 Welcome to the course on Transition Metal Organometallics in Catalysis and Biology. We have come to the 60th lecture or the last lecture of this course, and in this lecture we will be covering the remaining portion of our discussion, which we are talking about the applications of organometallic compounds in biology and then provide an overall summary of the topics that has been covered in this course. In the last lecture, we have looked into the scope of applications of this newly evolving applications of organometallics in biology and which is sort of now defined as the field of bio organometallic chemistry, and we have looked into the scope in terms of applications of these compounds in biology, and also we have started the discussion by looking into molecules, organometallic molecules that are present in nature, and the discussion started off with two molecules, two vitamin molecules to be more precise, vitamin B12 that contains a cobalt carbon bond in terms of methylcobalamin as well as in terms of another coenzyme B12, which is also derived from vitamin B12. We have looked given a detailed description of the structures showing the presence of organometallic compounds. Now proceeding further, we are going to talk about another interesting enzyme, which is called methyl coenzyme M reductase or popularly known as MCR. Now these MCR functions via intermediate that is supposedly be proceeding by the formation of a nickel methyl bond, so that is why the organometallic connection, so MCR has a prosthetic group of the coenzyme, MCR with the coenzyme converts, and the function of the MCR is that it converts methyl thioethyl, which is a coenzyme M, and the thiol. The reactants are thiol and the thiol, and the product is methane and hetero disulfide of coenzyme A and B, and what is important to the bio organometallic connection over here is a key intermediate containing a nickel methyl is supposed to be forming in the methanogenesis or methane production by this enzyme. So, let me show it further, for example, this is the thiol that has been spoken about, the thiol is of coenzyme B, and this is the thiol ether, which is of methyl coenzyme M. Now, these two react in presence of an enzyme called MCR to produce what is called methane and this hetero disulfide, this MCR uses the cofactor, which is called coenzyme 450, and the cofactor contains a big organic group as is shown over here, and inside it is a nickel in plus one oxidation state. So, this has been reported very recently in Nature 2010, volume 465606 to 80608, and request the reader to look up to get more knowledge about this particular enzyme. So, this enzyme converts this thiol ether and thiol to the disulfide along with formation of methane. Methane is formed from this methyl and this hydrogen to give this methane, so these are methane producing the enzyme, and it goes through a organometallic intermediate, which is shown over here. So, for example, this is the cofactor, which contains nickel one, and this is the thiol coenzyme B, as well as the thiol ether. So, nickel sort of gives electron and gets oxidized to nickel 3, and it forms a nickel methyl bond, and this thiol gets deprotonated and the proton is then subsequently absorbed on the thiol coenzyme M, which is shown over here, and then there is an electron transfer that occurs from the thiol to nickel 3, and nickel becomes nickel 2, and what you have over here is a radical cation, and the nickel to species with the anion in coenzyme B thiolate, so now this the methane attacks this hydrogen to eliminate methane, and in process this radical cation is attacked by the anion, which is shown over here, and as a result the formation of a radical anion is observed with nickel 2, and finally the electron transfer reduction of nickel 2 back to nickel 1 happens with the elimination of hetrodisulfide. So, this is an interesting very nice example, and the organometallic connection is the proposed nickel methyl bond, which has been suggested to occur, so this nickel methyl species is something which is formed in the production of methane by this enzyme MCR, which contains a cofactor coenzyme F420, so this is another enzyme whose intermediate is a nickel methyl bond, so we are going to now move on and moving to another important compounds, these are organo arsenic compounds, there is a drug called as Arcefenamine or Salversan, this is a drug for treatment of syphilis and Trimphono, so may I say, this is the first, this organic also is the first modern chemotherapeutic agent, so organometallic being used for pharmaceutical property, this is the first example synthesized in 1907 by Paul Elric's lab and then antisyphilitic activity was discovered in 1909, so now let us take a look at this molecule initially was thought to have arsenic-arsenic bond, but later on this structure was proven to be incorrect and the correct structure is supposed to be containing a arsenic-arsenic single bond in a three-membered or five-membered trimer or pentamer and this arsenophenamine is supposed to be a mixture of these two structures 2 and 3, so this is another organometallic compound which has direct metal carbon bond and are being used in medicinal purpose, so we move on to another interesting arsenic compound which is over here, it is an arsenic organometallic compound which contains a bond, but this was used for negative purpose actually used as a poison gas in the first world war and these are lung irritant and contains like you know leads to blister formation and then, but this is also used as a poison organometallic compound being used as a poison, so this is this arsenic compound and then as a remedy antidote to this ligand which has this diethyl ligands were developed as a antidote to get relief from this arsenic poison gas which was done in world war, so here we see the applications some benign some good and some bad applications of organometallic compounds another use of organometallic compounds is with mercury, so these are organometallic mercury compounds which are despite being toxic, they have been used in medicines in ancient time and here are two mercury compounds which mercury chrome and mercury phthalate, these are organometallic compounds which contains metal carbon bond over here and they are used as local mild antiseptics, so here we see a organometallic compounds of mercury being used for antiseptic purpose, so we have also talked about the applications in medicines and one important area of organometallic applications is this radiopharmaceuticals, so organometallic compounds are used for radiopharmaceuticals, this field is highly technical and is developing fast with various technology like positron emission tomography or single photon emission computed tomography and so on and so forth are taking the front set, so the organometallic connection is about the use of radio organometallic compounds for detection and imaging purpose for this and in this compound some common radioisotopes are shown over here whose organometallic compounds are often used and technetium is one such important radioisotope and the compound which has bearing for our discussion at this moment is this isonitrile complex of technetium which are used for radiopharmaceutical purpose and this is marketed by DuPont with a trade name called Cardiolite and this is used to detect coronary artery disease, so heart disease and stuff has a application from organometallic compound of technetium, so with this we come to the end of our sort of coverage for the bio organometallic chemistry, so applications of organometallic chemistry in biology and let me just summarize that we have started off by looking at the field of bio organometallic chemistry, how the field has evolved in various directions from the presence of bio organometallic compound in biological nature to the use of bio organometallic compounds for medicinal purpose by imaging, detection so on and so forth and then we have started our discussion by looking at this vitamin B12 methylcobalamin and coenzyme B, then we have looked into this nickel cofactor for MCR activity and then looked into the organometallic compounds of arsenic and which are used for arsenic and mercury which are used for therapeutic purpose and then we have also looked into the technetium compounds for imaging purpose, so with this we come to the conclusion of our discussion of bio organometallic chemistry and now I am going to summarize what has been taught the topics that have been covered in this 60 lecture in this course of transition metal organometallics in catalysis and biology, so we started off in the beginning with repi synthesis repi synthesis followed by repi synthesis followed by types of repi reactions particularly metallative and conventional repi, the repi chemistry sort of revolves around the utility of acetylene which are obtained for the coal, so this is sort of like expansion of the coal chemistry or chemistry derived from the coal to other various compounds bearing functional groups, so to make evaluated chemicals out of the source obtained from coal and then these are of these processes are of tremendous industrial importance and mainly have been worked out by repi while you was there at BASF. Then we have looked into another interesting reaction which is metathesis olefin metathesis reactions, we have looked into their origin as well as mechanistic aspects and we had also noted that metal carbene are the important catalytic intermediates which carry out these catalysis and in that context we have looked into types of carbene, we have also discussed that this metathesis is not a singular reaction but actually engulfs a family of reactions and we have looked into various types of metathesis reactions that have been reported for olefins and their classifications in the topic of types of metathesis reactions, we have also seen that how the knowledge of metathesis reaction gets translated in alkyne metathesis and made a parallel completion of the reactivity of alkyne metathesis with the from the context of alkene metathesis and what we have noted that in alkyne metathesis the active species again is a metal carbene species which carry out the alkyne metathesis reactions. We have further discussed about the catalyst development aspects of olefin metathesis and we have looked into some special applications with regard to cross metathesis. Now, cross metathesis reactions are thermonutrile reactions and then there are conditions required with regard to driving the reaction forward. Many times it is the evolution of a small molecule olefin for example, ethylene which are formed as a part of cross metathesis that leads to the forward development of the reaction. We have looked into ring opening metathesis, the version of ring closing metathesis. We have also looked into alkyne alkyne metathesis as a part of it. Then there is this ring closing alkyne alkyne metathesis which in short is called enine metathesis. We have looked into this. After the metathesis we looked into another big reactions which are oligomerizations of alkenes and alkynes. In this we have looked into shop catalysis which is shell higher olefin polymerization catalysis. We have seen that how the shop development of the shop catalyst was an industrial problem which was developed for practical need, need-based development. That was three different reactions which involved olefin oligomerization, olefin metathesis as well as isomerization reactions. Three important organometallic reactions were put together for a singular goal of making some feedstock for detergent in the form of shop catalyst. We have also seen the development of evolution of olefin polymerization that started with the heterogeneous Ziegler-Natta system. We have also looked at the classification of these polyethylenes in terms of their texture, their properties, their hardness and their softness. That is a very important criteria. Then these properties were ranging from high density polyethyls, HDPE, then linear polyethylenes, then branched polyethylenes. Each of these structural changes would give different attributes to the overall polymer properties. There are catalysts which could exclusively synthesize this type of polymer. We have looked into the development of catalysts from the basis of organometallic reasoning and organometallic logic that led to the direct achievement of these individual polymer properties. In this context, we have looked into classification of polyethylenes. We have looked into mechanisms by which these polymers are formed like step growth and the chain growth. How does the molecular weight vary as one changes the polymerization method from step growth to chain growth mechanisms? We have also looked at this ethylene polymerization, polyethylene, the heterogeneous catalysis, which is this Ziegler-Natta catalysis. Ziegler-Natta catalysis is titanium tetrachloride TiCl4 diethylaluminum chloride, which is this system. We have looked into how this Ziegler-Natta system can be moved over from methylene to propylene. We have looked into various classifications of propylene depending on the orientation of the methyl groups, which sort of leads to the tacticity of propylenes, isotactic, atactic, syndiotactic. We have looked into the fallouts of the properties as a result of the toxicity. We have also seen how the catalyst can be changed, geared towards preparing polypropylenes of particular tacticity. Tacticity is an important term, which we have covered. The importance of tacticity and subsequent exploitation, the importance of this exploitation was rightfully realized by Natta. He has singularly developed this field of polypropylene with Ziegler-Natta systems. We have also looked into copolymerization. We have looked at out of two types, particularly the copolymerization between olefins and alpha olefins. There are two types of monomer and also we have looked into the copolymerization of ethylene with olefins with functional groups. There are a lot of challenges in this area, which we have discussed particularly one is that of selectivity, because the rates of homopolymerization of individual olefins are different as well as the functional group on the olefins tend to poison the catalyst that are used for polymerization. There are issues of selectivity as well as catalyst poisoning with surface of acutely while designing catalyst for such systems. We had also observed that how organometallic chemistry plays a big role in solving the problem. What we had seen that the problem of differential reactivity of olefins versus alpha olefins were more acute for heterogeneous Ziegler-Natta systems. However, for metallocene based homogeneous system, this differential activity of olefins and alpha olefins were not that acute. Hence, the catalyst development moved from multi site heterogeneous Ziegler-Natta systems to more well behaved and controlled metallocene homogeneous single site system. They were much effective for copolymerization of olefins as well as for copolymerization of olefins bearing polar functional monomer. In this case, another point to note is that these on developing catalyst for copolymerization with functional group bearing monomer moves on from early transition metal to that of the late transition metal, which are more electron rich. Hence, they do not get poisoned by the presence of functional group as to the extent that an early transition metal would do. We have looked in great detail the catalyst development in the copolymerization of olefins. Now, moving beyond, we have looked into the catalyst used for polycyclo olefins synthesis of polycyclo olefins. We have looked into two methods, which were used for polycyclo olefins. Then, the first method, which was just addition polymerization, what we had observed that the catalyst was chosen as such that the metathesis reaction was suppressed and only the polymerization reaction was utilized. In the second approach, what we had seen, we had seen that addition reaction using intermolecular and intramolecular alternate polymerization occurred that result in the formation of desired polycyclo olefins that too in a highly selective fashion giving a particular type of stereochemistry. Another important thing, while we discussed this polymerization, is that with the advent of the signal of polymerization, the focus of catalyst development had been mainly on group 2 metals, as the group 2 metals had been the one, which was extremely good for carrying out olefin and alkyne polymerization. However, when the field evolved to develop catalysts for copolymerization bearing polar functional monomers, the requirement shifted and the focus also shifted to producing catalysts from non group 4 or early transition metal catalysts for polymerization. In this regard, we have looked into lanthanide systems as well as nickel and palladium, which are late transition metals for olefin polymerization. In this context, we have looked into iron, nickel and palladium for the polymerization. After that, we moved into the bio organometallic aspects of this course, where we looked into utility of bio organometallics in biology. In the beginning, we noted the development of the field of bio organometallics, which is a highly evolving field. However, given the fact that it is only emerging, it still had made its footprint in several areas, ranging from imaging radiotherapy applications to sensing and so on and so forth. And we started off with the naturally occurring bio organometallic compound by looking into vitamin bitwell, particularly methylcobalamin and coenzyme bitwell, which does contain metal carbon bond in the nature. Now, this is counter-inputive and very interesting, given the fact that organometallic compounds are extremely moisture sensitive and water sensitive. And here, we have a biology occurring organometallic compound in the form of methylcobalamin and coenzyme bitwell, which carry out vital functions in biology. We have also looked into another interesting compound called methyl coenzyme M reductase, which with its nickel cofactor prosthetic group goes through an active species containing nickel methyl bond formation, which results in methane production. We have looked into the utility of various metal ions in biology as well as medicinal property of organometallic compounds. So, this is how we have spread the topic according to their utility in catalysis and biology. And with this, we come to the end of the conclusion of today's lecture, as well as the conclusion of this course. I must really acknowledge my heartfelt thanks for the teaching assistants. Both of them are graduate students here at IIT Bombay, Ms. Sreeta De and Ms. Shalini Tripathi. Both are extremely diligent, hardworking graduate students who had helped me tremendously in preparing the material for this course and they had been of great assistance. I must also acknowledge the whole of NPTEL studio team. They have been extremely diligent, hardworking and supportive in getting this recording done. I must start with Mr. Amin Sheikh, Mr. Tutsar Daspande, Mr. Vijay Kaderi, Mr. Devendra Parabh and Mr. Ravi Paswan. So, with this, I thank everybody involved directly or indirectly with the course. I also thank you for taking this course and for being with me in all through these 60 lectures. I hope this course really helps you in getting a better perspective of organometallic chemistry. Remember, in the beginning, I had said that this is an important area where about nine Nobel Prizes have been conferred in a span of 120 years of history of Nobel prize. So, that sort of highlights how important is organometallic chemistry in today's world. So, with this, once again I thank you for being with me in this course and I hope you had a productive time in taking this course with best wishes and good luck for your future endeavour. I conclude here. Thank you.