Ei-ichi  Negishi (2011) - Magical Power of d-Block Transition Metals: Past, Present and Future

So, I really like the young lady saying: "I love organic chemistry." (laugh) That's my message, one of my key messages. And I also fully understand the excitement of a young man shortly after his discovery. I think those are the things that will keep us going and this is a wonderful profession. So, in a limited amount of time what I want to discuss is a very, very simple fundamental sort of understanding or knowledge that can support all kinds of activities. Even a rather traditional half worn out discipline like organic synthesis which, I believe, is fundamentally still very, very important well into the 21st century and beyond. If you look at the world food shortage, energy shortage, of course many disciplines can join force and try to solve. But at the heart of this problem, world solution must come from chemistry and the chemist's responsibility is very, very heavy. What I talk about today, the magical power of transition metals. I truly believe that the magical power of d-block transition metals... You know, I'll show you 23/4 of them in a periodic table. Some of them like iron, copper, you know, gold, silver, platinum and so on, these are all d-block transition metals. They had been until recently mainly used as precious material. So the structure beams, are they wooden? (laugh) Anyway. But probably half a century or so ago, well actually discovery came earlier, but through appreciation of catalytic ability of d-block transition metals came. And that's the essence of my talk today. So, I can only talk about the left half of this mainly. This story actually is... This represents the future of magical power of transition metals. But you probably have to come back to this meeting a few years later. So, as I told you, I believe that this organic synthesis continues to play a very important role in our society. But today some of the most capable synthetic organic chemists claim that they can make anything, any small molecule including some drugs like palytoxins, like amphotericin which I will show you and a palytoxin and so on. Yes, they have synthesised but what is increasingly important is how to synthesis them. And if you think about that, in your head that's all you need, any organic compound. We must do it in a green way and here is my definition of a green chemistry. First of all we should make any organic compound. Any is a very important term, any synthesizable. In high yields, Y, in high efficiency, E, in high selectivity without producing any other isomers and so on preferably, S. In YES, in a yes-manner as someone in America said and succeeded with this YES word a few years back. I can add another E and S. We should synthesise any organic compounds economically, obviously, and then safely. So my message, key message is that I think we should be focusing our attention on how to synthesise but not what to synthesise, from what to synthesise to how to synthesise. And this I began thinking when I came to America for my baccalaureate degree, knowledge in chemistry. So everything at the graduate level and beyond I learned in America. And I began thinking as a graduate student: Probably we should, you know we as chemists, consider all useable elements Simply all you need is this one cube box here. Avoid radioactive ones -maybe close to 30 of them, 25 or 30 of them- and inert gas obviously, several of them, and then inherently toxic elements, I can count up to 10. If you subtract all these, then we are still left with about 70. When organic compounds are mostly made of about 10 or a dozen elements, this is still a large, large number. Then I soon realised that this is actually rather small, frustratingly small number. And if we are to do organic synthesis in a YES(ES) way, in other words in green way consider even their binary combinations, then all of a sudden your options jump up from about 70 to 5,000. And indeed I truly believe that there is this 2 is better than 1 principle operating. And of course second ones are usually... even the first one can be catalytic ideally. The second one should definitely be catalyst. This is where our d-block transition metals come in. So use metals for desirable reactivities. Grignard had the right idea 100 years ago. Next year we're going to be celebrating Grignard's centennial year for winning the first Nobel Prize. Together with Sabatier I think. Anyway, the first Nobel Prize in organometallic chemistry, 1912. So use metals for desirable reactivities. And use transition metals mainly as catalyst. That's the essence of my talk today. So when you look at periodic table as I said, you see 112 or so metals. You can divide them roughly into... or you can colour them in 7 different ways. Of course here you have 10 or dozen so-called organic elements. Ok, we need to deal with them. And then as I told you all these red ones are fundamental ..., you know, intrinsically radioactive and we for the moment avoid them and then we avoid several inert gas, grey ones. Then we are left with, still left with these blue, so-called main group elements. They are... some of them are relatively cheap, inexpensive and you get to use stoichiometrically, like magnesium or like zinc and so on. About 20 of them. And then you are left with this golden -it's not yellow, it's golden (laugh) in my opinion- golden coloured, 3 by 8. You take away tegnesium and your left with 23 d-block transition metals. So together we have a few others of f-block transition metals. So these 3 groups combined we have close to 60 metals. Again it's 10 or dozen organic elements. So as a graduate student, why should we not bring in all these usable metals to promote organic synthesis? That was my dream and it is still my dream today. Of course getting back to YES, we have to worry about yield, number of steps and yield. Even if the average yield is 90%, after 30 steps you are almost down close to zero, not quite, 4%. If it is a very, very precious medicinal compound, then we may still be practically go through this. But not beyond 30. After 40 steps of excellent, excellent yields, series of excellent yields, you're almost down to nothing. So I would say maximum number of steps in a linear organic synthesis should be about here. If the average yield goes down to 80% it's reduced to half, 15 steps. If it's down to 70% then 10 steps. So number of steps efficiency, in other words efficiency, is very, very important. So as a graduate student at Pen, University of Pennsylvania, in 1962 or so I began thinking when I was doing acetoacetic ester synthesis and malonic ester synthesis, some of those kinds of reactions: You bring in maybe big molecule, then you only get to use a CH2 or something like that, very inefficient in my opinion. I'm sorry to say that. So one notion came to me that is this Lego game approach, in other words cross-coupling. Without a catalyst of course. Grignard reaction, some of the Grignard reactions are known in this way. And some people say that, well, this reaction goes this way and then you get what you want, organic compounds, but along with by-product MX. That's not very green. But I say that's not true because of the formation of this by-product MX, we gain tremendously number of things. One is we gain some dynamic advantage. In other words most every reaction like this when you use highly electropositive metals like magnesium, then it's going to be fundamentally downhill. And the metals and M and X they tag various positions in organic compounds. They are regio and stereo tags. So actually use of these metals in X, they are beneficial and they make the whole process green. I say that loudly. But even so without catalyst the overall picture... You know, these are about 10 or so kinds of organic groups that we normally think. And if you can fill all of these close to 100, actually only 72 shown here, but if we can do that then you can begin saying that we can deal with a synthesis of most of the kinds of organic compounds in one sort of a uniform way. That is a cross-coupling way. Turned out when I checked the literature as a graduate student, it looked like this. When these groups are unsaturated organoalkali then practically nothing works here using Grignard reagents here. If they are SP3 hybridized alkyl, then you have a better chance but still there are all kinds of problems, elimination, isomerisation and so on. Today I can show this and hopefully this change was recognised by the Nobel committee (laugh). So, the same chart and I counted once 45 or so out of 72 in green. So the majority fundamentally worked very well. When we use alkyl halide, this is a very active area now. So I should look forward to some additional progresses but it is a fundamentally difficult thing. The worst part is here when you mix 2 allyl, benzyl or propargyl, then you have all kinds of problems. Some efforts were made half a century ago by Bielmann in France, that came up with some of the best. Even so it takes so much effort. And having dealt with this for some years I have decided to give up on this one because we came up with this wonderful alternative to come up with the same molecule. So this is where we are but we still have to go further. And I have emphasised the use of metal, one as a stoicheometric creation, the other as a catalyst. Ok, so if you mix alkane and alkene, usually nothing happens under normal conditions. But if you replace this alkane with carbocations, then of course you see a rapid reaction. So shows a power of perhaps positive charge as well but mainly the presence of the empty orbital. These simple considerations can, if you think right, then give you some powerful, powerful principle. Then of course if you compare this carbocation and boron hydride, they are isoelectronic. No wonder hydroboration works very well, very rapidly. And then if you generalise, now this is a powerful principle, you know, the presence of this empty orbital. Electron deficiency is, if anything, a source of chemical reactivity. And then of course someone translated, of course Geoffrey Wilkinson and others, Australian group, came up with a "hydrosiliconation". So "iso-lobo" kind of relationship and then they came up with "hydrosiliconation" which we use extensively. Ok, so you think that as I told you electron deficiency is a main source of chemical reactivity and then if you mix acid and base then they should form AB salt. Looks easy but there is one problem. If this works very well, then Grignard reagents and organic halides probably should cross-couple readily. Thermodynamically they are fundamentally more downhill. But there is a kinetic issue which I didn't notice until recently. Sorry to say this but let's say A and B are neutral and then as they come close and then they start transferring pair of electrons, then the problem starts. So B let's say neutral one. But as it gives up electrons then it will be positively charged and A as a recipient will be negatively charged. What are these 2 charges do? Well, this positive charge will attract this pair of electrons back to B and the negative charge at A will start sending back. So I talk to my physical chemical colleague and then he came up with this paper, rather recent and in a respectable journal. And then indeed my concern was born out. So this is attracting force that I was showing here. But then there's this repulsive force. So at one quantum level there is a problem. But fundamentally this had already been solved through the use of d-block transition metal. This is one magical power of d-block transition metals, one of the essences of my talk today. Namely by definition d-block transition metals can have in the valence shell both empty orbital ... (inaudible19:57) and then filled non bonding orbital, dehybridised. With this pair they can interact with alkenes for instance in a HOMO-LUMO and HOMO-LUMO fashion. And notice that this interaction mode here inside is from bottom electron flow, from the bottom to up, and then outside it is from the top to bottom. So this nasty charge separation issue can be mostly cancelled. And indeed d-block transition metal, one thing they love to do is to interact with neutral pi-bonds. Alkenes, alkynes and arenes are very highly reactive and readily form complexes. This is a kind of binding action that make all of these processes kinetically very facile. And as shown here... Ok, so here we have "alkeneliadised" and "alkyliadised" Grignard reagent will attack here or here maybe but d-block transition metal, palladium species, they love to interact here based on this and then like this. Ok, so that's the one principle, very fundamental, very basic principle. And we mostly know but you have to believe in that and then you have to use it, then you can come up with some discoveries as shown in one of the pictures earlier today and then you have a eureka. Anyway, yet another very important thing which is current and the future of this use of magical power of d-block transition metals current is hydrometalation and perhaps carbometalation. But we can expand this hydrometalation, carbometalation further to include heteroatom metalation, which I call for simplicity heterometalation. This carbometalation was a term I coined in 1978 and gradually people have started using this one. Well heterometalation, I'm a little bit dubious about this thing but anyway for simplicity I call this heteromelatation or metallometalation. Then the hydrocarbon and the hetero, you can cover the whole periodic table. In other words you can do almost anything in terms of addition like this. And then why do we believe that they should go well. Well, if you compare this pi-complexation with hydrometalation inside here in this triangle, everything is dead same. Only difference is that here we have a dehybridised orbital. That is replaced here, substituted with a sigma orbital. We should believe in this. I mean if this works, this should work. Then all kinds of, actually... As long as there is this empty orbital here we can fundamentally observe all kinds of hydrometalation reaction, beginning with Brown's hydroboration or hydroelimination, hydrosiliconation, you name it. Ok, but then you should realise that by replacing this hydrogen with a carbon group, you should also fundamentally observe all kinds of carbometalation. Probably the overall scope is more limited because you replace this small round hydrogen orbital with a larger, more sterically demanding and more highly oriented carbon group. But this is how we have come up with carbo-zirconium catalysis, catalysis was needed, zirconium-catalysed carboelimination. Then only I realised: Well, this had already been discovered by, long ago Karl Ziegler in the form of polymerisation. Ours is a one step single stage better suited for wider, you know, organic synthesis. And we are still in the process. If you think about that, you can think of various other kinds of related reactions that can be represented by this simple molecular orbital scheme. That's how we want to do research and come up with some eureka moments. And then I recently realised and some facts are already known, we can go beyond, cover all the periodic table. Heterometalation, like bromo- or haloboration, halometalation, this sounds surely contra thermodynamic. With most metals, more electropositive metals they may be. But with the boron, rather highly electronegative metal, they can be thermodynamically downhill. And they can be kinetically very facile as long as you can buy this kind of scheme. Haloboration was first discovered by Mike Lappert in the UK in the '60s and about 20 years later Akira Suzuki made use of it but there were some difficulties, fundamental difficulties which we have overcome recently. Now it's synthetically very useful reaction. So here under this term you can have a wide range of possibilities. And of course the other part, the second part of the d-block transition metal, their magical power of course is their ability to go up and down the oxidation-reduction scale. Well, of course many other atoms can do, sulphur compounds can be readily oxidised, sulphur compounds can be readily reduced. But not in the same one, same flask or same vessel. With the d-block transition metals you can observe... You know, some atoms, d-block transition metal atoms are getting oxidised as well others are getting reduced. They go around and around and around in our hands million times or more, sometimes close to billion times. In other words they can go around because of this ability, getting oxidised and reduced under one set of reaction conditions. Wonderful property, we should try to take advantage of that. And that is a second secret or magical power of d-block transition metals. The 2 together I think we can, if I may exaggerate, we can save the world in the 21st century. I believe so. Anyway, so in a limited amount of time I was telling you that 2 is better than 1. And when 2 metals, electron deficient metals species are mixed, the one thing they love to do is to cuddle up, try to eliminate empty orbitals like this but electron counts, electron deficient. And these processes can often be dynamic and in a dynamic process they generate species like this. This part is of course very reactive, same as this one but compared with this one, this one is super-hyper-duper-acidic because this one is right next to dipole which is positive or negatively polarising. In other words positive charge close to this electron deficient centre and negatively charged away from there. So this interaction makes this centre super-acidic. And this is the secret of the ... (inaudible 29.31) chemistry, polymerisation chemistry. Why should we not take advantage of this in a general sense? That is the message. And I'm going to have to go through this and net result of our cross-coupling, discovery of cross-coupling reactions and their development is that now we can claim that we can synthesis the majority of organic compounds. We can, you know, in a YES(ES) manner. For instance, I will wind up my talk if I may have couple of minutes. Traditionally alkenes, people selective synthesis alkenes were done by so called carbonyl olefination. This one has a fundamental problem in my opinion because this one is addition elimination process. Addition is a problematic but more problematic is the elimination. Of course when they work well they work well, of course. But here it is concerted additional to alkyne, we start like this. This process, there is a bit of issue, chemical issues but other that it is essentially 100% in addition. Once we set up this group like this, R1M group, then palladium catalysed cross-coupling comes into play to rescue and then it will retain this whole group integrity and then produce the alkenes of your choice. And let me end my talk with half, nearly half of the synthesis of amphotericin B which the whole thing has been only synthesised once by K. C. Nicolaou. Many, many steps, many more than 50, 60 steps. We figured out that we should be able to synthesise as I told you within 30 steps overall and then we chose this one as our first intermediary target. If we can synthesise this part in less than 15 or 10 steps we might be in business and which we did. So using our Negishi coupling to form this part as you see here, 40% yield overall in 5 steps. And then you note that there is nowhere any figure less than, greater than 98% in our synthesis. Believe me. So I show this one. And then another breakthrough is that we were able to go from here to here in 4 steps. The second shortest is by Erick Carreira, 13 or 14 steps. But you need to do this in 4 steps, overall 57% yield. And here again you don't see any figure less than, greater than 98%. So now we got this and from here we use Heck reaction. Heck reaction is overall less green, less green, even though we use CH. We lose the power of metal. But in this case it was the best option because we end up with this terminal alkene so we can get this one under Geoffrey's conditions and then get this one. I told you how we got this one. And then we hook up by... not by palladium catalysed cross-coupling but HWE. Because of this conjugation here and here we can maintain this, we can do that in highly selective way. So the combination Negishi, Heck and HWE turned out to be so far the best. And overall we did it in 8 steps. So we are hopeful that we can do the rest and overall thing in less than 30 steps. That's the kind of 21st century synthesis. You know, it gives us hope for being practical. And I have a lot of things that I can show but in view of time I think I should stop here and I only want to... So here I am showing that we can make any kind, any of 8 possible trienes. These 2 had never been synthesised selectively in any more than several percent yield. But look here, yields and then the selectivity. You can do that. And even this one is one of my favourite, so-called 1, 5-dienes, representing all kinds of terpenoids and others. You can control every aspect if you avoid the allyl-allyl cross-coupling or allyl-propoxyl and then shift to homoallyl and alkenyl. So, even molecules like CoQ10 can be synthesised in less than 10 steps starting from these compounds. Ok, so that's the second part (laugh). So in the area of palladium catalysed cross-coupling more than 100 people worked but still the first quintet, Doctor Baba, Tony King, Okukado, Kobayashi and Van Horn, they had their eureka moment every other month or so (laugh). I thank them. So, thank you very much for your kind attention. End.

Ei-ichi Negishi (2011)

Magical Power of d-Block Transition Metals: Past, Present and Future

Ei-ichi Negishi (2011)

Magical Power of d-Block Transition Metals: Past, Present and Future

Abstract

Until recently, most of the 24 d-block transition metals had been used primarily as useful materials for (i) construction and also as tools and containers, etc., (Ti, Zr, Fe and their alloys with V, Cr, Mn, Co, Ni, etc.), (ii) precious and ornamental items (Au, Pt, Ir, Os, Ag, etc.), and
(iii) electromagnetic applications (Cu, Nb, Ta, W, Re, etc.). Over the past several decades, their superb properties as chemically useful substances, especially as catalysts for chemical reactions, have been increasingly recognized. “Why are they so useful as catalysts?”

In most cases, their superb catalytic properties may be attributed to one or both of the following two: (1) ability to provide simultaneously both filled nonbonding valence-shell orbitals (one or more) and empty valence-shell orbitals (one or more) within thermally stable species and (2) ability to undergo simultaneously both reduction and oxidation under one set of reaction conditions in one reaction vessel.

A combination of these two properties can be exploited in devising a wide variety of useful catalytic reactions for formation and cleavage of C–C, C–H, C–O and other bonds.

For critically important C–C bond formation, a) reductive elimination, b) carbometalation, and c) migratory insertion may be exploited. As representative examples of reductive elimination and carbometalation, the Pd-catalyzed cross-coupling proceeding via reductive elimination and Zr-catalyzed asymmetric carboalumination of alkenes (ZACA) proceeding via carbometalation will be discussed.

Many more novel catalytic one- and two-electron processes via organotransition metals will be discovered and developed.

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