 In this lecture, we will discuss catalytic metathesis. Metathesis, as we had discussed in the last lecture, it is a change in place. In the case of olefins, when you have alkylidine groups and if alkylidine groups change places, then you would have a metathesis reaction. In the slide that is there before you, you will notice that two alkenes and they are the same alkene A B, which is basically indicative of two alkylidine groups joined together. If we do a metathesis of this A B olefin, then you can get both A A and B B. If you remember this allows for a change in the size of the olefin. So, if you take a small olefin and you do metathesis, you can get a bigger olefin and a smaller olefin. This is very useful for the petroleum industry. In fact, metathesis was originally discovered in the industry and eventually it was understood better through the work of Chauvin. He discovered what is called the non pair wise mechanism for the metathesis. We will just briefly revise what we have discussed earlier. I have before me a set of four olefins, which are represented by these green, magenta, blue and black alkylidine groups. The alkylidine groups that are going to be exchanged are the ones which are shown in round as a round figure. The alkylidine groups which are stationary or will remain in the same place are the ones which are in square shape. So, you will notice that if you take four different olefins, you can have a complete random distribution of these olefins. The gray round figure which is attached to the metal which is basically having M double bond CH2 here is going to be exchanged with the green one to start with. Then the green alkylidine group is exchanged with the magenta and the magenta is exchanged with the one in the transposition. So, you will notice that the round magenta has gone here. The green one has come here and the blue which was here has come over to this position. So, this is just to indicate that you can have a completely random distribution of the alkylidine groups. This non-pairwise mechanism was suggested by Chauvin and you will recollect that Chauvin got the Nobel prize in 2005 for this very reason for discovering the actual mechanism that was behind this famous metathesis reaction. Pictured here is the mechanism. You start with M CH2 M double bond CH2 and then you can exchange it with another olefin in such a way that you can eliminate ethylene. That is what is happening here. Ethylene is eliminated and a new alkylidine metal system is generated which can interchange with another alkylidine group of another olefin in order to finally generate a completely new olefin. So, these are the two products. This is product 1 and this is product 2 and these two olefins are generated starting with two olefins which is the reactant 1 and reactant 2. This is reactant 1 and this is reactant 2. So, based on this type of a non-pairwise mechanism it was possible to explain all the reactions that were observed in the metathesis reaction. So, what we have not discussed in the last lecture where we discussed the mechanism of this process is a fact that the catalyst required for metathesis were often very complex. Originally it was discovered by a standard oil company and patented also by Philips petroleum for a specific case. Most of these companies used very complex mixtures for carrying out metathesis. In general it could be said that early high oxidation state metal ion or a metal complex an oxide or a chloride was used and this was followed by a reducing agent. So, a high oxidation state metal. So, this is the high oxidation state metal that I am talking about and then this was combined with a reducing agent. Very often this was an aluminum alkyl species aluminum alkyl or aluminum alkyl chloride and then surprisingly small amounts of ethanol or water were required in order to initiate the reaction. There were several disadvantages for this particular mixture. One was a fact that the catalytic species was not known. It could be a variety of different species which were generated starting from this mixture. So, the catalytic species itself could not be modified. It was an unknown species and there was very often an initiation period that was required in order to start the reaction. So, the reactions were slow to begin with before they took off. This means that the reaction itself would lead to in terms of when you have reactions which lead to polymers, you have a large range in the molecular weight. We will talk about this a little later on during the course of this lecture also. So, this is a big disadvantage, but nevertheless the petroleum companies found it extremely useful to do metathesis reaction in order to generate more useful fractions from the petroleum fractions that were isolated directly from the crude that were isolated from the crude. So, it was a useful reaction, but then the catalyst was not known. After Chauvin unraveled the mechanism of the reaction, it was clear that one needed a carbene. So, this carbene catalyst was used or was one of the first ones which was rationally designed. You will notice that this species, this carbene species was the catalyst, but it was still in a high oxidation state. It required an aluminum alkyl species, aluminum halide in order to activate the species. So, Lewis acid was apparently for some reason it was required in order to carry out this reaction forward. This Lewis acid activation is presumably to generate a vacant coordination site on the tungsten. So, this was better than complex mixtures. The complex mixtures that were originally known for carrying out metathesis reactions were extremely complex. This was better. It was too component, but still it was not as good as what one would desire. So, the first breakthrough came from the work of Schrock and Grubb. We will discuss these two in detail. We will take up the Grubb's catalyst first and then we will talk about the Schrock's catalyst. Grubb's catalyst was a modification of the carbene systems that were known which were derived from fissure carbene. Fissure carbene were those species where you had a late transition metal along with a carbon bearing a heteroatom. However, when you replace the heteroatom with all alkyl groups, the carbene became lot more reactive and especially reactive towards the metathesis reaction itself. So, this catalyst which was first made by Grubb's which is called the first generation catalyst from the Grubb's group is extremely important for several reasons. First of all, it was the first single component catalyst which means that it did not require another species in order to initiate the reaction. Secondly, it was the precursor for several other second generation and third generation Grubb's catalyst. This is also important and the fact that it could be easily generated and the reaction that is used for making this complex is shown here. In fact, R U C L 2 P P H 3 thrice is the starting material and this starting material can now be reacted with a diazo carbene precursor. This leads to transfer of the carbene to the ruthenium and this molecule is a stable molecule which can be isolated and characterized. This species which is generated by attaching a carbene to the R U C L 2 P P H 3 thrice turns out to be less reactive. It is not as good a metathesis catalyst, but when you replace the tri phenyl phosphine with tri cyclohexyl phosphine with a simple substitution reaction, you end up with the first generation catalyst. This is the first generation catalyst from the Grubb's group and it turns out to be a good metathesis catalyst. So, there are advantages for this catalyst system. First of all, it can be readily synthesized very easily synthesized in the laboratory. It is a stable system which can be stored and used again and again without difficulty. You do not have to make it fresh every time you want to do the reaction. So, this is the primary advantage and it is a single component catalyst. As I said, that is the major advantage of the Grubb's catalyst. Now, after Grubb's declared the synthesis of this catalyst, it turns out that several people wanted to make better metathesis catalyst. Something that would be more reactive than the first generation catalyst which could not be used with several substrates. Three people, Nolan, Grubb's and Fusner, discovered that if you can attach n-heterocyclic carbene. This is a n-heterocyclic carbene which we have encountered earlier. If we can attach n-heterocyclic carbene to the ruthenium replacing one tricyclohexyl phosphine on the ruthenium with a carbene, then the catalyst turns out to be much more reactive, much more useful and presumably the electron density on the ruthenium is increased. It is also true that you have large aryl groups which protect the ruthenium center from unnecessary reactions and decomposition. Now, all three of them published this about the same time, but following this initial result Grubb's showed that if you replace the unsaturated n-heterocyclic carbene in the present system, you have an unsaturated heterocyclic carbene. If you replace it with the saturated variety of n-heterocyclic carbene, then it turns out that the reaction is much much better. The variety that Grubb's made actually had simple methyl groups to protect the aryl to give steric protection to the ruthenium and you have a stable ruthenium complex. In fact, you for the sake of our understanding, we will convert that single bond into a double bond because we normally talk of this as a carbene and the carbene coordination to the ruthenium is the one that promotes the reactivity of this center. During the course of this reaction, it is usually P C Y 3 which leaves and generates a vacant coordination site on the ruthenium. In general, if you want a catalyst to function, in the resting state you would have a ligand, an extra ligand which leaves and generates a vacant coordination site which initiates the reaction. Grubb's published the synthesis of this compound and its reactivity just a few months after he had published the unsaturated variety, but it was very clear that the unsaturated variety was the most active form. So, it became what was called popularly as a second generation Grubb's catalyst. The second generation Grubb's catalyst turns out to be a lot more reactive, stable and useful for carrying out metathesis reactions. Now, during the course of this study, if there were other attempts to modify the N-heterocyclic carbene in such a way that it would give you a system which would generate a very reactive catalyst and this time mentioned should be made above the Hovayda Grubb's catalyst. This was a combination of the Grubb's catalyst system. Basically you had an N-heterocyclic carbene which was a saturated variety and you also had a carbene which was the essential reactive component of the metathesis catalyst, but the P C Y 3 was replaced with a pendant group on the alkylidine such that it coordinated to the ruthenium and blocked that site. So, the vacant coordination site at the ruthenium was very readily generated by loss of this R U O bond. So, this R U O bond was lost initially and that led to a reactive form of the catalyst. Now, this turns out to be a little more useful it is less reactive, but it is more stable because of the internal coordination of the alkylidine. So, when you design a catalyst, it is very important that you design a catalyst that is as reactive as possible, but at the same time it has a long shelf life and that is what we consider by more stability. However, these two things are very often working at cross purposes because if you make the complex very stable then it will be less reactive. So, let us proceed further after Hoverida made this modification for the Grubb's catalyst. The Grubb's second generation catalyst was the one which was most useful, but it was not very reactive. Grubb's showed that if you replace the pendant group with a pyridine unit, a substituted pyridine and if you react the Grubb's second generation catalyst with pyridine, specifically broma pyridine then it turned out to be an extremely useful catalyst. It was extremely reactive. In fact, it initiates metathesis a million times faster than the second generation catalyst. This like I said earlier, it turns out to be an extremely important fact for polymerization. If you do polymerization, metathesis polymerization, which we will talk about in a few minutes, if you do metathesis polymerization and if there is a long initiation time for the catalyst to start functioning, then you will end up with polymers with a variety polydispersity which is undesirable. So, it is important to have as low a polydispersity as possible. That means the molecular weight range is very small. Then you get much better polymers with better physical characteristics. So, it is important to have a catalyst which is extremely fast, which has no lag time for the initiation of the reaction. So, this catalyst which is called the third generation catalyst is an extremely fast catalyst, which initiates metathesis a million times faster than the second generation catalyst. Now, let us take a look at Schrock's design. Schrock was a person who was working with early transition metals and high oxidation state carbene compounds. If you remember, the metathesis catalysts that were initially designed, that were known in the patents, were all early transition metals oxides or chlorides, which were activated with an alkylating agent. Either a tin or R 4 tin compound or it was an AL R 3 compound, something that would alkylate early transition metal. So, Schrock's design is quite natural. It starts with a molybdenum species, which is there in the high oxidation state. He showed that if you take a carbene, a Schrock carbene, which surprisingly has no hetero atom to stabilize it. If you take the Schrock carbene and if you attach to alkoxide units, then it can function as a metathesis catalyst. But surprisingly, the alkoxy groups which are attached to the metal have to bear some electron withdrawing groups. If they are not electron withdrawing, then they are not as reactive as one would like them to be. So, the Schrock's catalyst, the most celebrated form of the Schrock's catalyst is what I have shown here. This has got two trifluoromethyl groups attached to the tertiary butyl, tertiary butoxy unit that is attached to the molybdenum. This is a Schrock's catalyst, which turns out to be the most useful form of the catalyst. It has got an alkylidine group. So, M double bond CH2 is still the basic unit, which is the catalytically active unit for metathesis. That remains common for both Grubbs's catalyst and Schrock's catalyst. The only difference is the fact that the molybdenum catalyst that is the basis for the Schrock's catalyst has got two alkoxy groups, which are electron withdrawing in nature. Now, Schrock's catalyst also had another advantage and that advantage is shown here. That is the fact that you can generate a chiral Schrock's catalyst. Now, if you remember, the catalyst center has got two alkoxy units and binol, which has got an axially chiral molecule, which means that there is no single carbon, which bears a asymmetric unit. The chirality comes from the fact that you cannot rotate these molecules around this carbon-carbon bond very easily. So, the chirality resides in the fact that these two planar rings are oriented in such a way that they have a helical axis to them. So, now you have two alkoxy groups. This is the binol unit, which is attached to the molybdenum and it bears a chirality at the molybdenum. Now, if you can do a catalysis using this alkylidine unit, the molybdenum center, which is carrying out metathesis always has a chiral center. So, whenever you have the possibility for generating some stereo selective carbon-carbon bond formation, then it would be possible to do it in a selective way when you have this chirality or this handedness on the molybdenum center. So, the grubbs catalyst at the moment at least the ones that I have shown you do not have the chirality inbuilt in them. Whereas, the Schrock's chiral catalyst has this major advantage in that there is a chiral center, which is attached to the molybdenum and which is retained right through the reaction. So, it turns out to be an extremely useful center for inducing chirality. So, let us see how these systems are being used. So, we have discussed the catalyst in detail, but in all the cases it is only the M double bond CH2 that is really important for carrying out the reaction. So, it is only the M double bond CH2 that is a catalytically active center and whatever we have described, the rest of the paraphernalia that is attached to the metal purely provides assistance in terms of stabilizing the molecule, stabilizing the catalyst or providing the right electronic input into the metal so that the catalysis can be carried out. So, let us go to the actual examples where reactions can be carried out. I would call self-metathesis as a first example. Suppose you just have two alkali-dene groups which are identical and you carry out metathesis, you would end up with reactants and products which are the same. I would call this self-metathesis and there is no thermodynamic loss again in this whole process and there is no effective reaction also. So, it is not of great utility to have the self-metathesis. So, the more useful reaction is the one where you have cross metathesis. Now, let us imagine the extreme scenario where you have four different alkali-dene groups attached to the olefin. So, in other words two olefins are undergoing metathesis and there are four different alkali-dene groups. I have labeled them as A, B, C, D which means A is one alkali-dene group B is a different alkali-dene group. Similarly, C D is a different olefin. Now, you just imagine the metathesis reaction carried out in this case will lead to almost 10 different olefins because the alkali-dene groups unless they have very strong electron withdrawing or donor groups on them, you will not have a major difference in the delta H of this reaction goes from left to right after metathesis. So, if you have A A, B A B, A C and A D, they are four different olefins that can be generated starting with the alkali-dene group which is A attached to the alkene and then it is transferred to the metal and then it can be transferred to any one of the other olefins. Similarly, you can write out the remaining number of olefins that can be generated with each one of these alkali-denes and you will realize that there are 10 of them. So, 10 different alkenes can be generated. In the event that the alkali-dene is symmetrical, you will have only 10. If you have an unsymmetrical alkali-dene group which means that you have let us say C H 3 C H group. So, if the alkali-dene for example, has got this type, this is the alkali-dene group that we are talking about, then you can have both cis and trans olefins generated from this alkali-dene. So, a maximum of 20 alkenes can be generated just starting with two alkenes and four alkali-dene groups. This is the maximum that can be generated starting with four different alkali-dene groups. So, now let us take a look at how one can utilize such a reaction which leads to a complex mixture of 10 alkenes or 20 stereoisomers. How can that be of any use? So, this is something that we need to consider. Very often the cross metathesis reaction which is what we are talking about when you have different alkali-dene groups is designed in such a way that it will give us only the product which is of importance and the other product is conveniently eliminated from the reaction mixture either because it is volatile or in such a way that it can be isolated very easily. So, let us take a look at this reaction which I have indicated here whether it is cis or trans alkene if you can combine it with ethylene let us say and carry out a metathesis reaction. I have indicated the metathesis catalyst as alkali-dene as a carbene metal carbene unit. In principle it can be either a shock catalyst or a grubbs catalyst, but in this in the case of olefins very often it is convenient to just take the more readily available and less air sensitive grubbs catalyst and carry out the reaction and one will end up with these two alkenes during the course of this reaction. If you want to control this reaction in such a way that I want to make only the alkali-dene only the alkene which is pictured here I can push this reaction to the left very simply by allowing the ethylene to escape from the reaction mixture. So, the Lysiatelius principle will be operating and one would go from the right side of this reaction to the left side and ethylene would be allowed to escape. Suppose I want to split a very large olefin which has got say C 18 olefin which has got the double bond in the middle and I want to convert it into two olefins which are smaller in size then I can just have a high pressure of olefin. So, if I control the concentration of ethylene I can move the reaction from left to right. If I increase the ethylene concentration I can very simply make the smaller olefins and move the reaction from left to right. So, this turns out to be a useful way of controlling the metathesis using the Lysiatelius principle. It is also known that there are some electronic factors which control the reaction. Here I have shown an example where I have an electron withdrawing group on the olefin in which case then the reaction turns out to be useful if I have more amount of this electron withdrawing group attached to olefin which is marked as this aldehyde the substituted butyl aldehyde here and that is taken in a slightly larger amount. You will notice that this can again end up with elimination of the two CH 2 groups and ethylene is eliminated during the course of this reaction and very conveniently you have generated a useful aldehyde which is now having a much larger molecular weight. And you will also notice that although you had an unsymmetrical alkylidine group. So, in other words this alkylidine could end up with both cis and trans you will notice that this reaction mixture ended up with the e by z ratio that means the trans compound the trans product was formed in a ratio of 20 is to 1 for the cis compound. So, this turns out to be a very easy way of generating starting with here I have shown this reaction was done with the Grubbs second generation catalyst and you ended up with a 92 percent yield just by adding two equivalents of the aldehyde that you started out with and you ended up with an aldehyde which is more useful and in 92 percent yield. So, this was carried out with Grubbs second generation catalyst and it allows for a reaction where you have an aldehyde as a substituent. Now, a similar reaction with a modified Grubbs second generation catalyst here again you get an silil substituted alkene and this can also proceed from one side to the other side purely by removal of ethylene from the reaction mixture and you end up with as 81 percent yield of the desired product and a e by z ratio of 11. So, in all these cases ethylene the amount of ethylene that was used was a amount of ethylene that was removed from the reaction mixture was key for pushing the reaction from left to right and generating the product that was useful. So, here I have shown you another example where you ended up with a useful product 80 percent yield again with Grubbs first generation catalyst is only 5 mole percent of the first generation catalyst very mild conditions you can convert the compound which is of use in this particular case it is the side product is a product that is reasonably volatile and can be removed from the reaction mixture. So, you can see that least at least principle is a key for generating useful products. So, you can also have some steric effects during the course of this reaction. Now, you will remember that olefins have a tendency to coordinate to metal atoms to a lesser extent when they are substituted. So, since the olefin has to be coordinated to the metal during the course of the reaction the reaction works well when you have less substituted olefins. Here I have shown you the first step in the whole metathesis process and that is the formation of the elimination of the alkylidine group which is attached to the ruthenium center on reaction with the starting material. So, here I have biased the reaction in such a way that I end up with only the substitution initial substitution of the alkylidine group on the ruthenium. So, if you look at the rates of these reactions at the rate at which the reaction proceeds this reaction proceeds from left to right you notice that if I have a single substituent on the ethylene so that is the fastest that proceeds at the rate of say 100 arbitrary units then the moment you have 2 substituents on the olefin in a cis position then the reaction slows down by almost 10 orders of 1 order of magnitude it comes down to 10 relative units. And similarly if you have a heavily substituted alkene and if you have a trans substituted alkene then the reaction falls by another factor of 2. So, you can see how the reaction goes slower and slower as you have greater and greater number of substituents and the cis substituent is substitution pattern is better than the trans substitution pattern. And this turns out that if you have a heavily substituted olefin especially one with a phenyl group so if you have a styrene then the reaction is practically virtually non-existent with when you have the grubs first generation catalyst. So, this gives you an idea about how it is important to have very reactive olefins and if you want to carry out the reaction in a fast manner. So, there are various ways which allow you to control the reaction and these are used very effectively for doing cross metathesis. Now, we come to a special class of reaction which is called ring closing metathesis reaction. The ring closing metathesis reaction is a special case when the two olefins which are undergoing metathesis belong to the same molecule. So, if I have two double bonds which are positioned in such a way that you can eliminate two alkaline groups and form a ring. So, basically what we are doing in this particular case is we are eliminating these two CH2 groups we are eliminating these two CH2 groups and forming ethylene. And as I told you earlier elimination of ethylene is very often a convenient way of pushing the reaction from one direction to the other direction. So, this itself drives this because ethylene is a volatile species which can be eliminated from the reaction mixture. More than that the reaction is entropically favored by having the two groups which are joining together form a single molecule. So, in other words two different olefins are not formed a single olefin is formed and that leads to a five membered ring which is entropically very favorable. This is a five membered ring which is formed and the new bond that is formed in between these two carbons turns out to be a very favorable situation. So, Grubbs first generation catalyst is convenient for carrying out these type of reactions. And you will notice that E is actually a electron withdrawing group and very often it is it is C O O E T or C O O M E. And this you will recognize as a species which is coming from a dialkylation of diethyl malanate. So, if you take CH2 C O O M E C O O M E di methyl malanate and you alkylate this active carbon then you will end up with this particular starting material. And it is a very convenient starting material and you can generate this five membered ring very readily using a ring closing metathesis reaction. This turns out to be useful and it can even be done with larger size ring not necessarily with a five membered ring. And once again Le Chatelier's principle is utilized so that you can remove ethylene and form a very nice ring system. Let us take a look at the mechanism of the ring closing metathesis. Why is it that it is so convenient to carry out the metathesis reaction? I have color coded the alkylidine group which is present on the ruthenium to start with. And you will notice that the replacement of this P C Y 3 on the ruthenium with the olefin from the starting material or the reactant led to a ruthenium alkylidine alkene complex. This is a key intermediate. Now, starting with a ruthenium 2 center you end up with formally a ruthenium 4 center. Here you carried out what we call as a oxidative coupling reaction where the ruthenium undergoes formal oxidation. And you have coupled two carbon centers basically the two carbon centers which are coupled are marked here in the dotted lines and so you end up with a new bond which is a metallocyclobutane a ruthenium metallocyclobutane is formed. And this ruthenium metallocyclobutane can now break in a different fashion. Earlier you had the formation of you had the formation of a new carbon carbon bond between this CH 2 group which was coming from this starting material. And the alkylidine alkylidine group which is present on the metal. Now, I can eliminate this alkene I can eliminate this alkene and I shall show it in a different color. So, that you can follow it very easily I break these two bonds and form a new carbon carbon double bond. If I form a new carbon carbon double bond then I end up with this product is eliminated. And I have an alkali alkylidine group where the starting material is now coordinated to the ruthenium. I have an alkylidine group which can now carry out another metathesis reaction. Now, with this olefin which is attached to the same molecule. So, an alkylidine group which has got an alkene inside as an internal reactant turns out to be a very fast reaction. And that is what we have written here. Now, we move this CH 2 double bond to this position. If you move it to this position then you end up with a cyclic intermediate and the cyclic intermediate once again forms a bond. This time the ruthenium carbon bond is formed here and the carbon carbon bond is formed here. The new carbon carbon bond the metal now again goes from plus 2 to plus 4 oxidation state. And this can now eliminate can break in such a way that you form R U CH 2 as a final as a catalyst again as a regenerated catalyst and the cyclic product which is listed here. So, we can write these two systems together. Now, I will start with the R U CH 2 which I generated in the previous reactant step. Now, we can go through the catalytic cycle fast. You have the formation of a metallic cyclobutane which is listed here. And it can eliminate cyclo pentene which regenerates the catalytically active intermediate. So, this is the mechanism of the ring closing metathesis. This is the mechanism of the ring closing metathesis. Now, you will notice that the same reaction can be pushed in the opposite direction if you have a large amount of ethylene. Suppose, I have a high concentration of ethylene. If I have a high concentration of ethylene and I take the ring closed product then I can have a ring opening metathesis. So, this is called ROM. The previous one is called RCM and this one is called ROM ROM and the ring opening metathesis can push the reaction from the ring closed system to the ring open system. Now, exactly the same reaction can go back. The same steps can be retraced in order to generate this product. In this particular instance, this is the product. So, you can realize how the reaction can be used to very effectively go from one direction to the other direction in a very effective fashion to generate a wide variety of static materials and products. So, once again I can take the reactant which I had shown you earlier which is the diethyl malonate which has been alkylated, dialkylated using two allyl groups. That again is an easy step. If I take these two diallylated species, I can in fact eliminate ethylene once again. From two different molecules, now that will lead to a new diene. This time it will be actually a triene. It is a triene because you have generated a new double bond in the process. So, two dienes come together and form a triene. Now, you will realize that you can keep adding these molecules together in such a fashion that you can form a polymer. So, I can remove two CH2 units from one of these molecules and another one of the starting material and lead to a polymer. So, this is a polymerization reaction which is executed through metathesis. In each step, ethylene is eliminated and because ethylene is a volatile molecule that can be quickly removed from the reaction mixture and you can have a very efficient way of polymerizing diene. So, this is called acyclic diene metathesis polymerization. Acyclic diene metathesis polymerization is a system where you eliminate ethylene from a diene molecule in such a way that you form a polymeric molecule. How do you push the reaction? The same reactant has been used for three different reasons. One is to do ring opening metathesis, another is to do ring closing metathesis, another is to do acyclic diene metathesis polymerization. So, here the concentration of the diene is a key. Concentration of the diene if it is very high, then the polymerization results and if you remove ethylene during the process, then you can very effectively make a large high molecular weight polymer starting with an acyclic diene. If you add a lot of ethylene to a cyclized product, then of course, you can go from the ring closed product to the ring open product. So, you can push the reaction in different directions based on the concentration of the reactant which is there. Polymerization is a competing process whenever you do ring closing metathesis polymerization or a ring opening metathesis polymerization. So, the lower concentration always prevents polymerization. If you have a large amount of the diene, large concentration of the diene, then the possibility of the diene reacting with itself is higher and that of course, leads to polymerization. If you have high temperature, then the ring opening and the elimination of ethylene is promoted because delta S t, delta S increases in the process and you can have larger free energy change, negative free energy change. As a result of the reaction, so that would be a more favorable process when you have the reaction proceeding in a forward direction. That means you have ring closing during the whole system. If you remove ethylene, of course, you want to do ring closing reaction. You should remove ethylene from the reaction mixture, so that it does not come back and compete for the reaction. So, you can see that how this particular metathesis reaction is extremely useful and it has been used extensively for the synthesis of a variety of natural products. The natural product synthesis, especially for unusual ring systems, has been conveniently accomplished using the metathesis catalysis. Here, Schrock, the Schrock catalyst has been used very effectively. You have two reactive groups. You have an amide functionality which is present here and you have a ether functionality and in the presence of these functionalities, if you want to do a metathesis reaction, it is convenient to do it with the Schrock catalyst. The Schrock catalyst carries out this whole reaction in 95 percent, in 98 percent yield and if you, but you need a large amount of the catalyst for this whole process to function. Nevertheless, this is a very efficient way of making such a large ring natural product and very effectively you can generate the ring system and a ring recent synthesis of another natural product, manzamine, manzamine A which has been isolated from a marine organism is shown here. This was accomplished by a ring closing metathesis in the presence of very labile functional groups. This is a very complex natural product with so many ring systems and in spite of all that, the reaction could be carried out and Fukuyama and co-workers have recently published the total synthesis of such a complex natural product. The last step is the ring closing metathesis which was accomplished which led to the generation of this chiral natural product being synthesized very efficiently. So, with this I would like to end today's lecture. I will show you some of the key options. So, we will summarize today's lecture by saying that metathesis requires a carbene complex. It can also be carried out with a carbene complex with acetylenes. We have not discussed this in today's lecture, but it is also possible. The most important point to note is the fact that there is non-pairwise exchange. This non-pairwise exchange means that you will have a plethora of products in this whole reaction. In order to carry out this reaction effectively, you need to utilize thermodynamics to the health. So, if you have to use Lysiatoly's principle, that is the most important principle that can be used to advantage. In order to push the reaction in the direction in which you want to carry out the whole push the reaction from the reactant to the product side, you have to utilize Lysiatoly's principle very effectively. Temperature and concentration also are important when you have to carry out polymerization reactions. You can utilize the whole thing with efficiently when you use high temperatures and T delta S is large. So, you can push the reaction to the side in which you want to carry out the reaction efficiently. So, the metathesis reaction, although it seems to be such a non-specific reaction, it generates a large number of products very easily. You can use it very effectively if you remember that the importance of, if you remember the importance of thermodynamics, you can push it in the direction in which you want to proceed. So, in the case of carbines, you can use the reaction with acetylenes and you can generate metathesis of carbines and that leads to acetylenes, polyacetylenes which are very difficult to make otherwise and you can make very interesting materials which we shall cover in a future talk.