Sciencemadness Discussion Board - 4-Ethoxyphenol / hydroquinone monoethyl ether

4-Ethoxyphenol / hydroquinone monoethyl ether

turd - 12-7-2009 at 08:54

Klute presented a nice OTC method for preparing 4-methoxyphenol via reaction of hydroquinone with methanol: https://sciencemadness.org/talk/viewthread.php?tid=9835
I'm not posting in this thread, since resurrecting old threads is undesired AFAIK.

So I was wondering if using ethanol instead of methanol would give the corresponding 4-ethoxyphenol. The interest in 4-ethoxyphenol mainly stems from the fact that it's a potential precursor to the 5-ethoxy analogues of the 2,5-dimethoxyphenetylamines. Apparently they are less dramatic but with a similar dosage and longer duration: http://www.erowid.org/library/books_online/pihkal/pihkal023....

Being a lousy organic chemist my only chance was to find out by trying. The answer is yes it works, but the yield was quit low (which may be caused by my inaptitude in preparative organic chemistry).

The catalyst benzoquinone was obtained by reaction of 10 g hydroquinone with H2O2 in EtOH and a catalytical amount of I2 as huge canary yellow crystals. The reaction had to be heated to 45°C for a few hours to ensure complete conversion of the intermediate quinhydrone. The crystals become black over the course of a few weeks, probably due to reduction to quinhydrone.

20 g Hydroquinone, 20 ml H2SO4, 2 g benzoquinone and 200 ml EtOH (denat. with MEK) were refluxed for 6 h and stirred for another 12 h at RT. Approx. 100 ml EtOH was distilled off, and approx. 100 ml brine was added to the residue (massive precipitation of an inorganic salt). The reaction was extracted three times with EtOAc (inorganic salts go in solution) and the combined organic phases washed in succession with brine and water. The EtOAc was distilled off at atmospheric pressure and the residue vacuum distilled (122-125°C) into a cold trap. The still head was tilted upwards to avoid spills contaminating the destillate. Only wide joints (29/32) were used to avoid clogging of narrow paths with crystallizing product. The product gave a single sharp peak in the DSC (I don't have the scan with me, will check the exact location). Yield: 14.6 g (58%)

A first try with refluxing for merely 4 h and no additional stirring gave unreacted hydroquinone (yes, even in the distillate), which was apparent by a broad DSC signal in the 170°C range.

Klute - 12-7-2009 at 10:59

Very good work! The yield you obtain seems like the one claimed by the patent as far as I remember..
I always wanted to try this reaction, but never found the time in doing so...

Are you going to try and formylate this compound? I would recommend the Mg/HCHO method for this!

Thanks for sharing!

Nicodem - 12-7-2009 at 13:42

Quote: Originally posted by turd

Being a lousy organic chemist my only chance was to find out by trying. The answer is yes it works, but the yield was quit low (which may be caused by my inaptitude in preparative organic chemistry).

According to the patent US1557237 the conversion of this reaction when using ethanol is only 40% under their conditions and reagents ratio. So, I would tend to say that your self critique is a bit exaggerated.
You used the same amount of p-benzoquinone as in that patent, but much more H2SO4. In Zhurnal organicheskoi khimii, 27 (1991) 1828-1831, they used a ratio more similar to what used but they do not report yields for ethanol, only methanol (80%), propanol (64%), butanol (49%), isobutanol (17%), pentanol (30%), hexanol (28%) and heptanol (7%).

turd - 13-7-2009 at 10:14

Argh, silly DSC! I remembered the DSC giving a melting point of 74°C, which distinctly above the literature value, which usually means that you made the wrong molecule. So I checked again, and indeed 74°C. This is not unusual for compounds with a high vapor pressure, since I work in a closed system, so I repeated the measurement with holes in the sample container and indeed a typical huge sawtooth sublimation peak from RT->200°C (no residue), but still melting at 74°C. Then I measured an older sample which I believe to be more pure and this one melts in the 64°C region!

I cannot explain this at all. There shouldn't be any unreacted hydroquinone inside, since that would cause a melting point depression. And I don't see what different molecule I could have got. I still hope that it's an artefact of the measurement. So when I find time, I will have to recrystallize some to get an analytical pure sample and see what it does. And check it on a thermo microscope.

Apart from that... I have to admit that I didn't read the original literature and wasn't aware that higher alcohols have been tried as well. I just used Klute's version replacing methanol by ethanol and increasing reaction time. The decrease in yield is interesting - if it was only the acidity of the hydroxyl it should quickly stabilize, so I can only fathom poor solubility in the higher alcohols?

Yes, ultimately I plan to formylate it, but unfortunately not anytime soon, since I will spend a few months abroad.

Klute - 13-7-2009 at 13:16

Maybe it's ome benzoquinone left in the mix? I don't think you have made any di-ethoxybenzene, this method only mono-alkylates IIRC. Let us know ho wit goes after recrystallization. I think AcOEt and Pet ether should work as well as for p-methoxyphenol.

Nicodem - 14-7-2009 at 00:10

There are melting points for p-ethoxyphenol reported in the literature that go up 67°C, but none as far as 74°C. But then again, except for some special cases, no organic chemist would use DSC just for a simple mp measurement, so maybe it has to do with the instrument. Is it even calibrated for such low temperatures?
Don't you non-organic people have any IR instruments? If DSC shows a single sharp peak then it must be relatively pure. The IR spectra would then also show what it is.

turd - 14-7-2009 at 04:49

Yes, sorry. I forgot that there are compounds which absorption spectra beyond 500 cm^-1.

If I upload the spectrum do I get an interpretation?

But seriously, it looks exactly like the one from the Sigma-Aldrich site. Just the 2500-3500 cm^-1 region shows proportionally less absorption compared to the rest (because I used an ATR cell and didn't bother with a KBr pill?).

The DSC is well calibrated (and is used for low temperature measurements), but there's a reason you don't use it for melting points of organic compounds: the method is unreliable for compounds with a significant vapor pressure. Like I said, when I find time I will recrystallize some and check it under the thermo microscope.

turd - 9-8-2009 at 12:29

Hi Klute,

I couldn't resist and had a quick stab at your wonderful Mg-mediated formylation. Due to time and equipment restraints and general clumsiness I think I made every error which is possible (apart from dropping the flask).

So I was really surprised that when removing the toluene I got an orange/red oil, which then crystallized rather quickly to give a yellow crystalline mass and didn't smell anything like the 4-ethoxyphenol.

I didn't want to vacuum distill it, since I believed my pump to be too weak, so while pondering whether to perform steam distillation (of a solid - does that even work?) or to recrystallize it from cyclohexane - I just decided to try methylation according to Hest (https://www.sciencemadness.org/talk/viewthread.php?tid=4287#...). And there happened the next surprise: my nice crystals were turned into a nasty dark red oil (is it possible to overmethylate?). So I extracted with chloroform, washed with water and distilled (at only 89-93°C!) to get actually quite some yellow oil which didn't crystallize so far. It has only a faint smell, which reminds me of the 3,4,5-trialkoxy benzaldehydes. So now I am a proud owner of what I believe to be 2-methoxy-5-ethoxy-benzaldehyde.

Of course this will have to be repeated in a more controlled setting. Still I'm happy.

[Edited on 9-8-2009 by turd]

5-EtO-2-MeO-benzaldehyde

Ullmann - 15-8-2009 at 11:23

5-ethoxy-2-methoxy-benzaldehyde :

1) para-ethoxy phenol :

In a 1 liter RBF there is placed:
10 g benzoquinone
100 g hydroquinone
400 ml EtOH (denatured with Et2O)
40 ml H2SO4 d 1.84 MM 98 95% => 700 mmol (~0,7 eq.)

The solution is stirred 1 night @ 70°C (bath temp) with a air condenser

Workup:

There is added 30 g NaOH in 40 mL H2O. The pH of the solution was 2. The solvent was evaporated, the residue was taken up in EtOAc/H2O, decant, wash brine, dry on MgSO4. The residue was distilled in vacuo without fractionating column to give 110g of a pale solid (there remained 10 g of black insoluble solid in the RBF). The crystals were recrystallized from toluene to yield 91 g of beige crystals (660 mmol ~66%). Their were still contaminated by unreacted hydroquinone but nonetheless used as such for the next step.

2) Formylation : 5-ethoxy-2-hydroxybenzaldehyde

Following exactly the (excellent) write-up of Klute (https://sciencemadness.org/talk/viewthread.php?tid=10124), under argon, with the exception I did not use any other special measure to not have moisture (RBF were dry but not oven dried, I did not use syringe technique, liquids were poured normally, solvent were from freshly opened analytical grade bottle but not sieves-dried nor distilled prior to use).

In a 3 necked RBF with argon inlett, a condenser and an addition funnel.

Magnesium methoxyde was prepared from 5.8 g Mg turning in 60 ml MeOH with catalytic Iodine, reflux 30 min under argon. To this solution was added 56 g recrystallized but still impure para-ethoxy-phenol (~400 mmol) in 220 ml degassed toluene in one portion.

The color of the solution was successively:
Dark blue then dark red then grey suspension after 40 min reflux @ 80°C.

The condenser was replaced by a distillating setup a thermometer was put in the solution. The bath temp was fixed at 120°C and the distillation was effectued until internal temperature was 75°C. At that moment it start to become a gel hence without waiting an addition funnel with 40 g of paraformaldehyde suspended in 100 ml of toluene is attached and the addition is started. The addition speed was controlled to have a regular distillation. The temperature climbs to 90°C then stabilize. When half is added everything dissolved. At the end it is no more the MeOH/toluen azeotrope @ 60°C that distill but the distillate temp climbs to 80°C while the pot temperature is 100°C. This signal the end of reaction as controlled by HPLC (1h30 total addition time). The solution is stirred 30 min more at 100°C then cooled to 30°C. In total 170 ml of distillat are obtained.

Workup :

The cooled solution is poured on 400 ml of 15% H2SO4. It is extracted twice with toluene, combined organics are washed with 5% aq H2SO4 then 2x H2O. After evaporation of the solvent the red oil is distilled. The fraction boiling at 95-100°C@0.1 torr is recolted. This is a yellow solid : 48 g (72%) . It is recrystallized from EtOAc/hexane or toluene to yield 40 g of beautiful yellow crystals.

3) Methylation : 5-ethoxy-2-methoxybenzaldehyde

Preparation of 1M methyl-methane sulfonate (MMS) solution:

In a 250 ml RBF with a silicagel tube. To a suspension of anhydrous Na2CO3 (300 mmol, MM 106, 43 g) in MeOH (125 ml) there is added dropwise during 30 minutes and with cooling (ice bath intermittently) 225 mmol methanesulfonyl chloride (MM 115, 105 g, d1.48, 17,3 ml). An exothermic reaction occur. After the addition is done the mixture is let reach RT over 30 minutes. It is filtered on buchner (CAUTION!! POTENT DANGEROUS CARCINOGEN, THIS WAS DONE UNDER A HOOD WITH ALL PROTECTION) and the salt washed with twice 50 ml MeOH. The filtrate was used as such for the alkylation. With the rince MeOH the volume is 225 ml hence 1M solution. THE SALT WAS THEN POURED IN EXCESS 25% AMMONIA with an equal volume of methanol and left to destroy any remaining MMS for one night.

To the pre-formed MMS solution in MeOH there is added 16,6 g 5-ethoxy-2-hydroxybenzaldehyde (MM 166, 100 mmol) followed by 7 g of powdered KOH (MM 56, 85%, 100 mmol). The reaction was refluxed for a night at a bath temp=90°C. A thick precipitate (MsOK) occured after ten minutes heating.

Workup the next day :
quench with slight excess 25% ammonia, 30 min at 50°C
Evaporate MeOH
Take up in EtOAc/H2O, decant, extract twice more with EtOAc
Wash with 5% aq NaOH twice
Stir the combined organics with excess HCl 3 N to hydrolyse any imine.
Decant, wash H2O, brine, dry on MgSO4

Yield 11.5 g (64 %) It is an oil hence cannot be recrystallized. It can be distilled in vacuo (122°C@0.1 torr).

NB : This is unoptimised MMS alkylation, it is better to do it like this : For that amount of MMS 1M in MeOH (225 ml) add 100 ml water and stir at 50°C. Then add at that temperature 1,5 eq of 50% KOH solution in water dropwise. Let 6h at 50°C and do the workup as above.
Or like that : Add only half the MMS solution and half the water at 50°C, dropwise add 50% KOH in water (1 eq) during one hour then add alternatively the remaining MMS solution in MeOH and 50% KOH by portion by controlling the pH to remain > 10 during three hours. If MsOK precipitate add some water. Left at least 6 hours. Do the workup as above. Yield are good.

Methyl Ethane sulfonate can be used in place of MMS as an OTC methylating agent as explained in my previous post https://sciencemadness.org/talk/viewthread.php?tid=9921&...

[Edited on 15-8-09 by Ullmann]

Klute - 19-8-2009 at 06:08

Beautifull! Thanks alot for sharing your notes! I am glad my write up inspired you! ANd this is a brillinat use of your excellent MMS write up! Have you not considered removing the methanol and using the sulfonate in a different solvent, such as DMF for example? You might get to those >80% yields MeI and TMP give...

Anyway, brilliant work! A pleasure to read!

Ullmann - 19-8-2009 at 08:20

No i havent used it with success in another solvent than MeOH (or better aqueous MeOH)

Once I had tried in DMF after evaporation of MeOH for 5-hydroxy-1,3-benzoxathiol-2-one to 5-methoxy-1,3-benzoxathiol-2-one with no success :

To a stirred solution of 5-hydroxy-1,3-benzoxathiol-2-one (0.4 mol, MW 168, 67 g) in DMF (200 ml) there was added finely powdered anhydrous K2CO3 (MW 138, 0.60 mol, 83 g) and then MMS in 100 ml DMF (MW 110, 55 g, 500 mmol) and the brown mixture was stirred at RT for 20 h with a guard tube. LOTS OF PPT I HAD TO ADD 300 ml DMF with NO SUCCESS it is unstirrable. Next day : one big paste unstirrable. I had 2L water that dissolved the salt but nothing went out. (The product should precipitate at that point with DMS it works)

--> Failed reaction

Abit off topic but there is the same reaction with dimethylsulfate :

To a stirred solution of 5-hydroxy-1,3-benzoxathiol-2-one (0.5 mol, MW 168, 84 g) in DMF (250 ml) there was added finely powdered anhydrous K2CO3 (MW 138, 0.72 mol, 100 g) and then DMS (MW 126, 80 g, d 1.33, 60 ml, 630 mmol, ) EXO temp --> 70°C and the brown mixture was stirred at RT for 20 h with a guard tube. The next day it was diluted with 2,5 L H2O which precipitated a product. This was filtered, washed with plenty of water and abit cold MeOH and recrystallized from 400 ml MeOH to give long beige needles (50 g, MW 182, 275 mmol, 69 %) :-). To the filtrate was added ammonia to destroy excess DMS but ammonia should not come in contact with the product as it reacts with it.

This is a very good precursor for thio compounds... but it is another story ;-)

With MMS using the procedure with multiple alternate addition of KOH and MMS I gave in the post above yield of 75%+ had been obtained with some substrates using 2 or 3 eq... In the same solvent (aqueous MeOH) with KOH as a base it is quicker and give better yield than DMS as DMS hydrolyse quicker than MMS in those conditions... As far as I am concerned MMS (and MES) are very suitable alternative for DMS but not in DMF...

Klute - 19-8-2009 at 10:07

Thanks for the details! So that's the product obtained from reaction of benzoquinone and thiourea, correct? You methylate the free hydroxy, then hydrolyse to obtain the methoxy-hydroxy-thiophenol, right? Looks very promising...

Ashame that MMS doesn't seem to work in DMF.. Did you follow the reaction in any way, or is your assumption only based on the lack of precipitate after addign water? If there is still quite some DMF in there, maybe your product was there after all...

turd - 21-8-2009 at 05:48

Wow, thanks for the great writeup.

Quote: Originally posted by Ullmann

The bath temp was fixed at 120°C and the distillation was effectued until internal temperature was 75°C. At that moment it start to become a gel hence without waiting an addition funnel with 40 g of paraformaldehyde suspended in 100 ml of toluene is attached and the addition is started.

Yes, I had the same problem. I continued distilling up to ca. 85°C internal temp and the whole thing turned into an unstirable mess. I had to add quite some fresh toluene and had to stir with a glass rod (which broke of course) at the beginning of the addition of the paraformaldehyde. The reaction then became stirable rather quickly and eventually everything went into solution.

Quote: Originally posted by Ullmann

[5-ethoxy-2-hydroxybenzaldehyde] boiling at 95-100°C@0.1 torr is recolted. [...] [5-ethoxy-2-methoxybenzaldehyde] can be distilled in vacuo (122°C@0.1 torr).

The phenol has the lower boiling point? Now I feel really dumb, since I made the methylation reaction because I thought it was the other way round.

My product partly crystallized in the last ten days, and is now a mass of yellow crystals and some yellow liquid at room temperature. Looks like its not very clean.

behemoth - 21-8-2009 at 08:59

Quote: Originally posted by turd

Wow, thanks for the great writeup...

Quote: Originally posted by Ullmann

[5-ethoxy-2-hydroxybenzaldehyde] boiling at 95-100°C@0.1 torr is recolted. [...] [5-ethoxy-2-methoxybenzaldehyde] can be distilled in vacuo (122°C@0.1 torr).

The phenol has the lower boiling point? ...

This might well be the case. In o-hydroxyaldehydes there is a hydrogenbonding between the -OH and the -CHO which makes such compounds more volatile. For example, the 2-hydroxy-5-methoxy-benzaldehyde can be steam-destilled at normal pressure whereas the parent compound 4-methoxyphenol cannot.

Ullmann - 21-8-2009 at 10:43

@Klute :
I do not remember, maybe some product was there but as none crystallized even with seeding and cooling it looked crap... But the stirring was impossible from almost the beginning because of the salt hence when I saw this I added DMF and let it for one night but more DMF was useless as this is a gel-like ppt and nothing can stir really... I did this reaction with DMS several times and each time the produt ppt at the end by dilution in water all in all I just dumped it. If there is no access to DMS for this particular reaction I would try MeBr (or MeI) not MMS.

Yup you are right it is the product of benzoquinone and thiourea prepared like posted in https://www.sciencemadness.org/whisper/viewthread.php?tid=11...
I have updated that thread for the higher homologues to show how the thioxolones can be used for thio compounds as this is off topic here. Please continue this discussion there if interested.

@Turd :
Yup the first time I did heat it more and more and it was unstirrable hence when I did it the second time I added the HCHO directly when I saw it was gelifying to complex more Mg salt and it worked very nice.

About the bp I do not remember if I used the same apparatus for both compounds, I used the same pump, but nonetheless there is no point in separating both product by distillation as with the NaOH washes the free phenol is washed by water as the phenolate while the methoxylated one remain. By TLC you can check the purity of the product.

[Edited on 21-8-09 by Ullmann]

turd - 22-8-2009 at 00:32

Quote: Originally posted by behemoth

Interesting. So, naively speaking, the preference for intramolecular H-bonds reduces the amount of intermolecular H-bonds and therefore the liquid has a lower boiling point?

Quote: Originally posted by Ullmann

About the bp I do not remember if I used the same apparatus for both compounds, I used the same pump, but nonetheless there is no point in separating both product by distillation as with the NaOH washes the free phenol is washed by water as the phenolate while the methoxylated one remain. By TLC you can check the purity of the product.

I had the impression that the methylation produced a lot of by-product (red tar), but of course it could have been by-product from the first reaction.

turd - 29-12-2009 at 01:27

Quote: Originally posted by turd

My product partly crystallized in the last ten days, and is now a mass of yellow crystals and some yellow liquid at room temperature. Looks like its not very clean.

Update (even if nobody cares

): I finally got around to isolate the crystalline parts and its without doubt the desired 2-methoxy-5-ethoxy-benzaldehyde (or is it 3-ethoxy-6-methoxy-benzaldehyde?). Analysis data available on request. The oil (which is orange by now) obviously contains some impurities, but I'm not too sure of what to do with the NMR. So I tried to clean the crystals as much as possible from oil (this stuff sticks!). They melt quite sharply at 43-44°C.

not_important - 29-12-2009 at 02:25

Did you try the old school method of spreading the crystals onto unglazed ceramic tiles? Pick a fine grained tile, the oils will generally soak in with little loss of solids; although it's worth making sure the tile is cold and stays so to reduce solution of the solid by the oil.

Ullmann - 31-12-2009 at 14:37

@Turd :

As far as I remember the product 2-methoxy-5-ethoxy-benzaldehyde is an oil. Mine did not crystallize even after distillation. I do not know what you have as a solid but it is peculiar for sure. If I were you i would do the formylation then you purify the 5-ethoxy-salicylaldehyde by distillation under vacuum and then by recrystallization : it forms very beautiful yellow needles. Then when you have got it pure you methylate it and you separate the product from its unreacted phenol by washing with 5% NaOH solution two times in the workup. At that moment the product will be pure enough to use in say a condensation step with nitromethane and the NS is a solid and can be recrystallized from MeOH.

If you cannot do the reduced pressure distillation you can try the steam distillation as is suggested by behemoth.

Quote: Originally posted by behemoth

Then you will not need a big vacuum pump and it is more OTC. But really if the 5-ethoxy-salicylaldehyde is recrystallized and pure you do not need to do a distillation step after the methylation for the product ether and the unreacted phenol are easily separated by simple base workup and an oil is OK. Sometimes i use benzaldehyde of say 70% purity like for the 4-chloro-2,5-DMB and when the NS is made by recrystallisation of it it becomes an homogeneous compound (with sometime a few % of the cis-NS as an impurity but this is unavoidable as the cis and trans NS interchange during recrystallization).

If you want a procedure for NS that work most of the time there is one in the Sulfuric Duff thread with methylamine acetate as a catalyst it is the same than Barium's on old Hive but with the correct order of addition of reactants (Ba's didnt put acid before the end of condensation and if you do like him the NS will polymerise but if the NS ppt readily from the solvent but it is quite rare and is not the case with this NS IIRC). If the NS do not ppt during the reaction (like this one) the yield will not be 80%+ but more like 60% but the purity will be excellent. Or you can use ammonium acetate in GAA of course.

My advice : trash this unkown solid and do it again from the beginning and purify the 5-ethoxy-salicylaldehyde thoroughly by recrystallization before continuing.

turd - 1-1-2010 at 04:17

@ not_important: I used a similar technique with a bunch of filter papers. The slight yellow crystals look dry to the eye, but under the microscope it's an entirely different matter...

So the real mp may even be higher than the 43-44°C I obtained.

@ Ullmann: I'm 100% positive that the solids are the desired benzaldehyde. I will send you the data so you can see for yourself. I'm not wondering that the stuff didn't crystallize for you: DSC experiments showed a huge hysteresis. The freezing point after an initial melting was determined at -10°C(!). And even then it did not solidify completely, as the melting point on the next heating cycle was significantly depressed.

Unfortunately I still have very little time, so condensation with nitromethane will have to wait.

First I want to get the methylation reaction under control.

turd - 13-2-2010 at 01:30

Well..., not perfect, but already much better!

Used Ullmann's modification of the formylation on 35 g p-EtO-phenol. A larger excess of Mg was used (5 g). The magnesium ethoxide/MeOH cake was prepared a week before use due to time constraints (after the first night of standing, H2 overpressure was released). The reaction showed no signs of gelation at an internal temperature of 75°C, yet addition of paraformaldehyde was started at that point. Unfortunately the idea of using a paraformaldehyde suspension in toluene did not work out, since the paraformaldehyde was in the form of small pellets and hopelessly clogged the stopcock of the addition funnel. (Note to self: Next time powder it!) Instead 25 g paraformaldehyde was added portion wise through a sidearm of the flask over the course of ca. 1h30. Inadvertently made 5\% instead of 15\% HCl and the reaction stayed at the green phase during acidification.

Thankfully the error was spotted in time and could be corrected by addition of more HCl. One observation I already made the last time: there is a small amount of black solid which gives nasty emulsions and is a filter clogger (some Mg sludge?). Once this is removed by filtration extractions work much better. After removal of the toluene, a reddish crystalline mass was obtained which was used directly in the next step.

This time finely powdered and dried (at 250°C) K2CO3 was used for the methylation, and what a difference that made!
The crude product from the formylation was dissolved in ca. 200 ml DMF and 45 g of dry K2CO3 added. Ca. 22 ml DMS was added using an eye dropper. Scarily strong exothermic reaction! A water bath got everything under control. The reaction was stirred for 3 h at RT and poured into 400 ml water. The crude product was extracted three times with toluene and the combined organic phases washed twice with 5% aq. NaOH solution and twice with water. The first NaOH washing was very dark, hinting at significant amounts of non-methylated product. The toluene solution was dried over MgSO4, the solvent stripped under aspirator vacuum and the residue distilled at 94-95°C in two fractions with a prerun of 85-95°C. Thus 28 g (64% from p-ethoxy-phenol) of a yellow oil with characteristic smell was obtained.
The oil crystallized in the fridge. The product probably contains small amounts of unmethylated material, since at room temperature the prerun and the first fraction contain (very minor amounts) of an oil. The second fraction is completely solid at RT.

Not too shabby, I think! The formylation reaction seems to be very forgiving! Next time add a second batch of DMS and wash thrice with NaOH.
Again I have to thank Klute and Ullmann for this gem of OTC chemistry.
And I want to stress the fact that with the exception of DMS all used chemicals were indeed obtained OTC. DMS can be replaced by MeI which can be made from OTC materials. What I like about this sequence of reactions is that it starts with symmetric hydroquinone and gives arbitrary asymmetric 2-alkoxy-5-alkoxy-benzaldehydes in very decent yields.

Ullmann - 13-2-2010 at 11:19

Congratulation for the good work. Yes it is a very good procedure Klute did provide us. I am much grateful to him for this one.

I just wanted to add that the cheapest OTC methylating agent one can use is MES (Methyl Ethane Sulfonate) prepared like posted here. I would forget about MeI and use this one. It is easy to prepare and works good in aqueous MeOH at 50°C. It works better than DMS in aqueous MeOH. Another advantage is that it can be generated in situ avoiding the storage of such dangerous chemicals as DMS or MeI. The only disadvantage of MES is that it does form gels in DMF hence do not work in DMF. For good yields use 1.5 eq of MES for each group to be alkylated at a concentration of more or less 0.5 molar solution of 75% aqueous MeOH at 50°C using an excess of aqueous KOH (but NaOH works too) as a base added dropwise at that temperature (higher than 50°C it hydrolyse more, lower than 50°C there is crystallisation of the ethanesulfonate salt).

Hehe with those compounds they say you can remember books and become very smart, have a nice upgrade of your mind software

turd - 17-5-2010 at 13:31

D'oh, fail.

Not of the epic kind, but still.

So what do you do with excess nitrostyrene? What about one of the BOx compounds ( http://www.erowid.org/library/books_online/pihkal/pihkal013.... )?
A chiral 2-carbon-phenetylamine without some awkward substituent on the ring ( http://www.erowid.org/library/books_online/pihkal/pihkal030.... ), now that is something.

9 g of the 2-methoxy-5-ethoxy-nitrostyrene was dissolved in 80ml warm MeOH. Under vigorous stirring 2 g Na dissolved in 80 ml MeOH was added to the still warm solution. Not much of a colour change - maybe from orangeish to reddish. After ~10 min 40 ml of AcOH was added followed by 250 ml H2O. A dark oil separated.

The whole shebang was put in a fridge (~8°C) for two days. The oil had solidified to a dark brown mass and additionally bright yellow needles had precipitated. The needles were filtered off to give 0.8 g of pure beta,2-dimethoxy-5-ethoxy-phenylnitroethane (confirmed) with a mp of 65-66°C. An attempt to recrystallize the brown impure product from MeOH was unsuccessful. In total 4.2 g impure and 0.8 g pure nitroethane were obtained. If anyone wants to repeat this, I think it's a good idea to cool before adding the strongly basic NaOMe solution.

The combined products (minus 100 mg for analytics) and a small amount of HgCl2 were dissolved in a warm mix of 75 ml IPA, 40 ml AcOH and 20ml H2O. 10 g Al foil was added in three portions over 1 hour to maintain a very faint reflux. The reaction was left stirring for another 2.5 h. A cooled solution of 65 g NaOH in 120 ml H2O was added. After practically all unreacted Al was eaten, the organic phase was separated and the inorganic phase extracted twice with a small amount of toluene. The combined organics were washed twice with brine and dried over Na2SO4. The bulk of solvent was distilled off under atmospheric pressure (because the membrane pump caused excessive bumping, but mind the formation of carbonates!) and the remaining solvent stripped under vacuum to obtain a small amount of orange solid. The solid was distilled under vacuum (105-110°C), which was quite annoying due to solidification, to give 2.6 g of snow white beta,2-dimethoxy-5-ethoxy-phenethylamine. At least I guess that's what it is, structure still unconfirmed.

So quite the horrible yields, but should be enough for a few active doses.

Edit: add a missing "MeOH"

[Edited on 17-5-2010 by turd]

Barium - 18-5-2010 at 04:44

Great work Turd!

Nicodem - 18-5-2010 at 04:57

Please post the 1H NMR if you can get one. I would like to see a positive confirmation.
I never had luck in reducing alpha-methoxy-ketoximes or alpha-phenoxyketoximes using aluminium amalgam. They were always recovered unaffected. Hydrogenation over Pd-C also did not work (Raney Ni would probably work, but I did not try). I'm glad to see this Al-Hg reduction system at least works for this type of alpha-methoxy-nitroalkanes, but kind of tend to believe it would not work on Ar-CH(OMe)-CHMe-NO2 substrates (because oximes/nitrosoalkanes are supposed to be intermediates in the reduction of nitroalkanes - aldoximes are more easily reduced than ketoximes). Yet, if someone confirms I'm wrong it would make me feel better.

Barium - 18-5-2010 at 05:33

Before I got my equipment for pressurized hydrogenations I had terrible problems reducing all kinds of oximes, untill I stumbled upon Al/Ni-alloy in this article:
Reductions with Raney alloy in alkaline solution. B. Staskun, J. Chem. Soc. (C), 1966, 531-532.
For hydrogenations I'd use Rh/C (or Rh on acidic alumina) instead of Pd/C. If Raney Nickel is chosen you would have to use a really active version or a freshly prepared one in order to avoid having to use high pressures.

turd - 18-5-2010 at 22:03

Thanks Barium, but I think Nicodem's objections are justified. What I probably got _is_ the oxime. Shulgin describes all amines as oils and this was very eager to crystallize. I will try to organize an NMR to get a definite answer, but a small scale chemical test should also discriminate between oxime and amine.

Sorry for the noise.

Barium - 19-5-2010 at 07:13

I can't recall ever seeing a nitroalkane being reduced to a oxime. It can be a hydroxylamine though as those are very prone to crystallize and are known intermediates in the reduction of nitroalkanes. A simple test for hydroxylamines is to react it with Tollen's reagent. A positive reaction forms a silver mirror in a clean test tube.

turd - 24-5-2010 at 02:34

Sorry for the delay. To make a long story short (don't drink while doing chemistry, I'll spare you the details): the product was quite basic, isolated as the acetate and - there is no doubt about it - is the amine. The whole matter is still very curious. Why is it a very rapidly crystallizing solid (matters of seconds) when Shulgin describes all related amines as oils? How comes it didn't need significantly higher temperatures to distill than the corresponding amine without beta-methoxy functionality?

Methansaeuretier - 24-5-2010 at 05:09

Is it prossible to monomethylate toluhydroquinone by the same way? Yes, right?

What's the product? 2-Methoxy- or 5-methoxytoluene or a mixture?

[Edited on 24-5-2010 by Methansaeuretier]

turd - 25-5-2010 at 01:32

Yo, in the thread referenced in the first posting of this thread Nicodem posted a mechanistic interpretation of this reaction. Accordingly you will have to use toluhydroquinone as reactant and toluquinone as catalyst. Since both expected products are quite different, you will get one in excess, the question is by how much. If you have access to the necessary analytics, this would be a very interesting experiment. There is a Japanese patent in which a similar reaction is performed, but unfortunately I can't read it. :-P

turd - 9-6-2010 at 10:54

Update: The beta,2-dimethoxy-5-ethoxy-beta-phenylethylammonium acetate was brominated in AcOH and distilled to get a slightly yellow oil of beta,2-dimethoxy-4-bromo-5-ethoxy-beta-phenylethylamine. Isolation of the HCl salt and recrystallization from IPA afforded a pure product (structure confirmed) with a melting point of ~194°C (with decomposition).

Yields were terrible, among other things because my distillation gear is not suited for such small-scale work.

In any case, I hope I have shown that BOx type compounds are easily accessible in a home-lab setting. Maybe one day a better preparative chemist with the ability to resolve enantiomers will explore the "provocative pharmacology" (Shulgin PIHKAL #13) of this class of coumpounds.

Ullmann - 12-6-2010 at 03:41

Good work Turd!

Was the distillation of the freebase really necessary? Recrystallisation of the hydrochloride would not have being sufficient?

I think your amine did catch CO2 from the air and made the carbonate salt.... It is described for certain amine.

Anyway thank you for sharing the good work!

Best Regards,

Dr Ullmann

[Edited on 12-6-10 by Ullmann]

turd - 13-6-2010 at 04:27

Thank you, dottore.

Yes, yields probably would have been higher without distillation, especially after bromination. But if it is possible I prefer distillation to recrystallization because it means less experimenting around with solvent systems, temperature, etc. Anyway, got a little less than 1 g, that should be enough for some initial experiments into the BOx area.