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Hi welcome to this tutorial on paracetamol synthesis so this is a structure of paracetamol it’s a phenol group here and in the para position we have an acetamide that’s why sometimes it’s referred to as acetaminophen in the us but in the uk we call it paracetamol because the um it’s a para acetamide uh phenol group but these are these are just uh common terms
For the same compound okay so that’s paracetamol a very common analgesic and we’ll have a look at how we can use the freeze and the bacon rearrangements to synthesize this molecule so first of all we’ll draw phenol that’s phenol and the first thing we need to do is sterify it with an acetal group so we use acetic anhydride we use aluminium chloride as the lewis
Acid in this case so the freeze rearrangement actually uses a lewis acid and it can go in the ortho or the power position so this is uh acetic anhydride that’s an acetar group there and that’s acetic anhydride i just got an oxygen in the middle so it’s just a very good source of the esl group so we’re going to put on the female i’ll just get rid of them okay
So first thing to do is stir-fry the phenol so basically we’re going to make that let’s just get rid of that so here’s the mechanism the first thing to do is actually activate the acetic anhydride with the lewis acid and the most available oxygen lone pairs are on the carbonyl the so they’ll coordinate into the lewis acid aluminium chloride in this case making
It susceptible to attack of that carbonyl carbon and you just get a quick rearrangement and the acetal group goes on quite nicely here’s a structure so we’ve got our uh methyl ester there now we just need to sort out the charge so we go all the charges are balanced i just need to sort them out a little brought on to the solution we’re in acidic conditions
Anyway so that’s perfectly acceptable and that gives us the acetal group so the next stage is the freeze rearrangement as you can see here so let’s just draw that structure out again let’s draw the ester out again we still will continue to use the aluminium chloride as the lewis acid and basically we need to activate that ester and we’ll do that by coordinating
To the aluminium chloride like that just put a bond in there i’ve used kind of a dare tiff bond because it’s gonna it’s gonna rearrange a little bit over there so that oxygen coordinate though giving the electrons back to the carbonyl oxygen so you get the activated species so it’s a bit like activating the phenol now no one’s too sure about how this mechanism
Pursues there’s been quite a lot of mechanism studies and um i urge you to have a look at the uh tutorial on the free use rearrangement i don’t think it’s up at the moment but it should be up pretty soon it’s quite an interesting reaction to uh investigate from a mechanistic point of view so basically the uh the activated complex collapses like that and you get
A rearrangement i’ve drawn it in this in this fashion here but the actual carbonium in the from the carbonyl actually still coordinates to the benzene ring so it doesn’t doesn’t quite leave the vicinity and you prefer to either go on the author or the power position depending on the temperature really so we just adjust the temperature to make it go in in the
Right position and then all we’ve got after the rearrangement is re-aromatization so we’d lose that proton there that indicated so the next stage after that is formation of an oxymoron in order to do that we use uh hydroxylamine have we got here in acidic conditions so that that carbonyl should be protonated first actually so it’s an activated carbonal which
Then gets attacked with the hydroxylamine now hydroxylamine is actually a very strong nucleophile because it’s got um the oxygen next to it it’s called the alpha effect and i’ll do a tutorial on that and all we’re doing now we’ll just very quickly uh we’re just gonna um condense the product to lose water here so the overall aim is to lose water as a leaving
Group and give us our oxime and we do that in a series of protonation steps so the first one was performing the tetrahedral into media and now we’re going to protonate the hydroxide from the carbonyl and then the nitrogen lone pair will push out water just like this here we go and then all we’ve got then to do is sort out our um charge so if you see here we’ve
Got the protonated oxime in order to isolate that and have it in our hands if you will just need to neutralize it it gives the oxy there okay so that’s that’s how we make the aux seam just make that red so we can see it okay so that we’re nearly there now you can see he’s almost got the the shape of uh paracetamol we’ve got the uh airsound group in the form of
An oxy now so this is when we come on to the second stage of the i’ll just get rid of these come on to the second stage of the rearrangement synthesis of you all which will look at the beckman rearrangement i need you to have a look at the beckmann rearrangement tutorial it gives in a bit more detail than we’re going to do here it’s a very good rearrangement of
Box seams so the final stage now is batman rearrangement so again we’re in the city conditions we’re just going to protect the water or sorry the hydroxy group of the oxime to give us a good leaving group in the form of water now i’ve cheated a little bit you might might notice the uh uh the hydroxy groups i’ve gone trans to the phenol group there and that’s
So i can do the mechanism this way it’s always going to be an equilibrium there’s going to be a mixture of the sisoid and the transoid form of that oxy uh but it’s going to be the transoid form that will migrate so the phenyl group will migrate out of the greater migratory aptitude um because of the electron density around that carbon atom there so we’ve lost
Water we get this uh nitrilium iron if you will and then it’s just a matter of water coming back so water comes back i’m just going to draw the the resonance form here showing that it’s reasonably stable polar intermediate there because the nitrogen lone pairs will stabilize that group and it doesn’t matter which which one you attack you can either attack the
Positively charged vacant orbital on the carbon they have carbon to the nitrogen or you can attack as i’ve done here on ah acetylene type of carbon and that gives you this species here which still looks quite similar to the oxen and just sort the charge out but if you uh if you’re familiar with amis and and how things tautomerize then you’ll recognize that
That’s actually just a tautomer of uh an air mite so we just all we need to do there is rearrange that tautomerism rearrange that to the more stable form which is the double bond on the carbon and the oxygen to give you a carbonyl and that gives us our acetamide product which is paracetamol so bye for now
Transcribed from video
Synthesis of Paracetamol (acetaminophen). A chemistry tutorial By chemtubeuk
