Sciencemadness Discussion Board - 4-methoxyphenol syn using hydroquinone methyl iodide

4-methoxyphenol syn using hydroquinone methyl iodide

mechem - 25-1-2008 at 15:33

Hi
Can methyl iodide be used to methylate hydroquinone, in order to obtain 4-methoxyphenol, or would the iodide ion cause side reactions. If possible does anyone have any experimental details on using methyl iodide. I suppose lithium carbonate could be used to remove the acidic proton, but could someone tell me the solvent to use, reaction conditions, quantities and time etc.
Thanks

smuv - 25-1-2008 at 15:56

I think you would get a lot of dimethylated product.

Hydroquinone can be selectively monomethylated by strong acid in R-OH where R is the alkyl group you wish to substitute onto one hydroxyl group in the presence of some benzoquinone. See British patent 1,557,237. There are other patents out there that make subtle modifications to this procedure, but this should get you started. I admit though I have no experience with this reaction.

[Edited on 25-1-2008 by smuv]

interesting article

chemrox - 25-1-2008 at 23:52

check this out:

Attachment: MeOphenol green.pdf (164kB)
This file has been downloaded 4419 times

Klute - 26-1-2008 at 05:10

There absolutly no need of using such a reageant for monomethylation of hydroquinone!

The patent mentionned above works wonders. Just add conc. H2SO4 to MeOH with stirring, add your hydroquione, then cat. amount of benzoquinone (easily made in 1H from hydroquione, H2O2 and cat. I2), and either reflux for 4h or stir at room temp for 24H. Than evaporate half the MeOH, add equivalent amount of brine, extract the black oil with DCM, wash with water and brine, dry evaporate the solvant, and vacuum distill the remaining dark oil, using a condenser without cooling water. The p-MeO-phenol passes as a clear yellow oil between 140 and 150°c at water pump pressure. Be carefull, keep a hot air gun or hair dryer at hand to keep the setup warmish to avoid cristn of the oil. There will be a largish amount of residu left, but yields are always in the 80's after distn. Then recrysatllized the material from ethylacetate/pet ether to obtain beautifull cristals of very pur material. Have a look: :cool:

Distilled oil:

After cristalization:

After recrystallization:

Keep your MeI for better uses.

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. ALso, no need of doing a A/B with the phenol, it incredbly messy, you get a very dark emuslion with is impossible to break, and yields don't change after distn. Vac. distiling this compound is much more easy than what has been suggetsed previously. I can't understand why people spent so much time/effort to directly recrystalize the crude oil, it would take 1/10th the effort to build a vac. source and open doors to beautifull cristals.

[Edited on 26-1-2008 by Klute]

solo - 26-1-2008 at 05:30

Very impressive results .....what is the yield?.....there is also another page to read is not already...............solo

http://erowid.org/archive/rhodium/chemistry/4-methoxyphenol....

Klute - 26-1-2008 at 05:57

Quote:

Originally posted by solo
Very impressive results .....what is the yield?

Never under 70%, most of the time around 80% (did the reaction 3 times..) after distn and recrystalization. So the reaction itself must not be far from quantitative!

A short reflux (4H seems as effective as a 24H RT stirring. But stirring for 12h after reflux seems to lower the yields. Also, adding the BQ gradually *could* give slighter better yields, in both the reflux and RT procedure. Didn't do any comparative work.

I usually used 10mL conc. H2SO4 with 100mL MeOH for 10g HQ and 1g BQ, but I think the amount of MeOH can be diminished, aswell as the amount of BQ. Everything is dirt cheap anyway.

[Edited on 26-1-2008 by Klute]

smuv - 26-1-2008 at 06:00

US 4469897 is also interesting.

Essentially, methanol CuCl2 and hydroquinone were refluxed for 8 hours while air was allowed to percolate through solution using a bubbler; 75% conversion 90% selectivity (4-methoxyphenol).

Anyone care to rationalize how this works? I could see how the Cu++ could oxidize hydroquinone to 1,4-benzoquinone and then be regenerated by the flowing air. From there though...I am stumped.

Klute - 26-1-2008 at 06:07

Maybe the CuCL2 could act as a weak Lewis acid, as per the paper chemrox posted, promoting the same mechanism.
Thanks BTW, I was curious as to what the mechanism was with HQ/BQ, there was this issue a while back as too wich species was alkylated, the benzoquinone or the hydroquione.

BTW, I plan on trying out this reaction one other hydroquinone, when I can make/buy some. Not sure what substarte to use though yet.

smuv - 26-1-2008 at 06:27

Are you asking this because you would like to use a substituted hydroquinone and wonder if you need to use a corresponding benzoquinone?

The patent shows that the benzoquinone and hydroquinone if ring substituted should have the same R group. This implies that the benzoquinone gets alkylated and in the process oxidizes hydroquinone to the corrisponding benzoquinone.

mechem - 26-1-2008 at 06:36

Thanks guys you have sent me in a totally different direction which looks really easy. Klute although I have read the patents, can you elaborate on the quantities of reagents you used and why do you only evaporate half the methanol before adding brine.( As a saturated solution I take it)? Do you try and separate unreacted hydroquinone prior to short bulb distillation under reduced pressure, or do you use the difference in boiling points to aid purification or maybe purify product with toluene separation.

Hydroquinone bp 287-C
4-methoxyphenol bp 243-C at std pressure

PS nice pictures Klute

mechem - 26-1-2008 at 07:08

Klute, just read you extract the black oil with DCM which I think would leave behind any unreacted HQ, am I right in thinking HQ is not soluble in DCM.

Nicodem - 27-1-2008 at 01:47

The previous thread on the same issue:
https://sciencemadness.org/talk/viewthread.php?tid=6284

PS: It is nearly impossible to get useful yields of p-methoxyphenol from hydroquinone by (mono)methylation since p-methoxyphenol is more acidic than hydroquinone. It would only be a total waste of MeI.

Klute - 27-1-2008 at 05:42

I evaporate half the MeOH before adding brine to avoid heating the phenols in a conc. solution of H2SO4, causing much more side reactions. This is mentionned in the patent; they add an equal amount of water when half the MeOH is distilled, dist the binary mixture, add water etc I also did that at oone point but you can't recyle the MeOH without another fractionnation. The seperation was easier, as when cooling the oil crashes out even before adding brine.
Most of the HQ stays in the aq. and the washes, and some in the rediu I take it. Aslo, all the quinones and other shit stays in the flask, there is quite a large residu after distn, but the p-MeO-Phenol seperates well you get shrap fractions. There's always a little amount of colored impurities, even if I purged the setup with Ar before distn. Hence the reXlization.

I've already given the amounts I used, a few post back, gathered rather arbitraly from the patent. I'm pretty sure the amount of MeOH can be cut to a reasonable extent, aswell as the amount of BQ. The number of runs they did to compare the ratios of reagents is very informative, pretty rare to see such work in patents, my results seems to correspond to their, so I doubt it's BS.

@Smuv, yes this is what I had on mind. I wasn't sure if it was the carbocationic alkylated benzoquinone was actualy a alkylating species, or if it was reduced to the phenol, or both. I think it's pretty unclear from the article:

"The next step is the reaction between DS [carbocationic alkylated benzoquinone] and BS [protonated hydroquinone] to
produce the product ES [protonated p-MeO-phenol] , and the cocatalyst is released as CS [carbocationic unalkylated benzoquione]."

This lead me to think the benzoquione is always regenerated as such, and isn't reduced to the phenol. But when using a substitued hydroquinone, could it be possible that the unsub benzoquinone could oxidize the sub hydroquione to give respectively unsub hydroquinone and sub. benzoquinone? It would depend of the oxidation potentials I guess, wich would depend on the substituants. Could anyone be able to clear this issue up? Nicodem?
In any case, I think if this reaction was to be tried with sub. HQ, I'd better just follow the patent and use the corresponding BQ; it's just for the sake of curiosity regarding the mecanism.

Nicodem - 27-1-2008 at 13:55

Its just a matter of redox potentials and equilibrations among the hydroquinone, p-benzoquinone and methyl hemiacetals of p-benzoquinone. No O-methylation or any type of alkylation is ever involved. p-Benzoquinone is in equilibrium with its hemiacetal which gets reduced to p-methoxyphenol by hydroquinone which itself gets oxidazed to p-benzoquinone... and so on the cycle cycles until no more hydroquinone is left. At least that would be the classical mechanistic interpretation of this reaction.

p-MeO-phenol.gif - 4kB

smuv - 27-1-2008 at 14:38

@Nicodem: In the article chemrox posted the authors pretty extensively explained the mechanism of a seemingly identical reaction (using a different acid) however they made not mention of hemiacetal formation. I agree that what you have proposed does seem pretty textbook however why have the authors of the above paper proposed such a novel mechanism? I guess what I am asking is, does the mechanism proposed in chemrox's paper seem valid too (other than repeated erroneous drawings benzoquinone)?

I suppose though, in terms of how it applies to substituted hydroquinones, both proposed mechanisms would require an analogously substituted benzoquinone.

Reference Information

solo - 27-1-2008 at 19:11

what is it?

4-METHOXYPHENOL

SYNONYMS p-Hydroxyanisole; p-Methoxyphenol;
Hydroquinone monomethyl ether; Mono Methyl Ether Hydroquinone; Mequinol;

APPLICATIONS
It is used as an inhibitor in vinyl and acrylic monomers, especially for clear products and as an antioxidant. It is used as a stabilizer to inhibit peroxide formation in ethers, chlorinated hydrocarbons and ethyl cellulose. It is also used as an intermediate to manufacture other stabilizers, dyes, pharmaceuticals and plasticizers.

..........................source,

http://chemicalland21.com/specialtychem/perchem/4-METHOXYPHE...

Klute - 27-1-2008 at 22:04

Quote:

Originally posted by solo

It is used as a stabilizer to inhibit peroxide formation in ethers, chlorinated hydrocarbons and ethyl cellulose.

That could be pretty interesting, for recylced ethers, redistilling them before use if need be. I wonder what the thereshold effective amount would be. I guess I could just aswell use some hydroquinone though.

@Nicodem: thanks for that clarification. I think that was the mecanism suggested back then.

@smuv:I think in the article the mecanism is presented differently to explicit the role of the solid acid catalyst (they speak of "chemiabsorbed" species). But I do find their mecanistic cycle a bit unclear....

Nicodem - 28-1-2008 at 11:22

Clearly the authors were not specialized in organic chemistry or they would not make so many mistakes (indeed it is terrible that they continuously write the structure of p-benzoquinone wrongly, but more so is terrible that the reviewers and editors never corrected them). The presence of the destabilized carbocationic intermediate formed from p-benzoquinone protonation, as they draw it, is not just formally wrong (what they surely had in mind is the O-protonated p-benzoquinone of which one of the resonance structures is indeed what they wrote) but in MeOH as solvent the hemiacetal immediately forms by methanol addition. All would be well if they had drawn the O-protonated p-benzoquinone as the intermediate to such hemiacetal formation (this mechanism of hemiacetal formation is described in most textbooks), but they insinuate that this carbocationic intermediate condenses with protonated methanol (MeO+H2

which is absurd. Why would an electrophilic center react with an electrophilic center?
Anyway, it is just a matter of them not following the formal rules for writing down mechanisms and not having much insight in mechanistics. But what they lack in insight they compensate with hard work. After all every mechanism is a just a hypothesis. Thus, they have all the right to propose their own mechanism as long as it does not go against the theory (and here is where the reviewers failed to do a proper job). We all do mistakes, but it is up to our peers to warn us about them...

PS: Using p-benzoquinone on a substituted hydroquinone should result in a mixture of the substituted p-methoxyphenol as major product and p-methoxyphenol as minor product (besides the usual black tar and other crap). That is assuming the substituent is an alkyl. If the substituent is an electron withdrawing group the reaction would be slower or fully inhibited (depending on the redox potential difference among the substituted/unsubstituted p-benzoquinones).

[Edited on 28/1/2008 by Nicodem]

smuv - 28-1-2008 at 11:32

Klute, I have considered this. However, overall the paper chemrox posted seems to be the same reaction as that of the British patent with a different acid catalyst. I find it weird that 2 seemingly similar procedures are explained by such different mechanisms.

P.S. I am not trying to prove the patent writers or Nicodem wrong, I am just trying to figure things out.

Edit: I was writing my message as you posted Nicodem; thank you for expressing your view upon this subject. I guess it makes sense as when I was drawing out the reaction mechanism for this (curved arrows and all) by the author's mechanism weird things were forced to happen.

[Edited on 28-1-2008 by smuv]

panziandi - 26-9-2009 at 17:26

IMPORTANT NOTE,

During a preparation of p-methoxyphenol via a similar procedure to Klutes, I encountered towards the end of the distillation of ethyl acetate I noticed a strong odour of acetic acid and a dark red liquid that did not crystalise on cooling (however crystals deposited), I believe that when heated in a the flask, p-methoxyphenol maybe strong enough to catalyse the hydrolysis of the ethyl acetate to acetic acid.

I strongly recommend removing the ethyl aceate solvent form the crude p-methoxyphenol on a hot water bath or rotary evaporator, do not use a mantle as I did. Sloppy mistake.

crazyboy - 27-9-2009 at 11:07

I found this when researching uses for 4-methoxyphenol http://en.wikipedia.org/wiki/Mequinol

Apparently in combination with "Tretinoin" it can cure vitiligo and liver spots.

I suppose it is also a good starting point for some substituted phenethylamines...

panziandi - 27-9-2009 at 17:55

Indeed it is a melanocytoxic agent, killing the pigment-producing cells in the skin.

Crazyboy you only need to quickly brush the surface of this forum to find this compound (and similar) being used in skeletons of phenethylamines/amphetamines. It's a shame really because it is a rewarding compound to make just for the nice crystals you can isolate. Also it (together with the o-formyl derivative) can be used as building blocks for substituted heterocycles amongs other uses.

crazyboy - 10-1-2010 at 10:39

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 will also add the hydroquinone more slowly. The only problem I ran into was when I was vacuum distilling I tripped the surge protector on my power strip a few times and when I restarted the vacuum pump the mixture bumped considerably splashing some of the impure compound into the collection flask. I don't have ethyl acetate or petroleum ether at the moment and recrystallization from acetone/DCM is a nightmare. I think I will evaporate off all the solvent and synthesize some ethyl acetate.

And now pictures!

The reaction apparatus:

Reaction refluxing:

Extraction:

Crude crystals:

Short path vacuum distillation:

[Edited on 10-1-2010 by crazyboy]

Klute - 10-1-2010 at 13:59

Thanks for the pics!

Ouch I'm scared for that little pump there, no protection? It's pretty sure you'll have some product passing into the oil of the pump, especially without a condenser..

At what temp does you phenol pass?

crazyboy - 10-1-2010 at 16:17

Quote: Originally posted by Klute

Thanks for the pics!

Ouch I'm scared for that little pump there, no protection? It's pretty sure you'll have some product passing into the oil of the pump, especially without a condenser..

At what temp does you phenol pass?

Yeah, I won't be doing that again until I get a buchner flask or something to bubble the vapor through. Luckily though the vapor that got pulled into the tube condensed in the first few inches and didn't make it to the pump, I'm more worried about the heat/moisture.

The product seemed to pass over at 140-150C but I had the paint stripper on the glass right where the thermometer bulb was so the temperature went to 160-165C.

Panache - 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.

schwabb - 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

turd - 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?

crazyboy - 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.

Fleaker - 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.

crazyboy - 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.

Klute - 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...

2,5-Dihydroxyacetophenone methylation

DrNoiZeZ - 10-9-2011 at 06:18

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?

peach - 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
<a href="http://img834.imageshack.us/i/img0444cs.jpg/" target="_blank"><img width="800" src="http://img834.imageshack.us/img834/6066/img0444cs.jpg" alt="Free Image Hosting at www.ImageShack.us" border="0"/></a> 
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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

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.
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.
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]

497 - 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]

Nicodem - 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).

497 - 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]

DrNoiZeZ - 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

turd - 24-10-2011 at 01:30

Quote: Originally posted by peach

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.

peach - 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]

lullu - 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]

DJF90 - 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.

lullu - 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.

lullu - 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]

Wolfgangg - 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

).

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

Crystals under solvent

Giant chunk

Filtered product

DJF90 - 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]

lullu - 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.