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Author: Subject: Picric acid from Paracetamol
rot
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[*] posted on 9-4-2006 at 00:51
Picric acid from Paracetamol


When Picric Acid is made from Aspirin (Acetylsalicylic Acid), the Sulfuric Acid in the nitration mixture breaks it down into Salicylic Acid and Acetic Acid, and then into Phenol and Carbon Dioxide, This is then nitrated. When ASA can be broken down into Phenol, is this also possible with Paracetamol? They're similar compounds, both are phenol derivatives. The reason is that for me Paracetamol is much cheaper then ASA based aspirin tablets.
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[*] posted on 9-4-2006 at 01:32


It should be possible, the nitrogen atom will get protonated by H2SO4, this will cause the bond break between the aromatic ring and the N-atom. The intermediate will be phenol and acetamide. Now the phenol can be sulphonated and then be nitrated, like in the classic picric acid synthesis.

I estimate the reaction to be like this:

.............................................H2SO4.........................+
HO-C6H4-NH-CO-CH3 <======>HO-C6H4-NH2-CO-CH3 <=>HO-C6H5 + NH2-CO-CH3

The dose in each tablet is 500-1000mg, the same as in Aspirin:)


[Edited on 9-4-2006 by hinz]
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[*] posted on 9-4-2006 at 03:06


This sounds very logic indeed...
The chemical name for Paracetamol is Acetamidophenol.
But when you add Nitric Acid (Or a nitrate salt for that matter),
won't the acetamide get nitrated as well and/or screw up the reaction?
/EDIT: I just did a little test:
I put one 500mg paracetamol tablet in 10mL hot ethanol, filtered it and let the ethanol evaporate. Added those crystalls to 4mL 70C Sulfuric Acid 96%, and added 1g Ammonium Nitrate in small portions keeping the temperature at 65C. The liquid got red and foamed up just like with Acetylsalicylic Acid, But unfortunately I got a runaway when dumping into water:mad:, But the principle is proved, now lets scale up and gimme some quantities!

[Edited on 9-4-2006 by rot]
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[*] posted on 9-4-2006 at 05:28


Isn't the hydrolysis of an acetanilidine supposed to yield the corresponding aniline? As far as I know, hydrolysis of paracetamol will result in p-aminophenol, not phenol. You can remove the amino functional group by a Sandmeyer reaction though.
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[*] posted on 9-4-2006 at 07:03


You're right Sergei_Eisenstein, the HN-CO-R group can't be protonated, since the electrons are delocalised over the carbonyl group:

..........................................+...........-
R-HN-C=O-R <===> R-HN=C-O-R

The same happens also at the acetyl-group, but the N-Atom is easier polarised than the O-atom, so I wonder why it works with Aspirin.

........................................+........-
R-O-C=O-R <===> R-O=C-O-R

If you have P.Sykes book:"A Guidebook to Mechanism in Organic Chemistry"(6Ed), watch at page 155. There I found this infomation.


[Edited on 9-4-2006 by hinz]
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[*] posted on 10-4-2006 at 05:33


I just found the following:

Quote:

The starting material for the commercial manufacture of paracetamol is phenol, which is nitrated to give a mixture of the ortho and para-nitrotoluene. The o-isomer is removed by steam distillation, and the p-nitro group reduced to a p-amino group. This is then acetylated to give paracetamol.


If the starting material is phenol, it should be possible to obtain phenol from paracetamol.

[Edited on 10-4-2006 by rot]
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[*] posted on 11-4-2006 at 10:09


Quote:
Originally posted by rot
I just found the following:

Quote:

The starting material for the commercial manufacture of paracetamol is phenol, which is nitrated to give a mixture of the ortho and para-nitrotoluene. The o-isomer is removed by steam distillation, and the p-nitro group reduced to a p-amino group. This is then acetylated to give paracetamol.


If the starting material is phenol, it should be possible to obtain phenol from paracetamol.

[Edited on 10-4-2006 by rot]

:mad::mad::mad:
So you start from phenol and by nitration you get nitrotoluens....spontaneous generation ex nihilo of a CH3- group in place of the OH...please think twice about what you expect to write before you post.

Also amides in acidic media will of course hydrolise except in very concentrated acids where it will form a salt.

With HO-C6H5-NH-CO-CH3 under conc HNO3/H2SO4 one might expect nitramide fomation, then fast deacetylation and reorganisation of the nitro group in ortho of the amino group then furter nitration of the ring and oxydation of the p-hydroxynitroanilin into nitroquinon ...The later might nitrate and oxydise further into polynitroquinon or to CO2, H2O and NOx.The acetyl moiety is also bad news because it wil oxydise. The general reaction is thus very promt to runnaway because of the great tendency of complete oxydation...
;):P:D:cool::)




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[*] posted on 11-4-2006 at 10:51


Maybe one thing to try is to sulfonate the paracetamol first, with 96% sulphuric acid, and then to isolate the intermediate sulfonic acid products. Maybe you get rid of the acetyl moiety that way, too. Then nitrate the resultant product, similar to a procedure with picric acid.



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[*] posted on 11-4-2006 at 13:26


I'm think that amides can't be protonated, since they can be used as a protection group in aniline.

Because aniline + some acid <==>protonated, inactivated aniline (phenyl-ring is positive charged, so no electrophilic attack is possible)

...............................H+..................+............+
C6H5-NH2 <=======> C6H5-NH3 <=> C6H5=NH2

And since R-NH-CO-CH3 can't be protonated, you add some acetyl chloride to the aniline and get phenylacetamide, et voila aniline can be attacked with an electrophile in acid media, because the acetamide group isn't protonated ay more=> no mesomeric positive charge on Phenyl group=>electros availabe for the electrophile.

Since Sykes wrote that the o/p nitration is possible with phenylacetamide, I assume the media is very acidic......
But maybe Sykes wrote bullshit or we're wrong.......

Attachment: Sykes p.155 (protonation of the acetamide group).doc (166kB)
This file has been downloaded 772 times

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[*] posted on 11-4-2006 at 13:50


So the ortho or para positions are attacked, in the presence of an activating group. Thing is, there are TWO activating groups, both in para positions.... so are all the respective ortho positions attacked? Probably not, because once an ortho position is nitrated, the corresponding meta-position will be disfavoured to nitration. Thus you should get a mixture of both 2,6 and 3,5 dinitro paracetamols, counted from the OH group.
I wonder if there's an easy way to remove the acetyl from the NH2 group....




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[*] posted on 11-4-2006 at 13:55


Para- Aminophenol from alkaline hydrolysis of paracetamol would be an interesting substance in itself, much more interesting than TNP, which you most likely cant make from paracetamol, no matter if you sulfonate it first or not.

How would one go about isolating p- aminophenol from the reaction mix (purified paracetamol boiled with NaOH)?
It is an amphoteric substance, so in basic media you have the phenolate, and in acidic media you have the hydrochloride...
Both are very well soluble in water... bad news for extraction.
Maybe the sulfate salt is sparingly soluble in water?
I'm wondering because aniline sulfate has low solubility in cold water, which allows for its easy separation from an aqueous solution in this form.
But the OH group would enhance solubility...

There is most likely a pH range in which neither the OH group nor the NH2 group are deprotonated/protonated, and at which extraction with e.g. ether from the aqueous solution is possible. A phenolic OH group isn't that acidic, H2CO3 is a stronger acid than phenol for example.
What do you think?

Maybe we should make a different thread about obtaining p- aminophenol from paracetamol, if one doesn't already exist.

EDIT: Hydrolysis of paracetamol with NaOH doesn't work... it instantly gets oxidised by aerial oxygen to a quinone, which forms polymers. A deep black solution results from boiling paracetamol with NaOH, from which nothing can be isolated.

[Edited on 11-4-2006 by garage chemist]




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[*] posted on 11-4-2006 at 15:01


I tried the hydrolysis of paraacteamol to p-aminophenol once, with the same air oxiation problem as you. I *think* that the hydrochloride seemed more stable in aqueous solution.



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[*] posted on 11-4-2006 at 15:19


I got the information off a website... I haven't experimented with paracetamol myself until now.

Maybe some NaBH4 added to the reaction mix can stop this oxidation? It is often used to stabilize solutions that are air sensitive. Though it is such a powerful reducer, iron(II) salts get reduced to the metal by it (tried it myself). Maybe it can even reduce the quinone to p- aminophenol...




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[*] posted on 12-4-2006 at 06:45


This all sounds waaaay to complicated for my simple mind to understand:D
I'll just stick to acetylsalicylic acid.
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[*] posted on 12-4-2006 at 10:09


Maybe a way to get to the phenol from paracetamol would be through :

1) hydrolysis of the acenatilide group with 20% HCl at reflux.

2) Treatment of the 4-aminophenol hydrochloride with sodium nitrite in hypophosphoric acid to yield the phenol through decomposition of the diazonium salt in the mineral acid.

I really dont know if the hydroxyl group might inhibit the reaction but removing an aromatic amine by decomposition of its diazonium salt is a well know process.


By the way, p-aminophenol tends to get heavily colored when heated in its basic form. It is not a measure of its purity though. It can be pure (over 99%)) and colored. Aldrich stuff can be blue-violet colored.




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[*] posted on 12-4-2006 at 10:14


You can make phenol from ASA by hydrolysing the acetyl group in order to get the salicylic acid. The latter can be decarboxylated at high temperature (over 200 degC) to yield phenol.

You can make salicylic acid by the reaction of sodium phenolate with carbon dioxide at 150 deg C (ref Org Syn) which is known as the Kolbe-Schmitt reaction




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smile.gif posted on 13-4-2006 at 08:46


HO-C6H4-NH2 isolation:

Indeed sulfate of anilin is unsoluble there is a chance that with a tiny exces acid the phenol won't help solubilisation.
So the salt will precipitate.

If it does stil solubilise...then aceton will help after neutralisation of the sulfate salt to yield less soluble and extractible compound, HO-C6H4-N=C(CH3)2

To get the phenol one might simply use the hydrochloride add some NaNO2 by tiny portions in the cold. Then add ethanol and water and slowly allow the mix to come to ambiant temperature. N2 evolution will occure.
HO-C6H4-NH2.HCl + NaNO2 --> HO-C6H4-NH2.HNO2 + NaCl
HO-C6H4-NH2.HNO2 --> HO-C6H4-NH-N=O + H2O
HO-C6H4-NH-N=O --> HO-C6H4-N=N-OH
HO-C6H4-N=N-OH -aq-> (-)O-C6H5 + N2 + OH(-)

As a side note the making of O=C(CNO2=CNO2)2C=O
tetranitroquinon involves no HNO3/H2SO4!
But instead are used:
1°)anilin, chlorate, HCl...strong oxydation and halogenation to tetrachloroquinon
2°)then further reaction with NaNO2 to substitute the reactive polyalfahalocetone with the nitrite anion...just like the reaction of chloracetic acid with NaNO2.

So definitely quinon precursor are not to hanlde like comon aromatic compounds but wel like ceton/enol compounds!

:D;):P:cool::)




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[*] posted on 14-4-2006 at 22:32


Regarding " paracetamol " , also called acetaminophen ,
( Tylenol is a brand name ) , 4 - Acetamidophenol ,
and 4'- hydroxyacetanilide ( p-hydroxyacetanilide )
Mole Weight 151.17 m.p. 169-172 , CH3CONHC6H4OH
d. 1.293 insoluble cold water , soluble hot water ,
very soluble alcohol ( CRC & Aldrich )

An idea I have is that this might possibly be converted to "hydoxy" sulfanilic acid ( aminophenolsulfonic acid ) by sulfonation with hot concentrated H2SO4 . If so , then the "hydroxy"sulfanilic acid possibly can be diazotized using NaNO2 to form diazophenolsulfonic acid as a precipitate . This precipitate is possibly convertible in high yield to picric acid by heating with ordinary concentrated nitric acid . The mechanism which I think is posible here
is parallel to a process in the patent attached .

See attached file . I posted this before in one of the other picric acid related threads maybe a year ago .

[Edited on 15-4-2006 by Rosco Bodine]

Attachment: GB16371 Picric Acid from Sulfanilic Acid.pdf (138kB)
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smile.gif posted on 18-4-2006 at 07:33


Starting from hydroxysulfanilic acid...you end up with the dihydroxy compound. The later is strongly oxydised to para quinon...



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[*] posted on 18-4-2006 at 11:24


Then perhaps omit any sulfonation intermediate ,
and attempt the nitrosation directly .

Possibly dissolve the acetaminophen in dilute HNO3
or dilute HCl and attempt its nitrosation in the cold
by adding NaNO2 to form an insoluble nitrosation product intermediate . Filter that precipitate if one is obtained , and nitrate by adding it in small portions
to hot concentrated nitric acid .

[Edited on 18-4-2006 by Rosco Bodine]
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smile.gif posted on 20-4-2006 at 06:55


Rosco,
The problem is not to convert NH2 to a hydroxy group... but rather what to do to get rid of the other hydroxy or to get rid of the NH2 and replace it by a H atom.

Your patent states TNP from anilin or sulfanilic acid thus:
NH2-C6H5 or NH2-C6H4-SO3H --> HO-C6H5 or HO-C6H4-SO3H
The later phenol or phenolsulfonic acid is submitted to mixed acids...to get TNP.

In the present case with parahydroxyaniline one would need to convert the -NH2 to a H atom in a way to get phenol...and this is not easy.

Now a good idea would be to react the free hydroxy with a base and then submit this to an alkyl halide in a way to get an alcohoxy group ...that would preserve the aromatic ring towards oxydation (blocking the phenol-quinon equilibrium).
Then one might get the othe hydroxy group and convert it aswel to an alcohoxy group.

In the case of CH3-X
Final product would be:
paradimethoxybenzene
CH3-O-C6H4-O-CH3

The later might be polynitrated...possibly to the tetranitro compound (CH3-O-)2C6(NO2)4...
:D:cool:;):P:)

[Edited on 20-4-2006 by PHILOU Zrealone]




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[*] posted on 20-4-2006 at 07:38


I was thinking of the amino ending up being nitro ,
but if you say it's not going to happen ........
I'll take your word for it . I've never explored the
nitrosation routes on any of these phenol cpds.
for picric acid or resorcinol , haven't even written
down the reactions on this one to see what might happen .

Lately I have been working on hardware ,
building the mother of all benchtop magnetic stirrers :D
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[*] posted on 20-4-2006 at 21:12


On the subject of OTC medicines as useful precursors
the aminoethanol derivative diphenhydramine hydrochloride which is often sold as a sleep aid may be a useful precursor in the production of Pentryl also known as
2,4,6-trinitrophenylnitraminoethyl nitrate.
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[*] posted on 21-4-2006 at 06:27


Sleep aid pills are not OTC available unless you've got permission from a doctor to buy it.
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[*] posted on 21-4-2006 at 06:35


Yes these are, its not a barbiturate or benzo, those need a precription.

But thinking about how little diphenhydramine they contain compared to 30 x 0,5g ASA for under 2 Euro (even cheaper in GB/US), it might become expensive!

Will dimenhydrinate work as well? IIRC they are related, but I might be wrong.
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