, you could write down the stereochemistry. And then a little bit later, we come to cyclo-arthenol. And this, 54.
31:22
And again, as soon as you could write the constitution, you could write the stereochemistry. And it's interesting that we're working with others, of course, in parallel, on the lanosterol problem and the cyclo-arthenol problem at the same time, and that they are both the key molecules in steroid biosynthesis now.
31:42
The cyclo-arthenol is the key molecule for plant steroid synthesis, and the lanosterol, of course, is the key molecule for the biosynthesis of steroids in mammals and animals. Now, the first exception. First exception is always interesting.
32:01
At this point, you see, in the early 1950s, everybody was saying everything's always a chair. So there were chairs everywhere, and there were never any boats. And then, in collaboration with Professor McGee, Chelsea College, we came across a boat. Now, there were some boats where the boat did not have the choice of being a chair.
32:20
But we all said, everybody said at that time, if a six-membered ring has a choice, it will be a chair and never a boat. We came across the first example where a six-membered ring decided to be a boat, even though it could have been a chair. But it is an exceptional case. We were brominating this molecule.
32:41
These are two methyl groups which are actually related to each other, and therefore, Hassell wouldn't have liked that, but that's the way it is in nature. And we expected, of course, to obtain two bromo compounds. A bromo compound with a bromine equatorial and a bromo compound with a bromine axial.
33:02
And instead of that, we got, indeed, two bromo compounds, a major isomer with a bromine equatorial and a minor isomer which should have had the bromine axial but had the bromine equatorial. Now, you could determine which was equatorial and which was axial by infrared and UV spectroscopy at that time.
33:23
It was a reliable technique, so we knew we were correct in our conclusions and we had to explain it. And the simplest explanation was to say that you had brominated it axially and then the molecule had flipped because it was a ketone, so it was easier to flip it.
33:41
And secondly, if you did this flipping, the bromine, which if it had been axial would interact with the two methyl groups, would have turned itself over and become equatorial instead. Well, everything that happened afterwards, this is a phenomenon which was studied very extensively, in fact, everything that happened afterwards has confirmed this interpretation.
34:02
And you notice that when you reduce this ketone with borohydride and you go back to a cyclohexane without a trigonal atom, then the confirmation changes back again to the preferred chair and you have this very hindered situation where a bromine is axial and pushing against two methyl groups,
34:21
which are also axial. So it's a very hindered, exceptional situation. And finally, in 1957 and later in 1960, we investigated what we call conformational transmission, which is our way of saying how a double bond
34:42
or a feature in a molecule can be transmitted from one end to the other. In triterpenes, we've made these kinetic studies. We've prepared the benzylidene derivatives and measured the kinetics of their formation and showed that the rates really varied quite remarkably with the kind of double bond that you had or didn't have in the distant ring.
35:03
So if we take this as 100, with a double bond shifted just one place, it's 17. That is a factor of more than five in rate, which is a very large rate difference. And over here, when we saturate it, we get 44. And in the steroids, it's even more impressive.
35:22
All the condensation goes into the two position, as we established, but the rates are quite different. The saturated case is 182 on this scale, scale of this lanestino. This is 47, the double bond in 7-8. And when you shift the double bond just one position in the ring, in the second ring,
35:42
the rate increases to 6-45. So the difference delta-6 over delta-7 is a factor of 14. And we said this is a clear example of conformational transmission from one ring to another. Now, Allinger, well, first of all, Henriksen, and then later Allinger, brought in this method
36:04
of force field calculations using much improved equations and using, of course, the computer. And that changes everything. What took me three months laboriously to do by hand in 1947, they can do in a fraction of a second and do it much better.
36:20
So that completely changes the conformational analysis, in fact, you can now do your calculation quicker than doing, much quicker than doing experiment. And Clark still is demonstrating exactly how you can do chemical synthesis in that way. Well, what Allinger did then was to recalculate all these effects and see if they existed
36:42
according to force fields. And happily, the answer is that they do. And there's a perfect correlation between our results and those calculated by Allinger using his kind of force field. So I've told you then how you can win this Nobel Prize.
37:00
You have to work hard. You have to have a slightly eccentric background. You have to be very Catholic in your taste. You have to look in all directions. You have to read a lot. And you have to think, and it's thinking, which is, I think, the most important thing. And it's thinking is something that we don't do enough of in organic chemistry.
37:21
And happily, I have five minutes in which to tell you about thinking. If you look at the great advances that have been made in organic chemistry since the war, I would certainly like to put confirmation analysis amongst those. There is also the correlation of orbitals
37:42
that we will be hearing about in the next talk. That's certainly very important. And then there are the various reactions which have completely changed synthetic chemistry. Herb Brown, I know, will tell us about hydroboration and borohydrides. That is certainly correct. We could cite the Wittig reaction.
38:03
That's correct, too. But have we finished? We could talk about Ziegler-Natta polymerization. That also completely changed organic chemistry. But nowadays, there are some pessimists around. And I met one yesterday, a journalist, who said there's nothing going on in chemistry anymore.
38:20
And I think this, well, I can't talk about other branches of chemistry, but I know a bit about organometallic chemistry, and I know something about organic chemistry. I'm completely opposed to this kind of talk. And the reason, the problem is with organic chemistry is that we don't think enough,
38:41
and that our professors don't have enough imagination. So when you go back, you should tell your professor he should have more imagination. Then things will be better. Now, let me prove to you that we have not come to the end of all the interesting and wonderful things
39:02
we can find in organic chemistry. Sharpless has announced a couple of years ago how you can attain efficiencies of optical synthesis, asymmetric synthesis, which nearly equal those of enzymes.
39:21
In some cases, do equal those of enzymes. And he does this a very simple way with titanium, for valent titanium as the key to the synthesis, using diethyl tartrate, it's as simple as that, as the asymmetric-inducing reagent, and vanadyl hydroperoxide and t-butyl hydroperoxide,
39:43
pardon, and then he mixes this together and you get these wonderful yields in asymmetric synthesis. In my opinion, this, unless someone does something better, this is going to be as important in synthesis as the Wittig reaction. And if I had not been instructed
40:00
to talk about conformational analysis today, I would have been talking, I think, about our work on the oxidation of saturated hydrocarbons, because we have developed a system now, which, in a very simple way, will oxidize saturated hydrocarbons very selectively,
40:21
and faster than it will oxidize olefins or aromatics, and faster than it will oxidize compounds of sulfur as well. So it's a very selective system. The yields are, if you allow for recovered hydrocarbon, I think more or less quantitative. And I would like to think that
40:40
by the time we have the next meeting, when I will talk about it, some very interesting things will have happened. And the system is based on an imaginary P450 enzyme as it was before we had any porphyrins around.
41:01
What was the world like before we had porphyrins when we didn't have any oxygen, or not much? And there was acid, of course, lots of acid around, because this, and we said, well, if we're going to imitate P450, what we need is a hydrocarbon, oxygen, triplet oxygen,
41:29
and two electrons and two protons. And this is going to give us the alcohol and water.
41:43
That's what nature does in P450 enzymes. Let us imitate it, but let us imitate it in an anaerobic way, prebiotic anaerobic way. So we just took iron powder, it was as simple as that, and acetic acid, and pyridine with a little water,
42:06
and triplet oxygen, and hydrocarbon. And with that system, you get excellent yields of oxidized saturated hydrocarbon with a preference for attack on CH2. So you get preferentially CH2 going to ketone.
42:28
Mechanism, we've shown that this is due to a complex acetate of iron, which is reduced by the iron powder, and which has this extraordinary property
42:40
to selectively oxidize saturated hydrocarbons. You can replace the reduction by the iron, it's not necessary, you can replace it by zinc, or you can do it electrochemically, which is more important. And using the complex acetate of iron,
43:01
you can have catalytic turnover numbers of two or 3,000, which is certainly the kind of numbers that our friends in industry like to see. They don't like to see one or two, they like to see two or 3,000. So I think this is going to be important. Anyway, I've told you about it, as that's my contribution in five minutes to creativity.
43:20
And thank you for your attention.
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