 Welcome back, in the last class we had looked at electrophilic catalysis, so we had looked at multiple interactions that lead to electrophilic catalysis. So you have electrostatic interactions, hydrogen bonding, metal coordination and acid catalysis. So acid catalysis we had already done quite a bit in detail, so we had focused on the first three and you would see that in biology or in nature enzymes use all of these together to catalyze reactions. So we had looked at examples of enzymes and we had also looked at some metal based catalysts and mimics of enzymes that are shown here like this bowl shaped molecule and what is shown here is you have all these oxygens here in the lower rim of the molecule, a positively charged species can interact with all these oxygens via electrostatic interactions and you have this hydrogen bonding donor here which can again interact with the reactant which had a carbonyl group to catalyze the reaction. So this is an enzyme mimic, we had also looked at several examples of metal based catalysis. So in this class what we are going to look at is first nucleophilic catalysis. So in nucleophilic catalysis a nucleophile adds or binds to the reactant to enhance the rate. So shown here is an example, so what you can see here is you have a tertiary amine and this tertiary amine can attack the electrophilic center to give you a tetrahedral intermediate and then you have this coming in and kicking out the Cl to give you this intermediate. Now what you see here is if you compare your amine this is a good nucleophile, so it adds into the electrophilic center and once you form this intermediate you have a very good leaving group here. So this is a very good leaving group. So then when you have a nucleophile add-in there are two ways in which this helps it is a good leaving group and it also improves the electrophilicity at the center. So it catalyzes the reaction in two ways, one is by improving the electrophilicity and two is by becoming a very good leaving group. So typically you see a lot of tertiary amines being used for nucleophilic catalysis. So I am showing you an example here, so if you have an alcohol and you are reacting it with an anhydride to form an ester what is seen is in the absence of the catalyst the reaction takes quite some time. So now you have a catalyst here this is called as DMAP, so the DMAP helps in catalyzing the reaction. So I have shown you the generic mechanism on the top, so what I want you to do is press the pause button and then go ahead and write the mechanism for catalysis by DMAP. So let us see if you were able to get the mechanism correct. So you start with your anhydride, you have two lone pairs here, the pyridine lone pair is not conjugated with the aromatic ring, the lone pair on the other nitrogen but is conjugated with the aromatic ring. So you will have the pyridine actually attack the anhydride. So if you attack the pyridine lone pair, you again form this tetrahedral intermediate and now you have a positive charge here. So once you generate this intermediate as I showed in the mechanism above, this will leave and now what you get is, so now you have a more electrophilic carbonyl center here. So now your nucleophile can add in and what you see here is even initially if you compare oxygen versus nitrogen, nitrogen is a better nucleophile which is why your DMAP prefers to interact as compared to the alcohol. So now your alcohol will interact, again you form this tetrahedral intermediate and here again you see when the lone pair comes in, you have a better leaving group here. So then you get your product after one more proton transfer. So this is the mechanism of nucleophilic catalysis. Remember this is very different from pyridine acting as a base. So when pyridine acts as a base, it will abstract a proton, here it is acting as a nucleophile. So you see it actually attack the electrophilic center. So remember there is a difference between an amine acting as a base and an amine acting as a nucleophile. So now I will introduce you to one another interesting concept when you talk about nucleophilic catalysis. You must have come across the tertiary amine example before but this is a fairly interesting concept. So what you can do is you can use a Lewis base to increase the electrophilicity of a Lewis acid. So you must have studied several reactions where Lewis acids are used to improve the electrophilicity. For example of a carbonyl, if you have the oxygen coordinate with a Lewis acid, it improves the electrophilicity at the carbon center. So here what you are doing is you are improving the electrophilicity of the Lewis acid further by adding a Lewis base. D here stands for donor. So this is your base, this is your acid. So this can add in here. So what you end up generating is, so this will kick out one X from the Lewis acid and what you generate is a more electrophilic species. Now how is this actually used? So shown is an example here where you have your Lewis acid. So you have your Lewis acid here and here what you see is you actually have a chiral ligand. So you have a chiral ligand here. So this is your donor here. So once it coordinates with the Lewis acid, what you end up generating is a more electrophilic species. So this species can further coordinate to say a carbonyl group to catalyze reactions and actually this catalyst has been used for an asymmetric synthesis because you are using this chiral ligand as your Lewis base. So this is a very interesting concept where you are actually increasing the electrophilicity of the Lewis acid by coordination of a Lewis base. So now we will move on to the next type of catalysis which is covalent catalysis. Now in covalent catalysis the catalyst forms a covalent bond with the substrate. So in a way the examples that we had seen earlier using the pyridine and the nucleophilic catalysis examples there also what you see is you can also call that as covalent catalysis because your catalyst forms a covalent bond with the reactant, alright? So some of these different classifications that we had seen of catalysis you can see that you can have one catalyst belonging to more than one of these classifications, alright? So here is a very interesting example. Now what is seen here is you must have studied this if you have a species like this, right? And if you heat it in an acidic medium what happens? This is something you must have studied in your BSE. It can undergo decarboxylation, alright? So typically what is seen is to undergo decarboxylation an acidic medium is required and you need to heat the reaction. But what is seen is if you add a small amount of aniline the reaction can go in several hours at room temperature, alright? Or slight heating in some cases. So now what I want you to do is I want you to think of what is happening here? So what is the mechanism here to give you the decarboxylated product? So decarboxylated means you are generating the ketone from this substrate here, alright? So you can press the pause button and work out the mechanism. So let us see if you got the answer, correct? So now here your nucleophilic species is here, right? You have two electrophilic centers here and here. So you have these two electrophilic centers. This is more electrophilic so you will have the aniline add in here. So what you would end up getting would be this tetrahedral intermediate. Now after you do this addition I am going to skip over multiple steps. I think you will be able to write the mechanism yourself because we had done a similar mechanism earlier for generation of the iminium ion. So after this what you see is you will generate, you will generate this iminium ion, alright? So these steps of the mechanism you should be able to write, alright? So just to give you a hint when we had looked at deviation from linear free energy relationships we had done a similar kind of mechanism. So if you are not able to write it you can check back the lecture where we were looking at deviation from linear free energy relationships. So now that you have this here, this will come in here, these bonded electrons will come here and this will come here. So what you would end up generating would be, so you will be generating this, enamine, alright? Now for conversion of the enamine to the ketone if you remember our very first week we had looked at the mechanism for that so I will not write it again. So what you end up doing is you end up hydrolyzing this to give you the ketone plus aniline, okay? So you should be able to write this mechanism yourself. So if you have any doubts you can look at week one where we had done a similar mechanism when we were doing arrow pushing, alright? Hopefully by now you would not need to look back and you will be able to write the mechanism but if not don't worry you can go back and look at the mechanism and write this, alright? So now what you see is formation of this iminium intermediate improves the reaction considerably, alright? Because now you have a greater driving force for this elimination to take place. So the formation of this iminium adduct has been used quite a bit even in asymmetric catalysis. So a very nice example of where covalent catalysis has been used is in peptide synthesis. So peptide synthesis involves coupling of two amino acids to give you a peptide bond as shown on your screen. So you have amino acid one interacting with amino acid two. So amino acids are interesting because they have an amine and a carboxylic acid. So what is done is this PG is a protecting group. It blocks an amine on one amino acid and a carboxylate on the other amino acid. So these two are the only ones that can interact to form an amide bond. So if you had not blocked it then all of these could interact with each other. So imagine putting things together using Lego or blocks. So what we are ensuring is that only these two blocks can fit together, alright? The other sides of the block are capped alright or protected using a protecting group. So reagent which is used to catalyze this reaction it is called as a coupling reagent or an acid activator is the reagent shown here. You might have heard it as DCC. So it is dicyclohexyl carbodiamide and a base to give you the product. So now what happens is this reagent helps in catalyzing the reaction. So what I want you to do is I want you to again press the pause button and try to write the mechanism yourself or to simplify it what you can do is you can call this as AA1. So you need not write the whole structure COO- because again as I told you everything else is capped and then we can write this as AA2, alright? You need not write the whole structure. So go ahead and try to work out the mechanism for this synthesis. So let us see if you got the answer correct. So what happens is in the reaction medium. So here again if you have your amine plus DCC, now this can undergo proton transfer. So you can have the nitrogen here pick up a proton to give you the free amine plus the protonated DCC. Now this process is in equilibrium and actually you have a very small concentration of this in your reaction mixture but that is enough to catalyze the reaction. So once you have this you can have your AA1 carboxylate. Now what is your electrophilic center here? So what is the sink? It is here and you can push the arrows here. So then what you get is, so you get this intermediate, alright? Now what you see in this intermediate is you have improved the reactivity of this carboxylate, right? Initially you just had it as the O- so it was not as electrophilic for reaction of your amine. Also you did not have a very great leaving group. So here what you have done is you have made this center more activated. So this is how your covalent catalysis has worked, you have formed this covalent bond which makes your electrophilic center more reactive. So now what will happen is when you have your amine, so the amine will come here. Again it will form the tetrahedral intermediate. So what you will get would be and then you will have this leaf to generate, I will just write CY because I am running out of room here for cyclohexyl plus. So you have formed your amide bond and now with a proton transfer you will get both these products. So one is a urea byproduct and the other is your peptide, alright? So this covalent catalysis concept is used a lot in peptide synthesis. I have just shown you one reagent here which is DCC but many other such reagents have been used to catalyze this coupling reaction. So now we will move on and we will look at strain catalysis. For strain catalysis like the name suggests what happens is the substrate distorts itself upon binding to a catalyst and gets activated, alright? So distorts means there is some change in the structure of your reactant and this helps it get activated. So in terms of the reaction coordinate diagram one way for you to think about it is, so imagine that you have your reactant which is A, as it goes to your catalyst it forms a more strained complex. So what you are doing is you are getting a higher energy as compared to your reactant. So it looks something like this, alright? Now what happens is after this you have the usual thing, the formation of the product. Now here what happens is as it goes to the transition state probably there is a release of strain, alright? So what happens is the transition state is stabilized but your reactant is more strained. So this kind of catalysis works when the strain is along the reaction coordinate and leads to this increase in energy of the enzyme substrate or I have written enzyme substrate but you can also call a catalyst. So since we are looking at A, so this would be a catalyst A complex and this would be catalyst P. ESEP corresponds to enzyme substrate because this is seen very often in enzymes I by mistake wrote ES and EP but you can equate it to cat A and cat P or cat B actually since B is the product here. So what you see here is you have the enzyme substrate or the catalyst reactant being more strained at a higher energy but you have the transition state at a lower energy. So you have a net stabilization. So that is what I have written here saying that the substrate distorts itself upon binding to catalyst and gets activated. So again back to our old analogy we think about climbing a mountain here the substrate is going closer to the mountain by binding to this catalyst and the transition state is lowered in energy because this strain is released in the transition state alright. So let us now look at an example of this. So this is a classic example of mustard gas which was used as a warfare agent in world war and what you see is with mustard gas so it is known to interact with DNA proteins and how it works is you have this compound here and you have an intramolecular reaction so you have the lone pair on the sulphur which can come in and kick out the chloride. So what you generate is this strained species. Now this is far more reactive than a direct substitution here because now the strain takes up or increases the energy of the reactant. So remember the reaction coordinate we had seen earlier. So what has happened is it is increased the reactant so here this is essentially a neighbouring group participation you have not added an external catalyst but it just explains the concept of strain catalyzing a reaction which is why I have shown it here. So you have the strain molecule and what is seen here is if you add water to it so you will have it add in here and this bond will cleave. So what you end up generating would be OH plus HCl and this HCl is known to cause the damage to human beings. The other thing is it is also known to interact with other nucleophiles and you can also think of it because of its charge interacting with the negatively charged DNA backbone alright. So shown here is now an example of how strain can help increase the reaction rate alright. So here you have not added an external catalyst it is a neighbouring group participation. As I told you in the previous slide is seen a lot with enzymes and one such enzyme is lysozyme. So when you have dirt coming in or something in your eye you have these tears that are formed you see this in the tears and this helps in killing the bacteria and how it kills bacteria is it destroys its cell wall and its cell wall has this linkage shown here. So these two sugars connected by this which is called as a glycosidic linkage. So the lysozyme chops this glycosidic linkage and destroys the bacteria. So how this works is for this linkage to be destroyed in the mechanism what you need is you need these lone pairs to come in and kick out your other sugar alright. But what is seen is when it fits into the enzyme it takes up a half chair conformation. Now if you remember studying the conformations of cyclohexane half chair is a very high energy conformation compared to the chair. So now what you are forming is a more strained conformation inside the enzyme and because of this strain you are essentially decreasing the activation energy for this transformation and this strain the conformation not only helps in increasing the activation energy but what happens is once it is in the half chair conformation the orientation of the lone pair with respect to the leaving group is also more favorable for the elimination. So what you get is you end up generating this oxo-carbenium ion and the sugar which leaves out but the transition state actually alleviates this energy due to strain. So that is how you have the catalysis where your reactant has the strain but the transition state does not see the strain. So a lot of other enzymes also use this concept for catalyzing their reactions. The last example we are going to see is of phase transfer catalysis. Now this is used to extract ions from aqueous media into organic media. So if you remember when we studied solvent effects if you have charged species in a reaction medium organic solvents are not that great in solvating them. So if you want to get it to react with an organic compound which is highly insoluble in aqueous solutions you would need some sort of catalyst to take this reaction forward. So shown here is a classic example you have an alkyl chloride getting converted to a nitrile using sodium cyanide in water. Now you can heat this reaction for 2 days, 3 days does not matter the reaction does not take place because your alkyl chloride is not very soluble in water and it does not react with your CN minus which is completely solubilized in water. So what is seen is if you add this reagent which is a tetra alkyl ammonium salt this acts as a phase transfer agent and helps in doing this reaction in like 2 to 3 hours. So now you can see the extent of catalysis using this reagent and what is the mechanism? So if you consider this as water so this is the aqueous part and this is the organic part. So in the aqueous part you have P is your tetra butyl ammonium so this is your phase transfer catalyst we will call it. So this is your phase transfer catalyst. So what it does is because you are using cation here you have a counter ion CN minus and this can exchange with Cl minus also to give you P plus Cl minus. Now in your reaction you have your alkyl chloride in your organic layer so that is your RCl and what happens is because this phase transfer catalyst has it typically has alkyl chains which are little long like tetra butyl attached to it. So it has some solubility in the organic medium as well. So what it does is it takes this to the organic medium that is why phase transfer it can transfer the ion from aqueous to organic. So it takes it to the organic layer the reaction takes place and once the reaction is done so you have the CN minus attack and once the reaction is done you have this salt here so where you have your phase transfer catalyst coordinated to Cl minus and that is brought back again to the aqueous layer. And again this is in equilibrium so you can have this process go on. So this is one explanation for the mechanism. So another explanation is where in the aqueous layer you just have the ions at the interface is where you have the phase transfer catalyst sitting along with the Cl minus and CN minus and what it does is it takes this in the organic layer and now it does the catalysis. So this is an alternate mechanism but experimentally what you observe is the phase transfer catalyst is able to take these ions from the aqueous layer to the organic layer. So to summarize what we have done over the last 2 weeks when we studied catalysis we looked at reaction coordinate diagrams where we saw how adding a catalyst helps in lowering the activation energy of a reaction. We also looked at several types of catalysts. So we looked at acid catalysis, binding, electrophilic and in this class we looked at nucleophilic, strain, covalent catalysis and phase transfer catalysis. So over this entire 8 weeks you have gotten a glimpse of how you can write mechanisms and how you can devise experiments to understand or to confirm whether the mechanism you have proposed is correct. So in the very last lecture of this course what we will be doing is we will be summarizing whatever we have learned from week 1 to week 8 and hopefully that will be useful for you in your final exam. So thank you and see you in the last lecture.