paracetemol synthesis help

mackg

Hi folks! I am currently doing a project in college where I have to synthesise paracetamol from phenol. I was working with two methods that involve the nitration of the phenol with nitric acid to give a mixture of o and p nitrophenol. Unfortunately o is favoured by both reactions so my potential yield of the desired p form is limited and this is being further limited by what I believe to be the competing oxidation of the phenol in the presence of the nitric acid.

Does anyone know a way of limiting or ideally eliminating this problem? I can post up the full details of my methods if they would be of help. I have gone through nearly all the org chem textbooks in the CIT library and come up with nothing, only one book even mentioned the problem of the competing reaction, before that my project supervisor was of the opinion that the unwanted products (brown-black) were bi and tri nitrated compounds.

I'm really at a loss as to where to go next any help would be greatly appreciated.

SOL

I think when they do the synthesis industrially they just accept that you get 2:1 ortho:para product or there abouts, but since the starting material is so cheap it doesn't really matter.

If you are worried about over nitration, you can cool the reaction down and this should stop any multiple nitro products, or , you should be able to use conc sulfuric acid and 1 equivalent of potassium or sodium nitrate to ensure only mononitration.

can you post up the reaction conditions you are trying at the moment and maybe I can offer more help?

When it comes to separating the two products, apparently (I say apparently because I haven't actually done this) it is easy to separate them by recrystallisation because the para product is far more amenable to forming crystals.

SOL

Alternatively you could do a Friedel-Crafts Acylation to make the para acetophenone and then form the hydroxyimine and do a beckmann reaarangment, but you still have the ortho/para problem...

AaronEnnis

Can you post the full reaction conditions? Also, have a look at this

http://journal.kcsnet.or.kr/main/j_search/j_download.htm?code=B060720

mackg

Method 1.

Nitration of phenols under mild and heterogenous conditions

M Ali Zolfigol, E Ghaemi, E Madrakian

A suspension of 1.88g phenol, 4.40g NaHSO4.H2O, 1.7g NaNO3 and wet SiO2 (50% w/w, 4g) stirred magnetically at room temp for 30min in 20ml CH2Cl2.


Method 2. (I scaled this down from what's here by 10)

250g conc H2SO4 in 400ml water.

150g sodium nitrate added and cooled in an ice bath.

94g phenol melted with 20ml of water and added dropwise from a sep funnel maintaining temp at 20 degrees.

Stirred for a further 2 hours after the last of the phenol was added.

^Taken from the Vogel Organic Chemistry textbook.

When it comes to separation of ortho and para, the nitrophenols can be separated by steam distillation or by the addition of n-pentane as
the para nitro phenol is insoluble but ortho is soluble.

mackg

AaronEnnis wrote: »

Can you post the full reaction conditions? Also, have a look at this

http://journal.kcsnet.or.kr/main/j_search/j_download.htm?code=B060720

That's very interesting!! But what's the story with the microwave radiation? How do you do that?

AaronEnnis

I'm assuming it's a modified microwave reactor, but not every college will have one. I'll post back in a while with help on the reaction conditions.

mackg

@aaronennis the only oxalic acid I have access to is the dihydrate form. Do you know if that is ok?

AaronEnnis

Not sure man, as I've only ever gone the easy route and synthesised it from 4-nitrophenol bought in I reckon you'd need oxalic acid though, introducing a hydrate form of it can't help the yield in any way...

But SOL has the nail on the head regarding the amounts of Nitro reagent, and also the cooling is important - perhaps even a slightly sub-stoichiometric amount of KNO3/NaNO3 will solve the polynitration problem. Could be wrong though, as I'm mainly analytical these days, and haven't looked at synthesis problems in a few months..

mackg

Yeah it's dead handy from 4 nitro on! My problem is the main guys for organic in our college just retired which has kind of limited where I can turn for advice. I'm going to see how I get on tomorrow with the method you provided and see what type of yield I get out of idle curiosity if nothing else. That's quick as hell anyway so should be able to squeeze in another synth as well, maybe try the solid salts again but keep the reaction vessel cooled with ice water to see if that makes much of a difference!

If it all worked perfectly first time out it wouldn't be much of a project anyway would it? :pac:

mackg

mackg wrote: »

That's very interesting!! But what's the story with the microwave radiation? How do you do that?

Carried out this method just there! Looks like very good conversion but again product is brown as opposed to yellow/orange as described in the paper I could post a photo of the product of it might help?

SOL

Ever heard the phrase "colour means nothing in chemistry"?

Well I first heard it attributed to someone who is colour blind, but to a point he is right. When you are dealing with many compounds that should be pure white you can have tiny impurities that turn it deep black, even though you have a 99%+ pure sample. Araomatic compounds have a real nack for this, especially anilines...



More interesting then the physical form would be a specta of some sort. Do you have an NMR? Failing that, how does the TLC look?

What are you using to guage conversion?

SOL

Of course before anyone takes exception, colour is also really usefull for some reactions like seeing if a grignard has started or if you need to add more iodine or whatever. But when assessing the purity of most compounds colour is fairly irrelevant.

mackg

SOL wrote: »

Ever heard the phrase "colour means nothing in chemistry"?

Well I first heard it attributed to someone who is colour blind, but to a point he is right. When you are dealing with many compounds that should be pure white you can have tiny impurities that turn it deep black, even though you have a 99%+ pure sample. Araomatic compounds have a real nack for this, especially anilines...



More interesting then the physical form would be a specta of some sort. Do you have an NMR? Failing that, how does the TLC look?

What are you using to guage conversion?

At the moment I have not determined conversion, I have been concentrating on different methods of synthesis and separation but still have been unable to isolate paranitrophenol. After steam distillation I have been able to isolate o-nitrophenol but the method I have used for the recovery of the para form from the distillation residue has failed.