 In organic synthesis, you very often want to combine two different fragments either through a single bond or through a double bond. In today's lecture, we will look at options where we can combine two organic fragments through a carbon carbon single bond. In fact, the problem is so important that a solution to this problem was awarded the noble price in 2010, at least some of the processes which brought about carbon carbon single bond coupling in a very interesting and novel way. Now, the three people who won the noble price are Heck Suzuki and Negishi, but there are many, many more who have contributed to this area and we will look at time permitting. We will look at some of the processes which are useful in bringing about a carbon carbon single bond coupling. We will start with some of the examples where these have been used. Here, I have shown for you on the screen three different naturally occurring molecules. These molecules are important as drugs. They have been useful for the treatment of various diseases. Surprisingly, the synthesis of these molecules in the laboratory so that they can be synthesized readily and administered to patients is critically dependent on some carbon carbon bond forming reactions. These carbon carbon bonds are shown in red in these molecules and you can see that if one develops interesting methods or green methods to couple these systems together efficiently, you would have achieved the goal of the goal which is in this case the synthesis of the molecule. So, the problem essentially boils down to making a carbon carbon coupling reaction and it can be generalized to say that there can be two different ways. You either couple them through a double bond or a single bond and today's lecture as I said it is for single bond coupling and you can couple them when they are two radicals. This would if the two fragments are two radicals, they would lead to indiscriminate coupling reactions where there will be homocoupling and heterocoupling of the fragments. You can make this more specific by combining a cation and an anion in which case the cation will react only with anion and not with itself. So, homocoupling would be avoided in this process. You can also have some metathetical reactions, a single bond metathesis reaction and this is something which would be valuable and we will consider this a little later. So, let us take a look at some carbon carbon bond coupling reactions. The first person who systematically examine this process is Negishi and so this coupling matrix that I have written for you is the matrix that was originally defined or written down by Negishi and he says that this is the way in which he systematically approach the problem. It took two fragments and for the convenience we have written it in such a way that the if you have an alkyl fragment and that is R C H 2 x which is functionalized. You can think of a metal fragment which can be generated from the same R C H 2 x in which case it will be R C H 2 M y. Coupling of these two fragments would then lead to a molecule R dash C H 2 C H 2 R and that would be in this product cell. So, similarly you can couple two allylic fragments and that would give you this. You can also couple the allylic fragment with the alkyl fragment in which case we would write the product in the cell which is indicated here. So, you can have a matrix of coupling reactions and this would be useful for making biorhyles and these are indicated here. You can also couple alkyl alkynyl species. So, R C triple bond C and this would give you conjugated triple bond C coupled products as we have written here R C triple bond C C triple bond C and R dashed. So, let us do that again. So, you can have R C triple bond C C triple bond C and R dashed. So, you can imagine all the products written down in this matrix and these will have to be coupled using various metals. Let us back up a little bit and talk about the historical development of this process. It was not Nagishi who originally developed carbon-carbon bond coupling processes. It was in fact a problem that has been tackled for a long time. There are reactions where Grinard reagents have been coupled together. They would be oxidized with copper 2 plus salt. There is this Karash coupling and the situation really became or the problem was taken up more seriously after Heck found out that palladium was able to carry out some very interesting reactions. At the same time, Tamura and Kochi have looked at copper, copper cuperate couplings and these are also important. But it was the work done by Kumada and Koryu with nickel based coupling reactions that caught the attention of Nagishi. Nagishi took that reaction and started investigating or developing that reaction in greater detail. The original observation at the time or the turn of the birth of organometallic chemistry in the late 1950s or the early 1960s was an observation made by Heck. He observed that if you took finely powdered palladium, finely divided palladium, if you generate the reactive form of palladium and reacted with a vinyl bromide, you could in fact generate a palladium organopalladium compound, which reacted as if it had the palladium between the carbon bromine bond. This compound could add on to olefins in order to generate organopalladium species, which I have pictured for you here. Simply put, you have a sigma carbon palladium bond, which now adds on to the double bond and that is how you would get this intermediate. Because this intermediate has got this hydrogen here, which can be eliminated in the presence of a base like triethylamine, you would eliminate and form these diolefins. So, if you took a vinyl compound, you would end up with a diolefin. Essentially, you have in the process, you have eliminated a molecule of HBr from these two species together in the presence of palladium in the presence of finely divided palladium. So, what is pictured here is a stoichiometric reaction and the question that we can ask now in hindsight is that, was that palladium that was used by HEC and nano palladium. Now, there is a lot of interest in nano catalysis and it is possible that the palladium that was used by HEC was in fact in the nano regime in terms of size, but whatever it may be, HEC's original contribution in this critical juncture was the fact that he converted this reaction to a catalytic reaction. This original reaction that I described to you was done in a stoichiometric fashion. Now, he found out that if you use palladium acetate and a phosphine in the presence of a base like triethylamine, you can in fact couple the vinyl bromide that we have here. These two species can be coupled to give you, if you couple it on both ends of this triene, this is the triene and if you couple it both ends, you would get this molecule. So, you can couple both ends of this triene to get this rather complex pentane, but notice that I have deliberately written this reaction in such a way that this particular coupling has been done in a trans fashion. This carbon-carbon bond has been formed in a trans fashion, whereas this carbon-carbon bond has been formed in a cis fashion. So, it is possible using the HEC reaction to form both trans and cis couplings. This is in fact a disadvantage, very often you would get mostly the trans compound. That is the thermodynamically most stable compound and that is what you would isolate in the reaction mixture, but at the same time this is a disadvantage for the reaction. So, in general form if you write out all the substrates that are capable of undergoing the HEC reaction, here are the compounds that have been used. You have Rx and olefin and the R can be either aryl, vinyl or an alkyl compound. So, all of them are capable of forming the palladium alkyl species or palladium aryl or vinyl species. These add on to the olefin in such a way that you form a substituted olefin. Notice here that the substituted olefin I have written it in the trans form in this case also, but the other product should also be written. Now, it turns out that because you are eliminating a molecule of Hx, you should have another atom or another hydrogen atom present on this olefin. Only then you would end up with the HEC reaction. So, the X group itself can be a halide or a triflate. It only has to be a good leaving group which can add on to the palladium to form the organo palladium species that we talked about. So, palladium can then be made into a catalytic reaction. This reaction can be made into a catalytic reaction in the presence of phosphines and that was again found out that if you have hindered phosphines, then they are good ligands. Then they turn out to carry out the reaction more efficiently. Similarly, if you have tertiary amines, they are the best in order to remove this acid that is formed. The acid that is formed can be removed readily and efficiently if you have a tertiary amine. So, let us take a look at the mechanistic aspects of this reaction now. This is the familiar catalytic cycle that is written for a HEC reaction. Initially, you have the palladium zero species which in the reactive form would react with an alkyl halide or a vinyl halide or an aryl halide and undergo oxidative addition. The number of ligands that we have specified here can go from n to n minus 1 during this process. It can also remain the same or it could lose more ligands as the reaction proceeds. So, here I have carried out oxidative addition and this oxidative addition gives you now a palladium two species. This palladium two species coordinates to the olefin and you end up with a vinyl species or an alkyl species which is adjacent to an olefin. So, this can now carry out an insertion reaction and in such a way that you end up with an alkyl organopalladium complex which is pictured here. Such that you this insertion reaction gives you the two R groups attached to this vinyl group that we or the olefin that we started out with and you should have this hydrogen in the carbon which is away from the olefin carbon which takes on the R dashed. So, now you have two hydrogens on the olefin and one of them can be eliminated and it is in general the hydrogen which is in the beta position next to the palladium. So, now if you eliminate H and X the two atoms which are rounded off. So, you could end up with a palladium H X species which would rapidly eliminate palladium. This is also palladium two you have only carried out a migratory insertion and a deinsertion. So, this is a deinsertion step in which the olefin which was initially added on had one R group and the olefin that is deinserted has got two R groups. You have only added and subtracted a vinyl group or an alkyl group and you have subtracted H X group. So, that you end up with a palladium two species and this palladium two species loses H X in a reductive elimination. This is a reductive elimination step and that gives you back palladium zero. So, this cycle is completed and you end up with a palladium zero compound which is stabilized again with ligands such as triphenyl phosphine or trialkyl phosphines. Now, this whole catalytic cycle is efficiently carried out only by palladium and that is a uniqueness of palladium. No other metal has been able to supplant palladium in this whole process and there are limits to this reaction. X has to be a good leaving group which is obvious because if you want to have an oxidative addition then the rate would become rate. The first step would become extremely rate limiting if X is not a good leaving group and the alkene as I mentioned because you eliminate H X it should have a hydrogen and the olefin that you originally carry out the HEC reaction with should be reasonably sterically free. If it is overcrowded with say three alkyl groups on the olefin then the reaction becomes extremely sluggish. In fact, you may not get HEC reaction at all if you have all three positions on the alkene which are substituted which are substituted by alkyl groups or vinyl groups. So, you need a minimum of one hydrogen that is technically true, but more hydrogen on the olefin the better it is. Now, you have the limits to the reaction defined. You also have one very important limit and that is the fact that the stereochemistry of the final product is not fixed. You can have both cis and trans products which are only the trans product is given here because that is very often the major product which is formed and that is why this reaction is still a useful reaction. You can have a carbon-carbon coupling very efficient carbon-carbon coupling which is useful. So, here I have for you the taxol synthesis which utilizes the HEC reaction and you will notice that the carbon-carbon bond which is formed indicated in red and the leaving group is a triplet. That is what I am circling in circling in the original molecule and the place where it is adding on is the vinyl position that you are adding it on to is right here. That gives you because of the ring size it gives you a single product and that becomes the key step in the taxol synthesis in one of the synthesis that utilizes the HEC reaction. So, you can see that the HEC reaction has been a useful reaction and that this time around late 1960s Negishi started investigating the coupling matrix which I talked about earlier and his investigation was a fairly systematic investigation and he found that if you combine two different metals palladium as a catalyst and a stoichiometric amount of a molecule which is indicated in this column if you have a stoichiometric amount of this metal alkyl and palladium as a catalyst you can carry out a variety of reactions very easily. In fact in his early in the early stages he had investigated quite a few of the metals but then he found that zinc was a unique metal and zinc was unique and it was good because zinc had the capability or the capacity to do reaction stereo specifically and he claims that is a key factor which makes the Negishi coupling in fact one of the best couplings that is known in the literature. So, the Negishi coupling which was mostly developed and popularized by Negishi involves a zinc alkyl zinc organo zinc compound which is reacted with an organo halide and this leads to a coupling reaction where x, z and y is eliminated. So, x, z and y is eliminated in this process and you have palladium only in catalytic amounts but we should note at this point that the organo zinc species that he utilizes is very often synthesized through organo lithium species. So, first you have to make a reactive lithium species and then the R Li is converted or is transferred to the zinc using zinc chloride to R Z N C L this is in fact the most efficient way of carrying out the Negishi coupling. So, let us take a look at the mechanism of the Negishi coupling now it and let us look at the differences between the Negishi coupling and the Hegg coupling. The first step is identical what you are doing is carrying out oxidative addition between an R dash x to palladium. So, that you get a palladium two species so, this is the oxidative addition and then you have a palladium x bond. This is the palladium x bond which I am marking for you in bold and red color and this palladium x bond can be converted into palladium R bond where the R is coming from zinc. So, if I have a zinc coordinated or a zinc alkyl or an aryl this aryl can be transferred to the palladium and m x can be eliminated. So, you eliminate m x and generate now you generate a di organo palladium complex and this di organo palladium species is capable of undergoing reductive elimination. So, that you end up with a palladium zero species and the coupled product and notice that you do not form you do not have a migratory insertion reaction where insertion reaction was the one which was a key step in the Hegg reaction. Here you carry out a trans metallation reaction which involves conversion of a palladium x bond to palladium R bond and so you also the nature of the metal which is indicated by R m is crucial in how this whole reaction proceeds and Negishi popularized the zinc version of this reaction and later on we will see that Suzuki who popularized the boron where m is boron, boron variety of the reaction is also a useful alternative. So, the generalized Negishi reaction in fact involves a whole range of aryl vinyl or alkyl groups in either R x or R m. So, it is a extremely versatile reaction and the x group that you can use for the transmit the oxidative addition can be again a halide or a triflate as I mentioned earlier that step is in fact common to both Hegg reaction and the Negishi reaction and the Suzuki reaction as well. So, you just need a very good leaving group on the x group. Now, you need to do a trans metallation and the trans metallation can be done with a zinc Z and Y and H what is given here as a generalized Negishi reaction. Later on we will see that B Z 2 or boron with two electronegative groups is what was developed by Suzuki. To give credit to Negishi in fact, Negishi was the first one who reported the boron reaction also. He had tested the boron, but it was popularized and made more useful by Suzuki by the numerous examples that he demonstrated later on. So, it is interesting that Negishi has in fact written a historical introduction to this palladium catalyzed cross coupling reaction. In this paper which is published in the journal Organometallic Chemistry, he describes the development of the palladium catalyzed cross coupling reactions. He notes that zinc, aluminum and zirconium and magnesium also were used extensively in the 1970s. Later on it was tin, boron and silicon were in fact taking second place in the carbon-carbon coupling reactions. It was Negishi's group which popularized in the 1980s mostly the zinc catalyzed variety which now holds one of the key ranks in the carbon-carbon coupling process. Let us take a look at one of the applications of the Negishi reaction. Here you have this coupling between these two units. You can see that Z n C l i can be eliminated and you can have this key coupling reaction which leads to this natural product which is shown here. So, this is only possible because you can have a very clear stereospecific reaction between these two fragments. It can be accomplished by the Negishi coupling very efficiently by simple palladium tetrakis triphenylphosphine palladium. So, what was interesting is that many times you need extremely active catalysts for the Negishi coupling cross coupling reaction and many people have come forward to design new catalysts for the Negishi cross coupling. Because if you have an alkyl halide like an alkyl chloride then the oxidative addition becomes more difficult and you need an active catalyst. It has been shown by people like Buchwald in this paper which is shown right here that you can have efficient coupling with hindered phosphines. The phosphine that he has developed recently is pictured here. This is the ligand which we will label which we will add to palladium 0. Palladium 0 itself in this particular instance is introduced conveniently in the form of a dibensalidine acetone complex. Dibensalidine acetone complex is palladium and keeps it at palladium 0 and this is a convenient way to store palladium 0 and add it to the reaction mixture. So, now the ligand that is used is highly hindered and they have shown that you can even activate aryl chlorides which are reasonably unreactive under the normal heck or the Negishi reaction conditions. Here you can see two very hindered molecules which are coming together and forming a new bond which we will highlight for you here. This is the new bond that is formed and you have eliminated zinc chloride from this reaction mixture efficiently at reasonably mild temperatures. This can be this can this is made possible only because you have this very hindered ligand and in this reaction a variety of very different functional groups are tolerated. So, you can have a variety of groups which are present in the aryl moieties and ester alkoxy or even an amino substituent is tolerated in this whole process. So, this makes it a very extremely and versatile useful coupling process. It is interesting to see the ligand synthesis in this particular instance. It goes through organolithium molecule and what transpires is that the lithium molecule initially forms a benzene and that intermediacy is through replacement of this bromine with a lithium and that is the exchange of a B R and L I and it is the same molecule which adds on to the benzene which then gives you this coupled product. So, this addition would lead to addition of these two molecules would give you a phosphine which a phosphine which is extremely useful. So, let us take a look at the Suzuki coupling now. The Suzuki coupling as I mentioned earlier is a coupling between an alkyl halide and the boron compound and the alkyl halide oxidatively adds to the palladium and the boron is a transmittal agent. The scope of the reaction is given here once again you need a good leaving group and that remains a constant consistently that remains an essential component of this reaction and you need you can have alkyl vinyl or aryl species, but the requirement for a base in this reaction which I have shown here is also a key factor in this reaction. You need a base in order to carry out the whole reaction. Now, a variety of examples are given in this transparency. Once again I have given you the coupling of two hindered arean molecules which can be carried out by palladium 0 and a simple boronic acid which can be coupled. This is an example which would couple two different aryls to give you a y aryl and this reaction is so efficient that it can couple naftile groups also. If you have these molecules are axially chiral around this bond and that is how you can make chiral compounds if you have a chiral agent. So, let us take a look at the palladium catalyst and the palladium. Let us take a look at a variety of Suzuki reactions which are which are possible and in the presence of a palladium catalyst and a base you can combine this whole set of molecules which are listed on my left two different molecules either a alyl vinyl or an aryl halide can be combined with a variety of boron containing compounds. Now, towards towards 2000 and so it was possible to combine even alkenyl species with a vinyl species and in in 2005 it was possible to carry out the combination of a alkyl boron with an alkyl halide and this was carried out by a Foo. This was done in 2005. So, let us take a look at the mechanism of the Suzuki reaction. Now, Suzuki reaction is also very similar to the Negishi reaction. So, Suzuki and Negishi fall into the same category of reactions where you have an oxidative addition to give you the palladium 2 species which undergoes transmetallation. The transmetallation step is a one where you either use a zinc species in the case of Negishi and in the case of Suzuki you use a boron containing compound and the palladium 2 species di organo palladium containing compound where there are two carbon palladium bonds. This undergoes reductive elimination in order to give you the palladium 0 species. Now, it turns out that the variety of Suzuki couplings that can be carried out are fairly large and so you can form mostly aryl aryl bonds that is what it is used for significantly. You can use a palladium 2 precursor or you can use a palladium 0 precursor. The precursor is very often reduced in situ if it is palladium 2. So, the active form of the catalyst is still palladium 0, but you can use a phosphine which can reduce it in situ to palladium 0. Now, you can use bromides or iodides and iodides are very good for oxidative addition, but you can also use chlorides under some conditions, but under normal conditions for the Suzuki coupling chlorides are extremely reluctant and they do not work they are not suitable. If the ancillary ligand that you use that is a L group is extremely electron donating then you can force the Suzuki coupling to work and that has been carried out also by people like Greg Fu and Stephen Buchwald. Now, here is a key reaction in the synthesis of a drug molecule dynamism and this again has been carried out by a Suzuki coupling that has been done. This case I am going to mark it out for you again in a different color so that you can see the bond that has been formed. Here is the boron containing compound and here is a triflate that was eliminated from using palladium to give you an oxidatively added intermediate and that couples with the arene to give you the key intermediate which would then be converted into dynamism. So, all three coupling reactions the HEC reaction, the Negishi reaction and the Suzuki coupling reaction have been used for the synthesis as key steps in the synthesis of a variety of organic drug molecules. So, they have become extremely popular and there are in fact similarities between the three, but as I mentioned to you between the Negishi and the Suzuki there is very little difference it is only the transmetallation reagent that becomes different that becomes different when you go from Negishi to Suzuki. For Negishi you use zinc for Suzuki you use the boron. So, as I was telling you in the introduction it is possible to you do the transmetallation with a wide range of substrates. So, after forming the palladium to oxidatively added product that product can transmetallate because it has a pd x bond and that transmetallation can be done with any electro positive element and so it just depends on what is available and here is a variant of this two coupling reactions that we have talked about and this is called the Hiyama reaction where you have a silicon substrate which does the transmetallation. Notice here that silicon has got three electro negative groups. So, these are not the ones which are transferred to the palladium it is only the R group which is less electro negative that is the one which is transmetallated to the palladium and the X group from the palladium is transferred to the silicon. So, what would be eliminated is SiObu thrice X and the X would come from the group which was present on the arial moiety which oxidatively added to palladium. So, here there is an interesting variation and that interesting variation is the fact that you can use tetrapodal ammonium fluoride as an additive and that seems to increase or accelerate the reaction Tbaf can also be used as the base for removing the compound that is formed. So, there is a there is another variant which is called the Stille reaction. The Stille reaction has also been an extremely popular variant of this type of reaction and again palladium and phosphine are essential and it adds on to the vinyl or aryl halide and here you end up adding a tin compound which will transfer this R dash group on to the palladium and once again you see that this reaction is a small variation you can accelerate this reaction using copper iodide. The base that can be used a simple metal salts which will promote the removal of the tin from the reaction medium. So, the reaction proceeds in the forward direction. So, the Stille reaction was also developed around the same time, but still the Suzuki became lot more popular because of its extensive use extensive tolerance of various functional groups and its efficiency. Here is one more example which is using a Grinard reagent. The Grinard reagent is RMG any RMG X and the only advantage of this reaction is that there is no base that is required in this whole process. MG X 2 is removed in this reaction and you can do the reaction completely in the absence of the base and if you have a base sensitive region then this would be a suitable way of carrying out this coupling reaction. The reaction is usually carried out in toluene or dioxin. Another variant which is extremely popular is the Sonogashira reaction. The Sonogashira reaction varies in the fact that you can now use alkenyl substrate. The alkenyl substrate and the alkenyl substrate just adds on exactly in the same fashion. You have removed an HX, so you need a base. You have removed HX, so you need a base and the base is very often triethylamine or trialkylamine or inorganic solid base like cesium carbonate. This leads to the formation of the coupled product in extremely high yields and this is once again a good substitute for this, for the type of reactions that we have been, for the negishi and this still a reaction that we have talked about. The Sonogashira reaction suffers from one drawback and that is the fact that there are situations where you can have homo coupling of two of the alkenyl species can be homocoupled to give you the di alkenyl species which is pictured here. So, this is a disadvantage and so one has to suppress that and usually the addition of copper is supposedly to transfer the alkenyl substrate directly on to the palladium. So, it leads to another complication which is the alkenyl species that is formed with copper can also do a coupling reaction and that gives you the di alkenyl species as well. So, you can see that the Sonogashira coupling although it is quite popular can lead to some complications depending on how reactive your organo copper species is present or your organo palladium species is capable of doing the homo coupling reaction. But nevertheless it can be used for coupling reactive R X with the alkyne and with the elimination of H X you would lead to a new carbon bond between the alkyne species and the R X. So, I mentioned to you earlier that the Suzuki coupling is not efficient if you have aryl chloride and it has been possible to use very electron deficient very efficient electron very electron donating tri alkyl phosphines and when they are also sterically demanding which means if they are bulky tri alkyl phosphines then they are very good and they can in fact activate aryl chlorides. This was a deficiency in the Suzuki coupling reaction that I mentioned, but it can be turned around and it would be possible to do this in the case of phosphines which are electron donating. Now, the first step as I mentioned to you is an oxidative addition. So, if the metal center has got a greater amount of electron density it would be possible to carry out the oxidative addition reaction. Usually the oxidative addition will become rate determining if the halide or the chloride or if the halide is reluctant to carry out oxidative addition. One should also remember that the presence of a sterically demanding phosphine leads to a low coordinated species on the palladium and low coordinated species is the advantage for carrying out oxidative addition because oxidative addition usually requires a lower coordination number on the palladium 0. So, that is how it is possible to have very efficient Suzuki coupling reactions and it has been applied for Suzuki coupling specifically with chiral ligands. We will meet these ligands later on also when we talk about chirality transfer. These are a variety of chiral ligands that are very popular in the literature and these ligands have been used for Suzuki coupling. Here are the ligands that are pictured although it is difficult to put them on the same transparency. You can remember that binapple which is axially chiral molecule and extremely popular for chirality transfer has got two phosphorous atoms and the ferrocene based molecules which are also again axially chiral have got a single phosphorous ligand on the ferrocene moiety. So, these two are extremely popular and they have been shown to carry out asymmetric Suzuki coupling and this Suzuki coupling can be done with enantiomeric excess which are fairly large. So, the advantage as I mentioned to you is the fact that you can carry out these reactions with unactivated aryl chlorides. So, here is another example and that example comes from the group of Gladys and they have carried out very efficient Suzuki coupling reactions by aryl coupling reactions using interesting concept and that interesting concept is a fact that if you have a very electron donating group on the phosphorous and that phosphorous will be able to give electron density to the palladium very efficiently. So, here is a phosphene which is attached to rhenium and the rhenium is a co-ordinatively saturated and also electronically saturated center. So, because of this it can transfer electron density to the phosphorous and the phosphorous in turn transfers electron density to the palladium and that makes this reaction very efficient with 1 mole percent of palladium and with 4 percent 4 equivalence of the ligand with respect to palladium you can now carry out this by aryl coupling very efficiently. So, this scope the importance of these reactions is a fact that you can have low metal loadings and here is another example where the phosphorous is coordinated to a D 10 system. So, this is a D 10 system which is electron rich and this is attached to the phosphorous and that makes the coupling reaction very efficient and this can be done with low metal loadings. So, in up to now we have talked about a variety of reactions where palladium has been used as a key reaction for carrying out coupling. Now, in recent years in 2002 it has been shown by Monterio that it is possible to carry out this reaction efficiently with nickel chloride. Only disadvantage is that this reaction has to be done in the presence of an inorganic solid base and dioxin, but the advantage is a fact that you have simple nickel chloride as the starting material and the price difference between the nickel and the palladium would is enormous. So, it is possible to carry out these reactions very cheaply. It is exactly the same reaction as the Suzuki reaction and you can see here a variety of couplings that have been carried out O T S is the leaving group and you have carried out coupling between O T S and the boronic acid that we have here common boron containing compound that does the trans metallation is the boronic acid and the coupling product is given here. You will notice once again that the yields are quite high and the conditions are a little bit severe. You carry out the reaction at 130 degrees, but there are some advantages to this reaction because you can carry it out carry out the whole reaction with nickel. So, the mechanism of the Suzuki coupling with tosylates is probably going through a similar reaction. What we have is initially nickel 0 this is nickel 0 and the nickel 0 this arrow should be pointing in this direction. So, if you have a nickel 0 and it oxidatively adds the tosylate oxidatively adds the tosylate to give you a nickel 2 species and this nickel 2 species trans metallates. Now, you have O T S which is trans metallating with a boronic acid. So, that you end up with again a nickel 2 species no change in the oxidation state only a trans metallation reaction has been carried out and reductive elimination in this step, reductive elimination in this step gives you the nickel 0 species and the coupled product which is shown here. Here is the oxidative addition step. So, there are two key steps here you have nickel 0 going to nickel 2 and a trans metallation. So, the mechanism is very similar to the Suzuki coupling that we talked about only thing is now we are doing it with nickel it is nickel which is a 3 D transition element. Now, let us take a look at these reactions which we can do as a cross coupling with a variety of arenas. The reaction the yields are extremely good and as I mentioned the only disadvantage seems to be the fact that you have to carry out the reaction at a fairly high temperature. So, by areals are synthesized readily using nickel catalyzed coupling and in one advantage is that you can couple it you can now combine it with a classical Suzuki reaction because one reaction needs a higher temperature than the other one can be done with a tosylate the other one needs a bromide. So, here is a reaction where a substrate which has got two leaving groups one is a bromide and other is a tosylate. So, with the palladium the bromide reacts ready very readily and you can have the coupling reaction between a boronic acid a substituted a methoxy substituted boronic acid and that gives you a single compound where the tosylate is left unreacted. So, here the tosylate has been unreacted you have the substrate which is capable of undergoing reaction on either end only the bromide is reacted with the palladium and with a nickel at a slightly harsher conditions you can see that the coupling can be carried out in the transposition that is the tosylate now leaves and that gives you a three triaryl if you will and that has been done with an overall efficiency of nearly 81 percent. So, that is an excellent transformation from the simple disubstituted a ring to give you a triaryl molecule. So, many of these molecules have got phosphine attached to the ferrocene and that again is probably because the ferrocene has got an 18 electron iron centre which is electron rich and that in turn can pump in electron density on to the phosphorous and that in turn can push it on to the palladium making the palladium more reactive. So, ferrocene or areene phosphines as I have mentioned to you have been developed by Greg Fu and this here is a chloride which is usually unreactive under the reaction conditions with palladium and you cannot carry out this reaction this carbon-carbon coupling reaction easily because you have to activate the chloride, but because the ligand that they are using is extremely electron rich with the ferrocene centre you are able to carry out this reaction efficiently and as much as 87 percent yield has been achieved in this reaction. So, let me now summarize what we have talked about today what we have talked about is is that the key reaction in organic synthesis in many of the drug molecules you need to couple two different fragments. So, that in a convergent fashion you can synthesize a fairly complex molecule and during this process you either need to carry out carbon-carbon coupling a single bond coupling or a double bond coupling and a transition metal turns out to be a key factor and so far there are very few reactions which will not use a transition metal for this key coupling reaction and interestingly palladium turns out to be a key element in many of these processes. So, much so that chemical engineering news article recently had the title the most important element in organic chemistry is palladium.