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Author: Subject: 4-methoxyphenol syn using hydroquinone methyl iodide
Panache
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[*] posted on 11-1-2010 at 00:10


Quote: Originally posted by crazyboy  
Well I just got finished performing this reaction using the ratios Klute posted, but I doubled everything. The reaction went very smoothly however it used a considerable amount of methanol, DCM and hydroquinone but gave very little 4-methoxyphenol. I plant to repeat this reaction on a larger scale but I will try to recycle some of the methanol/DCM. I


Perhaps you should try it on the 1/10th scale and get it right before doubling it again. I'm not being nit picky i just wondered if perhaps you did not see the silliness in those sentences.




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[*] posted on 11-1-2010 at 06:53


i was recently given a small vacuum pump by a friend, http://www.millipore.com/userguides/tech1/p30152, it pulls 25inHg, and i think its primary purpose is vacuum filtering, does anyone know if it would be suitable for this distillation?

I have an aspirator as well but i have no reasonable way of attaching it to my sink (previously used A LOT of electrical tape :P).
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[*] posted on 11-1-2010 at 14:50


Quote: Originally posted by Klute  
Ouch I'm scared for that little pump there, no protection?

The whole distillation setup is scary. The thermometer adapter, the tubing, missing clamps, no stirrer?
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[*] posted on 11-1-2010 at 17:57


Quote: Originally posted by Panache  

Perhaps you should try it on the 1/10th scale and get it right before doubling it again. I'm not being nit picky i just wondered if perhaps you did not see the silliness in those sentences.


Well 1/10 scale seems a bit too small, with equipment losses I would get almost no product. I agree modifications should be made and I will repeat this reaction without doubling again perhaps even to Klute's original measurements but I will not go 1/10 scale, there is no reason.


Quote:

The whole distillation setup is scary. The thermometer adapter, the tubing, missing clamps, no stirrer?


I don't follow... The thermometer adapter is solid PTFE, coated with silicone vacuum grease, the o-ring is an inert fluoropolymer and it is vacuum tight. The tubing is regular vinyl tubing it isn't dangerous. There is a Keck clip securing the receiving flask to the vacuum adapter, the vacuum adapter is held firmly in place with the clamp. I have more Keck clips but I removed them so they didn't melt when I heated them with a paint stripper. I have a hotplate/stirrer but find I generally get better heat control with a heating mantle.




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[*] posted on 11-1-2010 at 18:48


One thing I do not understand: why the DCM extraction?

Why not neutralize the sulfuric acid with carbonate, distill/rotavap off the solvent/water, and then flush with argon and vacuum distill the product? I think this would improve yields on the reaction and would be less solvent intensive. The crude product could then be recrystallized a la Klute solvent system.




Neither flask nor beaker.


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[*] posted on 11-1-2010 at 19:28


Quote: Originally posted by Fleaker  
One thing I do not understand: why the DCM extraction?

Why not neutralize the sulfuric acid with carbonate, distill/rotavap off the solvent/water, and then flush with argon and vacuum distill the product? I think this would improve yields on the reaction and would be less solvent intensive. The crude product could then be recrystallized a la Klute solvent system.


The DCM extraction followed by brine and water washes does help clean the product but now that you mention it I don't think they really do enough to justify their use as the product was heavily contaminated with black tar. I think I might try your suggestion, if it fails I can just dissolve the residue in DCM and continue as if nothing happened.




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[*] posted on 12-1-2010 at 08:06


Well, you would have to filter the precipitated Na2SO4, I tried this way once using conc NaOH solution, but near the end of the neutralisation, the pheno; gets basified locally and forms a slush of the phenolate which darkens immadiatly and gives a hell of a mess.. I abandoned trying to selectively neutralize the sulfuric acid, because if you cut it too low and there even a little sulfuric acid left, you get a goop of polymerized junk during distillation.

The whole neutralization scheme is proposed in one of the related patents, but to me it just doesnt seem feasible, except perhaps by sacrifying some p-methoxxyphenol by over basifying just a bit...




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[*] posted on 10-9-2011 at 06:18
2,5-Dihydroxyacetophenone methylation


I would like to know if anyone has tried to monomethylate the 2,5-Dihydroxyacetophenone using the same aproach used with hydroquinone in MeOH/H2SO4/Benzoquinone?
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[*] posted on 25-9-2011 at 04:31


Right, I'm off to drink wine and talk about weird stuff guys don't understand on a super saver coupon spa break, but here's what I've got thus far.

Two other people I chat to have been giving this a go and asked me to as well.

Synthesis of highly deuterium-labeled (R)-K-13675, PPAR a agonist, for use as an internal standard for low-level quantification of drugs in plasma - Bioorganic & Medicinal Chemistry, Yukiyoshi Yamazaki, Shin-ichiro Ogawa, Kimiyuki Shibuya

Quote:
4.6. Synthesis of 4-methoxyphenol-d7
To a solution of 1,4-hydroquinone-d6 (9) (98 atom% D, 4.48 g,
38.6 mmol) and benzoquinone-d4 (98 atom% D, 325 mg,
2.90 mmol) in methanol-d4 (99.8 atom % D, 25 mL) was added sul-
furic acid (4.80 g) over 5 min at room temperature. The reaction
mixture was stirred for 14 h, poured into ice-water and neutralized
with 4 M aqueous NaOH. The aqueous solution was extracted with
Et2O. The organic layer was washed with brine, dried over Na2SO4
and concentrated in vacuo. The residue was purified by silica gel
column chromatography (n-hexane/EtOAc = 5:1) to give 3 as a pale
yellow solid (4.83 g, 95%): 1H NMR (400 MHz, CDCl3) d 3.72–3.76
(m, 0.06H), 4.87 (s, 1H), 6.76 (s, 0.10H), 6.79 (s, 0.10H); 13C NMR
(100 MHz, CDCl3) d 55.06*, 114.59*, 115.80*, 149.41, 153.48; IR
(solid sample): 3381, 2521, 2262, 2069, 1419, 1141, 1112 cmÀ1;
HRMS (EI): m/z [M+] calcd for C7HD7O2: 131.09564; found:
131.09642; mp 56–57 °C.


From what they have already found, the neutralisation in large amounts of water and subsequent solvent extraction didn't seem to be working well, so they modified it to instead use sodium bicarbonate directly into the methanol - which does appear to work, although I have not tried the referenced method yet or looked at the solubility of my product in water; I will do some more when I get back perhaps.

I stick a 250ml beaker with a stir bar in it on the balance and tare it
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I add hydroquinone and retare
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Benzoquinone had been prepared the day before and sublimated in the morning. You can see the preparation of that in this link. The interface is going uber dark green / black, rapidly
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I measure out 125ml of methanol and add that
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Within the five minutes I spent measuring it out and adding the methanol, it has clumped from a free powder into annoying lumpy bits. I have to poke around in there with a glass rod to break it up again, then leave it to spin for ten minutes to get it all free flowing again
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In the meantime, I weigh a cute, tiny beaker and pipette.
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I measure concentrated sulphuric into this
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The beaker after a spin
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I film over both beakers and put them in the freezer for a while
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They come out around -8C and, with it spinning quickly, I drip the cold, concentrated sulphuric directly into the vortex over ten minutes.
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The addition is finished and the beaker has warmed to 34.5C. The room is at 17.5C.
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Checking for a transfer error. The balance will refuse to sit still when weighing concentrated sulphuric. Like sodium / potassium hydroxide, roasted drying agents and similar, the mass constantly goes up as they pick up things from the atmosphere. So long as measured soon after, the change isn't too much of an issue since it's well below the mass of one drop
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The beaker is covered and left to spin overnight
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14 and half hours later...
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The beaker is now at 24C. This is the temperature of the hotplate, which warms up a little when the motor is left going all night
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I measure out the sodium bicarbonate, I actually removed a little from this after checking the sulphuric numbers
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14 hours and 50 minutes after completing the addition, I begin to neutralise.
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2NaHCO3 + H2SO4 -> Na2SO4 + 2H2CO3
Then,
2H2CO3 -> 2CO2 + 2H2O

Because the neutralisation has stage stages to pass through and the bicarbonate is going in as a powder, it takes a long time to fully react and needs adding a bit at a time.

The novel thing here, as spotted by the guy who suggested the change, is that the neutralisation product is insoluble in the solvent and forms a decahydrate, so it'll scavenge the water as well. One consequence of this is that you will get some lumps in the beaker as it clumps. Stir away Toronto!
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As it gets going, it will thicken up to a gooy foam
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After two hours the fizzing was showing signs of dying away. After another hour it was close to dead. I left it for an additional hour until there was absolutely no sign of it. The temperature remained at 24C though out. Here's the sodium sulphate dropping out
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Having added what I'd calculated to be the precise mass of bicarbonate to neutralise the sulphuric, I tried dipping the pH probe in there
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Then a bit of paper
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Sodium sulphate begins releasing it's water of crystallisation at just 30C. Since this is now about that warm, I put it back in the freezer for a few minutes
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Filtering isn't much of a problem
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Rinsing the last bits out
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Rinsing the cake through with a bit more methanol
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Removing the methanol under vacuum
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Done. As the last few bubbles appear, the contents of the flask immediately thicken to a chip shop style gravy. Once the flask it's self is back at room temperature, around 17.5C, it solidifies. There appears to be a decent amount of some clean solid in there, coated in something brown. According to an independent, triple blind peer review, it smells like 'plastic'. I'd say calamine cream as well. I put a tap on it, put it under vacuum and then in the freezer, since I'm going to bed and don't know if this is going to go funny on me overnight.
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THE PROBLEMS BEGIN



The next day I set about transferring the contents of the 250ml flask to a 100ml, which went surprisingly well. When the flask was put into some warm water, it'd go back to gravy consistency and pipette nicely. A few squirts of methanol and I had everything from one flask to the next, and out of the pipette, and off the stir bars; so it's not as tarry as it may appear. The plan was, high vacuum fraction distillation.
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I have all this sat on the desk and it's not going through
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I tried this one first with hot water in the condenser
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Clogged at the point of the thermometer down, entirely
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Tried that one, same problem
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Best off with something like this, where there is no long spout. The product solidifies so quickly it's going to block as soon as it leaves the water jacket if not
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And one of these to hand
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'Bulb to bulb' style. The thing to be distilled also bumps a lot, meaning it's good to have some form of vigreux in the way if only to stop the initial splattering from crossing over
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By the time I'd tried it in one, had it clog, transferred it to another, had that clog, I had obtained some yield, which immediately solidified to a white crystalline mass. But by the time it'd been transferred into a third distillation setup, something must had happened along the way, because I was now getting some kind of weird white plastic like, unmeltable material in the hot flask. So here it ends for now.

10g is not bad, but it's not great either, it should have been more like 20 or 25g. I think a lot of the blame, if not all of it, is the messing around in the distillation. If I'd gone straight to the most simple, cheapest setup, I expect I'd have gotten close to that yield.

Also of note is that the pure white material was the first thing out the flask, the first drop solidified, and it was the dominant band, easily. The temperature sat still around 94C under hard vacuum.

This adds more weight to the idea of simply using a bulb to bulb method, as there doesn't appear to be any gross contamination that needs to come off first.
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There's what I've got.

What is there appears clean, as the stuff is near pure white, dry and crystallising all on it's lonesome.

You guys in the US have that shop 'Lush' right? That sells novelty soap.

You know that smell you get when you come within 100m of the door, before ever seeing it? That's what it smells like at the moment.
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Super quick summary because I am already late

I will have to give this a go on the TLC, check out the solubilities of what I've got and perhaps try some more basic distillation method.

The reference is likely using chromatography partly due to the difficulty of distilling this stuff.


Suggestions

  1. Weigh the BQ and HQ separately and dissolve them in a bit of methanol alone, then mix them together. It'll be less prone to forming clumps that way. It's not a major issue, since they break up easily enough, but it's an extra annoyance when they form.
  2. USE A BEAKER! It benefits from a lot of hard stirring. Doing it in an RBF is not at all necessary and the bar won't stir it as well as a big flat one in a beaker. Use a beaker that is twice the size of your solvent volume, in case it foams up and out. Mine didn't foam up more than an inch or so, but it could if not constantly stirred or the bicarbonate is added in bulk.
  3. Keep the distillation painfully simple. There's over a thousand dollars worth of glass on the desk there, yet it died on it's arse. It may be possible to use a recovery bend or straight tube with two male adaptors on to go between two flasks. A frit, splash head or virgeux somewhere in between is a good idea to avoid splattering.


[Edited on 10-30-2014 by Polverone]




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[*] posted on 1-10-2011 at 21:26


I don't want to detract from you efforts peach, that is a very nice post.

Wouldn't it be potentially cleaner and easier to hydrolyze paracetamol, diazotize, and react that with methanol? If you could avoid the vacuum distillation that way, it would be well worth it I think. And no need to buy hydroquinone. Has anyone brought this route up before? I really like the sounds of it.

The reaction can also form the benzene derivative, but that tends to occur more with longer chain alcohols. Benzenediazonium chloride or sulfate and methanol is said to give only methoxybenzene here: http://books.google.com/books?id=5eRYAAAAYAAJ&pg=PA226&a...
They say electron withdrawing substituents result in lower yields of the ether, but with methanol even a p-bromo or chloro yields mainly the ether.

Here they say m and p-aminotoluenes are converted to methyl ethers in 95% and 84% yield respectively. Not too bad.
http://books.google.com/books?id=FMziAAAAMAAJ&q=diazoniu...

If the reaction with methanol doesn't work, you could always methylate the paracetamol, then hydrolyze and diazotize. Not quite as elegant thought.

Edit:
Damn. According this paper paper p-hydroxybenzenediazonium salts react anomalously with methanol, forming phenol and tar only. That was fun while it lasted...

Still, what do you think of the potential for o-methylating and then diazotizing? I am certain those reaction will work.

[Edited on 2-10-2011 by 497]




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[*] posted on 2-10-2011 at 00:07


Quote: Originally posted by 497  
The reaction can also form the benzene derivative, but that tends to occur more with longer chain alcohols. Benzenediazonium chloride or sulfate and methanol is said to give only methoxybenzene here: http://books.google.com/books?id=5eRYAAAAYAAJ&pg=PA226&a...
They say electron withdrawing substituents result in lower yields of the ether, but with methanol even a p-bromo or chloro yields mainly the ether.

Here they say m and p-aminotoluenes are converted to methyl ethers in 95% and 84% yield respectively. Not too bad.
http://books.google.com/books?id=FMziAAAAMAAJ&q=diazoniu...

Please provide proper references, like book/journal title, volume and page. Google-books links do not work for all (I know they are country specific, but likely they are also cookie dependent). For example, if I click on your links I only get the book tittle instead of the page as you probably intended. In general, please avoid using dynamic URL addresses, as it is futile doing so. When giving references, either write them out in a classical sense or provide the DOI. Optionally, provide a quotation where possible, just like Peach does it.
Quote:
Damn. According this paper paper p-hydroxybenzenediazonium salts react anomalously with methanol, forming phenol and tar only.

I guess you meant that it reacts normally with methanol to give a phenol as the main product, rather than giving the anomalous product (ether).




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[*] posted on 2-10-2011 at 13:27


Okay sorry, didn't realize they were country specific.
From the first link:
"Decomposition of Diazonium Salts by Alcohols
The reaction between diazonium salts and alcohols may proceed in two different ways:
RN2X + C2H5OH --> RH + C2H4O + N2 + HX
RN2X + C2H5OH --> ROC2H5 + N2 + HX
The former of these was originally regarded as a general reaction, but more recently researchers have shown that the second is the normal change. The factors determining the course of the reaction are, however, numerous and complicated, involving (1) the nature of the alcohol; (2) the influence of substituents in the diazonium salt; (3) the pressure and temperature at which the decomposition is affected.
The tendency to replace the diazo- group by hydrogen increases with the molecular weight of the alcohol. Benzenediazonium chloride or sulfate with methyl alcohol give anisole exclusively. With ethyl alcohol these salts yield chiefly phenetole but benzene is produced. The diazonium salts of p-chloro and p-bromo-aniline furnish only p-chloro and p-bromo-benzene with ethyl alcohol, but with methyl alcohol they give rise mainly to the methyl ethers"

From the second link:
"Diazotized m- and p-aminotoluenes when thermally decomposed in methanol in the presence of air (to inhibit the radical process) gave the respective ethers in yields of 95% and about 84%."

Quote:
I guess you meant that it reacts normally with methanol to give a phenol as the main product, rather than giving the anomalous product (ether).


No, reread the first paragraph of the paper in the last link. It says:
"The anomalous effect of the phenolic hydroxyl, particularly with respect to methyl alcohol, is contrary to all other experience with it's reactivity, since here it promotes the formation of the same product as would a nitro-group, and no longer behaves like other o,p directing groups which favor the replacement of the diazo- group by the alkoxy-group."

I'm assuming this is because it is capable of forming a quinone, unlike other p-substituents?

[Edited on 2-10-2011 by 497]




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[*] posted on 5-10-2011 at 03:46


Hi, I have a question concerning that reaction: does it will work with ethylhydroquinone? The result would be 4-methoxy 3-ethyl phenol or 4-methoxy 2-ethyl phenol? I think I will get 50/50 but I am asking that because I need the first one to formylate using Mg formylation. Thanks
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[*] posted on 24-10-2011 at 01:30


Quote: Originally posted by peach  
From what they have already found, the neutralisation in large amounts of water and subsequent solvent extraction didn't seem to be working well, so they modified it to instead use sodium bicarbonate directly into the methanol - which does appear to work, although I have not tried the referenced method yet or looked at the solubility of my product in water; I will do some more when I get back perhaps.


Did you (or your friends) try the workup that Klute posted above (extraction instead of neutralization)?

Someone who may be the worst synthetic chemist that ever walked this huge ball of fire dissolved 100 g hydroquinone and 10 g benzoquinone in 750 ml MeOH and while stirring slowly poured in 100 ml H2SO4 (stupid - chemists with more than 2 brain cells would add first H2SO4, cool then add the rest). The flask was stoppered and stirring continued for 24 h at RT (~20°C). ~200 ml MeOH were distilled of under weak vacuum (bp ~40-50°C) and 500 ml of brine added. The dark oil was extracted thrice with DCM, the organic phase washed twice with water (good separation) and brine (catastrophe - emulsion straight out of hell). To break the emulsion, the aqueous phase was diluted with water, organic layer taken off, diluted more, etc. The last bit of emulsion was left standing over night and finally broken by vacuum filtration. The combined organic extracts were dried over Na2SO4 for 24 h, the DCM distilled off at atmospheric pressure and weak vacuum applied to remove remaining solvent. Vacuum was removed when a white solid started to sublime. The residue quickly crystallized and was distilled at reduced pressure (one of those ultra-cheap E-bay pumps) at 105°C until the distillate started to become yellow (without temperature increase!). Yield of crude mequinol: 81 g (~72%) of nice crystals which are slightly yellow and therefore need to be recrystallized. You probably would not even want catalytic amounts of benzoquinone in most reactions.
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[*] posted on 12-3-2012 at 15:37


Hi Turd,

I only just noticed this reply, months later, as the email hasn't been working for most of that time. But no, I didn't try the extraction, just what's above.

The neutralisation suggested by the others works really well. It seems your extraction did too, but the neutralisation is good in terms of not having to deal with the subsequent emulsion.

I am near certain the reason behind my yield being low was the distillation - it solidifying in the small passageways on the way out and needing swapping around. Just needs doing in something that can have it's sides heated in case that begins to occur.

Thanks for taking the time to post up your results!

[Edited on 12-3-2012 by peach]




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[*] posted on 30-10-2014 at 06:16


Quote: Originally posted by Klute  


The patent suggets neutralizing the reaction mixture, and then directly distilling everything. But it can tricky to get the exact amount of base in there, and so material is trapped in the formed Na2SO4, even after washing with fresh MeOH.
[Edited on 26-1-2008 by Klute]


I followed peach's way and neutralized it with NaHCO3 to ph7.
It yielded a very light pink Na2SO4 (which I think trapped a lot of product) where washing the cake with more methanol does not seem to help, vacuum filtration is nearly impossible even through celite.

Has anyone experience how I get the methoxyphenol out of this sludge?

[Edited on 30-10-2014 by lullu]
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[*] posted on 30-10-2014 at 09:27


I had no issue replicating Peach's work, and obtained granular solids on neutralisation. I suspect you have too much water present (wet solvent?) if you're ending up with a sludge.
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[*] posted on 31-10-2014 at 11:17


Thanks for your comment DJF90.
All solvents used where purum/synthesis quality, temperature was under 16°C the whole time.

Maybe it is of any interest or help anyone in the future:

I used 750ml pure methanol for 200g hydroquinone and 22g benzoquinone (quinhydrone/hydroquinone defiled) and a 1:1.81 mol acid ratio .
p-methoxy-phenol is very soluble in methanol and it yielded no solids after 24h stirring.

After neutralization there was no methanol left, only a very thick mush.
It was diluted with around 2 litres methanol and filtered/washed again with methanol.
The mentioned light pink Na2SO4 had still the distinct smell of the product after a lot of washing.

The filtrate needs destillation, I'll report on the yield if it is done.
Maybe a Water/DCM extraction on the sulfate sludge will work fine although if someone tried a steam destillation or direct destillation from it succesfully I would appreciate a comment on that.
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[*] posted on 31-10-2014 at 12:15


To draw a picture:

neutralization:


After neutralization, magnetic stirring was continued and it let to this sludge.


[Edited on 31-10-2014 by lullu]
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[*] posted on 24-2-2015 at 11:56


Just wanted to share my experiences with this reaction, as it's given me some problems in the past. After discovering xylene was a useful recrystallization solvent, I decided to try something a little unique in an effort to skip the vacuum distillation and recrystallize the product right out of the extraction solvent.

4.15 g p-benzoquinone was added to a solution of 41.5 g hydroquinone in 300 mL MeOH. The beaker was submerged in an ice bath and treated with the careful dropwise addition of 42 mL 96% H2SO4 over the course of ~15 minutes. With the addition complete, the beaker was covered and left to stir for 24 H at ~20 C. 150 mL MeOH was evaporated off and the mixture was allowed to cool before adding 200 mL saturated aqueous NaCl. The mixture was extracted with 4 x 75 mL xylene, washed once with 50 mL H2O, and washed with 2 x 50 mL saturated aqueous NaCl.

*With the exception of the use of xylene as an extraction solvent, here's where the workup differs*

A test was done. 5 g crude 4-methoxyphenol was recrystallized in xylene. When cool, the product + mother liquor had a volume of 17 mL. Expecting ~35-40 g crude product, the expected volume would be ~136 mL. The 300 mL of xylene was evaporated down to 135 mL and allowed to cool overnight.

No dice. The beaker was placed under draught and further evaporated down to 90 mL. The next morning, a crop of huge, surprisingly clean crystals had formed at the bottom of the beaker, under the nearly black solvent. There was one chunk the size of the palm of my hand (had to take a picture :P).

The crystals still had a tan taint to them, but considering what you get from extracting with DCM and evaporating to dryness, they are very clean.

The mother liquor was returned to the beaker and evaporated further under draught, eventually collecting 2 more crops of crystals that became progressively dirtier (but still rather clean in comparison) with repeated collections.

In the end, ~34 g of light tan 4-methoxyphenol was collected. I've never bothered recrystallizing with EtOAc (and am currently running low) as vacuum distillation always resulted in adequate purity for my needs, and so I don't know what the returns are like. If the crude product is collected in this way, it should be pure enough for recrystallization with EtOAc (or xylene) and vacuum distillation can be skipped altogether.


Extraction solvent
Extraction Solvent.jpg - 177kB

Crystals under solvent
Crystals.jpg - 180kB

Giant chunk
Big Crystal 1.jpg - 92kB

Filtered product
Filtered Crystals 3.jpg - 206kB
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[*] posted on 24-2-2015 at 23:59


It seems like a potentially easy way to bypass the vacuum distillation. Toluene has been mentioned to give small cleanish crystals, so I'm kind of surprised you see such a significant deviation from that using xylenes.

What would be nice to see is the recrystallisation of the isolated product, and whether that can completely control colour/impurities. A melting point before and after a recrystallisation ought to be indicative. You may find a little activated carbon is needed (followed by hot filtration).

Quote:

The mixture was extracted with 4 x 75 mL xylene, washed once with 50 mL H2O, and washed with 2 x 50 mL saturated aqueous NaCl


Out of curiousity, why do you wash the combined extracts with (two portions of) brine? It seems unnecessary to me, seeing how the solubility of water in xylenes is minimal. Concentration will remove any water present via azeotrope. I mention it because its odd how people sometimes follow a "standard" workup routine without thinking what each wash is removing (and if its actually necessary).

[Edited on 25-2-2015 by DJF90]
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[*] posted on 25-2-2015 at 02:19


I had problems getting it to deposit when vacuum distilling bulb to bulb.
Thanks for sharing your experience Wolfgangg.
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