00:00:00 🎵

00:00:30 So we have then started off in peptide chemistry, and I think we're looking for worthwhile objectives.

00:00:42 If you've got any worthwhile objectives in peptide chemistry, we'd like to hear about them.

00:00:47 We think we can do them. I've got a list already, but a few more would be welcome.

00:00:52 And now we'll talk about something else, which is that you can use a radical-generating system

00:00:57 not just to make carbon radicals, you can obviously use it to make any kind of radical.

00:01:02 All that is required is that the element from which you wish to make the radical will give a derivative COO.

00:01:11 And nitrogen, of course, is the first one that comes to mind.

00:01:14 And Professor Newcomb, who by chance is in the chemistry department at College Station,

00:01:21 learnt about our chemistry in St. Andrews, where he was attending a meeting,

00:01:25 and he straightaway said he'd like to work on the amino radicals.

00:01:29 And I said, well, why don't you? Because we can't do everything.

00:01:32 But the amino radicals, again, will be very useful in peptide chemistry, as you'll see in a moment.

00:01:37 And so the preparation is perfectly straightforward. This is his paper.

00:01:43 You take, for example, this is the phosgene derivative that I told you about.

00:01:48 You just react with the amine, and there you have the compound that you want to use.

00:01:53 And if you find the reaction sluggish, then you can make a reaction of the amine with phosgene,

00:02:01 and then have the chlorocarbonate react with the sodium salt of the thiopyridone,

00:02:07 and you get the same ester in good yield.

00:02:09 These carbonates, they are often crystalline and easy to purify and handle.

00:02:16 They're more stable than the esters.

00:02:18 And what can you do with them? Well, this is the sort of thing you can do with them.

00:02:21 You can put them in the presence of a thiol.

00:02:23 And you make little thiol radicals when you irradiate.

00:02:26 And the thiol radicals set off the chain.

00:02:28 The chain proceeds like this.

00:02:31 You get this radical, loses CO2, gives the amino radical, which is what you're looking for.

00:02:36 And the amino radical is quenched by t-butyl thiol, and you go back to amine.

00:02:40 So you've gone round from where you began, back to where you began, in a rather complicated way,

00:02:45 so that that doesn't get you anywhere in synthetic chemistry.

00:02:48 But it shows you that the idea works, and that you can make nitrogen radicals.

00:02:52 Now, the sort of things you can do with them are either to use them in synthesis,

00:02:57 or you can use them in physical organic chemistry.

00:03:00 And I'm not a physical organic chemist,

00:03:03 though I have done that kind of work in my time,

00:03:06 but I like to encourage physical organic chemists.

00:03:09 And when you encourage them, you should encourage them to do things which are interesting,

00:03:14 and not encourage them to do things which are less interesting,

00:03:17 like the solvolysis of carbonium ion.

00:03:20 And so, this is the sort of thing you can do.

00:03:25 You make your nitrogen radical, and you can ask yourself,

00:03:29 how quickly does it open, like this, compared with its quenching by the thiol.

00:03:35 And so if you know the rate of this reaction, you can calculate the rate of that one.

00:03:41 It's the sort of thing that pre-radical chemists do.

00:03:46 And you can then use it now in the cyclizations to make this as preparative chemistry,

00:03:53 not physical organic.

00:03:56 This is more moving towards preparative chemistry,

00:03:59 in which we're now going to make the nitrogen radicals,

00:04:03 which are not very reactive chemically,

00:04:05 but now we're going to make them in the presence of protons.

00:04:08 And this is, of course, what one does in the classical Hoffman-Freitag-Loeffler reaction,

00:04:13 which is where you take a chloroamine or a bromoamine,

00:04:17 and you put it in a fairly concentrated sulfuric acid, and you photolyze it.

00:04:22 And this is an interesting reaction.

00:04:25 But it's not—the conditions for doing it are totally incompatible

00:04:29 with the kind of natural products I'm interested in.

00:04:32 So we want to have reactions which go under more or less neutral conditions.

00:04:36 They must be gentle acids.

00:04:37 And that's what Newcomb has now managed to do.

00:04:41 Here is the same derivative as before,

00:04:46 a carbamate, and you make the radical.

00:04:49 And the radical, he thinks, is in equilibrium with the closed form.

00:04:54 And so you can get from the reaction the quenching of this radical

00:04:58 or the quenching of that radical.

00:05:00 And that radical can be quenched by hydrogen atom transfer from thiol

00:05:05 or by reacting with the thiocarbonyl.

00:05:08 Now, we've got three different results here,

00:05:11 three out of a large number, of course.

00:05:13 If we do it under neutral conditions,

00:05:16 in the presence of 2-t-butyl thiol,

00:05:18 we get only this radical being quenched.

00:05:22 So that's the reason for thinking it's reversible.

00:05:25 Now, if we add trifluoroacetic acid,

00:05:29 what do we see?

00:05:31 We see that we get 100% of this.

00:05:34 So now, the protonated nitrogen radical,

00:05:38 the iminium radical cation,

00:05:39 is much more reactive towards the double bond,

00:05:42 and it has cyclized and done the transfer reaction

00:05:45 and got a good yield of this product.

00:05:47 Now, if we add thiol plus trifluoroacetic acid,

00:05:50 we again have the iminium radical cation.

00:05:53 Again, it will cyclize,

00:05:55 but now, of course, the radical will be quenched by hydrogen atom transfer,

00:05:58 and we get 100% of this.

00:06:00 I say 100%, that's the proportions.

00:06:03 The chemical yield in three cases is 80%, 90%, and 80%.

00:06:08 So that's interesting.

00:06:10 That's the first beginnings in doing something

00:06:13 synthetically significant with the iminium nitrogen radical.

00:06:20 And now, we have this same kind of carbamate,

00:06:28 and we're looking at various cyclization processes

00:06:31 in the presence of the trifluoroacetic acid,

00:06:34 or even acetic acid,

00:06:36 to protonate the nitrogen,

00:06:38 and the t-butyl thiol to reduce the radical.

00:06:41 And so, we can get this cyclization to 70% yield,

00:06:45 this one to 75% yield,

00:06:47 and this one down here is 60%.

00:06:50 But this is rather a nice one,

00:06:52 because you've done it twice,

00:06:53 that is to say, the nitrogen radical has cyclized onto there,

00:06:57 to give a five-membered ring,

00:06:59 and that's gone and cyclized onto there,

00:07:01 to give a second five-membered ring.

00:07:04 And since it's in one go, in one pot,

00:07:06 that's a rather significant synthesis of that ring system.

00:07:10 Now, you see I've used some letters here,

00:07:12 potoco, poto, poto.

00:07:16 Now, this is my name, and that's Professor Newcomb's name.

00:07:19 I think my name's better, but it's easy to understand.

00:07:22 But it means this residue.

00:07:28 Now, let's talk about organometallic chemistry very briefly.

00:07:33 I'm hoping to convert organometallic chemists

00:07:36 to using radical chemistry.

00:07:38 As you know, most organometallic compounds

00:07:41 are made by lithiums or green yards,

00:07:43 they're made by anion chemistry.

00:07:45 And it would be nice to make them by radical chemistry,

00:07:49 because it's more gentle,

00:07:50 and it's much easier to do radical chemistry

00:07:52 than anion chemistry.

00:07:53 In anion chemistry, you've got to do it

00:07:56 In anion chemistry, you've got to get everything thoroughly dry

00:07:59 and no oxygen.

00:08:01 In radical chemistry, you don't want any oxygen,

00:08:03 but you don't have to have things dry.

00:08:05 Water has no effect on radical reactions at all.

00:08:07 It's quite compatible with water.

00:08:09 And so here was the idea that we would

00:08:12 take compounds of this general kind,

00:08:14 where phenolthio N, M.

00:08:16 M is a metal or a metalloid.

00:08:19 And we are going to use the phenolthio radical

00:08:23 to set off this minor standard process

00:08:27 to make the R radical.

00:08:29 And the R radical is then going to react with M

00:08:31 and eliminate P-H-S dot.

00:08:34 So you're going to have one less P-H-S at this point.

00:08:37 Now this works marvelously for

00:08:40 some of the elements in group 5.

00:08:42 And it works particularly well for antimony.

00:08:45 So what happens then, for example,

00:08:47 is that you have antimony here for the M.

00:08:50 And when you do it in air,

00:08:52 in the presence of air, or let in oxygen afterwards,

00:08:55 this R-antimony bond is broken by the oxygen.

00:08:59 And there is a rearrangement and a reductive elimination

00:09:02 so that you get the alcohol,

00:09:04 eventually after hydrolysis,

00:09:06 plus 3-valent antimony.

00:09:08 Well, the details do not concern us.

00:09:10 As organic synthetic chemists,

00:09:12 it's the product we're going to put in the bottle that counts.

00:09:17 We can also make phosphates.

00:09:20 We can replace a carboxyl by a phosphonic acid residue.

00:09:25 And this is something very desirable

00:09:27 in medicinal chemistry and in agricultural chemistry,

00:09:31 because when you do that,

00:09:33 you often alter the biology in a meaningful way.

00:09:36 You have biology, but it's been changed

00:09:38 when you replace carboxyl by phosphonic acid.

00:09:41 And so here is the way we did it.

00:09:43 We now use the phenolthiol 3-times phosphorus compound,

00:09:48 and we don't get exactly the same result.

00:09:51 Now, because this carbon-phosphorus bond

00:09:54 is much more stable towards oxygen,

00:09:56 we get our oxygenated products.

00:09:58 This is the product that we get in each case.

00:10:01 And in each case, the yields are not as high as I would wish,

00:10:05 but they are certainly useful yields

00:10:07 to make the compound for the first time.

00:10:09 So now you can manipulate your leukotrienes

00:10:12 or your prostaglandins

00:10:14 and replace the terminal carboxyl by a phosphonic acid,

00:10:17 or do the same thing in the side chains of peptides,

00:10:20 and I'm sure you will get modified biological activity,

00:10:25 but it won't be zero biological activity,

00:10:27 which is the danger in all experiments

00:10:30 in medicinal chemistry and agricultural chemistry.

00:10:33 Zero activity is bad.

00:10:38 Let's turn to quinones.

00:10:41 When we first...

00:10:42 Quinones have a well-known reputation

00:10:44 for reacting in radical reactions very well.

00:10:47 And when we first looked at quinones,

00:10:49 we got rather bad yields, and I was surprised.

00:10:54 Here is the theory of what could have been going on.

00:11:00 We would add the radical to the quinone,

00:11:03 would then be quenched by a thiopyridol transfer.

00:11:08 We would get an intermediate,

00:11:10 which would eliminate the thiopyridol group,

00:11:13 if it enolizes this way,

00:11:15 we would get quinone.

00:11:17 Alternately, we could have the enolization process

00:11:20 in the other direction,

00:11:22 followed by a second enolization,

00:11:24 and then, of course, we would get the thiopyridol quinone

00:11:28 with the R substituent.

00:11:30 And in the beginning,

00:11:32 we were isolating only this kind of quinone

00:11:35 in rather small yields.

00:11:37 When we went back to look at this problem,

00:11:39 we put in an excess of the starting quinone

00:11:42 to reoxidize any substituent quinone to quinone,

00:11:45 and we looked more carefully at what we were getting,

00:11:48 and we found that the major product in the reaction

00:11:51 had been overlooked in our first run

00:11:53 through this series of compounds.

00:11:56 And so, what we were really getting

00:11:58 was the thiopyridol derivative

00:12:02 in really quite respectable yields,

00:12:04 70-80% yield.

00:12:06 And what we had been isolating before in bad yields

00:12:09 was the monosubstituent quinone

00:12:12 in about 10% yield.

00:12:14 So that's a happy story.

00:12:16 And it seems like all kinds of residues

00:12:19 can be added to quinones now

00:12:21 in a synthetically meaningful manner this way.

00:12:25 And here is the case of a monosubstituted quinone

00:12:30 with an alkyl group there.

00:12:32 And again, we can do the addition,

00:12:34 and we find the addition occurs only in this position.

00:12:38 Not in this position, and not in that position.

00:12:41 And so you get another series of reasonable yields,

00:12:44 and again, we got some of the monosubstituted quinone,

00:12:48 rather more than before.

00:12:50 Now, this thiopyridol group is also a useful group here,

00:12:54 potentially, because you can oxidize it to sulfone,

00:12:57 and you can use it in anionic chemistry then.

00:13:00 We haven't done it, but it really can be done.

00:13:05 And finally, working with the NAFSA quinones,

00:13:07 it's the same thing.

00:13:09 We can get a good yield of the bis-adduct

00:13:12 and some of the mono-adduct.

00:13:14 Here is another one with a methyl group.

00:13:17 And we got, at first, only about 50%,

00:13:22 because we didn't realize that this was rather stable

00:13:25 and was eliminating slowly during chromatography.

00:13:28 But the real yield is quite reasonable.

00:13:31 And this is a sterically hindered one

00:13:33 where the addition occurred all right,

00:13:35 but the second step of oxidation

00:13:38 by excessive quinone did not take place

00:13:40 and we isolated the hydroquinone.

00:13:42 But that's a minor complication.

00:13:47 Now, we have also studied the addition of radicals

00:13:50 to very electropositive olefins,

00:13:55 like nitroethylene, sulfonylderapenylsulfonylethylene,

00:14:00 propylene, and so on.

00:14:02 And these reactions go very well.

00:14:05 That's rather to be expected,

00:14:06 because the radicals we're working with

00:14:08 are nucleophilic radicals.

00:14:09 They're very fond of electrophilic olefins.

00:14:12 And this is a short synthesis

00:14:14 of the 25-hydroxycholesterol side-chip,

00:14:19 which is important in the vitamin D3 field.

00:14:23 So what we do is take a bile acid,

00:14:25 we make the standard derivative,

00:14:27 let it add to the nitropropylene,

00:14:31 and you get this intermediate, which is not isolated,

00:14:33 was immediately reduced by titanium trichloride

00:14:36 to generate the keto.

00:14:38 We expected this reaction to occur,

00:14:40 and it does, in very good yield.

00:14:42 And then you have only one step to make the derivative.

00:14:44 You'll ask me why did we do it with a keto group here,

00:14:47 which, of course, is not effective,

00:14:48 because it's a very hindered position.

00:14:50 I will answer, because we happen to have a bottle

00:14:52 in the laboratory, which was given to us

00:14:54 by Rousseau-Nuclaf.

00:14:56 But we have repeated this synthesis since

00:14:58 without the 11-keto group,

00:15:00 and we've gone right through to the end

00:15:03 putting a dienone group here,

00:15:05 no keto, dienone here,

00:15:07 and we get a very satisfactory synthesis of that, too.

00:15:11 And that's a biologically significant compound.

00:15:16 Now, we can also add radicals

00:15:19 to protonated aromatics of any kind.

00:15:21 Protonated pyridines, for example.

00:15:23 It's known you can add radicals to them.

00:15:25 Professor Minishi, for example,

00:15:27 is an expert in that area.

00:15:29 And we're just making our radicals a different way.

00:15:32 Because our intermediate esters

00:15:34 are compatible with protons, with acid.

00:15:36 You can add acid at low temperatures,

00:15:38 and they do not hydrolyze.

00:15:40 So this gives another dimension to what you can do.

00:15:43 And here are three examples

00:15:45 from pyridine chemistry,

00:15:47 in good yield.

00:15:49 And here is some more chemistry

00:15:51 in which we're dealing now

00:15:53 with other protonated,

00:15:55 protonatable heterocycles,

00:15:57 which we got,

00:15:59 this is adding the adamantyl radical.

00:16:01 The yield is not perfect,

00:16:03 but the chemistry is interesting.

00:16:05 And this is the thiazole

00:16:07 that you have in vitamin B1 chemistry,

00:16:09 and that puts an adamantyl radical there.

00:16:11 Why adamantyl?

00:16:13 Well, because that's supposed to be

00:16:15 one of the more difficult ones to do

00:16:17 because it's hysterically hindered.

00:16:19 And secondly, I know of some

00:16:21 very interesting surprises in biology

00:16:23 when you put adamantyl groups

00:16:25 into the compounds.

00:16:27 And then, here is a couple

00:16:29 of examples from

00:16:31 nucleoside field.

00:16:33 Here in the bottom here is adenine,

00:16:35 which puts the adamantyl group

00:16:37 into this position.

00:16:39 And here is caffeine on the top,

00:16:41 which puts the adamantyl radical here,

00:16:43 or the cyclohexyl radical,

00:16:45 in less satisfactory yield

00:16:47 in this position.

00:16:49 And that means then we started manipulating

00:16:51 nucleosides. You want to do nucleoside,

00:16:53 nucleotide chemistry,

00:16:55 with this kind of

00:16:57 radical-generating system, you can do it.

00:16:59 Nothing to stop you.

00:17:03 Now, again, back to

00:17:05 Professor Newcomb. He has been now

00:17:07 again measuring rate constants

00:17:09 and Hoynius functions for

00:17:11 the octyl derivative.

00:17:13 If you look in the

00:17:15 literature, you will find this paper.

00:17:17 It's now published.

00:17:19 And, more significantly,

00:17:21 he's been looking again

00:17:23 at compounds as radical precursors

00:17:25 in kinetic studies.

00:17:27 This is again back to physical organic chemistry.

00:17:29 And the kind of results

00:17:31 he's got is shown here.

00:17:33 This is the same sort of thing as before.

00:17:35 This one is one where we study

00:17:37 whether it's going to be quenched

00:17:39 or whether it's going to rearrange.

00:17:41 This is a radical which is well known to rearrange

00:17:43 through a cyclopropane,

00:17:45 and you know the rate of that reaction,

00:17:47 so you can calculate the rates of the other reactions,

00:17:49 knowing how much product you get.

00:17:51 So they're pleased about that.

00:17:53 Here's another one. This is the famous

00:17:55 case where the radical

00:17:57 cyclizes onto the double bond.

00:17:59 This is used as a test by everybody

00:18:01 for radical chemistry, though it's not

00:18:03 100% certain. And, again, you know

00:18:05 the rate of the cyclization, so

00:18:07 you can measure this rate

00:18:09 or this rate. If you know this rate,

00:18:11 you can measure the other one.

00:18:13 And it's just standard

00:18:15 kinetics.

00:18:17 Now, this is what I want to show you.

00:18:19 This is really what I'm coming up to.

00:18:21 This is not the last slide,

00:18:23 but it's nearly the last slide,

00:18:25 and it shows you Professor

00:18:27 Newcomb's opinions about

00:18:29 our kind of compounds.

00:18:31 And he says

00:18:33 that they should have widespread

00:18:35 applications, since in many cases

00:18:37 the reagents are superior to the

00:18:39 corresponding alkyl halides as radical

00:18:41 sources. So this is what

00:18:43 he's saying about making radicals

00:18:45 with this method.

00:18:47 I agree with him.

00:18:49 But he doesn't say that

00:18:51 it's also very useful in preparative

00:18:53 chemistry, and I hope that I have

00:18:55 been able to show you that

00:18:57 today.

00:18:59 Now, one final thing is

00:19:01 that we can do this chemistry at any

00:19:03 temperature. You're not confined

00:19:05 to room temperature. You're not

00:19:07 going to have to heat anything. You can

00:19:09 go down to minus 80, if you like.

00:19:11 And this brings you into another dimension

00:19:13 where there are no radical chains.

00:19:15 You're just making radicals.

00:19:17 And when you're just making radicals, then

00:19:19 their primary radicals, they

00:19:21 dimerize. And so

00:19:23 here are the results we got at

00:19:25 minus 64 degrees, where

00:19:27 the major product from the reaction is the

00:19:29 dimer. And the

00:19:31 chain, radical chain product,

00:19:33 which is probably not made by a radical

00:19:35 chain now, is the minor product.

00:19:37 So this gives you then

00:19:39 a feeling of

00:19:41 how this thing can be varied

00:19:43 over a tremendous temperature range.

00:19:45 And of course, lowering the

00:19:47 temperature may well bring us to another kind

00:19:49 of useful chemistry that we haven't yet

00:19:51 explored. Of course, this

00:19:53 work is not done without

00:19:55 I should

00:19:57 say devoted collaborators, in some

00:19:59 cases, who seem to enjoy

00:20:01 it, if they

00:20:03 write me nice letters about it.

00:20:05 To this list, I should

00:20:07 this was a

00:20:09 pioneer here, David Kreitz, who

00:20:11 started off with

00:20:13 a thiopyridone after some preliminary

00:20:15 experiments with other things.

00:20:17 And these are two good post-docs

00:20:19 from Germany who worked on the problem.

00:20:21 And here is a Frenchman who just

00:20:23 finished his thesis, a very able young man.

00:20:25 Here are the two ladies who did all the

00:20:27 peptide chemistry.

00:20:29 There is Brigitte Lecher, whose name

00:20:31 I don't have on there, but who did the

00:20:33 fluorine chemistry. And Jean Guillaume,

00:20:35 who was responsible for the

00:20:37 X-ray crystallography. And finally,

00:20:39 these three people there, they're

00:20:41 the people who helped

00:20:43 me to look at the others working.

00:20:45 They're lookers like myself, observers.

00:20:47 And Dr. Motherwell,

00:20:49 who started with me in GIF.

00:20:51 And Samir Zard, who has been with me

00:20:53 in the last three or four years in this role.

00:20:55 And then, of course, Professor Potier,

00:20:57 who was the co-director of our institute

00:20:59 in GIF, where all this work was done.

00:21:01 And who helped me a great deal, particularly

00:21:03 in the peptide work, because he

00:21:05 knows about peptides and what's worth doing.

00:21:07 Now, I've got

00:21:09 one final thing to say.

00:21:11 And that is that I received a letter

00:21:13 from the American Chemical Society.

00:21:15 And

00:21:17 they say in this letter

00:21:21 the comments of our senior

00:21:23 chemical statesman

00:21:25 and established eminent chemist

00:21:27 program. Now, I am

00:21:29 possibly an eminent

00:21:31 chemist. I am certainly

00:21:33 not a chemical statesman. I deny

00:21:35 the insult which is contained in this letter

00:21:37 in saying that I'm a statesman

00:21:39 because a statesman is someone

00:21:41 who gives you advice, but is

00:21:43 incapable of doing it.

00:21:45 Doing what he says.

00:21:49 And finally, I have just one photograph.

00:21:51 The photograph of Sam Zard

00:21:53 and Dr. Togo. That's Dr.

00:21:55 Togo in the front, who did a lot of work

00:21:57 on protonated heterocyclic

00:21:59 compounds and radical reactions.

00:22:01 And that's Sam Zard, who's a very able young man

00:22:03 now at the Ecole Polytechnique

00:22:05 and with whom we are continuing a certain

00:22:07 amount of collaboration. So I thank my

00:22:09 colleagues very much for making this talk possible

00:22:11 and I thank you for your patience

00:22:13 and staying until the end.

00:22:15 Thank you.

00:22:17 Thank you.

00:22:47 .

00:22:49 .

00:22:51 .

00:22:53 .

00:22:55 .

00:22:57 .

00:22:59 .

00:23:01 .