Please criticize: route-Acetaminophen to DOB/DOC

[ning]

I like the part about acid hydrolysis, as this may bee the missing step that gives ning black goop time and time again in the hypochlorite oxidation. However, the rest of this route...ning's chem is not good enough to see exactly where you're going...How were you getting that methyl on there? DMO will O-methylate things, but not quinone...and certainly not perform ring methylation, that I know of...Unless you know some sneaky trick...

And what is this...manganese(III)acetate? How does this make a ketone?

That patent's looking kick-ass, though...hmmm...

Put some more flesh on the bones of that route, please, so ning can understand it...

[ning]

http://www.epsilon-web.net/Ec/materials/

Electrochemical Studies of the Kinetics and Mechanisms of N-Acetyl-p-Quinoneimine Hydrolysis, C.R. Preddy, D.J. Miner, D.A. Meinsma and P.T. Kissinger, 6 (1985) 57-61.

Metabolism of the widely used analgesic acetaminophen (APAP) is thought to involve initial microsomal enzymatic oxidation. The oxidized form, N-acetyl-p-quinoneimine (NAPQI) is readily generated and studied electrochemically. The mechanism of NAPQI hydrolysis is found to proceed by rapid, acid-catalyzed hydration of the imine bond. The resultant carbinolamide undergoes rate-limiting deamidation yielding benzoquinone and acetamide. The pH and temperature dependence of the rate and the mechanism of both steps is studied in detail by double step chronoamperometry. Evidence is presented for catalysis of hydration by HSO4-, suggesting a general alternate pathway. The lifetime and reactivity of the intermediates is discussed with reference to the overdose toxicity of acetaminophen.

Sounds like the man speaks sooth...All ye who crave p-benzoquinone may rejoice in extacy...

[Tengo]

SWIM tried the oxidation in bleach, all a mess... midnight black... perhaps the enviroment was too alkaline...?

But what about a neutral or slightly acidic oxidation!

http://electrochem.usask.ca/cc_ep/lab_exp.htm

Take a look at the oxidation-hydrolysis mechanism...
Well hello equimolar amounts of APAP, NaOCl and AcOH!

APAP + NaOCl -> BQ + CH3CONH2 + NaCl

done in AcOH and adding some extra of it towards the end, pushing the equilibrium to the right...

If it works, it's a rather convenient way to BQ and acetamide at the same time...

[ning]

We seek answers and find only further questions...why are we here? What are we doing? How can we make powerful psychedelics and useful precursors from household chemicals? Ning doesn't know the answers to any of these, this means it must be research!

Many thanks to tengo, for enthusiasm and a useful, though cryptic link. Does any other bee find it entertaining how to do anything, one seems to need to learn how to do everything? To interpret this, ning must now learn cyclic voltammetry.    Still, it is a start.

Now, the conceptual issue ning is having trouble with, is how an acid hydrolysis *makes* a quinone in the first part, then the same acid *changes* the quinone to a *hydroquinone* in the second part. Perhaps because the second part is anhydrous??? (ning grasps at straws...) Perhaps somebee understands this seemingly fine distinction better than ning does.

Now, ning is considering typing up that patent tengo found, for all to enjoy, for it is a most enjoyable work. And yet...yet...seems to be missing some important detail (as most patents do), most notably, pH conditions and more importantly, a description of how they manage to dissolve NaOCl in toluene...

For any doubters out there, who want to see p-aminophenol being turned into an imine, one hydrolysis away from their prized p-benzoquinone, read that patent. It is sweet.

Ning did another oxidation test or two, with Na-DCCA again, this time in methanol-h2o, and just h2o. The conditions were neutral, and a slightly different result happened.

First, the solution turned REALLY YELLOW, and was full of little bitty flakes that wouldn't dissolve in water. Ning thought "This is it...", but then they turned orange, then red, then brown... Not Good. An extraction with toluene left a large amount of insoluble brown gunk in the bottom. This is not acceptable. So perhaps the future holds some acidic oxidations. But everything ning has read...ugh.

Only thing is, in WATER, in these acidic conditions etc. etc., ning would expect hypochlorous acid, or even chlorine to be generated. Is this the anticipated oxidizing agent? Hmmm...


tengo: One thing ning is not sure about there...did you see that their stock solution was made with perchloric acid...that could bee how those guys are solving their oxidation problems

[ning]

Useful bits from that website:

The oxidation mechanism of APAP is as follows:


At pH values above 6, NAPQI exists in the stable unprotonated form (B).

Under more acidic conditions, NAPQI is immediately protonated (step 2), yielding a less stable but electrochemically active species (C) which rapidly yields (step 3) a hydrated form (D). [...] The pH of the media is 2.

Hydrated NAPQI (D) converts (step 4) to benzoquinone; however, the medium has to be extremely acidic for the rate of the process to be significant enough that reduction of benzoquinone is observed during the cyclic voltammetry experiment. The medium for the cyclic voltammograms detailed in Fig. 3 is 1.8 M H2SO4.
/snip/

This probably suggests what our oxidation conditions should be...

[Tengo]

Some theory first... (also see previous post)

Post 472609

(Tengo: "SWIM tried the oxidation in bleach, all a...", Novel Discourse)
And of course the already mentioned patent

http://l2.espacenet.com/espacenet/bnsviewer?CY=gb&LG=en&DB=EPD&PN=EP1068177&ID=WO+++9952860A1+I+

HOAc + NaOCl -> HOCl  + NaAc
APAP + HOCl -> NAPQI + HCl + H2O
HCl + NaAc -> HOAc  + NaCl
NAPQI + H2O -> BQ + CH3CONH2   (pH<6)

Summarized:
APAP + NaOCl -> BQ + CH3CONH2 + NaCl   (pH<6)

Assuming that HOCl does the oxidation, since it's used to oxidate cyclohexanol in the same way.


SWIM tried this with equimolar amounts of APAP, NaOCl and acetic acid.

15g APAP (unpurified, directly from 30*0,5g tablets)
25ml of 24% acetic acid
150 ml of 5% bleach

Starting at 0°C, slowly adding bleach to the suspension of APAP and acetic acid until the temperature reached 25 °C.

The suspension gets orange immidiately and darkens to orange/brown (brick color) at T+2h.

Another 25ml of 24% acetic acid is added to induce hydrolysis.

At T+5h the reaction has resulted in this:
Brown upper layer and an orange/brown lower layer with white suspended.
These layers are equal in height. If there were an organic layer it should be lower in height since the amount of organic substances are much less than the amount of water.
So it's probably the suspended white that is at the bottom due to gravity.

Adding NaCl (to salt out BQ), nothing visually changes.

Now BQ shouldn't like this polar enviroment and rise to the surface.
Having never seen BQ, SWIM doesn't really know what to look for... MSDS says grey to yellowish-white... Voices at the HIVE say pure BQ is a yellow fluffy powder (and green sparklies when it's contaminated with quinhydrone)

Adding toluene and the suspended white goes to the upper layer.
Probably plenty of unreacted stuff in there (but what, APAP or NAPQI? filler material?).

Adding some HCl and raising the temp (to hydrolize possible unhydrolized NAPQI) and the shit starts polymerizing.

Separating the organic layer and it's reddish-brown...

Conclusion: More or less none (SWIM doesn't now what's in there)

Since HClO is a stronger oxidizing agent than ClO- the equilibrium 2HClO + ClO- <-> ClO3- + 2HCl gets maximally shifted to the right at neutral pH, maybe this affects the reaction.
If it's ClO- and not HOCl that manages to oxidize APAP, then maybe a neutral or acidic reaction isn't the way to go.

[ning]

Since we don't know exactly what we're looking for,
ning would suggest this:

First, perform hydrolysis of acetaminophen to p-aminophenol by refluxing with HCl or whatever (posted that stuff).
By this, we know what p-aminophenol looks like.

Then, try the oxidation with p-aminophenol, which we know should work.

If the result is the same damn orange-brown gunk, something funny is happening.

If someone could try oxidizing the p-aminophenol with, say, KMnO4, under strong acidic conditions (H2SO4), then we could have something to compare with.

Ning may have to try that battery-stuff MnO2 oxidation again. Ning seems to remember getting a yellow layer out of that. But the bleach way Must Work!

Anyway, tengo, if you have any sodium sulfite(?) to quench the bleach, you could perhaps try refluxing it with acid for a bit, as I heard the hydrolysis may not always be so fast... if the color changes, it's a good sign.

Ning is working to acquire a refluxing setup, at which point more experimental data will be forthcoming.

By the way, that HOAc oxidation looks sharp. When ning did the oxidation, ze used 70 ml bleach to 1.5 g acetaminophen tablets, so it seems as though your ratio is a little low. Anyway, glad to see the data!

Any other bee want to try this simple experiment?

[Tengo]

I just found out the colour of NAPQI!
See this post for background...

Post 472990

(Tengo: "Some theory first... (also see previous post)", Novel Discourse)

The red-brown stuff is NAPQI, so the oxidation seems to run fine... It's only that last step, the hydrolysis, that needs tweaking... 
From what I can tell, it needs to be done under sufficiently mild conditions to prevent tar formation.
Evidently HCl seems to be to aggressive... But perhaps AcOH would still do it, only with longer reaction time and higher temp.

There is fine line between hydrolysis and polymerization

/T

[ning]

Ning hasn't forgotten this most-beloved thread. Hopefully some further experimentation will bee forthcoming.

Tengo, I'm actually rather interested in the hydrogen peroxide oxidation patent. It was you who posted that, right? I think that part of the tarring's cause may be halogenation, which of course H2O2 won't have a problem with. I'm thinking FeCl2, CuSO4, or some of my MnO2 will work nicely as catalyst, and IIRC, the patent diluted the H2O2 down to about 5% or so. Which suggests that 3% storebought will probably work too. I have a feeling this may be much cleaner reaction. They got nearly quantitative yields of quinonimine, also.

I want see what happens if the sludge is refluxed for an hour in dilute HCl. It wouldn't bee too surprising if something came out of it. I always got the feeling that the stuff wasn't hydrolyzing for some reason.

Bleach is powerful, but so annoying to deal with. Such complex chemistry it has!