Sciencemadness Discussion Board

A foray into phenethylamines of the Shulgin kind

Benignium - 21-5-2021 at 11:44

For a while now I have been fascinated by the work of Alexander Shulgin, the chemist who famously discovered the psychopharmacological potential of MDMA and designed an astounding constellation of related phenethylamine compounds by systematically modifying the mescaline molecule. There is a great deal of controversy not only surrounding the subject of psychotropic substances in general, but also the unconventional ways Shulgin went about the syntheses and assessments of the compounds he designed. Despite all that, I personally think that any development in this overlapping area of chemistry and medicine is nothing short of essential. We're just being awkward about it at this time.

In the spirit of appreciation and understanding, I have decided to explore for myself the various compounds that may one day have lead us to gracefully deal with the mental health crises of today. I intend to make this a perpetual thread in which I will cram all of my phenethylamine experiments, with the major exception of my ongoing (and nearly finished!) mescaline project.

First up, 2C-B (4-bromo-2,5-dimethoxyphenethylamine):

2,5-dimethoxybenzaldehyde (25 grams, 150 mmol) was dissolved in isopropyl alcohol (163 mL) and to the clear solution on a 100°C hotplate were added, in order, ethanolamine (1.28 grams, 21 mmol), nitromethane (11.30g, 185 mmol) and acetic acid (7.53 grams, 125 mmol). The mixture was heated for 30 minutes with stirring and cooled at room temperature for an hour. After some additional time in the refrigerator, the cool mixture was broken up with a spatula and vacuum filtered to yield 33.7 grams (94.5%) of 2,5-dimethoxy-beta-nitrostyrene as orange needles.

2,5-dimethoxybenzaldehyde under IPA

2,5-dimethoxynitrostyrene crystals

2,5-dimethoxy-beta-nitrostyrene (10 grams, 48 mmol) was added into a 1000 mL Erlenmeyer flask containing a mixture of isopropyl alcohol and water (250 grams, 1:1 by weight). With strong stirring, sodium borohydride (13.36 grams, 353 mmol) was added and the flask was fitted with a condenser. After refluxing the mixture for 10 minutes, a thick slurry of copper(II) chloride dihydrate in water (1.15g) was added and washed down using 40 mL of isopropyl alcohol. The mixture was refluxed for further 30 minutes and quenched with the addition of acetic acid (28 grams, 467 mmol).

The cooled mixture was filtered and most of the alcohol was distilled off. The remainder was basified using 20% NaOH (100 mL) and extracted with 4x25 mL of DCM. The DCM extracts were pooled, washed with water and acidified with 33% HCl (5.00 grams), followed by extraction with 3x40 mL of water. The aqueous solutions were pooled and washed with 3x20 mL of DCM. Once more the solution was made basic with 20% NaOH (50 mL) and extracted with 4x25 mL of DCM. This final extract was acidified using 33% HCl (2.46 grams) and stripped of solvent. The remaining water was removed via azeotropic distillation with toluene and a sudden precipitation of fine crystals took place on cooling. The crystals were vacuum filtered and air dried to yield 5.2 grams (50%) of 2,5-dimethoxyphenethylamine (2C-H) hydrochloride as an off-white crystalline powder with a greenish tinge.

Reaction mixture before addition of CuCl2

Reaction mixture after addition of CuCl2

Filtered reaction mixture

Initial combined DCM extracts

"Spent" DCM <-> aqueous product

Final pooled DCM extracts

2C-H hydrochloride crystals precipitated from toluene

Dried 2C-H hydrochloride

2,5-dimethoxyphenethylamine hydrochloride (5.2 grams, 24 mmol) was dissolved in acetic acid (10.76 grams) and with strong stirring there was added bromine (3.73 grams, 47 mmol) in acetic acid (6.67 grams). After a delay, the mixture turned into a tan slurry. Stirring was continued for an arbitrary 20 or so minutes and the solids were vacuum filtered and air dried to yield 5.27 grams of 4-bromo-2,5-dimethoxyphenethylamine hydrohalide salts as a slightly brownish white powder.

2C-B salts precipitating out of reaction mixture

Dried crude 2C-B salts

The Henry reaction to form the nitrostyrene has got to be one of my all-time favorites. It is straightforward, suitably quick and aesthetically pleasing beyond belief. Therapeutic, almost.

From what I've read, the NaBH4/CuCl2 reduction in the case of 2C-H should ideally afford a yield of 60-70%. I'm not exactly sure what the faults are with my procedure here, but fortunately the yield obtained is still very reasonable.

I was glad to see that, in the final bromination step, it's just as well to use the hydrochloride salt of 2C-H. In the future I would also like to try the bromination using N-bromosuccinimide.

There are two more steps to this procedure that I still intend to undertake: the conversion to anhydrous hydrochloride salt and subsequent recrystallization. I debated withholding the thread until then, but decided against it because it's going to take a while for me to get around to completing those steps and calculating the final yield. This will do for now.

karlos³ - 21-5-2021 at 13:05

Great stuff!
Have you used my writeup on 2C-H by the way? It looks like you did :)
Also, NBS bromination, what a neat pleasure it is, no?
Also from my posts? :D

I'll try to post a chromatogram of my 2C-B HCl and IR spectra, I have them somewhere on some of the PC's.

Now, absolutely non-scientific, have you thought about vaping the 2C-B HCl?
It is like a longer acting DMT trip, but without the psychological depth, just like a multicolored fun morphingtainment, acting for like two hours, with breathing walls and dancing pictures :D
But much deeper than that still, on the psychological level.
Its a competent teacher, not a fun-dealing substance, despite lacking the initial depth.
Very great to work on yourself!

Register, if you haven't already, and take a look at this bioassay thread regarding 2C-B HCl and its inhaled intake.
Makes a magnificent drug even much better!
You need to register to access it, but I'm sure you will enjoy that read.
No need for a real email etc either, just register with whatever fake mail you desire.

mr_bovinejony - 21-5-2021 at 17:27

You added all the nabh4 at once to a solution of the nitrostyrene and refluxed? Or they were partial additions? This is the first time I've seen the reagents added that way for 2c-h, usually its the nitrostyrene added portion wise to the solution of nabh4

Opylation - 21-5-2021 at 17:28

Beautiful pictures, and great workup. What did you use for your 2,5-dimethoxybenzaldehyde precursor? Did you go the 1,4-benzoquinone route or go a different route like PET->terephthalic acid->phenylenediamine->hydroquinone? Or did you work your way up from 4-nitrochlorobenzene? Or even starting with acetaminophen is another good one

Benignium - 22-5-2021 at 10:13

karlos³ - Thank you! I am ashamed to say I had not in fact encountered your writeup, but much of the information does originate from two comments of yours where you outlined the use of acetic acid and the distillation of alcohol out of the reaction mixture. The NBS I haven't researched much either, but I am aware that it is used.

Interestingly I have never come across any mention of vaporizing 2C-B, let alone the hydrochloride salt. What an interesting prospect! Thank you for bringing this thread to my attention. I feel bioassays are a central part of the subject and I will be thoroughly studying the information therein.

mr_bovinejony - Correct. The NaBH4 I used was in the form of 12 pellets, each weighing around 1.1 grams. They were added one by one, in quick succession. Adding the nitrostyrene to the mixture containing the hydride is certainly the more conventional and sensible way. I just felt like experimenting. It seems to work but is possibly a major reason for the relatively low yield observed.

Opylation - Thank you! I actually had the opportunity to purchase the benzaldehyde directly. I still wish to some day attempt its preparation from a more commonplace material, and paracetamol is one fascinating candidate for this. In the foreseeable future, though, that kind of extra effort will most likely be required for other substitution patterns, such as the one requiring a 4-methyl, which is of particular intrigue being part of Shulgin's "magical half-dozen".

arkoma - 22-5-2021 at 15:26

nice to see a discussion of these molecules and their chemistry without any "moral" histrionics

symboom - 22-5-2021 at 16:44

I agree I think we would be missing out on lots of organic chemistry. Same could be said with the energetics thread. Forget about the stigma of chemistry as bad. It just makes it sound like knowledge is bad.

[Edited on 23-5-2021 by symboom]

Texium - 22-5-2021 at 17:13

Benignium does it right. We come down hard on people who are clearly trying to make drugs to use or sell and don’t care about the chemistry behind it, and people who are trying to scale up procedures to make large quantities of illicit substances (that applies to energetic materials, too). If you aren’t in that crowd, follow Benignium’s example and you’ll have nothing to worry about.

arkoma - 22-5-2021 at 18:10

well said ^^^^

Opylation - 22-5-2021 at 19:51

[Edited on 24-5-2021 by Opylation]

njl - 24-5-2021 at 07:22

Quote: Originally posted by karlos³  
Great stuff!
Have you used my writeup on 2C-H by the way? It looks like you did :)
Also, NBS bromination, what a neat pleasure it is, no?
Also from my posts? :D


karlos³ - 24-5-2021 at 08:32

Its all on the vespiary, the reduction writeup in the NaBH4/CuCl2 thread, and the NBS bromination is all over the place, done by many.

njl - 24-5-2021 at 11:20

I have seen some CuCl2 write ups, I have not seen any NBS brominations. Sounds like you are familiar with them, therefore I would rather have your recommendation than rely on my own search skills.

Newton2.0 - 24-5-2021 at 13:58

You are interested in the 4-methyl-2,5-dimethoxybenzaldehyde! I actually very much would like the 4-ethyl variant! It looks like a very exciting project!

Question for anyone, really. I see a lot of 4-alkoxy substitutions, but not many aryl (4-phenyl), cycloalkyl (4-cyclopropyl), or branched alkyl substitutions at the 4 position. Is there a particular reason that these may not be worthwhile?

Running 4-iPr- and 4-cyclopropyl-, for example, through Swiss Target Predictions gives some extremely promising 5HT2A agonists, although the effect on 5HT2B may be somewhat worrisome.

[Edited on 24-5-2021 by Newton2.0]

[Edited on 24-5-2021 by Newton2.0]

mr_bovinejony - 24-5-2021 at 15:11

Dissolve 2ch in a minimum amount of gaa and add an equal weight of nbs! The product will precipitate after some time of stirring. But the 2ch has to be pretty pure, I've done it a few times myself

Newton2.0 - 24-5-2021 at 17:02

@mr_bovinejony I recently whipped up a batch of NBS so I wouldn't have to go through the nastiness of Br2 in GAA. Unfortunately, NBS is a little less versatile than elemental bromine, but from what I am reading it is perfect for brominating 2C-H. What an exciting project. On this subject, did you ever find that using NBSacc worked for brominations? From what I was reading, a lot of people were employing it as an oxidizer and it didn't add bromine to the molecule.

[Edited on 25-5-2021 by Newton2.0]

mr_bovinejony - 24-5-2021 at 17:28

Yes it did work, in fact it was as easy as replacing nbs with it in this bromination of 2ch. But for other compounds I can't say, there is a report on the vesp where I use it to make 2cb

Newton2.0 - 24-5-2021 at 18:33

Oh man, I will have to check that out! That is extremely cool :D

mr_bovinejony - 24-5-2021 at 20:23

Very!! Bromo saccharin is incredibly easy to make. And it's much less irritating than nbs, although that is barely irritating at all. If you plan on eating the product, which I don't advise for legal reasons ;) you would be better off eating saccharin than you would succinimide.

laserlisa - 25-5-2021 at 04:52

Nice pictures OP!

Quote: Originally posted by karlos³  

Have you used my writeup on 2C-H by the way? It looks like you did :)

OP performed a variant of the Cu/borohydride reduction where the original procedure is posted here

Im curious about your contributions though if you dont mind sharing!

[Edited on 25-5-2021 by laserlisa]

karlos³ - 25-5-2021 at 06:03

Its on here somewhere, its on the vesp, and its on the hyperlab.
You just need to use the search function.
I can't find it right now and no way I'm going to look through over five thousand posts.

E: here it is:

2,51g DMNS(12mmol) was added to 3,5g NaBH4(93mmol) in 32/16ml of IPA/H2O, 20min after the reaction(no cooling applied), a solution of 0,2g CuCl2*2H2O(1,2mmol) in 6ml 1:1 IPA/H2O was added at once, then refluxed for 40min After reaching r.t, a 25% solution of NaOH (20 ml) was added, the phases separated and aqueous phase extracted again with IPA(2x30 ml). The extractions combined, dried with Na2SO4, filtered, acidified. The IPA was distilled off then, but the residue was still dirty. So it was extracted with 3x15ml DCM, then basified and the freebase extracted greyish with 3x30ml DCM, the extracts acidified using diluted HCl, the aq. portion separated and evaporated, boiled in dry acetone then filtered, washed with acetone to give -1,84g of white HCl salt(8,4mmol or 70%)

The workup sucked, but we improved that in the meantime.
Etc... the rest is in the big NaBH4/CuCl2 thread at the vesp.

[Edited on 25-5-2021 by karlos³]

Oxy - 25-5-2021 at 12:06

Quote: Originally posted by mr_bovinejony  
you would be better off eating saccharin than you would succinimide.

Definitely, but I am sure if anyone is doing 2c-X he is not as dumb as methcathinone addicts who shoot the entire reaction mixture with all the manganese directly into their bloodstream :D

Benignium, very nice report (as usual)!

[Edited on 25-5-2021 by Oxy]

karlos³ - 25-5-2021 at 12:53

Yeah my NBS brominated 2C-B HCl was also totally free from any succinimide.

I have the GC-MS and IR-spectra on my other computer, I just need to remove the exif from then and then can post them.

But as for NBSac/NCSac, I can confirm they are VERY easy to prepare, starting from sodium saccharin and NaCl/KBr or whatever, and oxone.
I still have a nice batch of NCSac on hand and according to mr_bj's experience, I would like to try the chlorination of 2C-H with it when I got another reaction of that done.

[Edited on 25-5-2021 by karlos³]

Benignium - 16-4-2022 at 17:18

Nearly a year has passed since the creation of this thread and at long last I feel ready to share what I've been up to.
Fair warning: This is a long post. Remember to drink water.

In addition to the 2C-B of the first post, I have so far managed to prepare eight more psychedelic phenethylamines. One of these is mescaline, whose synthesis from vanillin I have covered in a dedicated thread. The rest will be presented here, in as chronological an order as possible according to the timings of the syntheses themselves. To outline the phenethylamines in question and further help to prevent confusion, here is a rough timeline of relevant events:

May 2021:

June-July 2021:
DOI #1
DOI #2
DOB #1

March-April 2022:
DOI purification
DOC purification
DOB purification
2C-C purification
2C-I #1
DOB #2
2C-I #2

One major obstacle for proceeding to purification following the experiments of 2021 was my inability to carry out satisfactory melting point tests in order to assess the purity of each compound. Up until this point, I had managed by using a mineral oil bath to melt haphazard samples in test tubes. However, these 4-substituted phenethylamine salts necessitated an improved method. Not willing to take a chance on the cheapest melting point apparatus from India, and struggling to justify the price tag for a more reputable alternative, I began investigating the alternatives for mineral oil. Silicone oil was rather unscientifically ignored due to its reported useful temperature range of up to 230-250°C in an open system. Concentrated sulfuric acid was similarly disregarded owing to its hazards. Another promising candidate, dibutyl phthalate, was prepared from a butyl acetate-based paint remover, during which the robust nature of BuOAc became painfully apparent. By the time DBP was abandoned due to its problematic tendency to rapidly darken past 200°C, a melting point apparatus already seemed like a sound investment. Triethylene glycol was forgone, and a refurbished Barnstead|Thermolyne MEL-TEMP was thus acquired.

One more thing: I'm trying out some new formatting techniques, such as the square bracket annotations denoting elaborations and other relevant notes as adjacent listings. I'm looking for constructive feedback and suggestions on how to improve the reading experience.

And away we go!

Purification of 2C-B
260.13 g/mol
296.59 g/mol (•HCl)
341.04 g/mol (•HBr)

Conversion to hydrochloride
The 5.27 grams of crude 2C-B hydrobromide was dissolved in water, and the solution was made basic by adding 30 grams of ~17% aqueous NaOH. The basic mixture was extracted using 3x15 mL of DCM. The pooled organic extracts were treated with 1.14 g of AcOH, followed by removal of the DCM by distillation in a water bath. The residue was then treated with 2.75 g of 33% HCl, thinned with 16 mL of EtOAc, vacuum filtered and washed with a small quantity (<10 mL) of EtOAc to yield 4.37 grams (61.7%) of cream-colored anhydrous 2C-B hydrochloride.

The product was refluxed in a 50:50 mixture of isopropanol and toluene, in which it was very poorly soluble. Refluxing in 150 mL of isopropanol likewise proved insufficient. Full dissolution was achieved in 49 grams of acetonitrile with the addition of 18.6 grams of methanol. Unfortunately, this solvent also proved excellent at dissolving colored impurity from the stir bar, and the obtained material was more discolored than what was put in. The recrystallization was repeated twice using a clean borosilicate stir bar to obtain off-white crystals melting at 237-240°C with decomposition.

Crude 2C-B hydrobromide dissolved in water

2C-B hydrochloride ready for recrystallization

Product is contaminated by recrystallization from MeCN/MeOH

Once-recrystallized product

Second recrystallization

Third recrystallization

Finally, a Soxhlet extraction of the off-white material from a bunch of borosilicate shards (as filler, to shorten the cycles and decrease the amount of solvent required) was attempted using isopropanol. The product and colored impurity were both extracted. Remarkably, the constant back-and-forth fluctuation during the gradual increase in the average concentration of 2C-B in the alcohol allowed for the formation and stable growth of extremely well defined sea urchin-shaped crystals. The material obtained after cooling down and vacuum filtering the mixture was somewhat disappointingly still slightly discolored and had broken down into a mass of fairly uniform sticks, though with their individually impressive proportions intact.

Large crystals of 2C-B hydrochloride from IPA

2,5-DMA (2,5-dimethoxyamphetamine)
195.26 g/mol
231.72 g/mol (•HCl)
244.30 g/mol (•1/2H2SO4)

223.22 g/mol

Experiment 1
2,5-dimethoxybenzaldehyde (3.33g, 20 mmol) was dissolved in 21.5 mL of isopropanol in a 50 mL flat-bottomed boiling flask. To the stirred solution was then added nitroethane (1.81g, 24.1 mmol) followed by ethanolamine (0.21g, 3.4 mmol) and finally acetic acid (1.00g, arbitrary). The mixture was heated on a 100°C hotplate for two hours and cooled to room temperature in ambient air. By vacuum filtration of the mixture, a mass of yellow crystals corresponding to a crude yield of ~50% was obtained. The filtered reaction mixture was heated for a further two hours, giving rise to more crystals on cooling. These were vacuum filtered out, dried and combined with the previously collected material for a total of 3.53 grams (79.7%) of crude 1-(2,5-dimethoxyphenyl)-2-nitropropene.

Experiment 2
2,5-DMBA (15.08g, 90.8 mmol) was dissolved in 140 mL of iPrOH in a 250 mL Erlenmeyer flask. There was then added EtNO2 (8.24g, 109.8 mmol), ETA (0.78g, 12.8 mmol) and AcOH (4.24g), and the mixture was magnetically stirred on a 100°C hotplate for four hours. After cooling, the cold mixture was filtered and the crystals washed with ~10 mL of cold MeOH to yield 19.30 grams (78.6%) of crude 2,5-DMP2NP.

Solution of 2,5-DMBA in iPrOH

Hot reaction mixture after 4 hours of heating

Nitroalkene product precipitating from cooled reaction mixture

Crude yield of 2,5-DMP2NP

The combined crude products were recrystallized once[1] from 150 mL of MeOH cooled to 10-20°C.[2]

[1]: A single recrystallization is not enough to ensure a good yield from the subsequent NaBH4/CuCl2 reduction.
[2]: The recrystallization mixtures should ideally be cooled in a freezer prior to filtration.

2,5-DMP2NP crystallizing from MeOH

Recrystallized product

Sodium borohydride pellets (15.35g, 406 mmol) were added to a 1000 mL Erlenmeyer flask fitted with a condenser[1] and containing a mixture of 190 mL of isopropanol and 100 mL of water. To this was then carefully added portionwise, and with strong stirring, a hot solution of the nitrostyrene (15.00g, 67 mmol) in 55 mL of iPrOH.[2] Additional water and hot alcohol were used to flush down the residue before adding copper(II) chloride dihydrate, as a solution in 10 mL of water, in one portion and flushing the way down once more with water.[3] 10 minutes after adding the catalyst, there was added a further 1.07g (28 mmol) of NaBH4, followed by a third portion of 2.15g (57 mmol) that was intended to combat the perceived rapid diminishing of hydrogen evolution some time later. The mixture was refluxed for a total of 30-40 minutes after the catalyst addition, cooled to room temperature and treated with AcOH (40.92g, 682 mmol).

[1]: Additions were made through this 200 mm Liebig condenser. This was a bad approach. The condenser could not contain all of the alcohol vapor and the accompanying trace amounts of highly irritating nitrostyrene. Ironically, this improved the other downside of additions cooling down prematurely.[2]
[2]: Adding the nitrostyrene as a solution should be discouraged. Keeping the solution hot is a hassle. Solids build up where the solution contacts glass and need to be flushed down. Exotherm on addition is exacerbated and thus harder to control. It is also my belief that significantly higher concentrations of the nitrostyrene in the reaction mixture are reached, which promotes a dimerization side reaction that is catalyzed by NaBH4.
[3]: In total, 20 mL of isopropanol and 100 mL of water were used for flushing.

The acid-treated reaction mixture was vacuum filtered and the clear teal filtrate was distilled until a collection temperature of 100°C was reached. The mixture was cooled and made strongly basic by addition of 150 mL of 20% NaOH. This caused the formation of a peculiar suspension that was removed by filtering the mixture which could then be extracted with several portions of DCM.[1] The organic extracts were combined and shaken with water and 9.74 grams of 33% HCl. After separation, the organic phase was washed with two more portions of water which were pooled with the first one.[2]
The resulting aqueous solution was stored in a stoppered flask at room temperature for ten days until the work on it could continue.

[1]: Undocumented quantities of DCM which most likely did not exceed 4x15 mL.
[2]: Undocumented quantities of water, totaling approximately 150 mL.

Filtered post-reaction mixture

Separation of mystery tar taking place as alcohol is removed

Alcohol-containing distillate

Alcohol-free hot mess

Change in appearance accompanying change in temperature

Chloride-containing aqueous solution

Ten days later, the acidic aqueous solution was washed four times with 10-15 mL portions of DCM.[3] The solution was made basic by addition of 45 mL of 30% NaOH and extracted with four 15 mL portions of DCM. Once again an emulsion was formed, though it was slight enough that only the separated organic phases were filtered through cotton. The extracts were pooled and stripped of solvent by distillation in a water bath.

[3]: In my opinion, as with 2C-H, the chloride salt of 2,5-DMA can be reasonably anticipated to be soluble in DCM, albeit to a lesser extent. For this reason I currently endorse the use of phenethylamine sulfates in similar situations.

Emulsion 2: Son of Emulsion

Steam distillation of the residue was attempted, producing ~70 mL of a clear monophasic distillate with a pH of ~9 and a distinct amine-like smell. A spot test with the Marquis reagent produced a yellow-green result (positive for DOx compounds), and oven-drying one gram of the HCl-treated distillate produced a colorless residue that refused to solidify. Steam distillation was deemed too inefficient and discontinued.

Impure product stirred under cool water

Above mixture at beginning of boil

Residue of HCl-treated steam distillate

The remaining mixture was acidified using five grams of 33% HCl, filtered through cotton and evaporated. After failing to facilitate solidification of the resultant residue,[4] the free base was obtained by adding a liberal 50 mL of 20% NaOH and extracting the mixture with DCM. After removal of DCM by distillation, 4.83 g of ~35% H2SO4 was used to form the hemisulfate.[5] After numerous failed attempts at obtaining a solid, the method that ended up working involved mixing the residue into a caramel-like paste with a ~5:1 mixture of ethyl acetate and heptanes, spreading the mixture on a watch glass and placing it in an 80°C oven. Vaporization of the solvent caused the mixture to expand and solidify as it dried. This crust was then crudely powderized and kept in the oven for a while longer.
The buff solid thus obtained weighed 8.43 g (51.5%) and exhibited considerable stickiness that was alleviated by trituration under acetone. This treatment resulted in an off-white material melting at 188-193°C, and a loss of nearly 11% by weight.
The steam distilled portion was likewise treated with H2SO4, but required less provocation to solidify. Intriguingly, this portion was also sticky to the point of being easily manipulated into a waxy clump weighing 240 mg (1.5%).

This acetone-washed material was used in all subsequent syntheses.
A much later recrystallization of 1750 mg from <10 mL of boiling isopropanol, to which some acetone was added after dissolution, produced 1584 mg of a nearly colorless, amorphous solid with a melting point of 192.3-193.9°C. Although perfectly free-flowing at first, this was still sticky enough to clump together and adhere to surfaces on standing.

[4]: At the time I believed that the hydrochloride was likely too hygroscopic to solidify, but I have since read reports of the solid salt being formed and handled with no mentions of deliquescence or exceptionally problematic hygroscopicity. Still, I find the sulfate to be a more useful form.
[5]: The amount of sulfuric acid was in a very slight excess, which may have contributed to some of the difficulty in getting it to solidify. However, I find it unlikely to be the reason for the persisting stickiness. It has been claimed that excess sulfuric acid generally leads to phenethylamine hydrogen sulfates that are supposedly dramatically more soluble in various solvents than corresponding hemisulfates. At present I can neither confirm nor contest these claims.

Residue of H2SO4-treated steam distillate

Crude product as paste with EtOAc/heptanes

Paste after oven-heating. Truly the stuff of croissant-related nightmares

Not quite done yet

Crude 2,5-DMA •1/2H2SO4

Less crude 2,5-DMA •1/2H2SO4

2C-C (4-chloro-2,5-dimethoxyphenethylamine)
215.68 g/mol
252.14 g/mol (•HCl)

2C-H hydrochloride (2.18 g, 10.1 mmol)[1] was placed in a 50 mL flat-bottomed boiling flask along with 50 mL of dichloromethane and N-chlorosuccinimide (1.34 g, 10 mmol)[2]. At room temperature and with stirring, four drops of crude aqueous perchloric acid[3] were added, causing the color of the mixture to shift to a slightly darker yellow. After four hours had elapsed with no visual changes, two more drops of the acid were added. At 24 hours, the reaction mixture had evolved an amber color that remained unchanged until at 48 hours there were added four drops of 33% hydrochloric acid. This caused the color to shift to a dark red by the 72 hour mark, at which point another four drops of HCl were added. Within 30 minutes, the liquid phase turned green with the formation of a massive, relatively colorless precipitate.

[1]: Same 2C-H as in the opening post. Melting point 138.1-139.4°C (lit. 138-139°C). The melting point is unchanged after 9 months in an airtight container, in the dark, at room temperature.
[2]: NCS was prepared by treating succinimide with fresh NaClO in aqueous AcOH. Succinimide was prepared via succinic acid from monosodium glutamate.
[3]: Crude perchloric acid was prepared by reacting NaClO4 (1.19 g, 9.7 mmol) with ~33% HCl (0.91 g, ~8.2 mmol) and extracting the liquid phase using a pipette.

2C-H •HCl dissolved in DCM


~20 minutes after adding acid catalyst

At 24 hours

At 48 hours

At 72 hours

At 72 hours, 30 minutes

The mixture was diluted with water and 1.02 g of Na2CO3 was added, followed by a few grams of NaOH beads. Transient separation of oil was observed along with the formation of some suspension in the organic phase. After separating and filtering the organic phase through cotton, it was washed with a small amount of water and treated with 3.37 g of 33% HCl. Three portions of water were used to extract the mixture, combined, filtered and washed with a small amount of DCM. To the aqueous solution was then added 10 g of NaOH as a 20% solution, and the basified mixture was extracted using several small portions of DCM. After adding 0.61 g of 33% HCl to the pooled organic extracts, the DCM was distilled off and water was added to the residue. The yellow aqueous solution was decanted off of the insoluble goop and evaporated. The residue was washed with acetone to yield 0.76 grams (30%) of an off-white powder with a melting point of 213-216°C (lit. 220-222°C).

Reaction mixture partitioned between water and DCM

Crude residue of 2C-C •HCl before acetone-washing.

Acetone-washed crude 2C-C •HCl

Later purification
686 milligrams of the crude 2C-C •HCl was stirred in 20 mL of boiling IPA with dropwise addition of water until, after adding 265 mg, a clear solution was obtained. This was poured into 40 mL of acetone, causing needle-like crystals to begin forming immediately. After cooling to room temperature, the mixture was moved to a refrigerator for a few hours. Vacuum filtration and rinsing of the separated solids with several small portions of acetone yielded 230 mg (9.1%) of incredibly flocculent colorless needles melting at 220.9-224.2°C.

Purified 2C-C •HCl. This is 230 milligrams!

DOI (4-iodo-2,5-dimethoxyamphetamine)
321.16 g/mol
357.62 g/mol (•HCl)

Experiment 1
2,5-dimethoxyamphetamine hemisulfate (490 mg, 2.0 mmol) was dissolved in 20 mL of ethanol in a 25 mL flat-bottomed round flask. The body of the flask was wrapped in aluminium foil and, with stirring, there was then added silver(I) sulfate (1.25 g, 4.0 mmol) followed by iodine (1035 mg, 4.1 mmol). The flask was capped and the remaining exposed parts were covered with foil.[1] The mixture was stirred for 18 hours at room temperature.

[1]: Light has to be excluded from the reaction to prevent photolytic decomposition of the reactive silver species.

Silver(I) sulfate, iodine and soln. of 2,5-DMA •1/2H2SO4 in EtOH

Finished reaction

The mixture was vacuum filtered and the filtered solids[1] were washed with several portions of ethanol. The filtrate was distilled to dryness in a boiling water bath, leaving in the flask a dark red residue from which the smell of diethyl ether wafted out, followed by a distinct scent of peppermint.[2] The residue was stirred with 30 mL of 5% aqueous NaOH for an hour,[3] and extracted with 3x10 mL of DCM. The extracts were treated with 1.11 g of 33% HCl and the product was taken up in water, which was separated and washed with 3x5 mL of DCM until almost colorless. 20 mL of 5% NaOH was added to basify the solution, and three 5 mL portions of DCM were used to extract the crude product which was converted to salt form with HCl, stripped of most volatiles by distillation in a water bath and, finally, washed twice with acetone in conjunction with vacuum filtration to obtain 469 milligrams (65.5%) of a slightly yellow powder melting at 195-198°C (lit. 200.5-201.5°C).

[1]: 1565 mg of filtered yellow solids, after drying in perfect darkness.
[2]: My immediate suspicion that I maintain to this day is that diethyl ether was indeed produced by action of sulfate ions in the anhydrous alcohol, along with diethyl sulfate which would be responsible for the peppermint aroma.
[3]: To hydrolyze potential Et2SO4.

Filtered solids from reaction mixture

Filtrate distilled to dryness

Crude DOI •HCl as residue in flask

Acetone-washed crude DOI •HCl

Experiment 2[1]
40 mL of ~96% EtOH was placed in a 50 mL flat-bottomed round flask, along with 2,5-DMA •1/2H2SO4 (980 mg, 4.0 mmol). With the flask protected from light as before, Ag2SO4 (2.50 g, 8.0 mmol) and I2 (1.07 g, 8.2 mmol) were added and the mixture was stirred for 29 hours.[2]

[1]: The repeat experiment was conducted with some water present, due to the suspicion of side reactions having taken place in the presence of Et2SO4. In hindsight this was unlikely. Indeed, this suspicion was later indicated as incorrect by melting point tests.
[2]: The mixture was stirred until beginning the work-up was convenient.

The reaction mixture was filtered, and the solids washed and dried before weighing and recycling the silver.[1] The filtrate was evaporated to dryness. The procedure was kept otherwise identical, yielding 1195 mg (83.5%) of identical off-white powder with a melting point of 192-198°C[2] (lit. 200.5-201.5°C).

[1]: 3140 mg of silver salts were obtained.
[2]: Early melting point tests were somewhat distorted by inexperience leading to rapid ramp-ups in temperature and confused determinations of the starting points of melting point ranges. A lower resolution thermometer was also used at first. It is likely that this particular value was in truth slightly narrower.

Later purification
The products from the two experiments were combined,[1] and dissolved in 40 mL of water. 1.56 g of NaOH beads were then added, and the mixture was set up for steam distillation[2] in a 100 mL Erlenmeyer. 100 mL of distillate was collected, and the mixture in the boiling vessel was cooled to ambient temperature before extraction using 3x10 mL of DCM. Most of the solvent was distilled off in a water bath, and the remaining bit was evacuated by gradually pulling a vacuum of 50-80 mmHg. The viscous amber oil was transferred to a small beaker using ~15 mL of IPA, and to this was added 0.74 g of 33% HCl, slightly acidifying it. After a moment, the amine hydrochloride began precipitating. After moving the beaker into a freezer for ~10 minutes, the cold mixture was vacuum filtered, and the solids were washed with ~15 mL of room temperature IPA followed by 5 mL of acetone. 1078 mg of nearly colorless powder was obtained, with a melting point of 201-202°C.

The filtrate was evaporated to dryness, leaving behind it 322 mg of a brown solid melting at 199-203°C.
A sample prepared from the evaporated steam distillate melted at 200-203°C, and contained a very small amount of NaCl that wouldn't melt.

[1]: The products were combined after determining similar melting points for separate samples as well as a mixed sample, and deducing that both contain the target compound.
[2]: This approach was arrived at by first forming the hypothesis that the most likely impurity, 2,5-DMA, is appreciably steam-distilled and therefore in this way the bulk of it should be removed with minimal loss of product. After examining the separated materials, however, it seems less likely that a significant quantity 2,5-DMA was actually present beforehand.

Oily DOI base under alkaline water

Beginning of steam-distillation

Final precipitation from HCl-treated IPA

Acetone-washed DOI hydrochloride

Residue from evaporated IPA/acetone

Residue from evaporated steam distillate

DOC (4-chloro-2,5-dimethoxyamphetamine)
229.70 g/mol
266.16 g/mol (•HCl)

In a 50 mL boiling flask, there was placed 50 mL of acetonitrile in which were added 2,5-DMA sulfate (2.01 g, 8.2 mmol) and N-chlorosuccinimide (1.1 g, 8.2 mmol). After stirring for a while with no observable change, two drops of 33% hydrochloric acid were added, which immediately caused a slight yellowing of the mixture. Within 20 minutes a clear solution was obtained. After 26 hours of stirring at room temperature, the mixture was transferred to a beaker to evaporate.

Beginning of reaction

At 20 minutes

At 2 hours

At 26 hours

The residue was dissolved in 50 mL of water and gravity filtered through cotton into a separatory funnel. 50 mL of 10% NaOH was added, and the base was extracted using 3x20 mL of ethyl acetate[1]. The combined extracts were washed with a small quantity of saturated aqueous NaCl, and most of the solvent was distilled off in a water bath. After the residue was treated with one gram of 33% HCl, all was transferred onto a watch glass with some ethanol and dried under a gentle stream of air. The resulting sticky crystals were washed once with acetonitrile, dried, and washed once more with acetone, resulting in 656 mg (30%) of nearly colorless material melting at 188-192°C (lit. 193-194.5°C).

[1]: Ethyl acetate is a rather poor choice of extraction solvent, being susceptible to hydrolysis in contact with the alkaline aqueous phase. Rapid extractions from mild mixtures work alright but are poor technique all the same. A better alternative is n-butyl acetate, which is considerably more stable as far as esters go.

Residue of evaporated reaction mixture

Filtered aqueous RM residue

Separation of impure base from alkaline aqueous phase

L to R: Extracted aq. reaction mixture, extracted EtOAc, aq. crude product

Separation of less impure base from alkaline aqueous phase

Distillation of solvent in a water bath

Exothermic reaction between HCl and amine base

Crystallization of HCl-treated crude base

Crude DOC •HCl

Later purification
656 milligrams of the crude DOC hydrochloride was made basic using one gram of sodium hydroxide pellets in water. The mixture was steam distilled until 50 mL of steam distillate had been accumulated.[1] After cooling down the mixture, it was extracted using three 10 mL portions of DCM that were pooled, distilled and stripped of remaining solvent under vacuum. The pale oil was transferred into a small beaker using ~10 mL of IPA, and ~0.2 g of 33% HCl was added until universal pH paper indicated slight acidity. No precipitate formed, so the whole solution was evaporated to a constant weight in a ~70°C oven. Slow solidification of the resulting thick clear goo was induced with the addition of a few drops of IPA, and manual stirring was employed to speed up the process. Once a thick mass of solids had been achieved, 10 mL of acetone was added. When no more formation of solid could be observed, the solid was triturated, vacuum filtered and washed with several portions of acetone totaling ~10 mL to obtain 510 mg of white powder with a melting point of 190-194°C.

This was recrystallized from 5 g of isopropanol to obtain 365 mg of colorless crystalline powder. Melting point 193.5-195°C.

[1]: Residue from HCl-treated steam distillate had a melting point of 178-188°C. Succinimide (MP 125-127°C) is a reasonably likely impurity in the crude product, though I haven't confirmed whether it is appreciably steam distilled.

Liquid/supersaturated DOC hydrochloride

Recrystallization from iPrOH

Purified DOC hydrochloride

DOB (4-bromo-2,5-dimethoxyamphetamine)
274.15 g/mol
310.61 g/mol (•HCl)

Experiment 1
25 mL of MeCN was placed in a 50 mL flask, followed by 2,5-DMA hemisulfate (1.00 g, 4.1 mmol) and N-bromosuccinimide (0.73 g, 4.1 mmol).[1] To the strongly stirred mixture, three drops of 48% hydrobromic acid were added.[2] 25 hours later, the dark red mixture was migrated to a 250 mL beaker to evaporate.

[1]: Commercial NBS with a slight yellow tint.
[2]: This was unnecessary and quite possibly detrimental since HBr is routinely used to cleave aromatic ethers.

Beginning of reaction

End of reaction

The beaker containing the residue from evaporation was covered with cling film and set aside for nine months.[1] Next, it was dissolved in water and vacuum filtered. The filtrate was made alkaline by addition of ~3g of NaOH as a 10% solution in water, and steam distillation was carried out to the point of ~65 mL of collected filtrate. The remaining mixture in the boiling flask was diluted with water up to ~60 mL, cooled to room temperature and extracted using 3x20 mL of butyl acetate. The portions of ester were combined, extracted twice using dilute aqueous sulfuric acid[2] and once more with 20 mL of plain water. The combined aqueous phases were decolorized by washing with 2x5 mL of DCM. Addition of 10 g of 25% NaOH and extraction with three portions of DCM afforded, after the removal of DCM, a brown oil which was transferred to a beaker using IPA, protonated using HCl and let stand until the slow formation of crystals seemed to have concluded. After filtering and acetone-washing with suction, there was obtained 435 mg of discolored crystalline solid that melted at 181-191°C (lit. 207-208°C). Acetone-washed residue from later evaporation the remaining liquor was off-white, weighed 70 mg, and melted at the same temperatures. The crude yield is therefore 39.6%.

[1]: Less than nine months is fine.
[2]: 1st portion: 0.36 g/20 mL. 2nd portion: 0.17 g/20 mL.

Reaction mixture residue being dissolved in water

Filtered aqueous residue

Aq. post-reaction residue being extracted with BuOAc. In a water bath. For some reason.

L to R: Extracted aq. residue, extracted BuOAc, DCM washes, DCM extract under aq. alkali, two keck clips

Crude DOB •HCl

The initial 435 mg from above was recrystallized from 5 grams of isopropanol, and to the clear boiling solution was added ~10 mL of acetone. Once at room temperature, the solution was still clear. Stirring the solution caused the formation of a white precipitate and was continued for a few hours after which the dish was put in a freezer where it was kept for several more hours with occasional agitation. When the formation of solids appeared complete, the cold mixture was vacuum filtered which gave 248 mg of white powder. Melting point 197-199°C.

Two more recrystallizations were done:
1. 4.5 mL of IPA, 11 mL of acetone. 125 mg, MP 203.2-203.9°C.
2. ~2.25 mL of IPA, 6 mL of acetone. 58 mg, MP 204.3-205.2°C.

Because the highest observed melting point was rather awkwardly in between the closest two of discovered literature values,[1] it was decided that a new sample be prepared. For this, a total of 300 mg of crude DOB •HCl was collected by evaporation of accumulated mother liquors, and fed forward to be treated as 2,5-DMA chloride.[2]

[1]: Low: 204.7°C ( High: 207-208°C (PiHKAL).
[2]: Though this approach would discount the overall value of gathered data, it would help to ensure as complete a conversion of 2,5-DMA as possible.
Also, it feels way better to discard tar.

Recrystallization of 125 milligrams of DOB hydrochloride from IPA

Small borosilicate stir bars can be made with some practice and a bit of luck
(torch lighter required)

Experiment 2
2,5-DMA salts (≥2.8 mmol)[1] were added to 10 mL of AcOH and to the stirred mixture were added four 250 mg portions of NBS (1000 mg, 5.6 mmol)[2], feeling for exotherm after each addition.[3] After 15 hours of stirring at room temperature, the clear, filthy red colored mixture was quenched by adding K2S2O5 (2 g, 9 mmol) in 8 mL of water, which caused an immediate color change to dark orange and the evolution of some SO2.

[1]: Not entirely 2,5-DMA; see experiment 1. Somewhat surprisingly, all chlorides dissolved.
[2]: This is overkill, even for a deliberation.
[3]: None was felt.

Crude DOB chloride (300 mg) in flask, 2,5-DMA sulfate (684 mg) in weighing dish

Before adding NBS

Mixture following first NBS addition, next to second 250 mg addition

RM after additions 2-4, RM at 3 hours, RM at 14 hours, RM after quenching

After being put aside for two days[1], the mixture was diluted to ~50 mL with water and 45 g of 20% NaOH was added. The opaque, greenish-brown mixture was briefly chilled in the freezer and extracted with 3x20 mL of BuOAc. The combined organic phases were shaken with 0.7 g of H2SO4 in 20 mL of water, and washed with two 10 mL portions of plain water which were added to the acid solution. The aqueous mixture was washed with 2x5 mL of DCM and made alkaline by adding 10g of 20% aq. NaOH. Three 15 mL DCM extractions were combined and stripped of solvent, leaving a pale brown oil that solidified completely within 15 minutes in an opened 50 mL flask.[2] The solid was dissolved in 25 mL of IPA and transferred to a beaker, where it was treated with ~0.4g of 33% HCl before being poured onto a watch glass and evaporated to dryness in a ~80°C oven. Trituration of the residue under acetone followed by vacuum filtration gave 736 mg of a nearly colorless crystalline powder with a melting point of 199.5-202°C

[1]: For unrelated reasons.
[2]: DOB carbonate, formed in contact with atmospheric CO2.

Diluted RM

Alkaline mixture from above

Alkaline mixture from below

Extracted RM, extracted BuOAc, DCM washes, crude aq. product

Crude DOB base

Crude DOB carbonate

Residue of crude DOB hydrochloride on a cocktail book

Acetone-treated crude hydrochloride

Three subsequent recrystallizations were carried out:
1. 736 mg dissolved in 12 mL of IPA, ~3g of heptanes added; 606 mg, MP 202.7-203.5°C.
2. 606 mg dissolved in 10.1 mL of IPA, ~3g of heptanes added; 521 mg, MP 203.2-204.1°C.
3. 579 mg[1] dissolved in 10 mL of IPA, ~3g of heptanes added; 506 mg, MP 203.8-204.8°C.

At this point, I was doubting the 207-208°C melting point given by Shulgin, and looked around for others' results. I found two publications citing PiHKAL and several experimental melting point reports up to ~204°C, but none that came close to agreeing with the 207-208°C.
Finally, I found a snippet from a 1973 paper[2] posted on the Hyperlab discussion board that claims a melting point of 203.5-204°C for the R-(-) isomer and 204-205°C for the S-(+) isomer.

Based on these findings I feel inclined to believe that 207-208°C is further away from the pure racemic product than the highest melting points I obtained. I recently found a claim that a solvent system consisting of CHCl3/CH2Cl2 and MeOH would provide a good enough separation to differentiate 2,5-DMA from the 4-halogenated derivatives,[3] and I might try that some day, although the impurities here are at least as likely to be something else, like phenolic side products arising from methoxy cleavage. In any case, if the way to highest obtainable purity is through another six or so recrystallizations, then quite frankly I'm not up for it.

[1]: Combined products from experiments 1-2.
[2]: doi:10.1021/jm00263a013
[3]: Somewhere on Hyperlab. A ratio of roughly 1:2 (or 2:1) was indicated, along with iodine vapor staining.

Once-recrystallized product

Single crystals from final recrystallization

Combined purified yield from both experiments

DON (4-nitro-2,5-dimethoxyamphetamine)
250.26 g/mol
286.73 g/mol (•HCl)

To a 25 mL test tube immersed in a cooling bath,[1] there was placed ≥60% nitric acid (2 mL, ≥260 mmol) and a slightly oversized stir bar. With good stirring, there was added dropwise a room temperature solution of 2,5-dimethoxyamphetamine sulfate (518 mg, 2.1 mmol) in 2 mL of acetic acid. The complete addition took 60 minutes,[2] after which the mixture was allowed to stir for some more minutes.

[1]: 100 mL beaker filled with ice and salt water. Bath temperature at the beginning of addition: -5.9°C. Highest bath temperature during addition: -2.7°C.
[2]: 60 minutes was needlessly long, and largely due to the rate of addition slowing down as the pressure applied by the solution to be added decreased. I feel like the addition could instead be accelerated as the vigor of the reaction mixture decreases with increasing heat capacity and decreasing HNO3 concentration.

Apparatus used for nitration of 2,5-DMA

Extremely brief darkening accompanying addition of amine to acid

Reaction mixture after adding all amine

Several grams of ice chips were added to the mixture, causing it to thicken with yellow precipitate. 10 g of 20% NaOH was added with manual mixing with a glass rod, bringing the pH up to around 7. The test tube was emptied into a beaker and a further 5 g of 20% NaOH was added, making the mixture strongly basic. Three 20 mL BuOAc extractions were done, and washed together using a few milliliters of saturated NaCl solution. To the organic phase was added ~0.35 g of H2SO4 in 14.5 mL of water, which was separated, and two more 15 mL portions of water were used to extract whatever salt was left behind. The three aqueous phases were combined and treated with 10 g of 20% aq. NaOH to deprotonate the amine which was then extracted using 3x20 mL of toluene. Following addition of 0.52 g of 33% HCl, the biphasic mixture was distilled until ~20 mL of dry toluene had been collected. The opaque mixture was chilled in a freezer and some acetone was added to see if more solids would form. None did, and vacuum filtration of the cold mixture gave, after acetone-washing, 49 mg of a light yellow solid with a melting point of 203-207°C (lit. 206-207°C). A large amount of solid promptly precipitated from the filtrate and, after some more time in the freezer, a second vacuum filtration gave a further 444 mg of a very slightly paler solid melting at 202-204°C. Crude yield 493 mg (81.1%).

After addition of ice chips and a small quantity of aq. alkali

Butyl acetate extraction of basified reaction mixture

L to R: Extracted RM, extracted BuOAc, aqueous product

Hydrochloric acid under toluene extract

Removal of water from product by azeotropic distillation of toluene

Partial precipitation of crude DON chloride from dried toluene

Separation of solid phase following vacuum filtration

493 mg of crude product

In a 25 mL flask fitted with a condenser, 493 mg of the above material was placed along with 3 mL of IPA. The mixture was refluxed and 12 more milliliters of IPA were gradually added in small portions. A small amount of solid persisted that seemed unaffected by the last 2-3 mL of alcohol. A single drop of water was added, which seemed about as inconsequential. 30 mL of a 1:1 mixture of acetone and heptanes was added, and the mixture was rapidly cooled down in a water bath. It remained clear, and was therefore vacuum filtered into a new flask and left to stand overnight at room temperature. The following day solids were observed, and the mixture was chilled before vacuum filtering to obtain 247 mg of a mix of bright yellow flakes from a powdery layer that had first formed along the glass surface, and comparatively pale crystalline clusters that had formed here and there on top of the former. A mixed sample melted at 206-208°C. Within a week there had formed 118 more milligrams of uniformly yellow solids melting at 207-208°C.

Recrystallized DON •HCl

2C-I (4-iodo-2,5-dimethoxyphenethylamine)
307.13 g/mol
343.59 g/mol (•HCl)

Experiment 1
2C-H chloride (845 mg, 4.0 mmol), silver(I) sulfate (2483 mg, 8.0 mmol)[1] and elemental iodine (2024 mg, 8.0 mmol) were placed in a 50 mL flask containing 43 mL of stirred ethanol. The flask was stoppered and protected from light using aluminium foil. After 25 hours, the foil was removed for a brief visual inspection. The presence of unreacted iodine was evidenced by the dark red coloration of the ethanol, and it was decided that the mixture be stirred for what ended up being five more days. The appearance of the mixture remained unchanged, and 625 mg (2 mmol) of fresh Ag2SO4 was added.[2] Within 22 hours the mixture had shifted to a straw yellow color, indicating that all of the iodine had been depleted.

[1]: 912 mg of this had been stored in the dark in a small resealable plastic bag, and had acquired a grey coloration. The other 1571 mg was freshly prepared by addition of sulfuric acid to an aqueous solution of silver nitrate.
[2]: 2 mmol was the amount calculated to have been depleted by chloride added as the amine salt.

Crystals of silver nitrate

Reaction mixture after 6 days

Reaction mixture after 7 days

The mixture was vacuum filtered, and the solids[1] were washed with several portions of EtOH totaling 15 mL. The fragrant filtrate[2] was transferred to a beaker with some water used to rinse the flask, and evaporated down to ~10 mL on a 150 mL hotplate at which point it had started to produce lachrymatory fumes[3] and was allowed to cool to room temperature. Once cooled, the mixture was diluted to ~50 mL with water and basified via addition of 41.5g of 20% NaOH.[4] 3x20g of BuOAc was used to extract the mixture, and once combined, the organic phase was shaken with 20 g of water containing ~0.7 g of sulfuric acid. 2x10 mL of water was used to wash the ester and combined with the acid solution. This was then made alkaline by 10 g of 20% NaOH and the amine base was extracted with 3x15 mL DCM. After removal of the solvent, the residue from the pooled extracts was transferred to a beaker in 25 mL of IPA and treated with ~0.5 g of 33% HCl until slight acidity was indicated by universal pH paper. Crystals formed, and the mixture was chilled in the freezer before vacuum filtering to obtain 230 mg of vaguely crystalline material melting at 236-241°C (lit.246-247°C). Residue from the evaporated alcoholic liquor was washed with acetone to yield 267 mg of dirty white solid melting at 131-145°C[5], and evaporation of the acetone gave 238 mg of a brown material melting at 122-130°C.
Therefore, a 16.7% yield of very crude 2C-I •HCl was obtained.

[1]: 4192 of silver salts with a strange greenish hue.
[2]: The filtrate exuded a powerful aroma of butterscotch.
[3]: Hydrogen iodide seems like a probable culprit.
[4]: This replaced the odor of butterscotch with a faint fruity odor.
[5]: This was mostly 2C-H.

Filtered solids from the reaction mixture

Concentrated reaction mixture

Butyl acetate extraction of basified reaction mixture

L to R: Extracted RM, aqueous product, extracted BuOAc

Addition of aq. NaOH to decolorized sulfate solution

Amine base with dissolved stir bar dirt, ironically originating from the RM

Precipitation of crude 2C-I •HCl from soln. of mostly 2C-H •HCl in IPA

Crude 2C-I •HCl

The 230 mg of crude 2C-I •HCl was dissolved in 7 grams of boiling EtOH. To this was then added a few grams of heptanes. 190 mg of colorless needle-like crystals were obtained. MP 246.5-249°C.

Experiment 2
2C-H sulfate (664 mg, 2.9 mmol)[1] and freshly prepared silver(I) sulfate (1.89 g, 6.1 mmol) were added to a 50 mL flask containing a stirred solution of 25 mL of ethanol and 2 mL of water. A solution of iodine (1.48 g, 5.8 mmol) in 25 mL of ethanol was added dropwise to the light-protected flask over 6 hours and 40 minutes.[2] Stirring was then continued for ~23 hours, after which the flask was stoppered and moved to a dark cupboard to await further processing.

[1]: 2C-H sulfate was prepared because using the sulfate form of 2,5-DMA worked so well. Although I'd assume this to be the 2:1 sulfate or "hemisulfate", at least one person has claimed that 2C-H forms a 1:1 sulfate salt with sulfuric acid. Either way, to be on the safe side, my calculations assume the molar mass of hemisulfate. A melting point range could not be established, as the material seems to only ever melt partially while it slowly goes through what looks like multiple stages of thermal decomposition before mostly partitioning between a red liquid and a brown solid.
[2]: The whole procedure took place in a dark room.

Crystals of 2C-H sulfate from dilution of EtOH soln. with acetone

Sample of 2C-H sulfate at 196°C

Sample of 2C-H sulfate at 222°C

Silver(I) sulfate, 2C-H sulfate under EtOH, iodine dissolved in EtOH

Addition of alcoholic iodine to suspension of sulfates

Reaction mixture after 23 hours of stirring

After 8 hours of standing, the mixture was vacuum filtered and 6.8 g of saturated NaCl soln. was added to precipitate any silver left in solution.[1] After a second vacuum filtration and dilution to about 150 mL with water, the mixture was distilled to remove the alcohol until a collection temperature of 99°C was reached and ~75 mL of distillate had been collected. A decision to wash the sulfate-containing mixture with 3x2.5 mL of DCM was made and on shaking the aqueous mixture with the second portion of DCM while simultaneously cooling it under cold tap water,[2] a seemingly abundant amount of solid phase separated from the mixture. The triphasic mixture was vacuum filtered to obtain a dirty solid suspected to be 2C-I sulfate. After trituration under acetone, the resulting grey substance weighed 391 mg and had a melting point of 247.2-248.6°C.[3] Dropwise addition as a solution in water precipitated a wispy solid from aqueous barium chloride.[4] After washing of the filtered aqueous phase with DCM was completed, the 2C-I sulfate was added back into the mixture which was then made basic by adding 20% NaOH. Three 11 mL DCM extractions were pooled and stripped of solvent to leave a residue that was dissolved in ~15 mL of IPA and acidified with ~0.28g of 33% HCl, resulting in a copious amount of precipitate. After filtering the freezer-chilled mixture and washing the solids with acetone, there was obtained 478 mg (48.0%) of an off-white crystalline powder that melted at 246.8-248.6°C with extensive decomposition (lit. 246-247°C). 17 mg of material was recovered from the evaporated filtrate, but not identified.

[1]: 2762 mg of initial silver salts plus a small, undocumented quantity of silver chloride precipitated by the NaCl addition.
[2]: This allows me to avoid having to vent, but it is not something I recommend.
[3]: Extensive simultaneous decomposition.
[4]: Barium sulfate is famously insoluble and therefore a good qualitative confirmation for the sulfate ion.

Crystals of 2C-I sulfate that separated during DCM-washing

Above solids filtered out

Trituration of 2C-I sulfate under acetone

Acetone-treated 2C-I sulfate

Spent melting point sample of 2C-I sulfate

Precipitation of BaSO4

Evaporation of DCM to confirm that no product is discarded with washings

Crude 2C-I hydrochloride

478 mg of crude 2C-I hydrochloride was dissolved in 14 g of EtOH. Once the mixture was cooled down in the fridge, vacuum filtration and acetone-washing of the solids gave 385 mg of fine needle-like crystals with a slight yellow tinge. MP 246.7-248.6°C.

Recrystallization from ethanol

Recrystallized 2C-I •HCl

That's about it! Thank you for taking the time to consume this content.
I have some more interesting projects lined up that I look forward to sharing with you all in due time, whenever that may be. Hopefully not all at once, though. These include the rest of Shulgin's magical half-dozen (2C-E, DOM, 2C-T-2 and 2C-T-7) as well as TMA-2 and TMA-6 to name a few.

[Edited on 17-4-2022 by Benignium]

timescale - 16-4-2022 at 18:50

Benignum, you're an inspiration. And all of this without any high vacuum!

Quote: Originally posted by Benignium  
[3]: In my opinion, as with 2C-H, the chloride salt of 2,5-DMA can be reasonably anticipated to be soluble in DCM, albeit to a lesser extent. For this reason I currently endorse the use of phenethylamine sulfates in similar situations.

I don't claim to know any better, but why do you suspect this? Could it be explained by water impurities in the DCM? I shy away from sulfates due to fear of residual H2SO4, and also stoichiometric difficulties.

Also, nice NCS synthesis, I did not know it was so easy.

Quote: Originally posted by Benignium  
I feel bioassays are a central part of the subject

I respect that this is really not the platform for reporting bioassays, but with that said, I am VERY curious. Perhaps elsewhere?

Excited for the 2c-t-x as well, whenever you get around to it! Are you going via the thiophenol a la Shulgin?

SuperOxide - 17-4-2022 at 08:40

I chat with Benignum outside of SM, so I've had some previews of this as he's shared some pictures and info on his progress. But I had no idea it was _this_ epic (literally, epic).

Benignum, thanks for sharing such amazing work. Definitely an inspiration! :)

Benignium - 17-4-2022 at 15:30

Thank you, both of you! I appreciate your positive feedback like you wouldn't believe. :)

timescale - This is a good question that I'm afraid I don't have a good answer to. The suspicion is very non-specifically based on reports I've read online as well as my own experiences working with these compounds and is, for all intents and purposes, just a hunch. Indeed, the moisture present in DCM, albeit very minor, could play some part in such a phenomenon, much like the impurities accompanying crude substances themselves are sometimes seen doing.
The thiophenols definitely seem like an attractive angle of approach in the preparation of the 2C-T-x compounds, but currently I'm undecided on the specifics.
As for the bioassays, I could consider posting thoughts on my subjective experiences here on this thread, though I would prefer to have the moderators' explicit blessing first. What's more, finding the time for those subjective experiences has proved somewhat challenging so far. Do let me know any specific questions you might have, however!

[Edited on 18-4-2022 by Benignium]

xdragon - 22-4-2022 at 16:14

Great content as always, Benignium.

I don't know if you remember, but I talked to you earlier outside of SM when I found you "in the wild" about stereo-selectivity issues/overchlorination of 2C-H which may form 4,6-dichloro-2,5-dimethoxyphenethylamine and was reported in the literature, which lead to some groups adopting to different synthetic schemes: chlorination and purification of the starting aldehyde and choosing a reduction which does not dehalogenate, starting from 2C-B, etc.

It would be nice if we knew how much of a problem this overchlorination is with NCS and N-chlorosaccharin. At the other place - the vespiary - a user lately reported NCS chlorination of 2C-H and had multiple spots both on TLC as well as an instrumental chromatogram (too tired to log back in, but see for yourself). Sadly, no qualitative analysis of the peaks could be done.

If you see any way of getting qualitative analysis of both your crude and purified 2C-C and DOC done, that would be very interesting to the whole community and some nice chemistry work.

All the best to your continued efforts at phenethylamine chemistry - or just chemistry in general, we don't always get to be picky :P

Snakeforhire - 10-6-2022 at 09:33

@Begnigium :
You sir, deserve the highest praise for such a comprehensive report, and I extend my deepest thanks to you for this tremendous effort. :D

[Edited on 10-6-2022 by Snakeforhire]

Snakeforhire - 11-6-2022 at 08:26

I'm new here and have just learned of nitroalkenes reduction with NaBH4 and a metal salt so y'all have to forgive my ignorant ass if this has been covered already (not in any post that I could find yet though), but I need some experts' advice :
Is there a significant yield difference between such a reduction done with Ni(II) and Cu(II) salts ?
I'm only asking because I might know where to get some 2,5-DMB, but NiCl2 dihydrate salts are kinda hard to find : all I can find is the hexahydrate, which I'd have to dehydrate myself and this is a major PitA...
It'd be way easier to find copper chloride actually.

clearly_not_atara - 11-6-2022 at 10:19

I think you probably want to reread the report because this reduction was carried out with copper catalyst and nickel is not mentioned anywhere.

Snakeforhire - 12-6-2022 at 10:02

I know, but I've seen in other threads that other people use nickel salts also.
I just wondered if the metal salt used can make a noticeable difference in the yield of amine.

karlos³ - 12-6-2022 at 11:18

Quote: Originally posted by Snakeforhire  

I just wondered if the metal salt used can make a noticeable difference in the yield of amine.

Yes it does, with a Ni(II) salt, you probably won't get any yield out.

So far, anecdotal reports of a successful NaBH4/NiCl2 reduction of a nitroalkene are very scarce.
And anecdotal reports from people who failed with it are plenty.

With Cu(II) salt, it will be easy and probably will work on the first try.
And so far, actually everyone has got it to work.
I would call that a "noticeable difference in yield" :D

lithiumion656 - 15-6-2022 at 03:42

Is there any known way to induce ring closure of phenethylamine to form indole? I know the chemistry doesn't make this likely but that doesn't discount some obscure paper/person having found a way to do so.

myr - 16-6-2022 at 21:08

Quote: Originally posted by lithiumion656  
Is there any known way to induce ring closure of phenethylamine to form indole? I know the chemistry doesn't make this likely but that doesn't discount some obscure paper/person having found a way to do so.

Not practically: looking at the synthons, the disconnection between the phenyl ring and the nitrogen would need some sort of Pd or Cu coupling between an aryl-halide, boronic acid etc. and the N, or SnAr (which would first need substantial modification of the aromatic ring)

If you want to go from a phenethylamine-like backbone to an indole, the best way (I think) would be a 2-nitroaryl nitrostyrene intermediate: acid and a reducing metal (Zn? Sn? Fe?) would give you an indole with OK yield, probably. I believe this is even used by Shulgin for one of the stranger indolic psychotomimetics, so it should be robust chemistry.

[Edited on 17-6-2022 by myr]

Snakeforhire - 29-6-2022 at 03:33

Quote: Originally posted by mr_bovinejony  
Dissolve 2ch in a minimum amount of gaa and add an equal weight of nbs! The product will precipitate after some time of stirring. But the 2ch has to be pretty pure, I've done it a few times myself

Forgive me for bumping up your (kinda) old post -and for cluttering Begninium's thread :) - but you wouldn't happen to have noted the yield you got from the NBS bromination, have you ?
I'm very curious as to what the difference between reactions done elemental bromine in GAA and NBS. I can't seem to find any definitive answer anywhere, not for lack of trying though. :(

clearly_not_atara - 29-6-2022 at 13:02

Quote: Originally posted by lithiumion656  
Is there any known way to induce ring closure of phenethylamine to form indole? I know the chemistry doesn't make this likely but that doesn't discount some obscure paper/person having found a way to do so.

You can, but you can only form 5,6-dihydroxyindole, and the reaction is spontaneous by cyclization of 4-aminoethyl-o-benzoquinone. This is the preparation of e.g. adrenochrome (which, despite repute, is inactive).

Benignium - 14-10-2022 at 07:21

xdragon - I do indeed remember – what a wild coincidence that was! So far there is no practical way for me to arrange for such analyses, but I agree with your notion and will act accordingly if an opportunity presents itself. The Sciencemadness user who goes by Ullmann has suggested that chlorination of the amine gives an impure mixture, and I feel inclined to assume that NCS yields similar results based on the impurity reported when they used it to chlorinate 4-methoxyphenol.

Snakeforhire - Much appreciated!

Since my last update, I've completed an endeavor comprising well over twenty steps’ worth of synthetic procedures. As the result, three different commercially available hydroxybenzenes have been modified to form a set of seven unique substituted benzaldehydes. I've placed a neat little infographic below to give a more detailed summary. In the next phase, my rather artisanal yields permitting, these synthetic products will be complemented with two additional commercially obtained benzaldehydes as part of an effort to prepare up to 13 amine targets, with emphasis on trimethoxyamphetamines and the remaining portion of Alexander Shulgin's magical half-dozen. Right now, however, it's time to begin gradually unburdening my brain and smartphone; there’s already quite a build-up of interesting chemistry to write up, so much so that I feel a bit swamped.

I plan to segment the documentation in such a way that each one of multiple upcoming posts will deal with an uninterrupted sequence of experiments leading to a discrete goal, starting with the 2,5-dimethoxy-4-methyl motif. Despite profuse overlap between the procedures, this approach should, with the correct ordering, allow for a decent sense of chronology.

IUPAC forgive me for what I'm about to do.

On a more general note, one of my aspirations in compiling this work is to provide reliable information by avoiding factual errors and by correcting myself wherever a mistake has been made. If you detect some falsehood or fallacy, I ask that you kindly point it out either by replying here or via a U2U. Likewise, in matters of uncertainty discussed as such, I wish to eventually reach conclusive levels of understanding that I can share, and I welcome any assistance to that end. Now let's segue into amending some previous content.

Amendments, 10/2022
Firstly, the experimentals concerning the preparation of 2C-H omit the fact that the nitroalkene was recrystallized once from IPA prior to reduction. In my notes, I have also neglected to specify whether the reported yield of 94.5% was calculated for the crude or the recrystallized material. Either seems like a realistic possibility as the particular recrystallization is very efficient, but I'm almost certain that 94.5% is the crude yield. Further, the mass of obtained product is incorrect, as 142.2 mmol corresponds to 29.74 grams – not 33.7. Moving on to the reduction, where I've chosen to give the mass of an arbitrary slurry of copper(II) chloride and water, it's worth pointing out that the reported 1.15 g of catalyst was, to the best of my recollection, calculated/estimated to correspond to 0.1 equivalents or about 0.82 grams of the pure dihydrate.

What I've referred to as the Henry reaction would be more properly called a Knoevenagel condensation. The Henry/nitroaldol condensation is a distinct reaction employing a dissimilar selection of catalysts to form β-nitro alcohols.[1][2]

Heating (and unnecessarily storing) methoxyl-containing phenethylamines in the presence of excess hydrochloric acid as I've done on many occasions should be avoided as it can lead to the dreaded acid cleavage of ethers.[3]

Finally (for now, anyway), I'd like to revoke my endorsement of phenethylamine sulfates in situations where there is the need for a water-soluble salt that won't partition into organic solvent washes. While the elusive phenethylamine hydrogen sulfates [said to form in the presence of excess (>0.5 molar equivalents) sulfuric acid] could potentially serve this purpose, the hemisulfates are oftentimes hydrophobic to the point of precipitating from even relatively large volumes of aqueous solution, which is reason enough for me to look elsewhere. So far, acetates work well.


[Edited on 14-10-2022 by Benignium]

[Edited on 2-11-2023 by Texium]

Romix - 22-10-2022 at 21:54

Anyone knows here how David were making 25B_NBOMe from 2CB? And NBOMEs with other halogens made from 2C's.
Never tried NBOME with Florine in it... But seen RC amph look alike with it...

Romix - 22-10-2022 at 22:00

Am I right guys?

Romix - 22-10-2022 at 22:06

It's hard to dose I heard... goes by micrograms... Offering someone a sniff of the hole in the filter of Pall Mall cigarettes will probably kill the cunt.

Benignium - 23-10-2022 at 10:21

Right, so.

180.20 g/mol

This one is a bit of a train wreck. But bear with me.

[a3] 2,5-dimethoxytoluene
152.19 g/mol

Methylation of phenols is a central issue when it comes to forming the various methyl ether incorporating phenethylamines. The approach I've chosen deals with dimethyl sulfate, whose cost-effectiveness and dependability come with the trade-off of, from the amateur perspective, rather prohibitive toxicity. There are several intriguing and, reportedly, worthwhile alternatives, like trimethyl phosphate and dimethyl oxalate,[1] and I hope to explore these in the future. For now, however, we're going with the partially phased out terror juice. For the purposes of decontamination and damage control, plenty of 1.33M ammonia solution (prepared by reacting ammonium chloride and sodium hydroxide) was always kept within reach.

The first experiment is a terrific example of how not to go about the methylation. My goal was to try out a solvent free procedure outlined in the patent US4065504A. Unfortunately, inadequate agitation, exacerbated by the coarse consistency of the reactants, undermined whatever validity this endeavor may have had. The reaction scale and reaction vessel were also out of proportion.
The solvent free approach was/is revisited later in more favorable circumstances.

The second experiment applies a very different approach from PiHKAL that is evidently much more practical.


Experiment 1
Toluhydroquinone (49.89 g, 0.40 mol) and potassium carbonate (145.79 g, 1.06 mol) were placed in a 250 mL Erlenmeyer flask filled with argon, and shaken until mixed. Dimethyl sulfate (133 g, 1.05 mol) was added using a 25 mL pipette, and magnetic stirring was established with manual assistance using a glass rod. The flask was fitted with a Liebig condenser. Beginning on the 100°C hotplate setting, the temperature of the mixture (measured by IR) was gradually brought up to 70°C over 134 minutes. By this point the evolution of CO2 had accelerated considerably, and the color of the mixture had become increasingly red. Not 15 minutes at this temperature had passed before the mixture had thickened such that stirring became ineffective. Parts of the gelatinous mixture, propelled by pockets of the evolving gas, began advancing menacingly toward the narrow tube of the condenser. Eruption was prevented by moving the flask to a cool water bath, and the contents were allowed to return to ambient temperature.

Using two 25 mL portions of acetone[1], the cooled reaction mixture was thinned and transferred to a larger 1000 mL Erlenmeyer. Heating (on the previously used 150°C hotplate setting) and stirring (with the same small stir bar[2]) were continued. As the mixture approached the boiling point of acetone, it darkened progressively from the heated and stirred center portion outward. Proper mixing by swirling the flask was performed twice over the next hour, leading to a dark red porridge with relatively few carbonate beads remaining. This was heated overnight and then allowed to cool.

[1]: In hindsight, simply using more acetone might have gone a long way toward improving the outcome.
[2]: My selection of stir bars at the time was severely limited.


Dry ingredients, mixed

Reaction mixture following addition of DMS

Stir bar working hard to keep the entire mass of K2CO3 moving

Dark coloration from contact between ammonia solution and reaction mixture on a stick

Reaction mixture cooling down in a water bath

Acetone-thinned horror porridge. Horridge?

Transferred reaction mixture after a while of reacting

What have I done?

Reaction mixture on the following day

Work-up (1)
150 mL of water was carefully added to the thick tarry sludge. The resulting lumpy mixture was warmed for two hours at ~46°C and then brought up to 74°C before heating was discontinued. The pH of the aqueous phase was determined to be 8–9. On removal of the respirator, there was observed a (freshly sharpened) cedarwood pencil aroma of such potency that it was clearly discerned a meter or two upwind of the opened 24/40 flask.[1] The water extract was poured into a separate container, and the remaining gummy mass was extracted twice more with 100 mL portions of hot water, followed by rinsing with a third, tepid portion. The combined aqueous phases were gravity fltered through cotton wool and extracted with three 50 mL portions of ethyl acetate. The organic extracts were, in combination with ~150 mL of fresh EtOAc and mild heating, used to extract the remaining mass in the reaction flask until only a very small amount of hard, plasticky material was left.[2]

The decantations of ethyl acetate extract from the reaction flask contained an enormous amount of fine solids which were separated by vacuum filtering the mixture in two portions. The filter cake from each half was rinsed with three 10 mL portions of ethyl acetate to obtain off-white material which seemed to quite rapidly discolor on air exposure. With stirring, these solids were suspended in 50 mL of water and 5 mL of ~35% sulfuric acid was added to make the mixture moderately acidic before setting it aside for further processing. Eventually, the solid was assumed to be mostly potassium sulfate and this mixture was discarded.

The aqueous extracts were similarly acidified using 25 grams of the ~35% sulfuric acid and set aside with the intention of attempting to recover unreacted starting material at a later date. However, due to constraints of time and glassware, no such attempt was made, and this partition was eventually discarded as well.

The ethyl acetate extracts were distilled to remove 250–275 mL of solvent before, during a brief absence of supervision, the mixture was accidentally overheated to ~160°C. It was then cooled back down to 25°C under a gentle flow of argon. The ~72 grams of black, bitumen-like residue was distilled at a reduced pressure to yield 16.5 g of a distillate that grew darker and more viscous toward the end of its collection, and retained the incredibly powerful scent of pencil. A further attempt to steam distill the petrochemical abomination was promptly terminated, as the mixture forcefully expanded like a kernel of flint corn and puked out beads of marginally refined tar that smelled of lightly aged household garbage and pencil shavings.

A gram of the vacuum distillate was steam distilled to obtain a yellow oil which solidified when placed in the freezer.[3] 13.3 grams of the vacuum distillate were dissolved in ~30 mL of toluene and washed with four 10 g portions of 10% NaOH. The toluene was then driven off on a 100°C hotplate, leaving 5.25 grams of a dark red oil which was steam distilled. The distillate was moved to a separatory funnel along with a small portion of dichloromethane. Work on this extraction was being performed outside when there was an interruption, and the funnel was left unattended for a few hours. During this time, the ambient temperature declined, causing the insufficiently tightened PTFE stopcock to shrink just enough (proportionally to the borosilicate) to allow the dense mixture of product and DCM to leak out while retaining the aqueous phase. To add insult to injury, a brief rain shower then dispersed the leakage further, ensuring that the eventual paper towel extraction would be destined for disposal. A profoundly sombre conclusion, though nowhere near as profound as the lingering smell of pencil.

[1]: Whatever was responsible for this aroma clearly had the vapor pressure of a pebble and, therefore, an extremely low odor detection threshold in the range of ppb, if not ppt. Interestingly, I found a close structural relative, called thymoquinone, that matches this description quite closely. Perhaps some derivative of it was formed?
[2]: This proved exceedingly tough to remove and was discarded.
[3]: The melting point of 2,5-dimethoxytoluene is 19–21°C,[4] so this is a good sign.

Water being added dropwise to reaction mixture

Lumpy mixture following addition of all water

Material left over from hot water extractions

Sample of above material mixed with ethyl acetate and water

Gravity filtration of water extracts

Slightly discolored filter cake from vacuum filtration of EtOAc decantations

Moderately discolored combined filter cakes

Suspended filter cakes being acidified

Bitumen-like residue from EtOAc extracts

Last of the collected vacuum distillate

Vacuum distillate in receiving flask

Aftermath of failed steam distillation

Steam vomitus

Vacuum distilled crude product

Toluene solution being washed with NaOH solution

Washed toluene phase <> Combined alkaline phases

Steam distillation of impure product

Steam distillate

"Is a man not entitled to the sweat of his brow?"

Experiment 2
Into a 1000 mL two-necked round-bottomed flask were placed toluhydroquinone (50 g, 0.40 mol) and 500 mL of water. After some minutes of stirring the suspension under flowing argon, a 250 mL separatory funnel, pre-loaded with DMS (83 mL, 0.88 mol), was attached to the angled neck, alongside a Liebig condenser on the vertical neck. Through the condenser was poured a freshly prepared 20% solution of NaOH (40 g, 1.00 mol), and the mixture was stirred until no more of the remaining particulate seemed to dissolve. Then, at first, a small portion of the ester was carefully added to gauge the vigor of its reaction. When it was clear that nothing exciting was happening, approximately half was added at once, followed by the other half soon after. The entire addition was completed in about six minutes. Formation of the permethylated product could be observed as the appearance of immiscible particles of liquid which, initially, gave the mixture a cloudy appearance before coalescing into larger droplets. The temperature of the mixture was found to peak at about 40°C. After two hours of stirring, the pH of the mixture was determined to be strongly basic (12–14). Stirring was continued overnight.

Dimethyl sulfate over suspension of toluhydroquinone in water

Dissolution of toluhydroquinone as its sodium salt in alkaline water

Initial cloudiness following addition of DMS

Agitated reaction mixture ~20 minutes after DMS addition

Still reaction mixture ~140 minutes after DMS addition

Aftermath of evaporated DMS spill

Work-up (2)
The post-reaction mixture was extracted thrice with 50 mL portions of DCM, and the combined extracts were distilled to leave an amber oil. This was distilled under aspirator vacuum, at a steady temperature of 102–109°C,[1] to yield 47.28 grams (77.1%) of a pale yellow liquid with a very pleasant aroma.[2]

[1]: Estimation, based on IR readings from outside surfaces.
[2]: Slightly sweet, herbal, woody, earthy, with hints resembling vanilla, toffee and menthol. Definitely similar to the purified product of the first experiment, but with no pencil whatsoever.

Crude product set up for vacuum distillation

Completion of vacuum distillation

[b4] 2,5-dimethoxy-4-methylbenzaldehyde
180.20 g/mol
300.37 g/mol (bisulfite adduct; potassium salt)

Another prevalent pursuit in building up to phenethylamines is the formylation of substituted benzenes. Here, one might easily argue that the challenges faced are more nuanced than they are with your average O-alkylation: for example, in a homologous series of three adjacent compounds, the intermediate might inexplicably give poor, inconsistent results from the very same procedure that consistently works well with the other two. Such is the case, reportedly, with 2,5-dimethoxy-1-ethylbenzene and the Vilsmeier–Haack formylation.[1] These surprising pitfalls most certainly do have explanations, but coming up with them is well beyond my current comprehension of the art. Another might argue that comparing O-alkylation to formylation is like comparing apples to oranges and therefore wrong, but they would be arguing for the sake of arguing which is obviously a bigger offense than comparing fruit.

Fortunately, the selection of tools with which substrates like the ones being discussed in this thread can be formylated is reasonably accommodating. A real beacon of amateur-friendliness among these is the Duff reaction, modified to supplement the action of acetic acid as a reactant by incorporating sulfuric acid as a strong acid catalyst, thus eliminating the need for trifluoroacetic acid. Now, watch me do it dirty by first displaying its application on the worst-performing of four substances and then moving on to an entirely different formylation.

In all seriousness, the Duff reaction is a valuable asset in the niche field of phenethylamine chemistry, and I genuinely want to believe that its full potential as such has not been realized just yet. The person working under the pseudonym Ullmann was, to the best of my knowledge, the first to make a case for the undeniable feasibility of the H2SO4-modified Duff procedure in formylating precursory benzenes with sufficiently activating substituents.[2] The work in question gives pertinent insight into the features that define the aforementioned sufficiency of substitution patterns, along with informative and thought-provoking suggestions pertaining to the reaction mechanism in general. Of particular intrigue are the connections drawn from the final step of the Duff reaction, where a benzylic imine intermediate is hydrolyzed to yield an aldehyde; to the Sommelet reaction, which proceeds from an imine to a benzaldehyde in a very similar fashion; and to the Delépine reaction as a side reaction to both (the Duff and the Sommelet) that produces an amine instead. If my interpretation of this triangular relation is correct, the core concept presented by Ullmann seems to be that, by altering the conditions following hydrolysis, a Sommelet-type conversion of the yield-limiting benzylamine side product to the desired benzaldehyde can take place to varying degrees.

The first experiment is me going in blind by applying a procedure, outlined long ago by the prominent Hyperlab user miamiechin, on the basis of its reported yield, which was the highest that I had seen for this particular substrate.[3] As I neglected the prescribed step of overnight mixing with ethyl acetate, my reproduction wasn't entirely faithful, but the results were comparable.

The second experiment took place almost two months after the first one, and was actually the last one in a sequence of six later Duff formylations. The reason behind a second attempt was my desire to investigate whether a modified procedure, which unexpectedly lead to a decent yield of the 4-ethyl homolog, had actual merit. Unfortunately, I failed to make the experiment a valid point of comparison.


Experiment 1
In a 250 mL round-bottomed flask, 2,5-dimethoxytoluene (10.07 g, 66 mmol) and hexamine (20.18 g, 144 mmol) were dissolved in stirred glacial acetic acid (152 g) with mild heating. On complete dissolution, the heating was discontinued, and concentrated sulfuric acid (15.7 mL, 289 mmol) was added dropwise from a pipette. Complete addition took about 20 minutes. A colorless precipitate formed, and the suspension was gently heated to its boiling point over the course of 50 minutes; there was an initial color shift to a vibrant yellow, which quite abruptly developed into a dark red as modest amounts of gas bubbled out and the solids disappeared. The resulting slightly hazy solution was heated under reflux for 90 minutes, allowed to cool and stirred at room temperature overnight. The following day, 50 grams of acetic acid was removed by distilling the mixture under reduced pressure. Water (104 g) was added, and work-up was undertaken immediately.

Initial white precipitate following addition of sulfuric acid

Transient yellow coloration during heating

Reaction mixture after 90 minutes of refluxing

Work-up (1)
The carrot-juice-resembling mixture was extracted three times using ethyl acetate in portions of 50, 40 and 25 grams, respectively. Each extract was washed with a few grams of water[1] and combined with the others by gravity filtering into a boiling flask through cotton wool. The mixture was distilled under atmospheric pressure to remove 90 grams of solvent, followed by further concentration under reduced pressure, in a hot water bath. The slightly viscous, greenish amber residue was placed on a watch glass to evaporate along with a <10 mL portion of methanol used to rinse the flask.

Because the third organic extraction was observed to leave crystals behind as it evaporated, the post-reaction mixture was extracted again using 45 mL of DCM. On the next day, residual DCM was observed to have aggregated to the bottom of the separatory funnel with newly formed solids. Shaking the funnel resulted in two clear layers, of which the lower organic layer was retained and combined with the previous extract for stripping of the solvent. The initial air-evaporated extracts had evolved into a triphasic slurry of impure crystals and two immiscible liquids (a dense dark oil and a less viscous orange phase). The residues were combined quantitatively using <20 mL of methanol, and set up for steam distillation. 250 mL of steam distillate was collected, which contained exactly one gram of mostly colorless[2] crystalline benzaldehyde with a melting point of 82–84°C (lit. 83–84°C[3]). Extraction of the vacuum filtrate using two small portions of DCM gave a further ~100 mg of yellow material that was added to the remaining impure product.

The remaining impure product was extracted from the water using a single portion of DCM, and stripped of the solvent. Next, it was exhaustively extracted with several portions of boiling heptanes which were decanted to a 250 mL beaker; the insoluble material was discarded. As the combined extracts cooled, a significant amount of red oil separated. Removal of the bulk of this oil was effected by treating the hot solution with 1.24 g of coarsely ground activated charcoal, waiting for most of it to settle, and decanting off the liquid. The decanted portion was then cooled in the freezer and vacuum filtered to obtain 7.92 grams of a soft, waxy yellow material mixed with specs of impure charcoal. This was (maximally) dissolved in 27.65 grams of 80% MeOH, and gentle vacuum filtration of the hot mixture followed by freezer-cooling of the filtrate gave, on vacuum filtration, 4.67 g of a beige crystalline material with slight residual stickiness and a melting point of 79–82°C. All of the used charcoal was discarded. Another recrystallization from 25 grams of boiling heptanes was done, followed by decanting off the solvent at room temperature[4] and rinsing the crystals with a small portion of fresh solvent. This gave 4.01 grams of crystals melting at 81–83°C.

Additional product (0.78 g) was obtained from combining the residues of evaporated mother liquors with whatever[5] was gained by carrying out two additional DCM extractions of the post-reaction mixture over the course of five days and recrystallizing twice: first from 5 grams of 80% MeOH (0.87 g was received), then from a 3.5:1 mixture of heptanes and MeOH (this solvent gave the nicest crystals).

The combined purified yield from the experiment, therefore, was 5.79 g (48.6%).

[1]: This wasn't likely to do much; a combination of brine and bicarbonate solution washings would be more par for the course.
[2]: Some yellow impurity came over toward the end of collection. I suspect that this is due to an increased concentration of either impurity relative to water, impurity relative to desired product, or a combination of the two. It also seems possible that the culprit is some kind of volatile degradation product.
[4]: Solubility in heptanes at RT was determined to be around 27 mg/g.
[5]: Next to nothing, most likely.

Concentration of combined ethyl acetate extracts

Crystals forming in evaporating residue

Steam distilled product

Crude product

Heptane-insoluble tar

Charcoal-treated crude product

Impure crystals from 80% MeOH

Fairly pure crystals from heptanes

Experiment 2
In a 100 mL RBF, 2,5-dimethoxytoluene (10.00 g, 66 mmol) and HMTA (18.42 g, 131 mmol) were dissolved in stirred acetic acid (82 g). A solution of 98% H2SO4 (26.33 g, 263 mmol) in acetic acid (41 g) was added dropwise during 43 minutes. Despite an interruption in stirring that occurred in the middle of the addition and lasted for several minutes, the overall exotherm exhibited a fairly stable plateau at 35–40°C. When the addition was complete, the suspension was stirred for 15 more minutes at room temperature before the flask was moved to a heating mantle, fitted with a Liebig condenser and brought to a boil in ~30 minutes. The dark red solution was refluxed for 150 minutes after which 30 g of 1-butyl acetate and 30 g of water were added. The mixture was then refluxed for a further 120 minutes, allowed to cool back down to room temperature and stirred as such for 20 hours.

Solids forming in reaction mixture toward the end of reflux period

Work-up (2)
A decision to add 25 g (181 mmol) of potassium carbonate was made, and a 50% solution in water was slowly poured in over a period of seven minutes.[1] The mixture, now brown and thick with solid precipitate, was diluted with 200 mL of water. A layer of undissolved cream-colored precipitate settled below two clear, immiscible layers of liquid. A bunch of pale, needle-shaped crystals had formed at the liquid-liquid interface during the time that it took to set up for vacuum filtration, and most of them were isolated by decantation and separate filtration followed by rinsing with two portions of water. Once dry, the crystals weighed 0.75 g and melted at 83.5–84.9°C.[2] The remaining solids weighed 13.32 grams and consisted mostly of potassium sulfate. Extraction of product from this material was first attempted by decantation and gravity filtration in boiling methanol, but this approach proved troublesome and was quickly abandoned. The methanolic mixture was diluted with water and vacuum filtered, and the solid portion was extracted using a total of 22 grams of BuOAc.

More crystals formed in the filtered post-reaction mixture, and a decision was made to distill it in order to remove the organic liquid phase and find out what would precipitate. Once the produced distillate seemed to merge exclusively with the aqueous phase (i.e. seemed like mostly water), the mixture was cooled down in a water bath, resulting in an initial mass of pale needles and the more gradual formation of a dark immiscible oil which eventually solidified. Separation was effected by vacuum filtering the mixture, washing the solids with water and then air-drying them on a watch glass; documentation for the obtained solids is missing (save for two images), so, unfortunately, there is no mass to report.

Next, the three product-containing liquid partitions (methanolic filtrate, butyl acetate and filtered post-reaction mixture) were combined with the biphasic distillate and a 10 mL portion of fresh BuOAc—and shaken. The organic layer was retained, washed with two portions (50 g, then 40 g) of 10% NaHCO3 and a 10 g portion of 25% NaCl. The two solid partitions were added and the resulting solution was dried using 3 grams of anhydrous magnesium sulfate.

Finally, a bisulfite purification was carried out. To a vigorously stirred solution of potassium metabisulfite (90 g) in water (200 mL), the filtered organic solution from above was added, followed by 10 mL of methanol.[3] Due to what seems like a remarkable affinity toward butyl acetate (or something else in it), the formed solid merged with the organic solvent, assuming its liquid characteristics to an uncanny degree without substantial dissolution. After stirring the mixture overnight, the solids were vacuum filtered out, rinsed with ~10 mL of MeOH and air-dried to a constant weight of 12.81 g. An additional portion of approximately 400 mg was obtained from stirring the filtrate (incl. methanol rinse) for two more days and filtering it again.

To decompose the adduct, it was suspended in 175 mL of water with stirring, and aqueous 20% NaOH was added dropwise until, after adding 9.75 g of the solution, a pH of 10–11 was indicated by universal pH paper. The end point coincided with the sharp evolution of a chlorine green color in the liquid phase. The mixture was then stirred for 10 minutes and vacuum filtered. The filtered solids were washed with 4–5 portions of water, totaling 100 mL, and air-dried to a constant weight of 6.85 g (54.9%). Melting point 80.9–81.6°C.[4]

[1]: The reason for adding potassium carbonate was to neutralize sulfuric acid, but the approach was poorly thought out; potassium leads to a bunch of unnecessary sediment, and an incomplete neutralization seems unlikely to do much else.
[2]: Unbeknown to me at the time, the thermocouple I was using was beginning to deteriorate, which seems likely to have caused a slight distortion here. Nevertheless, I believe that the crystals were quite pure.
[3]: Previous experimental findings imply a high likelihood of this (the addition of a small quantity of MeOH) significantly accelerating the formation of the adduct. This instance was no exception.
[4]: Measured on the day of posting this update using a digital thermometer meant for cooking; I've had the worst luck with K-type thermometry of late, and I'm still working on finding equipment that functions properly. The sharpness of this melting point seems indicative of high purity.

Post-reaction mixture following addition of potassium carbonate

Above mixture following dilution with water

Solids separated from above mixture by filtration

Mostly water depositing on liquid-liquid interface of biphasic distillate

Cooled filtrate after distilling to remove organic liquid phase

Solids separated from above mixture by filtration

Solution of combined crude product drying over magnesium sulfate

Freshly formed bisulfite adduct

Dry bisulfite adduct

End point of adduct decomposition from above

End point of adduct decomposition from side

Purified product

After seeing all of that you may be left wondering "But where's all the thin-layer chromatography?" And, well, the truth is that there is none*; I weaseled my way out of running a single TLC plate. But the good news is that I did retain samples of almost everything, although I'm having a hard time deciding on how best to implement them. The idea of finishing these writeups and following them up with some consolidated TLC experimentation seems most appealing to the master procrastinator in me.

* Whether it counts or not, I did practice the technique last month, and I might as well end with that. The less-than-exemplary result is this cut-in-half 2.5 x 7.5 cm plate loaded with samples of 2,5-dimethoxybenzaldehyde (A), 2,5-dimethoxy-4-methylbenzaldehyde (B) and 2,5-dimethoxy-4-ethylbenzaldehyde (C), developed using an approximately 3:1 mixture of heptanes:butyl acetate as the eluent, and photographed under UV-A:

UV-C inverted the fluorescence but revealed no additional information. No staining was performed.

[Edited on 24-10-2022 by Benignium]

SuperOxide - 23-10-2022 at 13:12

Benignium, your work is just pure art (as always). Love it :-)

Benignium - 24-10-2022 at 07:42

Romix - Indeed you are, my prolific friend! 25B-NBOMe is a remarkably receptor-selective and potent psychedelic that can be prepared from 2C-B by reductive amination of 2-methoxybenzaldehyde. 2C-C and 2C-I can be used in place of 2C-B, respectively yielding 25C-NBOMe and 25I-NBOMe. The fluorine analog (25F-NBOMe) is more challenging to prepare and likely several orders of magnitude less potent, which would explain the seeming absence of illicit trade.
The PsychonautWiki is valuable source of information on psychoactive substances from the perspective of harm reduction, provided that one is mindful of its open collaboration aspect; please check this article on 25B-NBOMe:

And please try to avoid posting multiple back-to-back replies—it's bad practice! You can edit previous replies to include the same content.

SuperOxide - I'm glad you enjoyed it. Thank you for making me smile! :)

[Edited on 25-10-2022 by Benignium]

DocX - 24-10-2022 at 10:04

This is extremely impressive. Following your progress, I would probably have given up at least four times during this synthesis thinking I messed it up and go back to making soap with the kids in a haze of disbelief in my own ability.
You make me want to be a better man.

arkoma - 24-10-2022 at 13:16

It is truly pleasurable (as in almost physical) to read your posts Beningium. Please never leave us!!

"Horridge" LMFAO

SuperOxide - 24-10-2022 at 13:56

Quote: Originally posted by DocX  
This is extremely impressive. Following your progress, I would probably have given up at least four times during this synthesis thinking I messed it up and go back to making soap with the kids in a haze of disbelief in my own ability.
You make me want to be a better man.

Seriously, right? His work is actually pretty inspiring. lol. I have a lot to learn before I'm on his level, but it's definitely something to aspire to.

Benignium - 5-11-2022 at 01:06

DocX, arkoma - Thank you for the incredibly nice replies; the positive reception of this thread is rocket fuel for my morale, and among the highlights of my year!

A small correction to the previous update: the reaction vessel used in b4 E2 was a 500 mL "RBF" (a flat-bottomed two-necked round boiling flask, to be more precise).

166.18 g/mol

When given the task to prepare 2,5-dimethoxybenzaldehyde from hydroquinone, it would be perfectly understandable if one were to directly set their sights on dimethylation, followed by formylation of the resulting 1,4-dimethoxybenzene. What I did was set my sights on the search engines of discussion boards—not because I somehow knew to expect shenanigans, but because frankly I was only beginning to learn about some of the basic concepts involved. Consequently, I discovered a somewhat novel approach that would prove to be more feasible for me as an amateur and is therefore the one whose application I'll be describing in this post.

The first phase of this critical deviation from intuition involves the monomethylation of hydroquinone or, more specifically, of 1,4-benzoquinone, via its reaction with methanol in the presence of a strong acid catalyst to form a hemiketal intermediate that the hydroquinone then reduces, yielding 4-methoxyphenol and more 1,4-benzoquinone.[1][2] Preservation of one of the phenols in this way offers multiple advantages: most importantly, it creates new opportunities that make introducing a formyl group considerably more manageable later on; precious methylating agent is conserved; and the inherently insightful process of becoming familiar with an intermediate compound involves, in this instance, a truly pleasurable scent of subtly phenolic[3] caramel.

Chronologically, if we look at the infographic from earlier, the preparation of 4-methoxyphenol (a1) took place in early May, making it the very first one of these catalogued steps. As an addition to the premise set by the above paragraph as well as the infographic, this post also kind of deals with the preparation of the required 1,4-benzoquinone, which took place in April, predating all but religion, March, and Arnold Schwarzenegger.

[3]: Smoky, but more akin to a fine Islay whisky, as opposed to a campfire.

Quinhydrone (and early attempts to produce 1,4-benzoquinone)
218.21 g/mol (quinhydrone)
108.10 g/mol (1,4-benzoquinone)

Our journey starts with the preparation of 1,4-benzoquinone, accompanied by a profuse bewilderment due to the fact that a seemingly slam dunk method for the oxidation of hydroquinone[1] did not seem to work very well, producing mostly some strange, dark, crystalline substance whose exact color seemed impossible to define. Eventually,[2] by using Ctrl+F to search the 27,695 page monstrosity that is Ullmann's Encyclopedia of Industrial Chemistry for the word "hydroquinone", this Lovecraftian oddity was identified as quinhydrone—a charge transfer complex arising from the equimolar combination of hydroquinone and 1,4-benzoquinone. This discovery then led to the revelation that the actual benzoquinone wouldn't be needed, as roughly twice its weight in quinhydrone could be substituted for it, essentially skipping a non-essential but inevitable step where some of the benzoquinone would react to form quinhydrone anyway. This was simply great, because as I had already learned empirically, 1,4-benzoquinone is quite irritating—not to mention toxic and carcinogenic—in the concentrations of vapor that it lets off at room temperature, whereas quinhydrone is odorless and in no apparent hurry to get anywhere. And so, I pivoted to preparing enough quinhydrone instead. But trouble was brewing. Literally.

In my preoccupation with the quinhydrone phenomenon and wondering about how little iodine would be too little, I hardly paid any attention to the subtle signs of a profound impact that using water as the sole solvent had. In fact, it was only after my second, more successful encounter with 1,4-benzoquinone much later that I would finally learn about what exactly was going on. In essence, the oxidation of hydroquinone by molecular oxygen in aqueous solutions is prone to producing new substituted species of hydroquinones and benzoquinones that can participate in mixed redox reactions with the existing compounds, giving rise to yet more new hydroquinones and benzoquinones, semiquinone and superoxide anion radicals, charge-transfer complexes, and different kinds of condensation products, all with their own physical and chemical characteristics.[3] In other words, an oxidative degradation which produces tar takes place. Although the rate of this oxidation is dependent on the pH, it apparently does happen at an appreciable rate when heat is applied, even in the absence of alkali. Catalysts can also accelerate the process, and it's entirely possible that something as seemingly innocuous as my permanently brown favorite stir bar could have played a part in this sense.[4] What I find fascinating is that no product was recovered from the attempt to recrystallize the second portion of product during the third workup; this, to me, seems to imply that pre-existing degradation products alone can effectively consume hydroquinone and 1,4-benzoquinone in proportionally large amounts. There's a zombie metaphor/simile to be made here.

[2]: By the time I was working up the second experiment.

Experiment 1
A 250 mL two-necked, flat-bottomed round boiling flask was fitted with a thermometer, and in it were placed hydroquinone (10 g, 91 mmol) and ethanol (30 mL). With mild heating, the mixture was magnetically stirred to obtain a clear, ~35°C solution before iodine (195 mg, 0.8 mmol) was added. With sufficient heating to maintain the temperature, a dropwise addition of 11.9% hydrogen peroxide (28.63 g, 100 mmol) was performed over a period of 12–22 hours.

[Fig. 1] Ethanolic solution of hydroquinone and iodine

[Fig. 2] Reaction mixture following partial addition of H2O2

Work-up (1)
The reaction mixture was chilled in the refrigerator and vacuum filtered to obtain a mass of black solids with yellow crystals in it. The wet filter cake was transferred into a 250 mL conical flask with ~150 mL of water, and steam distillation was attempted as a means of extracting the product. As the mixture was heated, long, yellow needles of the quinone began to form along the short path still head. As the water began to boil, a blockage began forming in the condenser tube, and the distillation was aborted. Accumulated crystals from the still head were mechanically extracted with the help of some water and spread onto a watch glass to dry. The amount of distillate collected was meagre, contained only a few crystals of the product, and was thus discarded. What remained in the flask, if anything, seemed to have decomposed into dark red tar. After air-drying overnight at room temperature,[1] the obtained product weighed 0.82 grams (8.4%).

[1]: With a vapor pressure of about 0.1 mmHg / 13 Pa at room temperature, the rate of sublimation is going to be significant enough to warrant avoiding prolonged periods in open air. In this instance, I didn't notice any visually discernible reduction in quantity.

[Fig. 3] Filtered solids added to water

[Fig. 4] Crystals of sublimed 1,4-benzoquinone

Experiment 2
Into a 250 mL Erlenmeyer, there was added hydroquinone (10 g, 91 mmol), followed by water (200 mL). The flask was placed in a cool water bath[1] and vigorously stirred. Once the solids had dissolved, iodine (45 mg, 0.2 mmol)[2] was added, and the flask was fitted with a Claisen adapter, an addition funnel, and a thermometer adapter by which a thermometer was suspended so as to measure the mixture below. When some undissolved I2 still remained after ~80 minutes, the addition of 11.9% H2O2 (28 mL, 101 mmol) was initiated despite it. During the 55-minute addition, the mixture became somewhat darker and browner, and a modest amount of sparkling black precipitate was formed. The mixture was stirred for four more hours.[3]

[1]: The goal this time was to more rapidly add the oxidizer while keeping the mixture below 30°C. The exotherm was found to be a non-issue; the temperature of the mixture never seemed to differ from that of the bath and stayed below 20°C during the entire addition.
[2]: The role of iodine in this reaction is that of a so-called simple catalyst, i.e. it catalyzes the disproportionation of hydrogen peroxide into water and oxygen. The amount added was therefore viewed as deciding of only the reaction rate and was determined based on the solubility of iodine in 200 mL of water (which itself was determined as a sufficient amount to dissolve the hydroquinone).
[3]: Oxygen was still being generated after the four hours of stirring.

[Fig. 5] Hydroquinone under water

[Fig. 6] Undissolved iodine floating around in aqueous hydroquinone solution

[Fig. 7] Reaction mixture at the end of peroxide addition

[Fig. 8] One hour after the end of peroxide addition

[Fig. 9] Precipitated quinhydrone settling

Work-up (2)
The mixture was cooled in the freezer for 30 minutes[1] and vacuum filtered. The solids were placed on a watch glass to dry. More crystals formed in the filtrate, and it was filtered a second time[2] for a total yield of 3.7 g (37.3%) of dry quinhydrone. As a final stab at producing 1,4-benzoquinone, the filtrate was heated to 50°C and 10 mL of 11.9% H2O2 was added to it in one portion. The mixture became dark red and then turned brown and opaque over 1–2 hours, after which heating was discontinued. A small amount of nearly black crystalline sediment was separated by filtration of the cooled mixture and subsequently discarded along with the filtrate.

Recrystallization of the obtained quinhydrone was attempted from water according to literature.[3] 108 mL of stirred water was heated to 66.4°C and quinhydrone was added in small portions until no more would dissolve; 2.28 g was added. Minimal water was then added to afford a clear saturated solution[4] that was removed from the hotplate and allowed to cool to room temperature.[5] The cooled mixture was vacuum filtered to obtain 1.81 g (79.4% recovery) of spectacular, long, flat strips that had two large, reflective facets with a golden shine, but otherwise looked quite black with a subtle green tinge.

[1]: In my particular freezer, this translates to the mixture being cooled to 5–10°C.
[2]: No more than two hours after the first filtration, according to the photos that I took.
[3]: W.L.F. Armarego (2017), Purification of Laboratory Chemicals (8th ed.)
[4]: Solubility in 65°C water was thus determined to be ~2.1 g/100 mL.
[5]: I vaguely recall an undocumented period of cooling in the refrigerator. In any case, cooling below RT is the way to go.

[Fig. 10] Filtered quinhydrone from reaction mixture

[Fig. 11] Second filtration of reaction mixture

[Fig. 12] Recrystallization of quinhydrone from water

[Fig. 13] Alternative lighting

[Fig. 14] Recrystallized product

Experiment 3
Water (150 mL), hydroquinone (30.09 g, 273 mmol) and a solution of I2 (45 mg, 0.2 mmol) in EtOH (1.84 g) were added to a 250 mL Erlenmeyer. The flask was placed in a 24°C water bath and, with vigorous stirring, H2O2 (95 mL, 343 mmol) was added over a period of two hours. Stirring was continued for approximately 15 hours.

[Fig. 15] About what you'd expect

Work-up (3)
The reaction mixture was filtered to obtain an unrecorded quantity of quinhydrone. A little over half of the product was dissolved in 750 mL of 65°C water, and the mixture was cooled to room temperature before vacuum filtering to yield 8.53 g (28.6%) of crystals that had only a dull shine and a strangely tattered appearance in comparison to the previously recrystallized quinhydrone.[1] Recrystallization of the other half was attempted from the filtrate of the previous portion, which resulted in the already somewhat murky mixture becoming considerably more brown and opaque. No crystals formed on cooling; there was observed only a modest amount of brown sediment that clogged the filter when its separation was attempted. Interestingly, the addition of some hydroquinone to the obtained filtrate resulted in the formation of some quinhydrone-like crystals. On heating, these too disappeared into the muddy fluid, never to be seen again.

The recrystallized product was combined with the non-recrystallized portion from the previous experiment. The mixture had a melting point of 172–174°C (lit. 173-174°C)[2].

[1]: Despite there being no mention of it in my notes, I distinctly remember adding a calculated amount of the solid material directly into cool water, and then wondering about the consequences of doing so as the water heated up. Indeed, this would be the most likely explanation for the malformed crystals.

[Fig. 16] Recrystallization of product (macro image)

[Fig. 17] Recrystallized product

[Fig. 18] Crystals from adding hydroquinone to filtered recrystallization liquor

[Fig. 19] Clogged filter paper being bathed in denatured ethanol

Experiment 4
Hydroquinone (20.01 g, 182 mmol), water (60 mL) and a solution of iodine (66 mg, 0.3 mmol) in ethanol (0.92g) were placed in a 250 mL Erlenmeyer. The flask was placed in a cool water bath, and with the mixture stirred vigorously, 11.9% hydrogen peroxide (26 g, 91 mmol) was added in one portion. Stirring was continued for several hours[1]

[1]: The documentation is imprecise, but, given the appropriate molar ratio of hydroquinone to H2O2 used, I'd assume that the liberation of O2 was waited out.

Work-up (4)
The reaction mixture was refrigerated for some hours, and vacuum filtered to yield 15.89 grams (72.8%) of quinhydrone with a melting point of 173–176°C. This was combined with all of the previously obtained product, and the mixture was used without further purification.

[Fig. 20] Filtered quinhydrone from reaction mixture (macro image)

[a1] 4-methoxyphenol
Also called: MeHQ, mequinol
124.14 g/mol

Not much remains to be said about the reaction itself. Regarding the execution, I remain puzzled as to why 1.65 moles of sodium hydroxide would make a mixture containing 0.84 moles of sulfuric acid as basic as it did; it doesn't seem like sulfuric acid would be consumed to any significant extent, but judging by the 0.58 moles acetic acid required for neutralization of the excess alkali there seems to be quite a discrepancy. Perhaps the acid reacts to form sulfonic acid derivatives or hydroquinone sulfate? I have no external reason to believe that there was fault with my measurements. It's worth pointing out that while proper neutralization of the acid makes the mixture significantly safer to handle, it is entirely optional.

Experiment 1
In a 1000 mL Erlenmeyer flask, hydroquinone (90.09 g, 818 mmol) was dissolved in methanol (464 g) with rapid magnetic stirring, and concentrated sulfuric acid (45 mL, 844 mmol) was added dropwise in ~10 minutes using a pipette. Quinhydrone (20,02 g, 92 mmol) was then added in small portions, along with a 20 mL portion of methanol used for flushing it down, and the mixture was heated under reflux for 4 hours and 10 minutes before allowing it to cool down.

[Fig. 21] Hydroquinone dissolved in methanol

[Fig. 22] Mixture following addition of sulfuric acid

[Fig. 23] Reaction mixture being refluxed

[Fig. 24] Alternative perspective

An aqueous 40% solution of sodium hydroxide (66 g, 1.65 mol)[1] was prepared, placed into a pressure-equalizing addition funnel, and added to the stirred reaction mixture at a rapid dropwise pace. Before half of it had been added, the mixture became too thick to stir magnetically, and agitation was continued by swirling the flask. The entire solution was added in 30 minutes, during which the temperature of the mixture peaked at approximately 40–50°C. The flask was stoppered, and the mixture was stored in the dark at room temperature for ~10h, after which its pH was measured to be strongly basic.[2]. The mixture was distilled in a hot water bath to remove ~280 mL of methanol over a period of about five hours. It was then diluted by adding 400 mL of water, allowed to cool, and extracted using two 100 mL portions of DCM. The first extraction seemed to form an emulsion and could only be partially separated, whereas the second portion of DCM was nearly inseparable due to a copious formation of small, needle-like crystals.[3] The liquids were maximally drained out of the crystal-filled funnel, and the solids were washed with a third 100 mL portion of DCM which was added to, and shaken with, the drained and separated aqueous phase. Following combination of the DCM extracts, the remaining aqueous phase was made acidic by adding of acetic acid (40 g).[4] This was then extracted with three further 80 mL portions of DCM.

The funnel contents were emptied into a 250 mL beaker with the help of some water.[5] The solid-containing mixture was then acidified by adding acetic acid (20 g) and gravity filtered. The solids in the filter were washed with several small portions of water, followed by three 10–15 mL portions of DCM that were separated and combined with all of the previous organic extracts for desiccation by stirring over CaCl2.[6] After some hours, the pooled extracts were distilled to remove the solvent, leaving ~106 grams of a thick, dark residue which solidified completely over the next 24 hours.

The waxy residue was distilled under reduced pressure[7] until a yellow hue was observed in the distillate. Among the solidified material in the collection flask there was a small quantity of clear, slightly viscous liquid which was initially decanted off, but had solidified after some days in an open beaker and was thus retained separately—this weighed 8.7 grams. Recrystallization of the outright solid portion was attempted according to literature[8] from water, but too much solvent seemed to be required. Starting with 20 mL (in 100 mL of water), more and more methanol was added in an iterative sequence of attempts to obtain crystals from a smaller volume of solvent; each time the product would oil out as a separate layer until, after adding a total of 90-100 grams of methanol, neither oil nor solid was obtained. The mixture was distilled to remove ~70 mL of methanol[9] and the denser product-containing layer was separated, mixed with toluene (39 g) and distilled to azeotropically remove the remaining water until only a single liquid phase was observed in the distilled mixture. This was then placed into a freezer. Crystallization ensued, and the solidified mixture was broken up and vacuum filtered. The filter cake was rinsed with small portions of petroleum ether, which caused more crystals to form as it mixed with the filtrate. After a second filtration to recover the newly formed crystals, the combined solids were dried to yield 57.50 grams of off-white mequinol with a peach hue. This, along with an additional 13.96 grams of slightly dimethoxybenzene-smelling material—obtained from vacuum distilling the previously mentioned 8.7 grams in combination with 9.4 grams of residue from evaporation of the recrystallization liquor—correspond to a yield of 57.5%.

[1]: Calculated with the intention of neutralizing most of the acid.
[2]: This was both surprising and alarming, as I fully expected to see a pH of <7 and had read beforehand that the phenolic product would rapidly oxidize in an alkaline environment. It was as much out of resignation as it was out of curiosity that I elected to carry on without first correcting the pH; I may need to try again, but at least I'd find out more about the extent of the degradation.
[3]: A significant drop in ambient temperature also coincided with the crystal formation and was likely the main cause.
[4]: According to universal pH paper, the solution was neutral after adding ca. 35 grams of AcOH.
[5]: The crystals seemed to generate a soluble discoloration as they came into contact with the fluids that were used to rinse them; the liquids became quite dark in color while the solids themselves retained a relatively clean appearance.
[6]: It might have been wiser not to include the initial extracts of the basic mixture, and to instead process them separately; I suspect that they might have contained only 1,4-dimethoxybenzene (a known side product that could be smelled in the extracts) and impurities.
[7]: An aspirator was used, but the pressure of the supplied water was weak and somewhat inconsistent, leading to a rather poor vacuum and an estimated boiling point of 190–200°C.
[8]: W.L.F. Armarego (2017), Purification of Laboratory Chemicals (8th ed.)
[9]: This seemed to cause a further yellowing of the solution. The methanolic distillate contained some 1,4-dimethoxybenzene which crystallized as clear, colorless plates following the addition of water; this was discarded.

[Fig. 25] Basified reaction mixture

[Fig. 26] Distillation of post-reaction mixture to remove methanol

[Fig. 27] Ground glass stopper

[Fig. 28] Initial DCM extract drying over calcium chloride

[Fig. 29] Unexpected crystalline precipitate in separatory funnel

[Fig. 30] Isolated portion of above solids; 17.19 grams of mostly Na2SO4

[Fig. 31] Solvent free residue of combined organic extractions

[Fig. 32] Close-up of gradual crystallization

[Fig. 33] Residue after ~24 hours

[Fig. 34] Residue transferred to a beaker

[Fig. 35] Apparatus used to distill crude product

[Fig. 36] Distillation of crude product

[Fig. 37] "Vacuum" distilled product

[Fig. 38] Product crystallized from toluene

[Fig. 39] Distillation to reclaim product from recrystallization liquor

[Fig. 40] Crystals of 1,4-dimethoxybenzene byproduct in diluted methanolic distillate

[Fig. 41] 12.46 g portion of 4-methoxyphenol used in subsequent formylation

[b2] 2-hydroxy-5-methoxybenzaldehyde
Also called: 5-methoxysalicylaldehyde (5-MSA)
152.15 g/mol
272.32 g/mol (bisulfite adduct; potassium salt)

Two particularly popular alternatives exist for the ortho-formylation of 4-methoxyphenol to form 5-methoxysalicylaldehyde: the Reimer-Tiemann, which employs dichlorocarbene, generated by basic deprotonation of chloroform, as the electrophile; and the more descriptively named magnesium-mediated ortho-specific formylation of phenols, which proceeds via the formation and predomination of a magnesium bis(phenoxide) complex at a temperature of 95°C, and its subsequent reaction with formaldehyde.[1][2][3][4][5] The former is somewhat notorious for its tendency to generate an impure product in modest yields, and its practicality is hindered further by the salicylaldehyde product being quite prone to oxidative degradation, which translates to something of a positive difficulty modifier to the workup; the latter, though less encouraging to look at on paper, really shines in contrast, being capable of giving excellent yields of material that need not necessarily be purified past crude isolation.

My replication of the procedure suffers somewhat from a persisting negligence in the handling of phenols, as well as a lack of effort to characterize the product. Nevertheless, the results indicate that with a bit of practice, a convenient, clean, and reliably high-yielding method is indeed within the amateur's grasp.

[5]: US6670510

Experiment 1
Magnesium methoxide (6.04 g, 70 mmol) was prepared by placing magnesium ribbon (1.70 g, 70 mmol), methanol (30 mL)[1] and a tiny crystal of iodine in a 250 mL two-necked, flat-bottomed round boiling flask (equipped with a stopper and a Liebig condenser with a K2CO3-packed drying tube), and magnetically stirring the mixture overnight on a 100°C hotplate.

The Liebig on the vertical neck was replaced with a water-cooled short path still head fitted with the drying tube, a 25 mL collection flask, and a dropper bulb used to plug the vacuum port. A solution of air-dried MeHQ (12.46 g, 100 mmol) in dry toluene (87.5 mL)[2] was prepared with mild heating, and poured into the methoxide-containing flask.[3] The stopper on the angled neck of the flask was replaced with a thermometer adapter and a mercury thermometer. The dark blue mixture was heated to its initial boiling point at 72°C,[4] and distillate was collected for 110 minutes until, at 95°C[5], the first of three equal portions of paraformaldehyde (3/9 g, 100/300 mmol) was injected by temporary replacement of the thermometer assembly with a powder funnel. Following each addition, the mixture was distilled to remove generated methanol byproduct so as to re-establish the temperature of 95°C.[6] All three portions of PFA were added in 20 minutes, maintaining the temperature between 93 and 96°C. After the final addition, the temperature temporarily rose to 98.5°C and was brought back down to 95°C within four minutes. The mixture was maintained as such until an hour had passed from the end of addition, and then allowed to cool down to room temperature.[7]

[1]: 16 mL was used initially, but solidification of the mixture necessitated the addition of a further 14 mL.
[2]: Dried over 4Å molecular sieves.
[3]: Adding the toluene first and then adding the phenol to the boiling mixture as a solid—or, better yet, as a separately boiled (i.e. dried and degassed) solution in additional toluene—would likely improve purity and yield.
[4]: The color of the mixture shifted via seaweed green to a swampy brown.
[5]: Ca. 25.6 g of distillate was collected before beginning the addition, at which point the mixture was quite pale and opaque with precipitate.
[6]: Ca. 9.3 g of distillate was collected during the entire addition.
[7]: Cooling down (and later acidifying) the mixture under a gentle flow of inert gas would likely improve purity and yield.

[Fig. 42] Beginning of magnesium methoxide formation

[Fig. 43] Progression of magnesium methoxide formation

[Fig. 44] Cue to add more methanol

[Fig. 45] Magnesium methoxide <> Solution of mequinol in toluene

[Fig. 46] Mixture of above materials prior to heating

[Fig. 47] Reaction mixture boiling at ≥72°C

[Fig. 48] Apparatus used to perform the experiment

[Fig. 49] Reaction mixture after distilling for 18 minutes

[Fig. 50] Reaction mixture nearing 95°C after distilling for 80 minutes

[Fig. 51] First addition of PFA after distilling for 110 minutes

[Fig. 52] Reaction mixture following third addition

[Fig. 53] Alternative perspective

[Fig. 54] Reaction mixture after maintaining temperature for one hour

[Fig. 55] Reaction mixture at room temperature after cooling down for two hours

To the cooled reaction mixture in a cool water bath, there was added ~23% sulfuric acid (30 g) such that the temperature of the mixture was maintained in the range of 26 to 33°C. There was a transient precipitation of the product as its bright yellow salt form, followed by the emergence of a biphasic mixture of mostly clear liquids with some debris floating about. The less dense organic layer was separated, and the aqueous phase was extracted with a further <20 mL portion of fresh toluene. The combined organic solutions were gravity filtered into a 100 mL conical flask where they were dried over calcium chloride. The drying agent was removed by filtration and rinsed with a bit of fresh toluene. After some initial trouble with setting up the aspirator vacuum pump, a configuration was achieved which allowed most of the toluene to be distilled off at an approximate pressure of 47 mmHg,[1] leaving 13.25 grams of a dark reddish-yellow oil that wouldn't crystallize when chilled to -15°C.[2] 11.22 g of this crude material was used in the subsequent methylation.

A gram of the oil was placed onto a watch glass where ~6% of its mass evaporated over 17 hours in open air, after which the smell of toluene was completely gone and a faint odor resembling methyl salicylate remained. This was steam distilled to obtain a pale-yellow oil which smelled the same and caused intense, fluorescent staining of the skin. No apparent visual or olfactory changes were observed on storing the sample in open air at 24°C for several weeks. A fraction of this sample inside a flame-sealed capillary tube did not solidify in the freezer.

By dissolving another gram of the crude material in a solution of potassium metabisulfite (2 g) in aqueous 35% methanol (20 g), decanting the solution to leave behind some bright red residue that stuck to the glass, and then washing the solution with an arbitrary mixture of toluene and petroleum ether, there was obtained 0.45 g of a crystalline adduct that formed overnight and was separated by vacuum filtration. A melting point sample was heated to 300°C; a sharp initial yellowing was observed at ~150°C, followed by a gradual decomposition to leave a tan solid from which a pale-yellow oil vaporized and collected outside the furnace. Evaporation of the organic washing gave a mostly solid residue with a slight odor of mequinol.

[1]: A 12V diaphgram water pump rated for 17 L/min at 2.8 bar, connected via minimal ø 15 mm tubing to a vertical brass aspirator with a ~195 mm length of ø 10 mm exhaust tube whose tip (10 mm or so) is immersed in a reservoir of recirculated water. Convenience is greatly enhanced by a stopcock in the vacuum line and a remote-controlled socket. A major downside with my particular pump is an overheating safeguard which doesn't allow for lengthy distillations.
[2]: According to Sigma-Aldrich/Wikipedia/Chemicalbook, the melting point of pure 5-MSA is 4°C.

[Fig. 56] Precipitation of product as its magnesium salt

[Fig. 57] Acidified post-reaction mixture

[Fig. 58] Removal of toluene by vacuum distillation

[Fig. 59] Crude product, stripped of most toluene

[Fig. 60] Sample of crude product

[Fig. 61] Front, L to R: bisulfite solution, organic washing, insoluble residue

[Fig. 62] Crystals of adduct in bisulfite solution <> Organic residue

[Fig. 63] Steam distillate

[Fig. 64] Alternative perspective

[c2] 2,5-dimethoxybenzaldehyde
166.18 g/mol
286.35 g/mol (bisulfite adduct; potassium salt)

Finally, the salicylaldehyde intermediate is methylated to give the desired 2,5-dimethoxybenzaldehyde. Dimethyl sulfate comes into its own here, as the deactivating nature of the benzylic aldehyde moiety can substantially hinder the action of inferior electrophiles (which is not to say that there aren't safer alternatives). The experimental procedure was based on US3867458.

Experiment 1
In a 100 mL Erlenmeyer, crude 5-methoxysalicylaldehyde (11.22 g, <74 mmol) was dissolved in acetone (38 mL). To the stirred mixture were then added K2CO3 (12.53 g, 90 mmol) and Me2SO4 (11.5 mL, 121 mmol). The flask was warmed on the 40°C setting of the hotplate to keep the temperature of the mixture above 25°C as it was stirred for 28 hours. After this time, more acetone (16.5 mL) and K2CO3 (10 g, 72 mmol) were added,[1] and the mixture was set aside to stand for seven days at ambient outside temperatures which fluctuated on either side of 20°C. Over the week, the mixture was shaken 3-5 times.

[1]: The point of adding more K2CO3 was to help avoid a situation where carbonate would be depleted, leaving only bicarbonate which wouldn't deprotonate unreacted phenol. Whether the late addition was beneficial is anyone's guess.

[Fig. 65] Crude 5-MSA, transferred using DCM which is being removed

[Fig. 66] Addition of acetone to crude 5-MSA

[Fig. 67] Reaction mixture following addition of K2CO3 and DMS

[Fig. 68] Stirred reaction mixture at 28 hours

[Fig. 69] Still reaction mixture at 28 hours

The reaction mixture was poured in ~500 mL of water and the resulting mixture was stirred prior to extraction with four 50 mL portions of ethyl acetate.[1] The organic extracts were pooled and distilled in a hot water bath to obtain ~52.6 grams of coffee-colored residue with the viscosity of water. A solution of K2S2O5 (45 g) in water (100 mL) was added to the strongly stirred residue and, after a few hours, the resulting thick porridge of crystalline solids was vacuum filtered and the filter cake washed with 33.6 grams of EtOAc to obtain an off-white solid which wasn't weighed.

The solid was suspended in ~60 mL of water with rapid stirring, and 8.25 g of an aqueous 20% solution of NaOH was added dropwise to bring the pH to 10–11. The alkaline mixture was then kept in the freezer for 16 minutes and vacuum filtered, rinsing the filter cake with water to obtain an off-white crystalline mass that was dried to a constant weight of 6.31 g. To further purify the product, it was dissolved in 15 g of 70% ethanol, filtered to remove a small amount of insoluble white solids, and cooled in the freezer obtain a crystalline pudding which was crudely coaxed out of the flask it was in and vacuum filtered to obtain 5.08 g of needle-like crystals with a melting point of 48.1–48.8°C.[2] Mechanical losses were gathered using ca. 25 mL of ethanol, and the residue obtained from overnight evaporation was recrystallized from 70% methanol along with the residue from evaporating the liquor from the previous recrystallization, to yield an additional 0.93 g of nearly colorless crystals melting at 47.9-48.8°C.[2] In total, there was obtained 6.01 grams[3] of purified 2,5-dimethoxybenzaldehyde. Interestingly, there's practically no odor to it, whereas the commercially obtained counterpart smells quite intensely like some mix of 1,4-dimethoxybenzene and my grandparents' basement; this implies that the formylation of 1,4-dimethoxybenzene has been deemed more viable commerically/industrially.

[1]: The fourth extract was colorless.
[2]: The readings from this thermocouple were checked against a mercury thermometer; an offset of about -1°C was observed, i.e. mercury would have given values that more closely correspond to the literature value of 50°C.
[3]: 49.1% based on crude starting aldehyde. 52.2% if accounting for the observed ~6% content of volatile impurity. 36.0% based on MeHQ.

[Fig. 70] Reaction mixture after a day of stirring and a week of standing

[Fig. 71] RM being poured in water

[Fig. 72] Waxy solid (ostensibly) containing most of the product

[Fig. 73] Dense, immiscible liquid phase

[Fig. 74] Distillation to concentrate pooled ethyl acetate extracts

[Fig. 75] Formation of bisulfite adduct

[Fig. 76] Filtered bisulfite adduct

[Fig. 77] Adduct set up for decomposition

[Fig. 78] End point of adduct decomposition

[Fig. 79] Filtered product

[Fig. 80] Above material after air-drying

The next post (3/5) will focus on the preparation of 2,5-dimethoxy-4-ethylbenzaldehyde! :)

[Edited on 5-11-2022 by Benignium]

SuperOxide - 5-11-2022 at 12:26

(wisely choosing not to quote your post, otherwise the scroll bar would disappear) I haven't finished reading your post, but the pictures themselves are absolutely breathtaking. Your photography skills are on par with your organic chemistry skills.

Benignium - 6-11-2022 at 01:39

Quote: Originally posted by SuperOxide  
Your photography skills are on par with your organic chemistry skills.

Aptly put! I appreciate you, man!

xdragon - 8-11-2022 at 03:54

I don't have the exact protocol anymore, but benzoquinone can be fairly easily synthesised by the oxidation of hydroquinone dissolved in IPA by 1 eq. Oxone in aq. solution, catalysed by 10 mol % NaBr and if needed a bit of heating. KBr will likely not work. This may be interesting for people who do not have access to iodine or useful H2O2 concentrations. Completion of reaction is fairly easily judged by disappearance of the ugly dark colour from the quinhydrone complex.

Some literature on which those findings were based:
(1) Yakura, T.; Ozono, A.; Morimoto, K. An Efficient Catalytic Oxidation of P-Alkoxypenols to p-Quinones Using Tetrabutylammonium Bromide and Oxone. Chem. Pharm. Bull. 2011, 59 (1), 132–134.

Also, thanks for your quality write-ups and pictures, Benignium. I'm getting excited for the 4-Et-2,5-DMBA, I got some of the acetophenon but haven't had the time to deal with it yet.

[Edited on 8-11-2022 by xdragon]

[Edited on 8-11-2022 by xdragon]

Benignium - 8-11-2022 at 21:46

You're most welcome, xdragon! :)
Great contribution! I've also wondered about the utility of persulfates in this regard, but unfortunately, I haven't looked into it yet.

Benignium - 24-11-2022 at 19:33

I'd like to formally welcome everyone to what could become the longest page on Sciencemadness! Not particularly desirable, but then again, neither are the world's longest fingernails, and yet someone has to have them.

194.23 g/mol

This process of forming 2,5-dimethoxy-4-ethylbenzaldehyde,[1] while reasonably established and straightforward, involves some elements that I found quite intimidating to plan for: in between the more familiar steps of methylation and formylation, there were two classical manipulations that, aside from being efficient in forming the desired alkyl substituent, coincidentally displayed tendencies to demethylate the neighboring methoxyl on the side. Fortunately, ventures outside PiHKAL to browse the usual discussion boards revealed that improved results could be obtained via simple modifications to make the reaction conditions milder.
Moreover, reports of unpredictability and poor yields, from those who had performed the final conversion to an aldehyde, had left me anticipating more of an eventual impediment. However, I was delighted to find out that my impression was substantially inaccurate.

[1]: PiHKAL: #24 2C-E.

[b1] 1,4-dimethoxybenzene
138.16 g/mol

The methylation of 4-methoxyphenol seems to be about as pleasant as methylations get: the phenol is readily converted, and not terribly fussy when it comes to oxidation, allowing for good yields of a remarkably fragrant[1] product, and doubtlessly the most satisfying substance that I've steam distilled to date.

[1]: The odor is quite unique, but there's something very familiar about it. I suspect that much of this familiarity stems from its resemblance to some species of clover that was (or were) abundantly present in my childhood.

Experiment 1
In a 250 mL round-bottomed flask, 4-methoxyphenol (20.16 g, 162 mmol) was dissolved in acetone (46 mL). Potassium carbonate (27.50 g, 199 mmol) was added to the resultant solution, and the mixture was stirred for 50 minutes prior to adding dimethyl sulfate (20.2 mL, 213 mmol). The mixture was then heated to reflux and shortly allowed to cool back down.[1] Stirring was continued for 20 hours,[2] after which there was a four-hour period of further refluxing. The mixture was allowed to stand for a further 42 hours[2] before the caked solids were broken up by adding, roughly 30 minutes apart, two 10 mL portions of water and an aqueous 10% solution of sodium hydroxide (4.1 g, 103 mmol).

[1]: My intention was to keep refluxing the mixture, but my mantle didn't register the low power setting that I tried to use, and heating was thus discontinued by accident.
[2]: At ambient outside temperatures, fluctuating on either side of 20°C.

[Fig. 1] Solution of MeHQ in acetone being stirred over K2CO3

[Fig. 2] Above mixture after 26 minutes of stirring

[Fig. 3] Reaction mixture following addition of DMS

[Fig. 4] Above mixture after 23 hours, during fourth and final hour of reflux

[Fig. 5] Caked reaction mixture following addition of 10 mL of water

Work-up (1)
After the solid mass in the reaction vessel had been broken up, and the suspension had been stirred for a while, the mixture was vacuum filtered. The filtered solids were washed with a few small portions of acetone. Acetone was then removed from the filtrate by boiling/evaporation under vacuum — initially without heating, until the temperature of the filtrate had reached ~0°C, and then on a 100°C hotplate until it reached 10°C. The mixture was vacuum filtered and the filter cake was dried overnight in open air to yield 19.40 grams (86.5%) of the crude product as brown platelets.

The brown material was mostly dissolved in 25 g of 36–40°C heptanes, leaving 0.53 grams of an insoluble tar in the flask. The flask was rinsed with 5 grams of fresh solvent that was gravity filtered through cotton wool along with the previous portion. The mixture was allowed to stand in a beaker, under a perforated piece of cling film, until it had lost ~11 grams of its mass. This was then cooled to somewhere below 0°C in the freezer, and vacuum filtered to obtain 17.45 g (77.8%) of cream-colored crystals.

Finally, steam distillation of the product from 350 mL of water was attempted. Initially, the short path still head that was used had cool water running through the condenser, which rapidly caused it to become clogged. Using 46°C condenser water (which gradually warmed up to 54°C on its own) allowed the steam distilled product to remain fluid until it was deposited, but necessitated the use of a jointed collection flask as some vaporized product also came over. Once the impure mixture had been depleted of product, the collected distillate was warmed to melt the solidified product, and pitched into a beaker. Filtration of the solidified product gave, after 18 hours of air-drying, 14.25 g (64.1%)[1] of 1,4-dimethoxybenzene as colorless, crystalline chunks.

[1]: A significant portion of the obtained product was lost to evaporation.

[Fig. 6] Post-reaction mixture after breaking up of caked solids

[Fig. 7] Solid product precipitating from vacuum filtrate as acetone boils off

[Fig. 8] Impure crystals of 1,4-dimethoxybenzene

[Fig. 9] 1,4-DMB crystallizing from heptanes <> Heptane-insoluble tar

[Fig. 10] Steam distillation of impure product

[Fig. 11] Premature freezing of steam distilled 1,4-DMB

[Fig. 12] Deposition of gaseous product in receiving flask

[Fig. 13] Purified 1,4-dimethoxybenzene

Experiment 2
In a 1000 mL two-necked RBF, there was placed water (395 mL) and NaOH (18.40 g, 460 mmol). To the stirred, degassed[1] alkaline solution, a separately prepared solution of mequinol (38.15 g, 307 mmol) in acetone (50 mL) was added. Lots of white solid precipitated, and remained undissolved until the addition of a further 50 mL of acetone (somewhat surprisingly) redissolved most of it. Me2SO4 (38 mL, 400 mmol) was then added from a separating funnel at a rapid dropwise pace; the mixture became opaque with precipitate, and the stopcock was fully opened to allow a more exothermic reaction to prevent any solid from negatively affecting the weak magnetic stirring of the heating mantle. A less dense, immiscible liquid phase formed, and the mixture was stirred for a further 4 hours until the formed product had crystallized.

[1]: Degassing was performed by pulling an aspirator vacuum over the stirred mixture twice, each time maintaining it for 5 minutes before normalizing the pressure using argon.

[Fig. 14] Appearance of poorly soluble 4-methoxyphenolate

[Fig. 15] Dissolution of phenolate due to additional acetone

[Fig. 16] Reaction mixture following addition of DMS

[Fig. 17] Crystalline product in alkaline post-reaction mixture

Work-up (2)
NaHCO3 (5 g, 60 mmol) was added to neutralize excess hydroxide, and a direct steam distillation of product from the reaction mixture was attempted. 60 mL of the initial distillate was collected (until two immiscible liquid phases were observed in the condensing vapor) and moved aside.[1] Once distillate was being collected at 90°C, the condenser water was heated up to 50°C, and the distillation was continued until (after collecting ~400 mL) no more product was observed in the distillate.

The steam distillate (collected directly into a separatory funnel) was extracted with dichloromethane — using just enough to dissolve all of the solid product, followed by a second portion of just a few milliliters. Most of the solvent was then atmospherically distilled off in a warm water bath prior to continuing its removal for a moment under reduced pressure. On cooling, the mixture crystallized partially, and it was poured into a recrystallization dish where it was stirred around by hand, under a steady flow of air, until there was obtained a crunchy solid that seemed perfectly dry. The dish was covered with a sheet of paper towel and kept as such for a few hours to afford 38.08 grams (89.7%) of a colorless, crystalline product melting at 54.3–56.6°C (lit. 54–56°C).

[1]: I believe that I discarded this head portion, but there are no records of its fate.

[Fig. 18] 1,4-dimethoxybenzene crystallizing from saturated DCM

[c1] 2,5-dimethoxyacetophenone
180.20 g/mol

Next, the 1,4-dimethoxybenzene is subjected to a classic Friedel-Crafts acylation — acetyl chloride is treated with aluminium chloride to form a strongly electrophilic acylium carbocation that gets attacked by the aromatic ring, yielding an arenium carbocation that then gives up a proton, thus re-establishing aromaticity, generating hydrogen chloride, and regenerating aluminium chloride.

The presence of HCl and AlCl3 makes for a harsh environment that is capable of methoxyl cleavage, giving rise to a 2-hydroxy-5-methoxyacetophenone side product. The reported yield of 2,5-dimethoxyacetophenone in PiHKAL is 77.8%, which is far from terrible, but seems possible to improve upon by taking more time to perform the reaction at lower, more controlled temperatures; a report by the Hyperlab user Pine_tar[1] seemed to suggest that a dropwise addition during active cooling in an ice bath, followed by maintaining the reaction mixture at 4°C for a further six hours, would produce next to no phenol. My intention was to find out, but my quest for evidence had its fair share of flaws.

My first experiment appeared to have been quite successful, up until a rather farcical vacuum distillation which compromised the yield as well as its purity. Luckily, I still had a bunch of mequinol, whose methylation to provide for a second experiment was no issue.

As an unwelcome surprise, I found my sample of aluminium chloride to be quite contaminated, from having completely eroded the material that was serving as the cap liner of the storage (and retail) bottle. With no real options to remedy the situation at hand, I ended up using the (crudely mechanically cleaned) contaminated material. Fortunately, it turned out to be viable, and I eventually decided to use it for the second experiment as well.


Experiment 1
In a 250 mL round-bottomed flask, in an ice bath, acetyl chloride (10 g, 127 mmol) was pipetted as a slow stream to a stirred suspension of aluminium chloride (17.63 g, 131 mmol) in DCM (50 mL). A separately prepared solution of 1,4-dimethoxybenzene (13.71 g, 99 mmol) in DCM (33.5 mL) was then pipetted in dropwise over ~15 minutes.[1] The mixture was stirred for a further 126 minutes, until all of the ice in the bath had melted,[2] before being stored for 4 hours in the refrigerator, followed by 20 hours in the freezer, below -20°C.

[1]: Both additions were quite exothermic, producing plooms of vapor as solvent boiled off. For the addition of the benzene in particular, the use of an addition funnel would have been ideal.
[2]: The temperature of the reaction mixture at the time of its removal from the bath was ~6°C.

[Fig. 19] Aluminium chloride of questionable integrity

[Fig. 20] Above aluminium chloride under dichloromethane

[Fig. 21] Reaction mixture following addition of acetyl chloride

[Fig. 22] Reaction mixture after adding ~20% of all 1,4-DMB

[Fig. 23] Reaction mixture after adding all 1,4-DMB

Work-up (1)
The chilled reaction mixture was quenched by pouring it into a 250 mL separatory funnel containing 125 mL of cool water; there was an exothermic reaction, and some DCM boiled off. Once the exotherm had subsided, the biphasic mixture was shaken, and the organic layer was harvested. Two more extractions were performed using 10–15 mL portions of DCM, and the combined DCM partitions were washed with three 20 mL volumes of 5% aqueous NaOH.

The organic extract was concentrated by distillation from a warm water bath to afford 28.63 grams of a clear, brown liquid that was distilled under aspirator vacuum. An initial 1.49 g of a low-boiling, low-viscosity fraction with a uniquely sweet and hydrocarbonesque smell was collected (and allowed to evaporate). Following the largely unsuccessful vacuum distillation and a subsequent remedial steam distillation,[1] there was obtained, by extraction using DCM, 14.93 g (≤83.5%) of a discolored liquid with a faint, agreeable aroma.[2]

Acidification and DCM extraction of the pooled alkaline washes gave, on evaporation, ~70 milligrams of an oily, yellow residue with a pleasant odor which resembled a mixture of carrot and root beer. This was discarded.

[1]: The vacuum line was leaking, which led to some visible scorching of the crude product. The leak was located and wrestled shut by hand, which caused an improperly tightened connection on the water pump to loosen and eventually become disconnected near the end of the distillation, spraying water in my face and allowing a backflow of water into the distillation apparatus. Some of the collected distillate was sucked back into the distillation flask with water, and some (<20%) was ejected through the vacuum line as that water then flash boiled. Fortunately, the water was pure, and none of the glassware broke. The dark red oil in the distillation flask was steam distilled to reclaim some of the sucked back product.
[2]: Bearing resemblance to unsubstituted acetophenone as well as 2,5-dimethoxytoluene, with a definite presence of some unreacted 1,4-dimethoxybenzene.

[Fig. 24] Reaction mixture, fresh out of the freezer

[Fig. 25] Pooled DCM phases

[Fig. 26] L to R: Alkaline washes, DCM-extracted aq. mixture, DCM extract

[Fig. 27] Concentrated DCM extract prior to vacuum distillation

[Fig. 28] Aftermath of blundered vacuum distillation

Experiment 2
A 500 mL two-necked round boiling flask was set up in an ice bath,[1] and a powerfully stirred suspension of AlCl3 (38.69 g, 290 mmol) in DCM (109.6 mL) was materialized inside it. Using a pipette, AcCl (16.8 mL, 236 mmol) was added dropwise over 10 minutes, and the mixture was then allowed to stir for a further two minutes or so before commencing the dropwise addition of a solution of 1,4-DMB (30.06 g, 218 mmol) in DCM (71.5 mL) from a 250 mL addition funnel. After 20 minutes, the addition was paused; the reaction mixture was allowed to cool for 5 minutes, and an additional portion of AcCl (3.1 mL, 44 mmol) was pipetted into the mixture.[2] The addition was then resumed for 75 minutes before pausing again to re-establish the magnetic stirring that had failed up to 10 minutes prior.[3] After about an hour had passed, with the stirring enabled once more, the remaining ~3 mL of solution was added from the funnel over a period of 9 minutes. Two hours after completing the addition, the cooling bath temperature was measured to be 6.5°C, and more ice was added. Stirring was then continued for 40 minutes.

[1]: Water was recirculated down the sides of the flask from below crushed ice using a submersible 12V water pump.
[2]: This portion of acetyl chloride was to be included in the initial addition, but there was a miscalculation. Whatever impact this late addition had doesn't seem to have been terribly detracting.
[3]: A DIY stirrer (elaborated on below) was used to agitate the mixture. Its distance from the ice bath was minimized by using an opportunely proportioned Donald Duck pocketbook as a spacer underneath it. An unforeseen consequence of this was the swelling that took place as the comic absorbed droplets of condensation falling from the underside of the bath, eventually jamming the stirrer. This meant that, for ≤10 overlooked minutes, the benzene was added to a stationary mixture. Not great, but as it turned out, not terrible, either.

Work-up (2)
The reaction mixture was poured in 300 grams of crushed ice, and the resulting biphasic mixture was stirred for 15 minutes. The dense organic phase was collected, and the aqueous phase was extracted twice more with 30 mL portions of DCM. After combination, basic washing with aqueous 5% NaOH (3x40 mL), and distillation of the extracts to remove the solvent, a residual amber liquid was obtained from the organic extract. This was then distilled under reduced pressure at ~170°C to yield 30.45 g (77.8%) of a yellow oil with a measured density of ~1.14 g/cm3 at 20°C,[1] and a familiar, faint aroma which implied a total absence of the starting material. This product was used in the subsequent synthetic step.[2] 5.13 g of a dark brown oil was retained from the distillation flask, but not processed further.

Acidification and organic extraction of the pooled alkaline washes gave a little over 1.5 grams of a yellow solid that had the previously encountered odor of root beer and carrots, a tendency to fuse with polystyrene, and a wide melting point range of 37–45°C; this was the crude 2-hydroxy-5-methoxyacetophenone side product.[3]

[1]: Fisher Scientific: Literature value of 1.1300 g/cm3.
[2]: The subsequent reduction took place (starting) 49 hours after this vacuum distillate was photographed (fig. 35) and stored in a 100 mL amber glass bottle. Strangely, when I proceeded to pipette it into the reduction mixture, I saw that it had become quite dark and brown in color. The remaining portion darkened further as time progressed, and was combined with the visually unchanged product from the first experiment pending a second distillation.
[3]: The sample whose melting point I report had been stored in a polystyrene cup for a month, crudely scraped off of the maimed plastic, stored in a cling-film-covered 25 mL beaker for two months, filtered as a solution in minimal MeOH, and obtained as a waxy residue on a watch glass (fig. 34) following the evaporation of said MeOH.

[Fig. 29] Reaction mixture next to crushed ice

[Fig. 30] Reaction mixture being poured in crushed ice

[Fig. 31] Quenching mixture being stirred

[Fig. 32] Merged organic partitions <> Aqueous partition

[Fig. 33] Combined alkaline washes being acidified

[Fig. 34] Crude phenolic side product

[Fig. 35] Freshly vacuum distilled 2,5-dimethoxyacetophenone

[d1] 2,5-dimethoxy-1-ethylbenzene
166.22 g/mol

Reduction of the acetyl moiety to obtain the desired ethyl substituent is commonly performed in one of two ways: via the Clemmensen reduction, which employs amalgamated zinc and hydrochloric acid; or by using the Wolff-Kishner reduction where, in strongly basic conditions, a deprotonated hydrazine condenses with the carbonyl carbon, eliminating water to form a hydrazone intermediate whose diimide tautomer collapses on deprotonation, liberating N2 and affording a carbanion that is then rapidly protonated. Both methods share the tendency to cleave methoxyls. Although I chose the latter, I would at some point like to attempt using the Clemmensen on the surplus of produced acetophenone, to find out if the mercury can be omitted for results that are comparable, or perhaps replaced by another alloy, such as one that contains zinc and gallium.

In PiHKAL, the described procedure takes place in triethylene glycol, and the reaction mixture is refluxed at 210°C for 3 hours. This has been criticized as too harsh for 2,5-dimethoxyacetophenone, and cited as the primary reason for the meager reported yield of ≤22.0 g (≤23.9%) of 2,5-dimethoxyethylbenzene from 100 g (555 mmol) of the starting material, with an additional 28 g (30.4%) recovered via isolation and remethylation of the 2-ethyl-4-methoxyphenol side product. As I had no reason to dispute these claims, I decided to plan and execute accordingly.

For my experiment, I opted to go with monoethylene glycol, as that was what I had on hand, having neglected to acquire beforehand the diethylene glycol which others seemed to have preferred. I surmised that with its boiling point of 197°C, the monomer would prove advantageous in helping to ensure that the mixture doesn't get too hot when it boils, and, after seeing the results, I believe that I was largely correct. It turned out that my issues lay elsewhere.

The very first issue encountered was the poor solubility of alkali in MEG. NaOH was chosen over the similarly soluble KOH due to its lower molecular weight and higher apparent purity,[1] and a a small quantity of water, extrapolated from documented instances of the use of hydrazine hydrate, was incorporated with the goal of achieving a consistency that wouldn't overwhelm the modest torque and magnetic power of my heating mantle.[2]

The second issue has to do with a problematic foaming, which, by some divine intervention, persisted on the cusp of ruining things, yet never escalated. The foam appeared to consist of bubbles that were, for the most part, remarkably small, and as someone who enjoys Guinness enough to occasionally purchase it in cans,[3] my immediate thought was that perhaps I was witnessing the evolution of nitrogen — and this would seem to make some sense timing-wise. As to the extent to which nitrogen causes or exacerbates the foaming, I can only guess; it's also possible that the foaming was more or less specific to the use of MEG, or that my particular MEG, obtained via the fractional distillation of an engine coolant, contained culpable contaminants (this could also explain the pronounced yellowing on dissolution of NaOH, which struck me as odd). In any case, I'd like to learn how to prevent the foaming, since it clearly prolongs the contact of glassware with the highly caustic (wet) reaction mixture.

[1]: My new (i.e. old, but unopened) sample of KOH turned out to be quite green for some unknown reason. The moisture content of KOH also tends to be higher.
[2]: Normally, I would have resorted to using my trusty Corning hotplate, but, unfortunately, we developed a prohibitive fault during the summer. The hotplate remains in disrepair to this day, but the void in its place has inspired some nifty solutions, namely the incorporation of PC-fan-based DIY magnetic stirrers in conjunction with accurately adjustable hot water baths utilizing a sous vide immersion circulator.
[3]: Guinness is a beer that is known for its fine, creamy effervescence. To achieve this, the cans are pressurized by the inclusion of liquid nitrogen inside a "floating widget" — a cryptic sphere which inspired my curiosity. Shout-out to Google.

Experiment 1
Monoethylene glycol (126 mL) was situated in a 250 mL two-necked round boiling flask, and to it, in an ice bath and with magnetic stirring, NaOH (29.95 g, 749 mmol) was added in portions, along with some water (7.35 g in total) to aid its dissolution. A sufficiently stirrable mixture was pursued for nearly five hours: not everything dissolved, and the subsequent addition of hydrazine sulfate (32.86 g, 253 mmol) had no perceivable effect on the high difficulty of agitating the mixture; a desireable thinning was achieved by immersing the flask in a 60°C water bath, and once the bath temperature had been brought up to 80°C, 2,5-dimethoxyacetophenone (14.64 g, 81 mmol) was added via pipette. The flask, fitted with a Liebig condenser, was then moved into a 1000 mL heating mantle where it was immediately heated toward reflux with magnetic stirring. After refluxing the mixture for 30 minutes, the heating was discontinued for two hours[1] prior to replacement of the Liebig with a water-cooled short path still head and the initiation of a delicate distillation to remove water: on boiling, a ~120°C foam appeared, and promptly climbed into the fractionating portion of the still head, despite attempts to suppress it by adding more MEG (20 mL was added in total) from a separatory funnel, as well as adjusting insulation and the application of heat.[2] Fortunately, the foaming readily equilibriated such that it never reached the condenser, and after observing no erratic behavior for three hours, the distillation was left to run unattended for two consecutive three-hour periods.[3]

After the six-hour period, the mixture was no longer foaming or boiling; the collection flask was emptied,[4] and heating was increased to raise the temperature of the mixture to 140–150°C, resuming the collection of distillate. After an hour, with the mixture now at ~170°C, only intermittent condensation of 140°C vapor took place in the still head, and the condenser was emptied of most water before incrementing the heat. Soon, the collection of distillate picked up again (to a rate of approximately one drop every two seconds), and a coolant tube was repurposed to observe gas exiting the system at a leisurely pace[5] as the collection temperature climbed past 180°C, eventually reaching 197°C before the reoccurrence of foaming made the short-lived distillation of glycol unsustainable. Combating the foam by adding fresh MEG (10 mL) proved futile once again, and the heating was stepped down, maintaining the mixture at ~190°C until 90 minutes had passed since distillate was first collected at >180°C. At last, the heating was discontinued, and, after concerted cooling of the reaction mixture in air and in water: the workup.

[0]: The temperature of the reaction mixture was exclusively monitored by measuring the outside surface of the flask using an IR thermometer. Hence, the reported values are crude approximations.
[1]: The duration of an external activity.
[2]: Adding an anti-foaming product containing emulsified silicone (for distilling spirits) crossed my mind since I had it on hand, but I refrained as I wasn't absolutely certain of its compatibility; such a strategy seems worth exploring in the future, if need be.
[3]: The foaming was still taking place three hours into this period of six hours, but had completely subsided during the second half.
[4]: 23.27 grams of distillate had been collected overnight/in total.
[5]: The escaping gas was most likely nitrogen. Dozens of bubbles were observed until its evolution appeared to cease, long before the heating did. Volumetric measurement of this gas should provide some worthwhile insight relating to the overall progression of the reaction.

[Fig. 36] Initial portion of NaOH being stirred under MEG

[Fig. 37] Later state of the above mixture after adding more NaOH

[Fig. 38] Mixture following addition of 2,5-dimethoxyacetophenone

[Fig. 39] Reaction mixture after 15 minutes in heating mantle

[Fig. 40] After 30 minutes in heating mantle; beginning of reflux

[Fig. 41] Reaction mixture after refluxing for ~15 minutes

[Fig. 42] Threat of foaming over just as the 30-minute reflux is up

[Fig. 43] Reaction mixture cooling down

[Fig. 44] Equilibriation of foaming

[Fig. 45] Overnight distillate

[Fig. 46] Reoccurrence of foaming

[Fig. 47] Ostensible nitrogen exiting the apparatus

[Fig. 48] Post-reaction mixture cooling down

600 mL of cold tap water was placed in a 1000 mL beaker, and the remaining cooled reaction mixture was poured in, followed by the pooled distillates (50 mL). The resulting mixture was stirred for a while and suction filtered into a separatory funnel through cotton wool. The filter was rinsed with several small portions of C7H16 (totaling 50 mL). After shaking the funnel and isolating the organic layer of rinses, two more 50 mL portions of heptane were used to extract the aqueous mixture, and the combined organic extracts were washed with a single 25 mL portion of water, which was deposited in the aqueous partition. The heptane was removed via distillation at a reduced pressure, leaving 11.69 grams of a yellow liquid with the viscosity of water and a strong, remarkably natural[1] carrot aroma with a hint of menthol. An exhaustive steam distillation (which took about three hours) gave 11.31 g (83.8%) of a slightly volatile,[2] perfectly colorless, dense and immiscible liquid phase via organic extraction of the distillate (140–150 mL) using three portions of DCM (10, 5 and 5 mL).

The aqueous partition was made acidic by addition of 33% HCl (45 g)[3] and extracted using three portions of DCM (30, 20, and 20 grams). The pooled extracts were treated with saturated aqueous NaHCO3 (20 g of ~10% soln.) prior to distilling off most of the solvent. After further evaporation on a watch glass, 2.20 g of an amber residue was obtained, which had the viscosity of sulfuric acid and a pleasant, sweet and phenolic carrot aroma. This was stored on the watch glass, at 24°C, for 22 days, during which time it had darkened further and lost ~8% of its mass (down to 2.02 g), before steam distilling it to collect 0.85 grams of a nearly colorless material, with properties[4] as before, floating on ~65 mL of distillate.

[1]: A clean and distinctive raw carrot profile, accompanied by the earthy, moldy character that I associate with some carrot farmers' cellar-like storage conditions. Interestingly, there's a clear resemblance between this and the comparatively subtle earthiness of the methyl homolog, 2,5-dimethoxytoluene.
[2]: The material appears to evaporate; the rate of evaporation seems slower than that of 1,4-dimethoxybenzene or 1,4-benzoquinone, but still significant.
[3]: After adding 40 g of the acid, a pH of 8–9 was measured.
[4]: Viscosity, odor, and gradual darkening on air exposure.

[Fig. 49] Pooled distillate and diluted post-reaction mixture

[Fig. 50] Crude phenolic side product <> Crude neutral main product

[Fig. 51] Steam distillation of desired product

[Fig. 52] Purified 2,5-dimethoxyethylbenzene

[Fig. 53] Steam distillation of phenolic side product

[e1] 2,5-dimethoxy-4-ethylbenzaldehyde
194.23 g/mol
314.40 g/mol (bisulfite adduct; potassium salt)

To formylate the finished benzene, I decided to attempt the Duff reaction, despite anecdotal evidence of impracticality,[1] as an interesting way to gain some initial material to experiment with; the achievement of a worthwhile conversion seemed to require more specialized methods. However, my expectations for the Duff were pleasantly exceeded, and, instead of attempting something different, I believe that a repeat experiment is appropriate, somewhere down the road.

[1]: (Hyperlab) Pine_tar: Purified yield of 40.5%.

Experiment 1
To a magnetically stirred solution of 2,5-dimethoxyethylbenzene (5.00 g, 30 mmol) and hexamine (8.46 g, 60 mmol) in acetic acid (39.08 g), in a 100 mL round boiling flask, there was added dropwise (in 40 minutes) a solution of 98% sulfuric acid (12.08 g, 121 mmol) in acetic acid (28.1 g) via a 250 mL addition funnel. The resulting suspension of white precipitate was stirred for a further 10 minutes, after which the flask was placed into a 1000 mL heating mantle, furnished with a Liebig condenser, and, with stirring, heated under reflux for 120 minutes. Next, the heating was discontinued, and the mixture was allowed to cool below its boiling point before replacing the condenser with a short path still head that was used to remove acetic acid (~33 g) by distilling the mixture for about 30 minutes. The Liebig was then reattached for the revival of reflux, and through it was added 1-butyl acetate (17.34 g), followed by a careful addition[1] of water (20 g) some five minutes later. The mixture was refluxed for a further 100 minutes[2], allowed to cool, and stirred at room temperature for 15 more hours.

[1]: Water and 1-butyl acetate form a low-boiling azeotrope which can boil quite violently.
[2]: During this time, the color of the mixture shifted from a rather dark brownish red (fig. 58) to a considerably lighter shade of reddish amber (fig. 59).

[Fig. 54] Solution of 2,5-dimethoxyethylbenzene and HMTA in AcOH

[Fig. 55] Above mixture following addition of sulfuric acid in AcOH

[Fig. 56] Beginning of reflux

[Fig. 57] Reaction mixture following addition of butyl acetate

[Fig. 58] Reaction mixture following addition of water

[Fig. 59] End of refluxing

A small quantity of a pale, needle-like precipitate had formed in the mixture, and was redissolved by adding 10 g of water. The mixture was set aside for about three hours before it was poured into a separatory funnel, rinsing the flask with some water and butyl acetate. The organic phase was separated and combined with two 15-gram portions of BuOAc that had been used to further extract the aqueous mixture. The organic mixture was treated with aqueous solutions of 25% NaCl (9 g), 10% NaHCO3 (9x10 g), and 25% NaCl again (5.5 g), followed by drying over 0.98 g of MgSO4.

0.10 grams of the desiccated extract was placed on a watch glass to evaporate, leaving approximately 10 milligrams of a clear, yellow oil that wouldn't crystallize spontaneously, even after tenacious rubbing with a glass rod. Interestingly, an immediate solidification to a waxy consistency was observed when the oil came in contact with liquid water. A sample of this semisolid material was fought into a capillary tube with the help of a second, thinner capillary tube, and a melting point range of 35.0–42.7°C was determined.

The remaining extract was concentrated by distilling off ~25 g of solvent and cooled back down to room temperature. A freshly prepared solution of potassium metabisulfite (45.25 g) in water (100 g) was added to the vigorously stirred solution of the crude product. After about 20 minutes, the mixture began rapidly thickening with the appearance of a solid adduct. The resulting porridge was stirred overnight (ca. 12 hours) and vacuum filtered. The filter cake was rinsed with some butyl acetate and air-dried on a watch glass to yield 7.33 g of a nearly white solid.

The dried adduct was suspended in 155 mL of stirred water in a 250 mL beaker, and the mixture was basified to a pH of 10–11 by dropwise addition of an aqueous 20% solution of NaOH (5 grams of the solution was used); the end point coincided with the evolution of a green hue. The suspension of benzaldehyde was stirred for five minutes or so, and instead of vacuum filtering it, butyl acetate was added dropwise: 20.58 grams was added, with the initial 2–3 grams being sufficient to dissolve everything, forming immiscible, milky droplets. The biphasic mixture was shaken in a separatory funnel and left to stand for 26 minutes before collecting the organic layer and extracting the alkaline mixture with two more portions of the ester (13 g, then 11 g). The combined organic extracts were washed with water (2.7 g) and 25% NaCl (10 g), followed by drying over 1.02 g of MgSO4 until, after 30 minutes, the solution was clear.[1] The extract was gravity filtered through cotton into a 100 mL round boiling flask along with a small portion of BuOAc used to rinse the flask and the desiccant, and most of the solvent was removed by distillation at standard pressure.[2] The remaining solution was transferred onto a watch glass where the complete evaporation of volatiles gave 4.13 grams (70.6%) of crunchy, unevenly discolored chunks of a glassy solid with a delightful odor of an obscure fruitiness coupled with the generic character of freezer burn on a dairy-based ice cream; this had a melting point of 45.5–47.9°C (lit. 47–48°C). Recrystallization from an unrecorded excess of isopropanol gave 3.45 g (59.0%) of a cleaner but still slightly yellow material which retained the aroma and melted at 46.5–47.6°C.[3]

[1]: The yellow discoloration that was present in the organic solution of the purified product seemed to be adsorbed (or otherwise migrate) to the chunks of magnesium sulfate.
[2]: Something in the mixture seemed to exhibit an adverse reaction to the heating, producing a yellow discoloration. Possible explanations include transformation of the benzaldehyde product as well as that of some impurity, stemming from the chemical extraction of the adduct decomposition mixture. There will be further evidence to support this in the next update, but I'm going to state it right now: I think that mechanical separation of the aldehyde following adduct decomposition is the way to go (where applicable).
[3]: Measured using a different thermocouple.

[Fig. 60] Organic solution of crude product <> Extracted RM and washings

[Fig. 61] Solidification of crude product following contact with water

[Fig. 62] Preliminary sample collected for melting point determination

[Fig. 63] Addition of bisulfite solution to crude aldehyde

[Fig. 64] Initial adduct formation

[Fig. 65] Above mixture prior to filtration

[Fig. 66] Isolated bisulfite adduct

[Fig. 67] Decomposition of adduct

[Fig. 68] Dissolution of purified benzaldehyde in minimal butyl acetate

[Fig. 69] Partitioning of decomposition mixture

[Fig. 70] Solution of purified product in BuOAc drying over MgSO4

[Fig. 71] Product obtained by distillation and evaporation of above solution

[Fig. 72] Recrystallized 2,5-dimethoxy-4-ethylbenzaldehyde

The next installment (4/5) will cover all of the sulfur chemistry, leaving the 2,4,6-trimethoxy motif for last. I aim to complete both before the year is out, but it seems about as likely that I won't quite make it.
Either way, thank you for checking out this one!

[Edited on 26-11-2022 by Benignium]

arkoma - 25-11-2022 at 05:47

Either way, thank you for checking out this one!

I thank YOU for posting the details of an obvious labor of love fueled by some kinda passion!!!

This was an epic thread when you started it Benignium, and now I fear I may run out of superlatives!!!

Pumukli - 26-11-2022 at 08:48

I'm stunned, again, by your work, Benignium.

A lot of effort went into these synths (and obviously a lot of amateurish silliness too), but in the end you still have the results!
(Results, that most of us are probably a bit "positively envious" about. :) )

Keep up the hard work and keep us informed (and entertained) with the rest of the remaining preparations too! I swallowed your last post slowly, bit by bit, during a several hours period, as if it was a small glass of the best beverage an amateur organic chemist could enjoy.

Your work is not only encouraging and entertaining but visually pleasing too!

[Edited on 26-11-2022 by Pumukli]

clearly_not_atara - 26-11-2022 at 15:01

For the acylation of p-dimethoxybenzene, I think you could probably use Ac2O with a Brønsted acid catalyst, e.g.:

Heteropolyacids are a lot of work but I think you can achieve similar results with H2SO4 or TsOH or something. Yields are already pretty good so won't get much better, but a cleaner reaction and no noxious AcCl would be nice.

Your Duff results are consistent with my understanding that the Duff on p-dimethoxybenzene is not so great but when there is an activating 4-substitution, even alkyl, the yield is significantly improved.

Overall, really great work, and nice pictures.

Benignium - 5-12-2022 at 04:44

arkoma - The thought of you, out there, supporting me with such vigor is an enduring source of improvement to my self-worth and morale. :)

Pumukli - Your feedback is oozing a palpable sincerity — it is truly incredible. Thank you!

clearly_not_atara - Thank you for your support and the astute intellectual contributions that come with it!

tyro - 12-12-2022 at 20:32


The methylation of 4-methoxyphenol seems to be about as pleasant as methylations get: the phenol is readily converted, and not terribly fussy when it comes to oxidation, allowing for good yields of a remarkably fragrant[1] product, and doubtlessly the most satisfying substance that I've steam distilled to date.

[1]: The odor is quite unique, but there's something very familiar about it. I suspect that much of this familiarity stems from its resemblance to some species of clover that was (or were) abundantly present in my childhood.

The steam distillation of 1,4-dimethoxybenzene is incredibly satisfying, isn't it? I ran a few rounds of synthesis on this compound two or so years ago, starting from hydroquinone and dimethylcarbonate. The product also tended to freeze in the condenser. I ended up having to stop the water pump a few times to let the steam melt the mass which was threatening to clog up. And the smell? Beautifully pungent, definitely filled the working space and then some... After smelling it in this context, I started to notice notes of it in cosmetics and perfumes.

Thanks for the incredible thread here, and all of your other fantastic contributions. It's really been a joy to read.

Benignium - 16-12-2022 at 12:55

Oh yes — I wasn't quick enough (or my mantle wasn't hot enough) to avert the blockage by stalling the coolant, but the fix was thankfully still simple enough to not devalue the experience.
Beautifully pungent is a great way of putting it; I wonder if there are those who genuinely dislike the scent. Overall, I've found the phenols and their methyl ethers thus far to exhibit perfume-worthy fragrances with an astonishing frequency — all the while offering fascinating insight into the relations of molecular structure and our olfactory perception.

I'd love to read more on your experiences with dimethyl carbonate!

Benignium - 5-1-2023 at 07:21

Maximum effort.

The 2,5-dimethoxy-4-(alkylthio)benzaldehydes
212.27 g/mol (R = methyl)
226.30 g/mol (R = ethyl)
240.32 g/mol (R = 1-propyl)

Historically, the formation of the 4-alkylthio substituent has been regarded as a pick-and-mix of excessively difficult, prohibitively hazardous, and/or atrociously malodorous procedures by the amateur chemist, leaving most with no other option than to give up the chase. At the same time, however, the technology to overcome these barriers has been out there, waiting to be commonly accepted and adopted through experimental rediscovery. ‏‏‎ [1][2] Such an initiative was eventually taken by the Sciencemadness user Ullmann, whose absolute treasure chest of a thread ‏‏‎ [3] I would have initially overlooked, were it not for a chance encounter with a more recent thread ‏‏‎ [4] in which another Sciencemadness user, turd, has done an outstanding job in presenting the core issues, and the ways in which Alexander Shulgin, Ullmann, and later they themselves tackled them. Without these contributions, my own efforts in this area would exist only in my dreams. 
  This post comprises my darnedest efforts to compile the entire diverging, 11-step sulfur chemistry portion of the overall endeavor into a concise narrative whose progression remains faithful to the staged approach, according to which the actual events unfolded and interconnected observations were made: in brief, a thiophenolic precursor was prepared, and divided into three portions (excluding an analytical sample), two of which were selectively alkylated at the sulfur prior to stages of jugate permethylation and formylation with the third portion. 
  Even though some of the materials did sport a foul odor — mostly when impure — none were anywhere near as bad in terms of volatility or detection threshold, or even in the qualitative sense, as the simple thiols (encountered in alternative approaches) are purported to be. Honorable mentions should, however, be given out to a very impure sample of 2,5-dimethoxy-4-(methylthio)benzaldehyde, as well as a supposedly microbial smell which haunted the immediate vicinity of the sink where glassware was cleaned; shortly after trace amounts of several of the organosulfur materials were flushed down the drain, the exact same malodor would appear, and linger for a few days. Previously unknown, I would describe the aroma as being reminiscent of decaying organic matter, and decidedly sewer-like. Interestingly, although the phenomenon certainly seemed to coincide with the handling of everything from the thiophenol all the way to the methoxybenzenes (at least), disposal of several milligrams of the five-month-old thiophenol down the same (interveningly inactive) sink caused no odors whatsoever. 
  Finally, this sequence of syntheses spans the breakage of a K-type thermometer and two thermocouples, which (along with some strange values) is why, in December, I redetermined several of the melting point values — while also determining a few missing ones. This was done in one session, using a thermocouple whose readings are reliable, albeit depressed by ~1°C (depending on the temperature range). Although the materials had been stored for about 4–5 months (in airtight containers, at room temperature, and mostly protected from UV), they didn't appear to have degraded significantly: only some rather superficial darkening was observed on the sample of propylthiohydroquinone. The verified values are given in parentheses after the original values (not to be confused with literature values), and may be narrower due to a slower incrementation of temperature.

[1]: Lau & Kestner: Synthesis of 5-hydroxy-1,3-benzoxathiol-2-ones.
[2]: PiHKAL: #167 4T-MMDA-2.
[3]: (Sciencemadness) Thread by Ullmann.
[4]: (Sciencemadness) Thread by turd.

Chapter I


[a2] 1,4-benzoquinone
108.10 g/mol

Since the springtime experiments, I felt that I had unearthed sufficient evidence against water to revert back to using an alcoholic solvent. Because I was able to conclude that my rather dilute hydrogen peroxide was definitely capable of producing benzoquinone, I prioritized improving the other parameters over obtaining a higher concentration or seeking a different oxidizer altogether. Eventually, a striking experimental report by the Sciencemadness user homeslice ‏‏‎ [1] convinced me to trial the profound modification of bringing the complete reaction mixture to a boil for just 2–3 minutes. Even though this approach seemed to contradict my previous experimental findings somewhat, it did prove exceedingly efficient.

[1]: (Sciencemadness) homeslice: Experimental report.

Experiment 3 (-ish)
In a 1000 mL Erlenmeyer, hydroquinone (40.30 g, 366 mmol) and iodine (0.65 g, 2.6 mmol) were dissolved in isopropyl alcohol (150 mL) with mild heating and magnetic stirring. There was then added, in one portion, 11.9% hydrogen peroxide (140 g, 489 mmol), after which the mixture was promptly heated to its boiling point, maintaining reflux for two minutes under a 200 mm Liebig condenser [1] before cessation of the heating. The mixture was stirred for another 10 minutes on the synchronously cooling hotplate prior to measuring its temperature at ~71°C (using IR); observing no more liberation of oxygen; and moving the flask onto a lab jack, where it was allowed to cool to 50°C over 20 minutes. Further cooling was effected by placing the flask in a cold water bath, where an abundant crystal formation was observed after 30 minutes.

[1]: The condenser was fitted with a U-bend (made up of adapters), whose purpose was to direct any spillage into an empty 500 mL flask in the event of a runaway reaction. No boil-over occurred, but the vigorous evolution of oxygen did enable approximately a gram of quinone-containing solvent vapor to make it past the condenser.

[Fig. 1] Iodine and hydroquinone under isopropanol

[Fig. 2] Complete reaction mixture on the verge of boiling

[Fig. 3] Above mixture about one minute later

[Fig. 4] Post-reaction mixture cooling down

The crystal-laden flask was kept in the freezer for 90 minutes prior to vacuum filtering the mixture and rinsing the obtained solids with 5 g of i-PrOH. Then, once the filter cake had been compressed and suctioned free of most of the alcohol, it was recrystallized from 35 g of i-PrOH. The filtered crystals were placed (outside) in front of a fan in a crystallizing dish, where they were dried (with occasional mixing) over about two hours. These crystals, while considerably cleaner, retained a rather dark overall shade of yellow, with a generous sprinkling of ones that were outright reddish; a melting point of 115.5–117.7°C (lit. 115–116°C) was determined. [1] The material was placed in a brass mortar where it was triturated somewhat crudely under 35 g of i-PrOH. Filtration of the mixture gave a slightly reddish liquor, and a high return [2] of a crystalline powder which still appeared quite dirty. The solid was air-dried as before, and then recrystallized once more from 75 g of i-PrOH to little apparent avail; after cooling the mixture in the refrigerator, vacuum filtering it, and washing the filter cake using 20 g of room-temperature i-PrOH, the twice recrystallized, thrice air-dried yield of adamantly contaminated crystalline 1,4-benzoquinone was 31.14 g (78.7%).

[1]: The melting point test was expedited due to highly irritating fumes emanating from the heated capillary tube, leading to some broadening of the experimental value.
[2]: No more than a gram of the quinone seemed to dissolve in the amount of (room-temperature) i-PrOH used.

[Fig. 5] Crystal formation in cooled post-reaction mixture

[Fig. 6] Vacuum filtration to separate crude product

[Fig. 7] Separated crude product

[Fig. 8] First recrystallization; crystallized splatters of hot solution

[Fig. 9] Recrystallized product

[Fig. 10] Triturated product under fresh isopropanol

[Fig. 11] Second recrystallization

[Fig. 12] Alternative perspective (after about a minute)

[b3] 5-hydroxy-1,3-benzoxathiol-2-one
Also called: This
168.18 g/mol

Here's a very nifty little trick, and a key feature of this approach in terms of amateur-friendliness: when 1,4-benzoquinone is treated with an excess of thiourea in the presence of a strong acid catalyst, a thiouronium salt is formed that can then rapidly cyclize on heating to give an imine intermediate, which in turn hydrolyzes with the loss of ammonia to give the title compound. [1][2][3][4][5][6] Not only is this resulting heterocyclic intermediate valuable due to its convenient and high-yielding formation and subsequent hydrolysis (c3) — it also allows for the independent alkylation of each oxygen, paving the way to the fascinating 2- and 5-monoethylated tweetios, like the 5-ethoxy-4-ethylthio-2-methoxyphenylethylamine. [6] 
  Going forward, it should be kept in mind that the thiophenol is remarkably sensitive to oxidation, and any handling in basic conditions should be performed under an inert atmosphere, with care being taken to deoxygenate solvents beforehand.

[1]: Lau & Kestner: Synthesis of 5-hydroxy-1,3-benzoxathiol-2-ones.
[2]: PiHKAL: #167 4T-MMDA-2.
[3]: (Sciencemadness) Thread by Ullmann.
[4]: (Sciencemadness) Thread by turd.
[5]: (Hyperlab) Obtaining mercaptohydroquinone.
[6]: (Hyperlab) miamiechin: 2C-T-2-5EtO.

Experiment 1
Onto a jointed 1000 mL Erlenmeyer flask were stacked, in order: a 200 mm Liebig condenser; a vertical vacuum distillation adapter with a length of tubing leading to a dilute NaOH solution (gas scrubber); and a loosely stoppered 250 mL separating funnel. To a stirred solution of thiourea (23.28 g, 306 mmol) in approximately 2.5N hydrochloric acid (~244 mL, 557 mmol) [1] in the flask there was added, at a rapid dropwise pace from the funnel on top, a solution of 1,4-benzoquinone (30.00 g, 278 mmol) in acetic acid (170 mL). The addition was completed in 30 minutes, and it caused the temperature of the mixture to gradually rise to around 40°C. Once 15 minutes had passed since the end of addition, the mixture had cooled to 37°C, and solids began to precipitate. The resultant, thick suspension was stirred for as long as it took to let it cool down to as close to room temperature as it was going to get [2] before adding a further portion of 33% HCl (18.50 g, 167 mmol) and then gently heating the mixture to reflux, where it was maintained until an hour had elapsed since it was heated past 80°C. [3]

[0]: The temperatures were measured from exterior surfaces of the glassware using IR.
[1]: Prepared from 61.56 g of 33% HCl and 192 mL of water. Estimating a normality like this (as opposed to calculating it exactly via titration of molarity) seems about as counter-intuitive as wearing sunglasses to bed, but there you go. In fact, full disclosure: none of my acids and bases are properly titrated (nor have they been thus far), and claims like the above 557 mmol of HCl quite frankly do a much better job at depicting my intentions with what I've been sold than they do the exact number of millimoles employed. That said, I'm not looking to advocate undue laxness; what we have in titration is a fantastic opportunity to improve. First thing tomorrow.
[2]: This is ambiguously expressed as "After 90 minutes [added...]" in my notes, and based on the available documentation, it's hard to tell whether this translates to 90 or 75 minutes following the end of addition. Either way, the mixture was slow to cool, and (IIRC) barely did so past 30°C; I believe that there was some exotherm accompanying the solid formation, and that if frictional heat from the stirring was a thing, it was in addition to a significant heat transfer from the active (i.e. perceivably warm) hotplate beneath.
[3]: The temperature of 80°C, while arbitrarily chosen for timing the reflux, was noteworthy for being roughly the point at which bubbles began evolving on heating; likely signifying that a reaction was taking place.

[Fig. 13] Addition of benzoquinone solution to thiourea in hydrochloric acid

[Fig. 14] Mixture following complete addition

[Fig. 15] Alternative perspective (6500K lighting)

[Fig. 16] Initial formation of solids

[Fig. 17] Suspension of supposed isothiouronium chloride

[Fig. 18] Alternative perspective

The post-reaction mixture was set aside to cool at room temperature. Crystals began forming from the solution at >60°C, and an impressive crop was observed after seven more stationary hours. This was stored below 10°C for some hours prior to cooling to a temperature of 0–4°C, at which the mixture was vacuum filtered. The unrinsed filter cake [1] was spread out over a coffee filter, which was placed on several layers of paper towel. Air-dried, the crystals weighed 42.73 g (91.5%), melted at 177.7–179.8°C (lit. 170.5–172.5°C; [2] 175.5–176°C [3] ), and had a rather pleasant, familiar odor with a low detection threshold. [4]

[1]: Not knowing much about the solubility of this product, and deeming it quite pure by appearance, I thought it best to not risk rinsing it. In hindsight, it would have made a lot of sense to at least do a quick rinse with water; the solubility seems negligible, and the obnoxious evaporation of acid fumes could have been mostly avoided.
[2]: PiHKAL: #167 4T-MMDA-2.
[3]: SpectraBase: 1,3-BENZOXATHIOL-2-ONE, 5-HYDROXY-.
[4]: Visually undetectable quantities on crudely wiped down surfaces could be smelled clearly. The aroma bears an uncanny similarity to that of an odorous sample of impure crystalline MDMA which I encountered many years ago; whose origin was completely unknown; and whose odor I have come to describe as resembling of root beer (which is entirely debatable). Having said all that, it's a distinct possibility that, just as back then, the odor belongs to an impurity, and that none of it is inherent to the actual product. Interestingly, I later found the odor of the crude 2-hydroxy-5-methoxyacetophenone (the phenolic side product of c1) to exhibit a nearly identical component.

[Fig. 19] Initial crystal formation

[Fig. 20] Above mixture after seven hours at 24°C

[Fig. 21] Obtained 5-hydroxy-1,3-benzoxathiol-2-one (in 6500K lighting)

[c3] 2,5-dihydroxythiophenol
Also called: Mercaptohydroquinone
142.18 g/mol

In this next step, the isolated intermediate is saponified using aqueous alkali to yield the desired thiophenol. While the obtained crude yield appeared to be nearly quantitative, the initial melting point tests indicated a significant degree of impurity. It's possible that the conversion via this described procedure may have been incomplete, as I certainly overestimated the purity of my NaOH. On top of this, there was observed what appears to be a tendency to discolor and degrade on heating, which I suspect to be a characteristic of the product, and thus mostly independent of the initial impurity. Prolonged storage in solution also seems like it could be problematic. All things considered, potential improvements include additional base, thin-layer chromatography and, weirdly enough, not bothering with further purification.

[0]: For references, see the previous step.

Experiment 1
In a two-necked 1000 mL RBF, 5-hydroxy-1,3-benzoxathiol-2-one (40.01 g, 0.24 mol) was added through a 200 mm Liebig to a magnetically stirred, deoxygenated [1] solution of NaOH (38.57 g, 0.96 mol) in water (320 mL), against a gentle overpressure of argon. Maintaining the argon flow throughout, the mixture was heated under reflux for an hour and then moved to a water bath, where it was cooled to ambient temperature prior to a colorful [2] acidification via dropwise addition of 33% hydrochloric acid (137.20 g, 1.24 mol).

[1]: Deoxygenation was performed by pulling an aspirator vacuum over the mixture several times, each time normalizing the pressure using argon: first for a period of 5 minutes, and then three more times for as long as it took to reach the final depth of vacuum.
[2]: Green → gray → red amber (with initial foaming) → green → gray → nearly white with a green tinge, and opaque from precipitation and effervescence.

[Fig. 22] Dissolution of starting ester in aqueous alkali

[Fig. 23] Above mixture after about two minutes

[Fig. 24] "Red amber" stage of post-reaction acidification

[Fig. 25] Acidified mixture

The acidified suspension was subjected to three vacuum-argon cycles, each giving rise (and fall) to a transient, pastry-like crust over an abundant liberation of residual (hydrogen sulfide-smelling) gas. The mixture was then vacuum filtered to obtain a portion of solid material with a dirty white color and a melting point of 109–116°C (lit. 118–119°C [1] ). Extraction of the filtrate using ethyl acetate, followed by evaporation to dryness, gave a comparable amount of solid which was visibly cleaner and melted at 118–120°C. The portions were combined (thoughtlessly, before knowing their melting points) for a crude yield of 33.19 g (98.1%).

Recrystallization of the crude product was explored. An unrecorded portion (presumably everything) was dissolved in 60 g of boiling ethyl acetate, and 20 g of heptane was added with the intention of lowering its solubility, but the liquids were immiscible. An initial crop of finer off-white crystals (12.8 g, MP ~114°C) was obtained, followed by a second crop (10.9 g) of larger, more distinct crystals with a green hue from concentration of the filtrate through distillation.

Evaporation of the concentrated mother liquor gave about six grams of a gooey, green, crystalline mass, from whence an extraction of product was attempted with two portions of boiling toluene (25, then 21 g) that were decanted off of a sunken brown oil. The combined extracts were heated together to redissolve everything. On cooling, a light-brown oil separated before the formation of crystals. A gram of n-PrOH was added in an attempt to keep more of the oil in solution; the oil temporarily dissolved, but reappeared at a lower temperature, coinciding with crystal formation and prompting the addition of another gram of n-PrOH. The mixture was heated to redissolve the crystals, and on cooling, the oil initially remained in solution while crystals formed. At 24°C, however, some oil had still separated. The mixture was placed in a freezer and the cold liquor was decanted off. Residual oil and solvent were removed by pressing the solids between layers of paper towel before air-drying them to obtain 2.57 g of cream-colored crystals which melted at about 106°C.

The 10.9 g portion was recrystallized from 32 grams of aqueous 10% methanol to yield 8.09 g of crystals (with a melting point of ~117°C) via vacuum filtration of the refrigerated (<10°C) mixture. The mother liquor was used to dissolve the residue from evaporation of the above toluene, as well as the cream-colored crystals obtained from it, and the solution was allowed to slowly evaporate from a cling-film-covered beaker for about seven weeks; the remaining liquid was then pipetted off, leaving yellow, crystalline solids which initially smelled like renally excreted asparagus metabolites (if you know, you know), until they were completely air-dried and odorless, and weighed 3.11 g. A melting point range of 178–191°C (180–188°C) was determined. [2]

The final yield of a uniformly off-white mixture of recrystallized materials seems to have been 23.58 g (69.7%). [3] Only the much later verified melting point value exists (110–117°C). The fresh material had a very slight green tinge, which seemed to give way to a beige hue with time. I would describe the odor as a faint, sulfury sourness, with some of the root beer of the ester precursor sticking through.

[1]: PiHKAL: #39 2C-T.
[2]: At ~120°C, the material acquired a waxy appearance, as if moistened by some trace amount of melted mercaptohydroquinone. As the sample melted, there was some simultaneous decomposition (i.e. reddening until orange), and a small amount of pale solid material remained on the bottom. Interestingly, the previously mentioned "root beer" smell was distinctly emitted by the melted sample; this could imply an incomplete saponification.
[3]: 19.22 g of the purified product was used and I still have 4.36 g left. This means that 2.69 g isn't accounted for in the notes, and was most likely obtained from two initial small-scale recrystallization attempts from aqueous methanol, whose details are likewise missing — the material should then originate from either the initial 33.19 g or [an unrecorded deduction that is missing from] the 12.8 g which was obtained from the EtOAc recrystallization.

[Fig. 26] Rise of "pastry-like crust" under reduced pressure

[Fig. 27] Combined fractions of crude product

[Fig. 28] Trial recrystallization from aqueous methanol

[Fig. 29] Combined impure fractions after seven weeks in beaker

[Fig. 30] Crystals from (the bottom of) above mixture

[Fig. 31] Purified material used in subsequent syntheses (surplus)

Chapter II


Another thoroughly fascinating feature of this approach is the exploitation of the differences between oxygen and sulfur as they relate to the atoms being stuck on a benzene ring. A base, such as KOH, deprotonates a thiophenol in preference to a phenol due to the thiophenol being more acidic. In a similar manner, an electrophile which is not particularly aggressive, like the alkyl bromides employed here, will have an overwhelmingly consequential preference for a thiophenolate, which in turn is more nucleophilic than a deprotonated phenol. Therefore, what ends up happening, in this context, is that even if one were to use more base than what is required to deprotonate the thiophenol — and even if there was a significant excess of the more electrophilic ethyl bromide present — the immediate end result would be similar: a virtually exclusive and exhaustive alkylation of the thiol. [1][2] 
  In light of the above, it is then clear to see that using more of each alkyl bromide (and quite possibly the base as well) would more than likely have improved the outcome of these experiments; unreacted starting material most definitely contaminated both of the products, and the same knowledge which could have been used to largely avoid the resultant issues was used to fix them in a bit of a leap of faith, whereby bicarbonate was used to remove the (presumed) thiophenolic impurity in open air. 
  Briefly, the alkyl bromides used in these reactions were prepared via dropwise addition of sulfuric acid to a cooled mixture of KBr, water and alcohol; refluxing the mixture; distilling the product from a hot water bath; washing the product with water, aqueous bicarbonate and brine; and drying over MgSO4.

[1]: (Sciencemadness) Thread by Ullmann.
[2]: (Sciencemadness) Thread by turd.

[d4] Propylthiohydroquinone
Also called: Hydroquinonyl n-propyl sulfide (probably)
184.26 g/mol

Experiment 1
In a beaker, potassium hydroxide (3.13 g, 56 mmol) was dissolved in methanol (50 mL) with magnetic stirring, and the resulting rather polluted solution [1] was gravity filtered into a double-necked 250 mL round boiling flask through a tiny swab of cotton wool. With the flask set up in a water bath, [2] a dual-port gas adapter was attached to the side neck, and used to connect both an argon bottle and a water aspirator; the vertical neck was stoppered. The alcoholic base was then brought to a boil by pulling a vacuum which was immediately counteracted with an influx of argon to the point of (with help) lifting the stopper; this was repeated two more times prior to replacing the stopper with a powder funnel and slowly adding 2,5-dihydroxythiophenol (7.11 g, 50 mmol) through the sustained argon outflow. The mixture was allowed a moment of idle stirring before 1-propyl bromide (6.47 g, 53 mmol) was added in four dropperfuls over about two minutes. Finally, the argon was terminated; the vertical neck was stoppered; and the mixture was stirred for 135 minutes.

[1]: The KOH (fig. 32) was green and contained some insoluble debris.
[2]: Both S-alkylations were performed in a ≤24°C water bath due to the unknown extent of potential exotherm. Aside from inhibiting the volatilization of the alkyl bromides somewhat, no apparent benefit was had from doing this.

[Fig. 32] Technical grade potassium hydroxide

[Fig. 33] Methanolic solution of KOH and mercaptohydroquinone

[Fig. 34] Reaction mixture within four minutes of 1-PrBr addition

[Fig. 35] Discoloration, likely caused by lingering atmospheric oxygen

[Fig. 36] Post-reaction mixture

The methanol was vacuum-boiled twice as before, and acidified (under argon) by adding a gram of 33% HCl. The walls of the flask were washed down with MeOH using a dropper, [1] and the mixture was vacuum filtered. The filtered, slightly off-white solids were washed using 12.7 g of MeOH and air-dried to obtain 4.67 g of (mostly) KBr which exhibited a slight, uneven darkening on air exposure. The filtrate was distilled under reduced pressure to concentrate it down to a volume of ~40 mL before evaporating the remaining methanol under a PC fan and transferring the residue to a water-containing beaker in order to examine its solubility (or complete lack thereof). The water was removed by pipetting and evaporation, leaving 8.3–8.6 g of a clear, honey-colored oil.

After a fruitless attempt to obtain crystals from dissolving exactly one gram of the crude product in heptanes (10.24 g) with a bit of propan-1-ol (1.5 g) — and subsequently converting it into a tarry mess by adding water, distilling off the organic solvents with a bunch of said water, adding sodium bicarbonate solution to the remainder (and the distillate) to see what would happen, and stirring the mixture in the open flask to see for how long [2] — the remainder was allowed to remain in open air on a watch glass. Not much change was observed after seven days, aside from some strangely isolated discoloration near the borders of the glass, and perhaps a shift to a greener hue which wasn't apparent at the time (fig. 41).

Inspired by the result of the preceding initial bicarbonate treatment of the ethylthio derivative (see d3), the entire quantity of material was transferred to a beaker using 3.6 g of ethyl acetate, and 50 mL of a 5% sodium bicarbonate solution was added. The biphasic mixture was stirred magnetically for 5 minutes and then poured into a 250 mL separatory funnel. More EtOAc was added until, after adding ~12 g with occasional swirling, the entire organic phase had risen on top of the aqueous one. The aqueous layer was drained into a beaker, where it was further extracted by stirring with a 10 g portion of the EtOAc prior to being separated and acidified with 3.5 g of 33% HCl. The combined organic phases were washed with 40 g of 25% NaCl, and acidified with 0.78 g of 33% HCl. The acid-treated organic layer was gravity filtered through cotton and distilled to remove the bulk of the solvent. The concentrated solution was poured into a shallow borosilicate dish where it solidified, affording 7.32 g (79.5%) of a cream-colored, crystalline solid with a melting point of 69–72°C (70.4–71.4°C); this had a faint, fruity odor with hints of rubber and dehydrated onion. Nothing was extracted from the aqueous portion.

[1]: The intention was to minimize discoloration from any residual deprotonated material getting oxidized before assimilating to the acidified portion.
[2]: There was an immediate, progressive darkening which resulted in a nearly black mixture overnight (fig. 39). I don't have an explanation for why this happened; the baking soda was reasonably fresh and appropriately stored, and I'm quite certain that the distilled mixture had completely cooled beforehand.

[Fig. 37] Acidic vacuum filtrate and separated solids

[Fig. 38] Crude product (mostly) under water

[Fig. 39] Oxidative degradation of one-gram sample <> Also distillate

[Fig. 40] Freshly isolated crude product

[Fig. 41] Crude product after six days in open air

[Fig. 42] Above material dissolved in butyl acetate

[Fig. 43] Above solution being stirred with aqueous sodium bicarbonate

[Fig. 44] Purified propylthiohydroquinone

[d3] Ethylthiohydroquinone
Also called: 2-(ethylsulfanyl)benzene-1,4-diol
170.23 g/mol

On its surface, the ethylation appears identical to the previous propylation. However, there are a couple of considerations which were not taken into account in performing this next experiment: firstly, ethyl bromide needs comparatively little provocation to peace out prematurely due to its remarkably high vapor pressure; and lastly, it would then follow that continuously pumping an inert gas through the system which contains ethyl bromide is strictly inadvisable — that is, unless there was an actual need to do so, as well as an excess of the bromide which was sufficient to compensate. Which there wasn't.

Experiment 1
A solution of KOH (3.13 g, 56 mmol) in MeOH (50 mL) was gravity filtered into a two-necked 250 mL reaction flask, which was positioned in a cool water bath and connected to argon and vacuum lines via a dual-port gas adapter on the angled neck. Four cycles of deoxygenation were effected in the same manner as in d4 prior to adding the thiophenol (7.11 g, 50 mmol), followed by EtBr (5.80 g, 53 mmol), and stoppering the vertical neck — this time maintaining a slight, continuous efflux of argon into the aspirator reservoir while the mixture was stirred for two hours.

To acidify the mixture, a gram of 33% HCl was added, followed by an additional portion of 10 drops. [1] The mixture was vacuum filtered to separate 3.77 g of KBr with an air-sensitive whiteness, and the bulk of the MeOH in the filtrate was removed under vacuum before an exhaustive evaporation to leave a dark yellow oil.

In a bid to remove any unreacted thiophenol, the crude product was treated with bicarbonate. Using an unrecorded amount of ethyl acetate, the crude product was transferred to a beaker, where it was magnetically stirred with 50 mL of 5% aqueous NaHCO3 for a few minutes. The separated organic solution was washed with 20 g of 25% NaCl, and then acidified using 6 g of 5.5% HCl prior to evaporating the solvent and thus obtaining 6.32 g of a yellow oil. [2] No written descriptions of the odor seem to exist. [3] The bicarbonate partition was acidified using 2.38 g of 33% HCl and extracted using EtOAc to obtain 1.46 g of a crystalline residue which was surprisingly light in color, [4] and practically odorless.

Eventually, after storing the product on a watch glass in open air for 19 days, [5] it was decided that a second bicarbonate washing be carried out. The previously bicarbonate-treated product (6.25 g) was transferred to a beaker in 5.6 g of butyl acetate. The solution was stirred with 50 mL of aqueous 5% NaHCO3 for 12 minutes, after which the mixture was poured into a 250 mL separatory funnel along with 8.4 g of additional BuOAc. Unlike before, the funnel was shaken, and quite a bit of discoloration immediately took place. The aqueous layer was drained, acidified, and later extracted to obtain no residue. The organic layer was washed with 26 g of 25% NaCl, acidified with 1.06 g of 33% HCl, gravity filtered, and dried over 0.33 g of MgSO4. To estimate the amount of product in the solution, 0.33 g (out of 20.5 g) was placed on a watch glass, leaving ~90 mg of residue after the evaporation of volatiles; this indicated ~5.59 g of product (65.7%).

Finally, ~11.7 g of the solvent was distilled off to leave a dark, viscous, reddish-brown oil in the flask. Prior to methylation, the flask was warmed to ~50°C and swirled around while simultaneously purging it with argon to further remove residual volatiles.

[1]: Assuming a total volume of 0.5 mL and a density of 1.16 g/mL, this would be approximately 0.58 g.
[2]: A small sample of the oil was placed on a watch glass. Cooling in the freezer produced no crystals, but hardened the oil such that its viscosity was comparable to something like barely malleable glass. The sample acquired a reddish discoloration on standing in open air (fig. 46); over the same span of time, the main portion remained unchanged.
[3]: I vaguely recall a modest, predominantly rubber-like smell, similar to what could be picked up from propylthiohydroquinone and later its methyl ether — soft and sort of sweet, comparable to rubbers that are used in some worn and household items; footwear and cleaning equipment, perhaps?
[4]: Part of my original assumption concerning the efficacy of a bicarbonate treatment was that any unreacted thiophenolate might rapidly oxidize all the way to a hopeless tar following deprotonation. Moreover, I was quite certain that the tar would then immediately partition into the organic solvent, tainting the hydroquinone. In a fascinating twist, the sort of dramatic oxidation that I was expecting didn't seem to take place (unless the mixture is shaken with air in a funnel, apparently). Initially, I supposed that the presence of ethyl (and later even butyl) acetate had a protective effect which allowed for the atmospheric isolation of 2,5-dihydroxythiophenol. However, when its melting point was finally determined five months later; the isolated material was observed to gradually begin browning at ~120°C; partially melt into a chocolate-colored semisolid lump at ~167°C; and then quite sharply blacken and liquefy completely at ~170°C — while the similarly stored actual thiophenol simply assumed a chlorine-like color as it melted at 110–117°C. That said, I imagine that the impurity could still have been impure thiophenol, at the time.
[5]: On the first (or second) day, two tiny specks of the bicarbonate-extracted solid were placed in contact with the edges of the puddle of crude product on the watch glass, with the intention of seeing whether they'd facilitate further solid formation or something else of the sort. After seven days, pale streaks of ultra-fine particulate appeared to be spreading out from the solids (fig. 48), and at the end of the 19-day period, the entire puddle was observed to have become opaque, with a ring of red discoloration around the edges (fig. 49); this was what prompted the second bicarbonate treatment.

[Fig. 45] Impurity in BuOAc (aq. NaCl in the back) <> Product in BuOAc

[Fig. 46] Discolored sample of product

[Fig. 47] Bicarbonate-extracted impurity

[Fig. 48] Streaks of particulate spreading over crude product

[Fig. 49] Above sample after ~18 days in open air

[Fig. 50] Aftermath of second bicarbonate treatment

Chapter III


While the process of methylation itself is nothing out of the ordinary, the importance of protecting the hydroquinones from atmospheric oxygen is highlighted, particularly in the first experiment, where the thiophenol is only now alkylated. To that end, I figured that I would try incorporating acetone — which was previously used in the aqueous methylation of 4-methoxyphenol (b1) without issues — the idea being that boiling it under vacuum would drive out most of the dissolved oxygen. It has also been suggested that the presence of acetone can significantly inhibit the saponification of dimethyl sulfate by the aqueous alkali, [1] which, if true (and applicable here), would be a nice perk. Overall, the deoxygenation seemed to work well, but the yields were mediocre; this, along with the nearly identical dark brown coloration that each of the post-reaction mixtures acquired on standing, seems to imply an incomplete conversion. 
  Because the territory felt somewhat more uncharted, the initial workup in particular involves a bunch of, as Cave Johnson from Portal 2 might put it, "throwing science at the wall . . . to see what sticks". Out of the things that were attempted, the obvious organic extraction and its treatment by repeated washing with aqueous alkali appeared to be the most effective, and I would consider these steps the bare minimum in terms of isolation — kind of like I would for any of the other methoxybenzenes.

[1]: (The Hive) GC_MS: Acetone as co-solvent.

[d2] 1,4-dimethoxy-2-(methylthio)benzene
Also called: 2,5-dimethoxythioanisole
184.26 g/mol

Experiment 1
In a single-necked, 100 mL round boiling flask, [1] acetone (10 mL) was added to a solution of NaOH (6.40 g, 160 mmol) in water (32 mL), and the magnetically stirred mixture was very briefly boiled three consecutive times by reducing the pressure and immediately replacing the atmosphere with argon, whose continued outflow was then utilized to purge the subsequent addition of mercaptohydroquinone (5.00 g, 35 mmol). The resultant solution was stirred for a couple of minutes, and a 250 mL separating funnel containing Me2SO4 (13.3 mL, 140 mmol) was attached, with simultaneous disconnection of the argon line to leave the apparatus open. The addition of DMS, initiated with a rate of about 10 drops per minute, was completed in exactly one hour, with the reaction temperature hovering right around 37.4°C (per IR). The flask was stoppered, and stirring was resumed for two hours before allowing the mixture to stand for about 52 hours at ambient outside temperatures (13–23°C), pending workup.

[1]: The reaction flask was fitted with a vertical vacuum distillation adapter, which was connected to an argon bottle via its gas port. A stopcocked 180° gas adapter was connected to a water aspirator, and attached to the female joint on the distillation adapter; once the vacuum pump had served its function, the gas adapter was removed, and the starting material was added through the distillation adapter. This configuration was utilized in all three of the methylations.

[Fig. 51] Reaction mixture prior to addition of DMS

[Fig. 52] Reaction mixture after adding most DMS

The post-reaction mixture was poured into a 250 mL separatory funnel, diluted with 50 mL of water, and extracted using three portions of DCM (20, 5, then 5 mL). The extracts were pooled and stripped of most solvent via distillation in a hot water bath, leaving approximately 5.8 g of a vibrant, reddish-brown oil that had a fairly repulsive odor, reminiscent of dimethyl sulfide and sewage.

The usefulness of steam distillation was gauged by adding 32.67 grams of water to the crude oil and collecting ~10 mL of a biphasic distillate whose bottom organic layer (<0.5 g) was pipetted onto a watch glass and evaporated along with two tiny portions of DCM used to crudely extract the aqueous layer (for not much apparent gain). After a day of standing in open (24°C) air, the residue had shed most of its unpleasant cabbage-like smell, and weighed ~90 mg. When no solidification was observed in over a week, the residue was placed in the freezer where it crystallized as a pale-yellow mass which appeared to melt upon reaching ~18°C on standing at room temperature (lit. 33-34°C [1] ).

NaOH (0.98 g) was added to the remaining ~25 mL of crude product and water, and the mixture was stirred for 15 minutes or so prior to extraction with three small portions of DCM; some color remained in the aqueous alkali. 20 mL of heptane was then added to the combined extracts in a 50 mL flask, and the mixture was distilled to remove DCM, causing some dark, solid impurity to precipitate. Another 20 mL portion of heptane was added, and distillation was resumed until ~15 mL of the mixture remained. This was then gravity filtered through cotton, rinsing the filter twice with fresh heptane. A heavy, red oil separated as the mixture cooled, but was retained due to it potentially containing dissolved product; an addition of 10 mL of toluene merged everything into a clear, amber solution.

0.57 g of finely ground activated charcoal was suspended in the solution at room temperature, and the mixture was then boiled for five minutes, cooled in a water bath, and stirred for two more hours at room temperature. The charcoal was removed by vacuum filtration through qualitative filter paper, affording a solution which was clearly less colored, but not dramatically so. A ~1% fraction of the solution was evaporated on a watch glass to obtain ~50 mg of an oil which crystallized in the freezer, but would melt at a significantly lower temperature (>0°C) than the previously steam distilled sample.

Three more alkaline washes were performed using 10-gram portions of 10% NaOH; the first two washes assumed shades of yellow, and the third portion remained colorless. A total of 3 g of methanol was then added to the third washing, until it caused some more of the discoloration to partition into the aqueous layer. [2] The bright-orange organic solution was further shaken with a small portion of water containing 0.52 g of 33% HCl, followed by an 11 mL portion of water with 0.51 g of dissolved potassium metabisulfite (both of which came out colorless), before evaporation on a watch glass. The residual oil contained some trapped moisture, dust, and a fruit fly, which were separated: the product wasn't soluble in plain heptane, but dissolved in a mixture containing 10% of toluene; this was then filtered through a ball of cotton. Evaporation to a constant weight afforded 3.99 g of an amber oil with a faint, mildly unpleasant smell (4.08 g in total; ≤69.1%).

[1]: PiHKAL: #39 2C-T.
[2]: This methanol-spiked washing was evaporated; the yellow, hygroscopic residue didn't seem to contain too much of the desired methoxybenzene, and was discarded. All in all, the incorporation of methanol was not worthwhile.

[Fig. 53] DCM extract <> Aqueous partition

[Fig. 54] Removal of DCM by distillation

[Fig. 55] Activated charcoal <> Solution to be treated

[Fig. 56] Alternative perspective

[Fig. 57] Charcoal-treated solution of product

[Fig. 58] Evaporated and refrigerated sample from above solution

[Fig. 59] Solution of product over dilute HCl

[Fig. 60] Purified product with residual moisture and airborne impurities

[e4] 1,4-dimethoxy-2-(propylthio)benzene
Also called: 1,4-dimethoxy-2-(propylsulfanyl)benzene
212.31 g/mol

Experiment 1
In a 100 mL reaction flask, acetone (16 mL) was added to a stirred solution of NaOH (4.84 g, 121 mmol) in water (35 mL), and — in the same manner as before (d2) — the mixture was deoxygenated prior to adding 1,4-dihydroxy-2-(propylthio)benzene (7.00 g, 38 mmol) and setting up a dropwise addition of dimethyl sulfate (10.3 mL, 109 mmol). The entire addition took 30 minutes, with the reaction temperature remaining at ~36°C (IR) throughout. The mixture was stirred for some time following the addition, [1] after which the flask was stoppered and allowed to stand at ambient outside temperatures (above and below 20°C) for six days.

[1]: The exact time wasn't recorded, but most likely all three of the methylation experiments were stirred for two hours following the end of addition.

[Fig. 61] Reaction mixture prior to addition of DMS

[Fig. 62] Reaction mixture after adding most DMS

The mixture was diluted with 50 mL of water and extracted with four portions of DCM (20, 5, 5, and 5 mL). The bulk of the solvent was removed by distillation, and the remaining oil was dissolved in 10 mL of heptanes. The addition of a 10 mL portion of 10% aqueous NaOH generated a small quantity of dark sediment on stirring; the mixture was gravity filtered into a separatory funnel through cotton, and chased with a 10 mL portion of additional heptane. The organic phase was retained, and washed with three more identical portions of alkali, followed by 10 mL of water, before it was drained into a 50 mL flask. The separatory funnel was rinsed with a 10 mL portion of toluene which was also added to the flask. This nonpolar mixture was then distilled atmospherically to the point of more dark sediment appearing, after which the distillation was resumed under vacuum until the precipitate eventually redissolved in the residual oil. 10 mL of fresh heptane was then added, which once again precipitated the supposed impurity. The suspension was refluxed for ~10 minutes with a gram of freshly ground activated charcoal. Vacuum filtration (whereby the glassware and separated charcoal were rinsed with 2 mL of heptane) and evaporation of the filtrate to a constant weight gave 5.90 grams (≤73.2%) of a honey-colored oil with a mellow, curiously zingy odor of sulfury rubber paired with some ambiguous middle ground of yellow onion and garlic.

Two weeks later, a ~0.80 g portion which wasn't used in the formylations was steam distilled. A coarse extraction of the collected slightly discolored oil (from 200–250 mL of distillate) using DCM afforded, on evaporation, 0.69 g of an off-white, crystalline solid melting at 31.1–32.9°C (32.1–33.7°C). The odor was unchanged.

[Fig. 63] Dark impurity resulting from treatment with base

[Fig. 64] Steam distillation of unused product

[Fig. 65] Solid 1,4-dimethoxy-2-(propylthio)benzene

[e3] 1,4-dimethoxy-2-(ethylthio)benzene
Also called: 2,5-dimethoxyphenyl ethyl sulfide
198.29 g/mol

The ethyl sulfide homolog was the last to be methylated. The digital notes on my phone seem to have encountered some deconstructive variation of pocket dialing, whereby, in between the addition of dimethyl sulfate and the recorded yield, there is a section which simply states " 6 ". Whatever was done was definitely very similar to the previous experiments: I recall reproducing the basic washing (also supported by fig. 68, which I couldn't place anywhere else), and noting that the product is insoluble in heptanes; conversely, I'm convinced that I skipped the activated charcoal treatment as well as attempting to steam distill the product.

Experiment 1
In a 100 mL reaction flask, a solution of NaOH (4.84 g, 121 mmol) in water (30 mL) was prepared. Acetone (10 mL) was then added prior to deoxygenation of the mixture and addition of the crude 1,4-dihydroxy-2-(ethylthio)benzene (<6.25 g, <37 mmol) [1] via the established method; similarly, the argon cylinder was disconnected as part of initiating the subsequent dropwise addition of DMS (10 mL, 105 mmol) which took 25 minutes to complete and generated a peak temperature of ~43°C (IR). After some additional stirring, the mixture was moved to the side where it remained — stationary and outdoors — for no more than four days.

[1]: The lowest estimate for the amount of starting material used is 5.59 grams (see d3 for details). Prior to its addition, the viscous, oily material was diluted with a small portion of acetone, which was also used to sparingly rinse the adapter through which said addition was made.

[Fig. 66] Reaction mixture prior to addition of DMS

[Fig. 67] Reaction mixture at the end of addition

The post-reaction mixture was diluted and extracted with several portions of DCM; the extract was washed with several portions of 10% NaOH solution, before evaporating it to constant weight on a watch glass to obtain 4.85 g of a honey-colored oil which had a tangy, sickly-sweet fruit drop aroma with a touch of rather off-putting, sulfury sourness. Depending on the actual amount of starting material used, the yield comes out at (≤) 66.6–74.5%.

[Fig. 68] Separation of dark impurity (supposedly on treatment with base)

[Fig. 69] All three dimethyl ethers, as utilized (Me \ Et / Pr)

Chapter IV


In recognition of my increasing vulnerability to failure, I began the formylations by dedicating a single gram of the most abundant intermediate to doing a pilot experiment. At this point I had run out of ethyl acetate, and switching to the decidedly more stable butyl acetate elicited the idea of incorporating it into the hydrolysis stage under reflux; this was done, and the crude yield from the pilot experiment ended up persuading me into trying a similar procedure on the 2,5-dimethoxyethylbenzene right away, which reinforced the wishful impression that I just might be onto something. The rest of the organosulfur compounds were then formylated — followed by the second portion of 2,5-dimethoxytoluene — and I have to admit: I still haven't the faintest idea as to where I stand on the issue. 
  Here, the yields really weren't great, which begs the logical question "Why?" as well as perhaps an emotional exclamation mark or two. Having pondered the matter, a slew of possible explanations has come to mind — none of which I can truly dispute, and many of which could have been taking place in tandem. Through furious speculation, I found myself in a bit of a rabbit hole which I've attempted to narrate in the hopes that it is of more interest to the chemist than it is to the psychologist. 
  Firstly, there's the Duff hydrolysis conundrum, elaborated on in the 4-Me post (1/5). Hypothetically, based on a statement by the Hyperlab user miamiechin, [1] I might assume there to have been an initial yield of up to ~80% in each case, minus whatever percentage of impurity was present in the starting material. As an interesting side note, it initially seemed like the crude yield of the propyl homolog from the pilot experiment could, by some metrics, [2] be estimated to contain as little as ~10% of impurity, which would have put the yield at roughly 84%. 
  Building on these arcane assumptions, and the observed discrepancy between the yields of the two propyl experiments, it would appear that a large chunk of each product might have been lost in the bisulfite purification. There's the distinct possibility of the formation and/or precipitation of the bisulfite adduct of each aldehyde having been significantly incomplete, which seems to be supported by the observed decelerating but seemingly everlasting precipitation of solids. Another correlation that stands out is how, instead of the usual dropwise addition of sodium hydroxide, a concentrated sodium carbonate solution was used to decompose the obtained adduct from all but the pilot experiment; indeed, at least one person has claimed that the use of (potassium) carbonate instead of hydroxide leads to lowered yields. [3] However, having tried the liquid–liquid extraction of each decomposition, the logistics for such a phenomenon seem somewhat improbable to me, as I wouldn't expect any such loss to be soluble in the aqueous phase. 
  As my newest piece of conjecture, I now realize that there is one more thing which I have managed to repeatedly disregard as if it kept curing scurvy: the acetic acid. In each experiment, 2.2–2.3 g of AcOH was used for every (supposed) millimole of starting material. Each reaction mixture was then diluted to an arbitrary degree with water before a likewise arbitrary amount of butyl acetate was used to extract it. Beyond this point, some interesting observations could be made: for instance, a mere 1.94 g of BuOAc per mmol (of starting material) was sufficient to extract what amounted to a 69.6% purified yield of the methyl homolog, but subsequently washing the organic solution with aqueous bicarbonate would then cause a significant quantity of the product to precipitate. Thus, it would appear that the amount of organically co-extracted acetic acid was decreased via neutralization as well as partitioning to the aqueous phase, forcing the poorly BuOAc-soluble and clearly very hydrophobic aldehyde out of solution. Similar correlations for the other two compounds aren't as conspicuous, but I believe that they're there. Mostly I'm just concerned that I've insufficiently extracted the two seemingly less hydrophobic aldehydes from the acid-containing reaction mixture, but really the bedrock that I keep unearthing here is that individual solubility of the [precursor/aldehyde/adduct] should be the constant main focus in deciding which variables to adjust. At the end of this post, I've included a table that I drafted for reviewing and comparing the experimental parameters; with some tweaks, I believe that it could be a great tool for planning and improving future Duff experiments as well. 
  Finally, I need to address the subject of melting points, as something strange seems to be going on with the separately S-alkylated derivatives. Assuming that the melting point values given in PiHKAL are indeed correct, it would appear almost as if my ethylated and propylated products had been switched at some point. However, I'm willing to risk the existential crisis of a lifetime in declaring that there is just no way that that could have happened. And even then, the melting points wouldn't quite match — which shouldn't be an impurity issue considering the fairly narrow ranges of 1.2°C and 0.9°C determined for the purest respective samples. Moreover, by (re-)verifying the melting point values in December, I have completely ruled out the possibility of a thermometer malfunction. But if Shulgin didn't mix up his values; and if I didn't mix up my products — what could have happened? Judging by the crude melting point of the pilot experiment, which at first seems to conform but then dramatically shifts as the material is purified, it seems like the anomalous behavior could originate from the bisulfite purification process. But then, why wouldn't something similar happen to the methyl homolog as well? It seems worth bringing up that Shulgin apparently used the Rieche (dichloromethyl methyl ether/Lewis acid) to formylate the methylthio compound, and purified it via the bisulfite adduct; [4] while the ethyl and propyl derivatives were formed through the Vilsmeier, and simply recrystallized from methanol until satisfactory [5][6] — with the latter apparently producing a perfect NMR spectrum. The best I could do is some last-minute TLC, but characterization of any products from subsequent syntheses should in time supplement this nicely.

[1]: (Hyperlab) miamiechin: 70–80% yield.
[2]: SRS - Rule-of-thumb: 1% of foreign substance will result in a 0.5°C depression.
[3]: (Hyperlab) ramboTT_1: [7] (KOH vs. K2CO3).
[4]: PiHKAL: #39 2C-T.
[5]: PiHKAL: #40 2C-T-2.
[6]: PiHKAL: #43 2C-T-7.

[f2] 2,5-dimethoxy-4-(propylthio)benzaldehyde
240.32 g/mol
360.49 g/mol (bisulfite adduct; potassium salt)

Experiment 1
In a 25 mL reaction flask, 1,4-dimethoxy-2-(propylthio)benzene (1.00 g, ≤4.7 mmol) and urotropine (1.32 g, 9.4 mmol) were mostly dissolved in magnetically stirred acetic acid (6.20 g). To the mostly clear solution was then added a solution of 98% sulfuric acid (1.88 g, 18.8 mmol) in acetic acid (4.12 g); the addition was performed dropwise, over 19 minutes, using a Pasteur pipette; and the ensuing cream-colored suspension was stirred for five more minutes at room temperature. The flask was then fitted with a condenser, and its contents were brought up to a boil in a 1000 mL heating mantle. After refluxing the mixture for 120 minutes, there was added butyl acetate (4.37 g) which separated a dense, dark oil. Once the heterogenous mixture had been refluxed for another 80 minutes, water (5.03 g) was carefully added, and the heating was kept up for 60 more minutes before allowing the mixture to cool to room temperature, at which it was then stirred for 13 hours.

[Fig. 70] Solution of substituted benzene and HMTA in AcOH

[Fig. 71] Reaction mixture following addition of sulfuric acid

[Fig. 72] Reaction mixture prior to addition of butyl acetate

[Fig. 73] Reaction mixture following addition of butyl acetate

[Fig. 74] Reaction mixture following addition of water

The bilayered mixture was poured into a 250 mL separating funnel and shaken with additional water (25 mL) and BuOAc (10 g). Once partitioned, the aqueous phase was extracted with two or three further 10 g portions of the ester, and the organic partitions were combined for treatments with water (10 g), 10% sodium bicarbonate (3x10 g), and finally a second portion of water (10 g). The treated organic solution was gravity filtered into a 50 mL flask through cotton (removing a small amount of dark sediment), and distilled until ~5 g of a yellow solution remained; this was evaporated to a constant weight on a watch glass, yielding 1.06 g (<93.8%) of a waxy, yellow residue with a melting point of 71–77°C (lit. 76–77°C [1] ) and a small amount of (likely inorganic) impurity which didn't melt. Dissolution of the material in 11.8 g of methanol was incomplete, even with a gram of butyl acetate as a co-solvent, but the residual solids dissolved in the plain ester (1.88 g).

A solution of potassium metabisulfite (7.53 g) in water (16.8 g) was prepared. The methanolic solution of crude aldehyde was funneled into the stirred bisulfite through cotton wool, and the mixture promptly thickened with solids that were pale apart from some dark orange bits here and there. The previous 1.88 g portion of BuOAc was then added, which appeared to dissolve the colored impurity. After about 30 minutes, the mixture was vacuum filtered, and the moist filter cake was strenuously rinsed with 8 g of fresh BuOAc before being placed on a watch glass to dry. The filtered mixture continued to develop solids; a second filtration was performed after about an hour, followed by a third one on the next day. The filtrate was retained for further observation.

In a beaker, the accumulated (partially dried) adduct was suspended in 50 mL of water with good stirring, and 2.35 g of a 20% NaOH solution was added to raise the pH to 10–11, followed by 5 g of BuOAc used to dissolve the solid phase. The mixture was then transferred to a separating funnel, using an additional 2.5 g of BuOAc to rinse the beaker. The phases were separated, and a further 0.44 g of the 20% NaOH was added to the aqueous portion [2] prior to extracting it with two more five-gram portions of BuOAc. Once combined, the organic extracts were washed with 10 g of 25% NaCl and a few grams of water. Most of the solvent was then distilled off, and as residual water was removed with it, a small amount of supposed salt precipitated; the residual organic solution was drawn into a pipette through a swab of cotton and deposited onto a watch glass to evaporate. Consequently, there was obtained 0.75 g (66.3%) of an odorless, slightly yellow, crystalline residue with a melting point of 82.9–84.6°C.

[1]: PiHKAL: #43 2C-T-7.
[2]: The presence of butyl acetate seemed to either buffer the pH down or distort the reaction between the mixture and universal pH paper; a pH of ~9 was indicated, hence the addition.

[Fig. 75] Initial organic extract <> aqueous partition

[Fig. 76] Residue from evaporation of above extract

[Fig. 77] Alternative perspective

[Fig. 78] Formation of bisulfite adduct

[Fig. 79] Wet bisulfite adduct

[Fig. 80] Bisulfite-purified product

[Fig. 81] Additional precipitation from retained bisulfite mixture

Experiment 2
To a well-stirred solution of the benzene (4.04 g, ≤19 mmol) and HMTA (5.36 g, 38.1 mmol) in AcOH (25.55 g) in a 100 mL reaction flask, 98% sulfuric acid (7.63 g, 76.2 mmol) in AcOH (18.13 g) was added dropwise (from a 250 mL addition funnel) over 22 minutes, causing the temperature of the mixture to plateau at 31–32°C. Following completion, the thick suspension was stirred for seven more minutes at room temperature prior to being brought to a reflux for 130 minutes. This was followed by one hour of stirring sans heating, after which there was added water (20.30 g) and BuOAc (14.68 g). Stirring as such was continued for ~30 minutes, and the mixture was refluxed for an additional 40 minutes before allowing it to cool once more.

[Fig. 82] Reaction mixture being heated

[Fig. 83] Above mixture 3 minutes later

Work-up (2)
After some 20 hours at room temperature, [1] the mixture was diluted with 15 g of water, and partitioned. The aqueous portion was extracted twice with BuOAc (12, then 21 g), and the extracts were merged with the organic portion. This was shaken twice with 25 g portions of water in a separatory funnel and then drained into a stirred suspension of NaHCO3 (10 g) in 90 mL of water; an additional three grams of NaHCO3 was required to retain alkalinity in the aqueous phase (one gram followed by four half-gram portions). The organic solution was separated and dried over 1.02 g of MgSO4.

Omitting distillation [2] to remove excess solvent, a solution of potassium metabisulfite (35.52 g) in water (78.63 g) was added to the dried organic solution with strong stirring. Solids began forming after about 10 minutes. After about 12 hours, the mixture was vacuum filtered. The filter cake was rinsed with methanol, [3] which appeared to give rise to further precipitation on mixing with the filtrate. [4] The cake was air-dried to a constant weight of 3.44 g, and a second filtration of the mixture ~18 hours later gave 0.38 g of additional solids for a total of 3.82 g.

The twice harvested bisulfite mixture was partitioned. The organic portion was used to extract the remainder of the reaction mixture (where the two 25 g water washings had also been deposited). Another extraction was done using BuOAc (10 g), and the combined organic extracts were washed with water (10 g), 25% NaCl (10 g), 10% NaHCO3 (8x10 g), and 25% NaCl (10 g) again, before being dried over 1.25 g of MgSO4 for ~20 minutes. Meanwhile, the aqueous bisulfite solution from before was replenished via dissolution of an additional 1.18 g of K2S2O5, and then combined with this new organic extract. The mixture was stirred for ~12 hours and filtered. The solids were rinsed with MeOH (2 mL) and BuOAc (6 g). The air-dried solids (3.03 g) were merged with the previously obtained 3.82 grams.

In an attempt to ensure that all of the available benzaldehyde would be retained, the spent bilayered bisulfite mixture was combined with that of the previous experiment. After 24 hours of standing, there had formed a bunch of additional solid material, which was separated by vacuum filtration and rinsed with 2 mL of MeOH. This, in combination with a later 0.68 g portion of even more solid material (rinsed with BuOAc), weighed 3.85 g.

The two portions of ostensible adduct were processed forth separately, beginning with the latter. The solid was added to a ~26.2% solution of Na2CO3 (17.49 g) in water (49.38 g), and the mixture was stirred for 15 minutes. There was then added 5 mL of butyl acetate, which was noted to dissolve the solid phase sluggishly (in 10–20 seconds). The mixture was left to stand for a little over an hour before the phases were separated and the aqueous portion was extracted with two 5 mL portions of BuOAc. The organic extracts were combined, dried over 0.31 g of MgSO4 and evaporated on a watch glass to yield 0.32 g of a crystalline residue with a melting point of 83.6–84.6°C.

The former 6.85 g portion was similarly decomposed in 80 g of the ~26.2% Na2CO3. The solid phase didn't seem to dissolve too well, with most of it persisting after [probably 5–15 minutes] of being suspended in a stirred emulsion containing 10 mL of butyl acetate. Instead of adding more BuOAc right away, the mixture was vacuum filtered. The filtered solids dissolved partially when rinsed with a 10 mL portion of BuOAc, so an approach was chosen whereby the same biphasic mixture was repeatedly filtered through the solids into a separatory funnel, with BuOAc being added incrementally until, after adding three more portions (10, 10 and 5 mL) for a total of 45 mL, only a few dozen crumbs remained. [5]

The liquid mixture was partitioned, and the organic solution was dried over 0.64 g of MgSO4 for >24 hours. No longer omitting distillation (due to forgetting about [2] ) the dried solution was distilled to remove the bulk of the solvent prior to evaporation of the remainder on a watch glass to yield 2.38 g (52.0%) of a wintry, crystalline residue melting at 82.4–84.6°C.

A recrystallization of the combined product of both experiments (3.45 g) from ~19 mL of isopropanol gave 3.21 g (56.3%) of odorless, cream-colored crystals with a melting point of 84.1–84.9°C (82.9–83.8°C).

[1]: It isn't specified whether the mixture was stirred or just stood there for ~20 hours.
[2]: Caution due to the observed heat-induced discoloration during the preceding workup of the 2,5-dimethoxy-4-ethylbenzaldehyde, as well as a suspicious discoloration of the purified product from the pilot experiment.
[3]: The amount wasn't recorded; it was added in one portion using a 10 mL pipette, and was definitely no less than 2 mL. I seem to recall using 6 mL but am way too uncertain to conclude thus.
[4]: This could mean an improvement to the rate and/or quantity of adduct formation, but it could also just be the precipitation of a dissolved portion of the filter cake and/or some insolubilized undesired material. As mentioned previously, I believe that methanol generally has a beneficial effect on the adduct formation through acting as a phase transfer catalyst (where applicable).
[5]: These crumbs were identified as mostly product by their mixed melting point. However, they were pending characterization long enough to be excluded from the initial yield and its recrystallization, and, by extension, from the purified yield. I seem to have since misplaced the crumbs, but I'd say there was probably no more than 100 mg (fig. 90).

[Fig. 84] Organic extract over aqueous bicarbonate suspension

[Fig. 85] Treated extract being stirred with bisulfite solution

[Fig. 86] Above mixture after 11 hours of stirring

[Fig. 87] 3.85 g portion of adduct being added to aqueous alkali

[Fig. 88] Above mixture after 13 minutes of stirring

[Fig. 89] Above mixture following addition of butyl acetate

[Fig. 90] Extracts from the two individual decompositions drying

[Fig. 91] Undissolved crumbs of product on filter paper

[Fig. 92] Evaporation residue of bisulfite-purified product

[f1] 2,5-dimethoxy-4-(ethylthio)benzaldehyde
226.30 g/mol
346.47 g/mol (bisulfite adduct; potassium salt)

Experiment 1
1,4-dimethoxy-2-(ethylthio)benzene (4.60 g, ≤23.2 mmol) and HMTA (6.50 g, 46.4 mmol) were dissolved in AcOH (30.4 g) in a 100 mL reaction flask. To the stirred solution was then added, dropwise, over 33 minutes, a solution of 98% H2SO4 (9.29 g, 92.7 mmol) in AcOH (22 g). On completion, the mixture was refluxed for 90 minutes after which there was added (through the condenser) BuOAc (19.00 g), followed by a cautious addition of water (10.40 g). After refluxing the reaction for another 70 minutes, it was allowed to cool for 20 minutes prior to adding a second portion of water (10 mL). Stirring was then continued for ~19 hours at 24°C.

[Fig. 93] Addition of HMTA to substituted benzene in acetic acid

[Fig. 94] Reaction mixture prior to heating

[Fig. 95] Reaction mixture approaching reflux

[Fig. 96] Above mixture after 10 minutes

[Fig. 97] Mixture after 50 minutes of refluxing with water present

[Fig. 98] Monophasic post-reaction mixture

In a separatory funnel, the monophasic post-reaction mixture was shaken with 53 mL of water and 15 g of BuOAc, and the two layers were separated. The aqueous portion was extracted twice using 10 g portions of BuOAc. Once combined, the organic portions were treated with 10% NaHCO3 (4x20 g, then 2x10 g) until a washing remained alkaline. The amber organic solution was dried overnight over 1.15g MgSO4. A 0.17 g sample was evaporated to dryness in a 10 mL beaker to obtain an unweighed, crystalline melting point sample with an unpleasant odor. [1]

A bisulfite solution (38.7 g of K2S2O5 in 86.2 g of H2O) was added to the stirred, gravity filtered organic solution in a 250 mL flask, along with 10 mL of MeOH. In ~10 minutes, the mixture had turned into an unstirrable porridge. The flask was swirled occasionally over the next 14 hours prior to vacuum filtering the mixture, washing the filter cake with 6 mL of MeOH followed by a total of 20 mL of BuOAc, and air-drying the obtained solids to a constant weight of 6.28 g.

Because the dried adduct had a rather dirty yellow color which wouldn't wash away on the filter, it was magnetically stirred with 20 mL of methanol in a 50 mL flask for about two hours. Filtration and air-drying of the mixture afforded 4.40 g of a significantly less discolored solid. The filtrate was combined with the separated aqueous portion of the previously used bisulfite mixture; [2] powerful stirring of the mixture followed by vacuum filtration, and drying of the separated solids, gave 1.53 g of material which was likewise much less discolored than what was had before.

A dark, crystallizing oily substance was observed to appear on top of the mixture of washings and extracted reaction mixture; a ~40 mL portion of the distilled organic phase from the bisulfite mixture was used to re-extract the mixture. The extract was treated with two portions of 10% NaHCO3 (40 g, 30 g) followed by 10 g of 25% NaCl, and then stirred overnight with the pre-used aqueous bisulfite to receive 3.18 grams of additional precipitate.

The accumulated adduct was added to 83 g of stirred ~26.2% sodium carbonate solution. After waiting 15 minutes, 10 mL of BuOAc was added, and the mixture was stirred for 10 minutes. The solid phase dissolved partially. Two more five-milliliter portions of the ester were needed to obtain a clear mixture; these were added 10 minutes apart. A small quantity of unidentified debris appeared at the liquid–liquid interface of the still mixture, and was gravity filtered out. The organic phase was separated, and the aqueous phase was extracted twice more with 10 mL portions of BuOAc. The combined organic extracts were dried over 0.76 g of MgSO4 for ~24 hours, and concentrated through distillation under reduced pressure. Following evaporation of the residual volatiles, there remained 2.62 g of slightly sticky, yellow crystals melting at 73.6–79.8°C (lit. 87–88°C [3] ). These were recrystallized from ~28 mL of isopropanol, giving 2.38 g (45.3%) of crispy, odorless crystals which were lighter in color and had a melting point of 77.1–78.8°C (76.9–78.1°C).

[1]: For whatever reason, it seems that the melting point was never determined. But there is a picture of the sample (fig. 101).
[2]: In hindsight, it seems likely that much of the dissolved portion consisted of the adduct, and instead of just putting it back (and probably hurting the yield in doing so), it would have been prudent to evaporate the MeOH and examine the residue.
[3]: PiHKAL: #40 2C-T-2.

[Fig. 99] Aqueous portion of diluted reaction mixture <> Organic extract

[Fig. 100] Washed extract <> Washings and above aqueous portion

[Fig. 101] Underutilized sample of impure product

[Fig. 102] Treated extract being stirred with bisulfite solution

[Fig. 103] Above mixture after 12 minutes of stirring

[Fig. 104] Dried bisulfite adduct

[Fig. 105] Decomposition of adduct

[Fig. 106] Above mixture after adding 20 mL of butyl acetate

[Fig. 107] Evaporation of extract from adduct decomposition

[Fig. 108] Alternative perspective (distorted white balance)

[e2] 2,5-dimethoxy-4-(methylthio)benzaldehyde
212.27 g/mol
332.44 g/mol (bisulfite adduct; potassium salt)

Experiment 1
In a 100 mL reaction flask, there was prepared a solution of 2,5-dimethoxythioanisole (3.99 g, ≤21.7 mmol) and hexamine (6.08 g, 43.4 mmol) in AcOH (29 g). A solution of 98% H2SO4 (8.68 g, 87.0 mmol) in AcOH (19 g) was then added — dropwise, and with strong stirring — in 30 minutes, during which the reaction mostly took place at ~31°C. Following completion, the mixture was stirred for an additional 10 minutes at ambient 24°C prior to being refluxed for two hours. Water (10 g) and BuOAc (10 g) were then added, followed by another portion of water (10 g) after 45 more minutes of refluxing, at which point the heating was discontinued. After six hours of stirring, the mixture was warmed to 70°C (with a short-lived intention of further refluxing) and allowed to cool again. The mixture was stirred for 17 more hours and allowed to stand for another two.

[Fig. 109] Solution of substituted benzene and HMTA in AcOH

[Fig. 110] Reaction mixture following addition of sulfuric acid in AcOH

[Fig. 111] Reaction mixture approaching reflux

[Fig. 112] Reaction mixture after 110 minutes of reflux

[Fig. 113] Reaction mixture prior to second addition of water

[Fig. 114] Monophasic post-reaction mixture

The mixture was transferred to a separatory funnel where it was diluted with 50 g of water, causing a great deal of precipitation; the addition of 10 g of BuOAc redissolved the solid phase on shaking. The organic phase was collected and combined with two more ester extractions (12 g, 10 g), and the resulting mixture was treated with two 50-gram portions of 10% NaHCO3; this produced a pale precipitate [1] which required several iterative solvent additions to redissolve: in order, there was added, portionwise, BuOAc (12 mL), DCM (1, then 2 mL), water (20 mL), and DCM (7, 10 and 5 mL). Finally, only a few solid particles remained, and the biphasic mixture was partitioned. Treatment of the product-containing partition was resumed with a further 5 g of the aqueous bicarbonate, followed by 10 g of 25% NaCl. There was then added 0.97 g of MgSO4. [2]

The mixture was distilled to remove DCM, which was then used to further extract the remainder of the reaction mixture, where solids had now formed. [3] The latter extract was concentrated and then evaporated to yield 440 mg of a vibrant, reddish-orange residue with a rather vomit-inducing smell, reminiscent of the truly visionary delicacy known as stockfish; melting point 71–91°C. To the former extract, there was added a bisulfite solution (36.51 g of K2S2O5 in 81.01 g of H2O) and 10 mL of methanol; the mixture almost immediately became unstirrably thick. Vacuum filtration of the mixture was performed a total of three times, as the filtrate would thicken once more before finally producing a ~100 mg portion of additional solid. Thus, in total, there was obtained 8.74 g of dried precipitate.

The obtained adduct was suspended in 85 g of ~26.2% Na2CO3, and the mixture was stirred for 15 minutes before adding 15 mL of BuOAc, which resulted in no discernable dissolution but rather constituted a mesmerizing, doughy vortex with the hydrophobic benzaldehyde. When an additional 15 mL portion of BuOAc (and 10 minutes of stirring on either side of it) made no apparent difference to the quantity of solids, the mixture was vacuum filtered through qualitative filter paper, and the filter cake was rinsed with 100 mL of water to obtain, after air-drying, 3.01 g of a pale, greenish-yellow solid exhibiting a slightly incomplete melting at 97.6–99.6°C (lit. 99–100°C [4] ). The organic portion of the filtrate was washed with the previous 100 mL portion of water, filtered, and dried over 0.39 g of MgSO4; approximately two percent (0.51 g) of the solution was evaporated to obtain ~10 mg of a residue melting at 99.0–99.6°C.

Recrystallization was trialed by first gauging the solubility in 2-propanol: a 0.50 g portion of the solid material was dissolved in ~8 mL of the alcohol, and the boiling mixture was gravity filtered through cotton to remove a small quantity of insolubles; by visually inspecting the crop of crystals from cooling the liquor, the ratio of solvent was deemed apt. The rest of the solids were then dissolved in 32 g of 2-PrOH, gravity filtered, and combined with the two fractions in alcohol and BuOAc. The mixture was distilled to remove alcohol [5] and placed in the freezer. Vacuum filtration of the <0°C mixture gave 3.20 g (69.6%) of nearly colorless but deceivingly fluorescent, odorless crystals with a melting point of 101.0–101.5°C (96.2–96.9°C). [6]

[1]: This (along with the other instances of unexpected precipitation) was most likely the product, whose solubility in butyl acetate seemed to be the lowest of the three homologs (in fact, of all of the benzaldehydes so far). In the notes, I haven't specified whether it was the first or the second bicarbonate washing which caused the precipitation, and it could be that both portions ended up in the funnel at the same time with all of the additional organic solvent, with the third five-gram portion being used to verify complete neutralization of the acid.
[2]: It is unclear if the solution was actually dried (and filtered) prior to the subsequent distillation; DCM is a considerably better solvent for the product than BuOAc, ergo, its (sufficient) removal should precipitate the product — mixing it with the sulfate, if the sulfate was present. In any case, it does seem like I made it to the bisulfite purification with no such incident.
[3]: Another detail was omitted in not noting whether the re-extracted mixture contained the previous bicarbonate washings; as I recall, it did.
[4]: PiHKAL: #39 2C-T.
[5]: The final volume of solvent was crudely estimated (after the fact) to be ~35 mL.
[6]: The verified value was obtained by placing the sample in the furnace whose temperature was already quite close to the melting point; the abrupt heating seems to have been the cause of the slight depression.

[Fig. 115] Precipitation on rinsing reaction flask with water

[Fig. 116] Precipitation on aqueous dilution of reaction mixture

[Fig. 117] Precipitation on washing extract with aqueous bicarbonate

[Fig. 118] Spoonful of bisulfite adduct from the source

[Fig. 119] Precipitation during secondary extraction of reaction mixture

[Fig. 120] Secondary extract

[Fig. 121] Evaporation residue of above extract

[Fig. 122] Dried bisulfite adduct

[Fig. 123] Decomposition of adduct in aqueous sodium carbonate

[Fig. 124] Water floating on aldehyde floating on water — under BuOAc

[Fig. 125] Above mixture, vigorously stirred

[Fig. 126] Solids from vacuum filtration of above mixture

[Fig. 127] Purified aldehyde under 2700K white LED (corrected WB)

[Fig. 128] Purified aldehyde under UV-A

[Fig. 129] Illumination: Indirect evening sunlight <> UV-A

[Fig. 130] Table for reviewing experimental parameters

Thin-layer chromatography 
To lessen the ambiguity of this post, I decided to squeeze in some TLC; despite some initial perplexity, useful results were obtained. Samples in the approximate range of 3–6 milligrams were placed in test tubes, each containing a gram of isopropanol. Four identical plates (25 x 75 mm) were prepared by applying a spot of each sample, which were labeled as A (Me), B (Et), and C (Pr). Each of the plates was developed using a different mobile phase before being placed in chronological order and photographed under UV-A and UV-C lighting.

Mobile phases, from left to right:
[1] Toluene
[2] Toluene/Propan-2-ol (9:1)
[3] Heptanes/Butyl acetate (10:1)
[4] Heptanes/Butyl acetate (3:1)

Retardation factors (RF), from left to right:
[1] ~0.17
[2] 0.69–0.70
[3] A: 0.15; B: 0.19; C: 0.27
[4] A: 0.32; B: 0.40; C: 0.47

[Fig. 131] Samples being dissolved in isopropanol

[Fig. 132] Developed TLC plates under UV-A

[Fig. 133] Developed TLC plates under UV-C

[Fig. 134] Recrystallized benzaldehydes (Me / Et \ Pr)

So, here we are, with all three of the intended benzaldehydes* in modest quantities. I'd be lying if I said I wasn't thrilled with the result (and having gone through with sharing it to the best of my ability), but I'd also be remiss if I didn't disclose that I am sweating profusely from the mere thought of still needing to get to my ultimate goal of 3–6 amines with what I have. That said, there are other targets in the 4-alkylthio realm that I'm interested in (for instance, the rather spooky 2C-T-21), so, for better or for worse, having another go from scratch isn't entirely unlikely. Or undesired. 
*Assuming that PiHKAL contains a couple of bad melting points. Gulp. 

The final 2,4,6-trimethoxybenzaldehyde post will be somewhat more delayed, as I'll be unable to dedicate quite as much of my time to putting it together. 
But it will come.  
And it will be nice. 

[Edited on 6-1-2023 by Benignium]

SuperOxide - 5-1-2023 at 14:37

Bravo, Benignium.

I will read over your latest post in more detail when time permits.

Curious - are you planning on synthesizing every compound in PiHKAL?

[Edited on 5-1-2023 by SuperOxide]

Benignium - 6-1-2023 at 06:39

Please do, and let me know what you think!

Although I might enjoy trying my hand at synthesizing every single one, biology makes it so that my plan has to involve a degree of cherry-picking, and not all of the cherries grow on this one tree, either — phenethylamine or otherwise.

pihkameleon - 25-7-2023 at 12:21

I have previously shared this synthesis on a site which is a little more appropriate for this kind of chemistry, but after some talking with Benignium, it was decided to polish up the report a litle, add some photographs and post here too. It should serve as a further motivation to get out and do interesting chemistry (whatever that means to you!), document it, and publish it for the greater good (whatever that means to you!). The starting compound, 2,5-dimethoxyacetophenone, was a gift from a good friend and was lying around for over a year (during which it turned from slightly yellow to orange). But it would be easily enough made under the appropriate Friedel-Crafts conditions (a little more gentle than Shulgin, to avoid demethylation - check [1], the book should be available in its English version on appropriate "shadow libraries"). Had I known how simple it was to make my target compound in the end, I wouldn't have waited for so long. So, get out and do chemistry now! And don't forget to write home about it!

Please note that this chemistry is completely unoptimised, as often times, I'm more intrigued by the structures of the finished products than the road towards them. One day, I may fall in love with one of these compounds and decide to really optimise a route - for now I'm ever crushing on the next hot compound. I am planning to make the benzaldehyde again, and a couple of other compounds derived from it. Maybe this will be a chance for more meticulous chemistry and better pictures. Concerning the TLC, either dichloromethane or 1,2-dichloroethane was used for elution of the ethylbenzene, benzaldehyde and nitroalkene. Sometimes, the line for the solvent front was forgotten. I wouldn't trust any of the values you see for Rf anyways, as all my plates are old and wet. But it should give an idea.

2,5-dimethoxyethylbenzene [1]

In a 100 mL threeneck-RBF with stirbar, thermometer and distillation head, 10.618 g slightly impure 2,5-dimethoxyacetophenone(1) (MW 180.20, 58.9 mmol) were dissolved in 53 mL ethylene glycol, followed by 7.33 g ground up KOH (MW 56.11, 130.6 mmol, 2.2 eq., probably slightly wet), followed by 8 mL of hydrazine hydrate (MW 50.06, 164.1 mmol, 2.8 eq.). The flask was immersed in an oil bath and over the course of 3 h, water was continuously distilled out. When the internal temperature reached 180 °C, the distillation head was replaced by a Liebig condenser, and the contents refluxed at 180 °C for a further 3 h. Attempts at monitoring the reaction on TLC directly were inconclusive (micro-workup with extraction might be better!). The heating from the oil bath was discontinued, and the chemist left the reaction to sleep 4 h and work up in the morning. The aqueous distillate (which contains steamed-over product) was filled up to 100 mL with H2O and combined with the reaction mixture. This aqueous solution was extracted with 5 x 10 mL CH2Cl2, the combined CH2Cl2 layers dried over 3 A molecular sieves, filtered, solvents removed on the rotovap, and the remaining yellow-orange liquid vacuum-distilled, collecting the distillate at 86 °C @ ? mbar(2) (lit. 104 - 105 °C @ 7 mm/Hg [1]) as a slightly yellow liquid. Product was homogenous on TLC and weighed 7.613 g (MW 166.22, 45.8 mmol, 77 % yield).

(1) slight spot on TLC hovering over the acetophenone
(2) one day, I'll figure out how to read mercury manometers

2,5-dimethoxyacetophenone under ethylene glycol

Wolff-Kishner during reflux period - no foaming in sight, gentle

TLC of crude 2,5-dimethoxyethylbenzene from solvent extraction after reaction

crude 2,5-dimethoxyethylbenzene

simple vacuum distillation of 2,5-dimethoxyethylbenzene - lacked equipment (cow adapter/spider) for proper set-up, but there was no distillate before the product

remaining tar of vacuum distillation

TLC of 2,5-dimethoxyethylbenzene after distillation

4-ethyl-2,5-dimethoxybenzaldehyde [2, 3]

In a 100 mL threeneck-RBF fitted with reflux condenser and addition funnel(1), 2.543 g hexamine (MW 140.19, 18.14 mmol, 2 eq.) and 1.518 g 2,5-dimethoxyethylbenzene (MW 166.22, 9.13 mmol) were dissolved in 12 g AcOH. The flask was put on a cold water bath, and via addition funnel, a solution of 3.700 g H2SO4 (MW 98.08, 96%, 36.22 mmol, 4 eq.) in 10 g AcOH was dropped in over a timeframe of 20 min. This lead to the precipitation of a white precipitate. The suspension was put in a hot oil bath and refluxed for 2.5 h (upon heating, the precipitate dissolved and the solution turned from faintly yellow to yellow to orange), then the oil bath removed, and when the temperature dropped below 100 °C, 25 mL of H2O, followed by 25 mL EtOAc were added. The solution was stirred overnight (~ 14 h) at room temperature. 5 mL of aq. sat. NaCl were added, phases separated, and the aq. phase extracted with 4 x 15 mL EtOAc. The combined organic phases were washed with 3 x 45 mL 10 % NaCl solution, then 45 mL dilute K2CO3 (caution!!(2)), then 45 mL brine. The organic phase was dried over 3 A molecular sieves, the sieves filtered off, and evaporated to leave 1.666 g of a yellow oil (MW 194.23, < 8.58 mmol, < 94 %, impure by TLC, contaminations on baseline, eluent 1,2-dichloroethane).

(1) it was started with the addition funnel on the sideneck, but this lead to nasty precipitation at the corner, and as such the reflux condenser was removed and the addition funnel clamped to drop the solution in directly from above
(2) this step was performed in the seperatory funnel by me. Huge mistake, as there is still appreciable amounts of AcOH dissolved in the organic phase even with the aqueous washings. A small amount of extract was lost due to pressure build up with closed cork. Probably best to add K2CO3 carefully with stirring in an open vessel until CO2 evolution ceases.

at the relatively start of the addition of H2SO4 - addition funnel was clamped from above, as otherwise precipitate would have formed on the sides and wouldn't have been stirred, potential of clogging too

finished addition of H2SO4/AcOH, everything precipitated

precipitate gets dissolved during heating, reaction mixture turns from faintly yellow to bright yellow to orange

TLC of reaction mixture during hydrolysis

TLC of extracted benzaldehyde, used as is in the next step - long-wave UV vs. short-wave UV - 4-ethyl-2,5-dimethoxybenzaldehyde shows bright fluorescence


4-ethyl-2,5-dimethoxynitrostyrene (4-Et-2,5-DMNS) [4]

Above oil was used without further purification(1) (calculations for equivalents assume 100 % purity though!). The oil was dissolved in a mixture of 1.101 mg ethanolamine (MW 61.08, 18.03 mmol, 2.1 eq.) and 2.150 g AcOH (MW 60.05, 35.80 mmol, 4.17 eq.), diluted with 2.5 g propan-2-ol. 0.618 g nitromethane (MW 61.04, 10.12 mmol, 1.18 eq.) were added, and the mixture stirred at r.t. for 3.5 h, after which TLC showed completion (check via long-wave UV, where the benzaldehyde shows bright fluorescence!). The thick suspension with orange-yellow precipitate was diluted with 4 volumes of H2O, stirred for 10 min, and then filtered and washed with copious amounts of H2O. The resulting orange-yellow precipitate was dried crudely on the pump, and then recrystallised from excess isopropanol (~20 mL) for a week at -18 °C(2). After filtration and evaporation of solvents on the rotovap, this resulted in 1.125 g of 4-ethyl-2,5-dimethoxynitrostyrene (MW 237.26, 4.74 mmol, 55 % yield over two steps).

(1) the impure benzaldehyde was used because I trust these kind of conditions for clean nitroalkene synthesis, and because I was impatient. Would not recommend, given that bisulfite adduct will easily lead to a good product.
(2) random amount until I had time for the laboratory again

precipitated nitrostyrene after 3.5 h

TLC of reaction progress - compare fluorescent benzaldehyde to nitroalkene


4-ethyl-2,5-dimethoxyphenethylamine hydrochloride (2C-E HCl) [5]

In a 100 mL Erlenmeyer flask with efficient stirbar and Liebig condenser in a cold water bath, 1.335 g NaBH4 (MW 38.83, 34.38 mmol, 7.25 eq.) are dissolved in a mixture of 23 mL isopropanol/H2O 2:1. Over a timeframe of 10 min, 1.125 g 4-Et-2,5-DMNS (MW 237.26, 4.74 mmol) are added in small portions to the reaction mixture (by temporarily disconnecting the reflux condenser). After the addition, the water bath is removed, and the condenser re-attached. After 15 min of stirring at r.t., the flask is immersed in an oil bath, and heated up to reflux. When the oil bath reached 60 °C, 140 mg Cu(OAc)2 * H2O (MW 199.65, 0.70 mmol, 0.15 eq.) dissolved in 3 mL H2O are introduced rapidly by temporarily disconnecting the reflux condenser. The reaction is brought to reflux and stirred at reflux for 50 min. After cooling down to r.t., 3 g NaOH in 10 mL water are added. The organic and aq. phase are separated(1), and the aq. phase extracted with 2 x 15 mL isopropanol. The combined organic phases are washed with 3 x 20 mL aq. sat. K2CO3, then separated and slightly acidified by dropwise addition of conc. aq. HCl. The solvents are removed on the rotovap, this is aided by 2x addition of 10 mL IPA shortly before dryness. The resulting yellow salts are dissolved in 60 mL H2O, washed with 3 x 20 mL EtOAc (an emulsion broken by addition of a bit of sat. NaCl). The aqueous phase is basified with 3 g NaOH in 10 mL H2O, then extracted with 3 x 20 mL EtOAc, and the EtOAc washed once with 20 mL NaCl brine. The combined organic phases are dried over 3A molecular sieves, the sieves filtered off, then the solvents evaporated, yielding a not perfectly free of solvents slightly yellow oil weighing 918 mg. This is dissolved in ~15 mL isopropanol, neutralised with conc. aq. HCl(2), then 3 volumes acetone are added and the suspension dumped in the freezer for way too short time (1 h)(3). After filtering, washing with acetone and drying on the rotovap, this results in 691 mg 2C-E HCl (MW 245.7, 2.81 mmol, 59 % yield, mp 211 - 212 °C) as fine powdery white crystals.

(1) it is better practise to first filter off the cuprous sludge, but in some cases it can be omitted... not recommended though!
(2) even before addition of acetone, this turned into an almost solid chunk of crystals
(3) the pihkameleon has many time restraints for his laboratory playtime!

~ 100 mg of 4-ethyl-2,5-dimethoxyphenethylamine hydrochloride on a scale

[1] Trachsel, D. Psychedelische Chemie: Aspekte psychoaktiver Moleküle, 5. Auflage.; 2016. ISBN: 978-3-907080-53-5

Benignium - 25-7-2023 at 14:08

The pictures and overall layout do a fantastic job at complementing the impressive experimental work that you've done, pihkameleon! Thank you for posting this!

Benignium - 3-11-2023 at 13:39

For your consideration:

196.20 g/mol

In 1884, researchers Wilhelm Will and Karl Albrecht of the Friedrich Wilhelm University in Berlin published an article [1] in the scientific journal Berichte der Deutschen Chemischen Gesellschaft regarding their ongoing work on assigning the appropriate trihydroxybenzene building blocks to two natural dioxycoumarin compounds, esculetin and daphnetin. So far, daphnetin was known with certainty to be derived from pyrogallol (1,2,3-benzenetriol), but whether its constitutional isomer esculetin conformed to the structure of hydroxyquinol (1,2,4) or phloroglucinol (1,3,5) was still up for debate. The scope of their publication, therefore, was to identify the specific benzenetriol component of esculetin, while simultaneously producing precious experimental data on the derivatives through which they intended to do so. In essence, three distinct triethoxybenzoic acid isomers and their ethyl esters were to be formed from pyrogallol and phloroglucinol, [A] which could then be compared with analogous derivatives of the unidentified benzenetriol obtained from natural esculetin. [B]

[Fig. 1] Structures of daphnetin and esculetin

  In a surprising turn of events, when the carboxylic acid derivative of phloroglucinol was dissolved in ethanol and subjected to a strong acid catalyst in an attempt to form the ethyl ester, [C] an evident decarboxylation took place instead. Moreover, the observed liberation of gaseous carbon dioxide was accompanied by a further transformation into something which was found to crystallize as long, white needles. This new material withstood heating in alcoholic alkali, and its reaction with ferric chloride was neither the intense blue of the phloroglucinic acid nor the violet that was expected of phloroglucinol. Fascinatingly, it turned out that the main product of the procedure was, in fact, the diethyl ether of phloroglucinol. [D] What's more, it was also recognized that unlike phloroglucinol, this diethylated material could be exhaustively ethylated via the conventional Williamson ether synthesis to obtain pure 1,3,5-triethoxybenzene, whose novel melting point would then inform the accurate conclusion that esculetin bore the structural motif of hydroxyquinol. This pioneering work with its serendipitous discoveries garnered significant attention toward the onionesque morass that was phloroglucinol; an issue that would vex chemists for decades to come; enduring so far as to stare back at me from the pages of PiHKAL [2] — and while the thick, proverbial jungle which once dictated these paths of quasi-alchemical adventure and niche camaraderie may be long-macadamized by the migratory march of science, the occasional unsuspecting amateur remains likely to have their jimmies rustled by the perpetually gaping manhole of yesteryear. 
  But indeed, what does it mean? 
  In the context of this post, it is crucial to know that attempts at electrophilic methylation of the deprotonated phloroglucinol are prone to ending miserably: instead of the desired trimethyl ether, such a reaction would afford an overwhelming number of side products, with the neutral portion consisting mostly of alicyclic materials like 2,2,4,4,6,-pentamethylcyclohexane-1,3,5-trione, due to rampant nuclear alkylation at the three α-carbons. While the relative quantities of the formed side products are wildly unpredictable, the hexamethyltrione has been demonstrated as the major (ultimate) product. By all accounts, isolating any fraction of formed 1,3,5-trimethoxybenzene from this mixture would be deemed as an exercise in futility. [3] [4] [5] [6] 
  The issue was quickly likened to a ketone-like behavior by Adolf von Baeyer, who, in 1886, described the formation of the trioxime of phloroglucinol, and proposed that the facultative intermediary be called pseudophloroglucinol; [7] the term tautomerism had just been coined by Conrad Laar, in 1885, but was initially met with a pseudo label of its own. [8] By forming the trioxime, Baeyer had experimentally proven the existence of cyclohexane-1,3,5-trione — the triketone tautomer of phloroglucinol — whose exact identity and implications nevertheless remained indeterminate. At the time, experimental chemistry was in many ways constrained by its severely nascent theoretical foundation. Thus, finding new and improved ways through this particularly loosely comprehended polyolic black box of tautomerism would continue to rely on tentative experimentation for decades to come. 
  In the meantime, the early 20th century arrived, bringing with it infrastructural breakthroughs like the mass production of affordable cars, widespread electrification, electric toasters, and sliced bread; all of which contributed to an unprecedented rate of scientific development. In terms of chemistry, on the other hand, a revolution blossomed within the confines of the mind: Spurred, in part, by the maturation of August Kekulé's autophagous snake anecdote into the driving force behind Johannes Thiele's rudimentary yet pioneering prediction of resonance in 1899, [9] [10] those who sought chemical understanding at the atomic level would draw it increasingly from theoretical physics, and in doing so would align the two previously segregated fields toward an increasingly common goal. This shift in philosophical paradigm facilitated the formulation of groundbreaking heuristic techniques like the Lewis structure, and built the foundations of quantum chemistry. Then, finally—through the concordant invention of modern experimental tools like the concept of pH and NMR spectroscopy, that could supersede traditional staples like elemental analysis and spruce chips wetted with acid and alcohol [11]—the stage was set for demystifying phloroglucinol once and for all. 
  In 1956, by comparing the ultraviolet absorption spectra of increasingly alkaline phloroglucinol solutions with those obtained previously for 1,3,5-benzenetriamine at various stages of protonation, Hans Köhler and Günther Scheibe discovered correlations which led them to deduce the existence of analogous isosbestic points, and, notably, to predict the large prevalence of a ketonic dianion form through comparison with the dianion of filicinic acid, whose structure was known. [12] Corroborating the same phenomena, studies making use of 1H NMR in the 60s would then independently reveal ring protonation to form σ-complexes (i.e., arenium ions) in both superacidic [13] and alkaline [14] media. More recently, in a 1993 report by Martin Lohrie and Wilhelm Knoche, UV-visible and diode-array spectrophotometers were augmented with stopped-flow apparatus and temperature jump techniques in order to observe the chemical kinetics and thermodynamics of altering the pH in aqueous solutions of phloroglucinol; thereby arriving at a wonderfully comprehensive view of the different equilibria pertaining to its dissociation and tautomerism (fig. 2). [15]

[Fig. 2] Illustrated species of phloroglucinol

  The above Scheme II illustrates most of the structurally distinct species of phloroglucinol. Each horizontal row depicts the different degrees of dissociation (i.e., of protonation/deprotonation) within a single degree of conjugation; with each vertical column therefore representing the range of conjugation within a single degree of dissociation; and with structures A and B being intermediates for acid-catalyzed reactions of 1 to 7 and 7 to 9. On adjusting the pH in either direction, two distinct kinds of reaction were observed to take place: the horizontal double arrows indicate diffusion-controlled (unmeasurably fast) acid–base interactions that occur independently of tautomerism, whereas diagonal arrows denote the associated rate-determining keto–enol rearrangements. The embedded Figure 9 presents the species' relative concentrations on a logarithmic scale as functions of the pH. 
  In the following paragraphs, I've attempted to explain the phloroglucinol issue in a way that might have enabled myself to more rapidly grasp the basic concept some ten months ago; for this, I'll continue referring to structures from the above illustration as corresponding digits in bold. 
  From the perspective of organic synthesis — specifically, of electrophilic O-alkylation in polar, protic media — in order for an electrophile (like the dimethyl sulfate whose application is described in this post) to get attacked by the nucleophilic oxygens of phloroglucinol, each phenol needs to be activated through basic deprotonation; much like has been done to the previous phenols of this thread. This removal of what is essentially the bare nucleus of a hydrogen (and a major building block in heavier nuclei) results in the negatively charged phenolate (i.e. phenoxide) anion—the conjugate base of phenol (i.e., a better nucleophile than phenol)—enriched by a third pair of unbonded valence electrons, which, albeit delocalized due to being conjugated with the aromatic system (i.e., occupying a p-orbital on an oxygen that is coplanar and in phase with an adjacent benzene carbon), remains subject to the inductive attraction which oxygen exhibits owing to the higher number of the positively charged protons contained in its nucleus compared to the larger carbon (i.e., its higher electronegativity). This added charge density seems particularly significant in the phloroglucinol structure, as the three ortho- and para- (but not meta-)activating phenols are all located meta to each other, leaving the three α-carbons in their midst unusually electron-rich through π donation such that C-alkylation has been shown to occur and even predominate in the absence of base; when the neutral molecule exists almost exclusively in its aromatic form, 1. [16] The phenolate monoanion 2 (and by extension the appropriate monoether anion), in contrast, has been successfully reacted with dimethyl sulfate in the presence of carefully controlled quantities of alkali to produce the O-permethylated ether. [3] [17] [E] 
  As far as the dianion is concerned, however, it is by now evident that the prediction of a prevailing dibasic phenolate form (3) is turned on its head by the phenomenon referred to as keto–enol tautomerism—the proton-transfer equilibrium enabling transformations between a nucleophilic enolic form (an alkene situated adjacent to an alcohol) and an electrophilic ketonic form (a carbonyl with an accommodating α-carbon), catalyzed by both donors and acceptors of protons (i.e., acids and bases in the Brønsted sense, respectively). Judging by the previous observations of predominant C-alkylation, it follows, therefore, that the prevalence of the ketone-like character following a second deprotonation is high enough to almost completely exclude the oxygen atoms from interacting with the alkylating agent — while the α-carbons move up in pecking order, collectively consuming (in total) up to six molar equivalents of the same. 
  At a glance, the aromaticity that is ubiquitous in phenols might be expected to favor a desirable polyenolic arrangement — after all, the equivalent of this is known to be the case even for the symmetric benzenediol, hydroquinone, whose stability is accordingly greatest when there is a continuous ring of conjugated p-orbitals in a planar conformation (i.e., aromaticity) — However, rather than going from 1 → 2 → 3 → 4 in a straightforward series of deprotonations, as the already unusual electron density of phloroglucinol is made even greater, it begins rearranging in exquisite ways to compensate, promptly doing away with its aromatic character; the urgency with which these rearrangements take place is equally striking, and likewise reflected by the overlap between the first two of its acid dissociation constants, pKa1 = 8.6–9.0 and pKa2 = 8.9–9.1 (with pKa3 = 14). [15] Nevertheless, even when staring at the above Scheme II, the reasoning behind this observed inclination is not immediately obvious. 
  In mulling the subject over, guidance was sought, and two hints were received which were found specially fruitful. 
  The first one points to structures with two carbonyls sharing an α-carbon: A well-established quirk of nature, these are commonly referred to as 1,3-dicarbonyls or (where applicable) β-diketones, and are almost universally introduced at a point during university lectures on organic chemistry in the form of a β-keto ester product of a Claisen condensation. Belonging under a larger phenomenological classification called active methylene compounds [where there’s a methylene in between two electron-withdrawing groups (e.g. -NO2, -CN, -COOR)], their distinctive feature is an sp3-hybridized carbon center with particularly labile (i.e. acidic) hydrogens, whose dissociation gives a highly resonance-stabilized conjugate base; communicated via a general approximation of pKa = 9. Indeed, implicit postulates of such a diketonic anion are many for phloroglucinol (as well as resorcinol and other similarly related substances), and the structures of Scheme II approach it as closely as limiting the portrayals of negative charge to the oxygens seems to allow. 
  The other concept deserving of a good grasp has to do with the stability of a structure as it relates to bond (dissociation) energies. On its own, this value, determined for a given bond at its equilibrium length, measures the amount of energy that would be required to completely negate the interactive forces between two covalently bonded atoms by pulling them apart. Consequently, the sum of these individual values contained within a given molecule can be calculated to evaluate the stability and thermodynamic favorability of said molecule. The total energies were calculated for the kinetic dianion (3) and the proposed thermodynamic dianion structure according to values obtained from a single literature source. [18] As such, these came out to be 5590–5804 kJ/mol and 5738–5959 kJ/mol, respectively, which would tip the scales in favor of the diketone tautomer. However, after correcting the former value through incrementing it by 151 kJ/mol according to the aromatic stabilization observed for benzene, the two values appear to converge, obfuscating whatever evidence is there. 
  It is my belief that the combined bond energy of the proposed thermodynamic product is complemented by a superior distribution of charge between a single enolate anion and the 1,3-dicarbonyl anion whose smear of electron probability (another cool way to think about electron density) quite exactly opposes the more localized charge of the former, reducing the overall dipole moment of the structure. Below is a somewhat streamlined illustration of the logistics for arriving at the discussed dianion structure as I currently understand them; referring to Scheme II, this progression would correspond to 1 → 2 → 3 → 6, at which point it splits into two distinct routes via 5, either through 8 or by way of resonance. Alkylation (particularly involving the smaller, less sterically hindering alkyl groups) of the dissociated active methylene in between the carbonylic oxygens will serve to further stabilize the charge toward the substituted α-carbon through σ donation by the alkyl substituent—facilitating geminal alkylation prior to a structural or canonical (i.e., mesomeric, as in "resonance contributor") shift to favor another one of the ring carbons in the same way. The six-membered ring structure of the dianion favors alkylation at the carbon by constraining the 1,3-dicarbonyl anion into a W-shaped conformation, where the nucleophilic middle protrudes, and the carbonylic oxygens are pointed away such that they do not hinder its access or affinity toward electrophilic substrates; moreover, this conformation minimizes the dipole-dipole repulsion at the site, which contributes to stability.

[Fig. 3] Favorable pathways to the thermodynamic dianion structure

But wait, there’s more! 
  What has been discussed on the theory so far leaves out a bunch of nuance which I’d like to touch on briefly before a few more words on the practical side of things. 
  As previously stated, the above focuses on changes that take place in prot(on)ic (i.e. hydrogen-bonding) solvents like water and alcohol. These can interact with the anionic species of phloroglucinol and its alkylated derivatives, as well as the cation and the alkylating agent. Interaction like this can significantly favor C-alkylation by solvating (i.e. surrounding) and thus effectively shielding the oxygen of an enolate anion; similarly, it can also hinder the desired reactivity by encumbering the alkylating agent. Additionally, a protic solvent can act as an acid or a base in tautomeric proton-shifts. The use of polar solvents in this context is a given, since a heterogenous reaction with an undissolved solid salt (whose oxygen anion is shielded by the associated cation in the crystal lattice) would vastly favor C-alkylation. The use of aprotic solvents—and especially dipolar aprotic ones [i.e., ones with a sizable dipole moment (e.g. DMF, DMSO, MeCN)]—on the other hand, tends to favor O-alkylation through not only the lack of hydrogen-bonding, but also a proportionally stronger solvation of the metal cation relative to the enolate anion, which is consequently freer to attack with its more electronegative atom. [18] [19] 
  Furthermore, the concept of hard–soft character (i.e. polarizability) in Lewis acids and bases has been found to correlate with a superior selectivity for O-alkylation exhibited (in some solvents) by dialkyl sulfates, whose hard sulfate leaving group is more amenable to coordinating (i.e. bonding) to the hard oxygen donor atom of an ambivalent metal enolate in comparison to a softer vicinal carbon donor. Conversely, the soft character of alkyl halides (which decreases with the atomic radius of the halogen) explains why their involvement favors C-alkylation. It is also worth noting that the carbon under nucleophilic attack in an SN2 transition state favors attack by the less electronegative site of an ambident nucleophile. Among the hard Lewis acids that are most often associated with a phenolate anion, the size of the ion has a significant impact on selectivity, whereby increased bulk (e.g., K+ > Na+ > Li+) corresponds to an increased tendency to dissociate, and therefore a higher reactivity of the anion as a nucleophile. [18] [19] 
  In the gas phase, where the enolate anion (of cyclohexanone) is completely free, there is only O-alkylation. [18] 
  A striking irony of the phloroglucinol subject is that so much of this newfound understanding on it from the past century seems to have had no bearing on the seldom undertaken laboratory preparation of its trialkyl ethers. The most commonly encountered procedure (among the amateur community, at least) still seems to be the same one that is featured in PiHKAL (which itself is only a slight variation of the 1884 procedure by Will and Albrecht), where phloroglucinol is reacted with an excess of alcohol in the presence of a strong acid catalyst; [F] followed by a bimolecular nucleophilic displacement (SN2) reaction of the resulting dialkoxyphenol with an electrophilic alkylating agent in the presence of a base (i.e., the Williamson ether synthesis). Nevertheless, interesting experimental discoveries have been made. In closing, here are some of the highlights: 
  As early as 1900, F. Kaufler suggested that the deprotonated phloroglucinol acts as a ketone toward methylation, but as a phenol toward benzylation; [20] a seemingly reasonable observation of steric effects, whose preciseness has since been disputed. [21] 
  In 1920, K. Freudenberg found that reacting the phloroglucinol diethyl ether with 5.32 molar equivalents of dimethyl sulfate (based on phloroglucinol) gave improved yields of up to 80%. [22] [G] 
  A 1953 publication by H. Bredereck, I. Hennig and W. Rau reports success in circumventing the C-alkylation-favoring tautomeric forms by employing a dropwise addition of 20% NaOH to a mixture containing 3.86 molar equivalents of dimethyl sulfate and 1.9 mL of acetone per gram of the anhydrous phloroglucinol while maintaining a constant pH in the range of 8–9; colorless crystals corresponding to a 93% yield were reported [17] [H] — in contrast, a dropwise addition of alcoholic base had previously been trialed by J. Herzig and F. Wenzel in 1906, with modest yields and some C-alkylation being reported. [3] 
  Arguably the most convenient-sounding procedure for direct trialkylation was presented by J. W. Clark-Lewis in 1957, involving the portionwise addition of DMS to a mixture of anhydrous phloroglucinol and potassium carbonate in acetone. [23] 
  The esterification using acetic anhydride proceeds in a straightforward manner to yield the 1,3,5-triacetoxybenzene, which has been subjected to alkylation in the presence of base so that the ethers form just as the electron-withdrawing acetates are saponified, keeping the electron density low enough to avoid C-alkylation. [6] 

Finally, I would like to state my heartfelt gratitude for my fellow SM member AvBaeyer, whose
compassionate gift of awe-inspiring expertise was pivotal for my learning and composing of the above.

[A]: The carboxylic acid moiety was introduced, in yields that were reported as nearly quantitative, by digesting the benzenetriols [in water, at 130°C, in a pressure reactor] with four equivalents of ammonium carbonate (or in the case of phloroglucinol, with potassium carbonate). 
[B]: In a later publication, Will outlines the processing of naturally derived glycosidic materials, including esculetin, as follows: A water-soluble cleavage product, usually a phenolic ester, is first saponified using potassium hydroxide, followed by treatment with methyl (or ethyl) iodide at reflux. The resultant ether is oxidized with potassium permanganate to remove the unwanted, mostly unsaturated aliphatic ring substituents. A dry distillation of the calcium carboxylate derivative is then employed to isolate the corresponding phenol ether, whose constitution (once further purified via steam distillation, in the case of esculetin) can be determined by comparison with the synthetically prepared phenol ethers. Additionally, this article reports the purification of 1,3,5-trimethoxybenzene via steam distillation after adding some KOH solution. [24] 
[C]: Interestingly, although the process is very similar to the Fischer–Speier esterification described in 1895 (also in Berlin), it is credited to Hugo Schiff, who in turn refers to the preparation of ethyl gallate by the French chemist Édouard Grimaux in 1864. 
[D]: More specifically, a mixture of products was determined which contained some 10% of the monoether. [25] 
[E]: Since the monoanion of phloroglucinol has been shown to not predominate at any pH, [15] I suspect that the successes of these procedures may be largely due to its diffusion-controlled formation and subsequent ability to react immediately in the presence of excess electrophile. 
[F]: The formation of phloroglucinol mono- and dialkyl ethers in Fischer–Speier-like conditions is thought to occur through a ketal intermediate: [26] a keto tautomer (initially 7 from Scheme II) first undergoes the addition of an alcohol across a protonated carbonyl, followed by a deprotonation to give a hemiacetal; a protonation of the hydroxyl then facilitates its elimination as water, allowing for a renewed C–O π bond, a repeated protonation of the oxygen, the addition of a second alcohol, and the formation of the ketal through a final deprotonation. However, since a neutral ether can result via elimination from either an acetal or a hemiacetal, the latter would be more likely owing to the fewer steps involved. Interestingly, the steps of an acetalization have been shown to occur in a concerted fashion. [27] 
[G]: The high consumption of methylating agent is probably due to the presence of the monoether, which is still very much susceptible to C-alkylation. 
[H]: This is a likely origin for the claim, presented by GC_MS on The Hive [cited in the permethylation chapter (III) of my previous post], where a protective effect against the saponification of dimethyl sulfate by aqueous alkali was ascribed to the presence of 2 mL/g of acetone. Here, however, the authors merely suggest a possibility.

[1]: W. Will, K. Abrecht (1884): Ueber einige Pyrogallussäure- und Phloroglucinderivate und die Beziehungen derselben zu Daphnetin und Aesculetin.
[2]: A. Shulgin, A. Shulgin (1991): PiHKAL. (#162 TMA-6)
[3]: J. Herzig, F. Wenzel (1906): Studien über Kernalkylierung bei Phenolen.
[5]: J. Herzig, B. Erthal (1910): Notiz über die Darstellung des Hexa- und Pentamethylphloroglucins.
[7]: A. Baeyer (1886): Ueber das Trioxim des Phloroglucins.
[8]: J.W. Baker (1934): Tautomerism.
[9]: J. Thiele (1899): Zur Kenntniss der ungesättigten Verbindungen. Theorie der ungesättigten und aromatischen Verbindungen.
[10]: F.E. Ray (1934): Thiele's Theory of Partial Valency in Terms of Electrons.
[11]: A. Bayer (1885): Ueber die Synthese des Acetessigäthers und des Phloroglucins.
[12]: H. Köhler, G. Scheibe (1956): Übergänge zwischen aromatischen und aliphatischen Formen bei Benzolderivaten.
[13]: A.J. Kresge, G.W. Barry, K.R. Charles, Y. Chiang (1962): The Protonation of Phloroglucinol and its Ethers: An Exception to the Acidity Function Concept.
[14]: R.J. Highet, T.J. Batterham (1964): The structure of the phloroglucinol dianion.
[15]: M. Lohrie, W. Knoche (1992): Dissociation and Keto-Enol Tautomerism of Phloroglucinol and Its Anions in Aqueous Solution.
[16]: A. Gissot, A. Wagner, C. Mioskowski (2004): Buffer-induced, selective mono-C-alkylation of phloroglucinol: application to the synthesis of an advanced intermediate of catechin.
[17]: H. Bredereck, I. Hennig and W. Rau (1953): Alkylierungen mehrwertiger Phenole mit Dialkylsulfat.
[18]: M.B. Smith, J. March (2007): March’s Advanced Organic Chemistry.
(6th edition; p. 29, 513–519)
[19]: H.O. House (1972): Modern Synthetic Reactions.
(2nd edition; p. 509–529)
[20]: F. Kaufler (1900): Über den Einfluss der eintretenden Radicale auf die Tautomerie des Phloroglucins.
[21]: E. Deme (1976): Synthesis of Authentic Tri-O-benzylphloroglucinol.
[22]: K. Freudenberg (1920): Über Phloroglucin Gerbstoffe und Catechine.
[24]: W. Will (1888): Ueber einige Reactionen der Trimethyläther der drei Trioxybenzole und über die Constitution.
[25]: J. Pollak (1897): Einiges über die Äther des Phloroglucins und eine Synthese des Hydrocotoins.
[26]: J.C. Touchstone, J. Ashmore, M.N. Huffman (1956): Ethers of Phloroglucinol.
[27]: E. Grunwald (1985): Reaction mechanism from structure-energy relations. 2. Acid-catalyzed addition of alcohols to formaldehyde.

[a4] 3,5-dimethoxyphenol
Also called: Phloroglucinol dimethyl ether
154.16 g/mol

Like so many others, I also opted for the procedure outlined in PiHKAL. [1] At the time of my experimentation (May, 2022), it never occurred to me to attempt to purify this product, and the fact that it would form crystals became clear only when composing this post. Removal [or enhanced conversion (via completely trapping/removing all water past the hemiacetal formation, or by repeating the acetalization procedure)] of the monoether should work to minimize the portion of methylating agent that is wasted on C-alkylation in the next step; quite possibly improving the yield.

[1]: PiHKAL: #162 TMA-6.

Experiment 1
Phloroglucinol dihydrate (12.99 g, 80 mmol) was dehydrated to constant weight in a 100°C oven [1] and dissolved in methanol (42 mL) in a 100 mL conical flask. With good magnetic stirring, concentrated sulfuric acid (7.1 mL, 131 mmol) was added from a dropper, causing the mixture to heat up to 45–50°C and take on a vibrant red coloration. After first stirring it at room temperature for two hours, the mixture was refluxed for ~8 hours and then allowed to cool.

[1]: Admittedly, this step (on its own) was probably unnecessary; with the excess of alcohol that was used, the reaction doesn't appear to be that sensitive to moisture.

[Fig. 4] Commercial phloroglucinol dihydrate

[Fig. 5] Reaction mixture following acid addition

The cooled reaction mixture was diluted with 65 mL of water. Two extractions were done using 25 mL portions of dichloromethane. The pleasant-smelling [1] extract was dried over some calcium chloride and filtered to remove the solids. This was then stored in the dark, at room temperature, for 14 days, after which it was concentrated; first by distilling it down to half its original volume, and finally by stirring the remainder magnetically on a 45°C hotplate while argon was gently blown into the flask to carry out the residual solvent. A clear, viscous red oil remained, weighing 7.89 g.

[1]: The odor of the extract was a mixture of floral indole and synthetic wild strawberry essence. There was a definite shared resemblance to methyl salicylate and (low vapor concentrations of) methyl anthranilate in terms of sweetness and texture.

[b5] 1,3,5-trimethoxybenzene
168.19 g/mol

With the foretold red oil in hand, I thought it the perfect opportunity to revisit the solvent free methylation [1] whose first replication involving the solid methylhydroquinone substrate (a3) was less than representative.


Experiment 1
To the 7.89 grams of red oil from the previous step, there was added potassium carbonate (39.49 g, 286 mmol), [1] followed by dimethyl sulfate (30.1 mL, 318 mmol), and the vessel was equipped with a water-cooled 200 mm Liebig condenser, which was topped with a bulbous anti-splash adapter. The mixture was stirred magnetically, its temperature remaining at ~26°C with no external heat being applied; its mobility improved over ~20 minutes as the beads of base grew less clumped together. Heating was commenced after the first hour to counteract a thickening consistency, bringing the mixture to ~35°C on a 60°C hotplate. The gradual addition of water was also deemed appropriate at this time, and was begun, five drops at a time. [2] 20 minutes later (at the 90-minute mark), 1.4 g of water had been added. The reaction temperature had reached 41°C, and the hotplate setting was raised to 80°C. Very suddenly, the rate of the reaction picked up dramatically, and the reaction temperature shot up to 75°C, by which point the heating was discontinued; dense fumes were observed exiting the apparatus, as the peachy gruel in the flask below curdled into a white, clumpy porridge from which a clear, red liquid phase separated. [3] Larger, approximately half-gram portions of water were added to just barely keep the stir bar functional. [4] Heating was resumed once the mixture had cooled to 66°C. Two hours into the reaction, a thinner, more homogenous consistency had been regained; 7 g of water had been added, and the internal temperature was a stable ~60°C on the 100°C setting — and yet, a slow thickening persisted, which prompted the addition of three more grams of water. Finally, the mixture was kept agitated for a little over 15 more hours, with the hotplate set to 125°C.

[0]: The temperatures were measured from the exterior surface of the flask using IR.
[1]: This time, the carbonate had been briefly ground down to a slightly finer consistency.
[2]: 10 g of water had been pre-measured for use as a lubricant in near-accordance with the patent that was followed; the instructions are to use an amount that is "at most equal to, but usually considerably less than, the initial weight of the hydroxybenzene compound". In hindsight, I do not believe that 7.89 grams would have been sufficient here — but then, I suspect that the embodying reactions of the patent were stirred mechanically.
[3]: I suspect that this sudden exothermic eruption was mostly due to C-alkylation of the monoether, to which the added water would seem likely to have contributed. Moreover, the observed generation of chromophores and the persisting reddish oil (during workup) would match literature descriptions of the C-alkylated pseudoethers.
[4]: Although the stir bar spun very fast and never decoupled, the parts of the mixture that had risen up against the sides of the flask stagnated momentarily as the reaction hit the peak of its vigor. Barring mechanical stirring, a larger (high-torque) stir bar could avoid this problem, particularly if powdered K2CO3 was added to a stirred mixture of the liquid components in the beginning (however, the presence of the monoether bears consideration). One might also be more liberal in their use of the allocated water early on, and consider using a water bath that can act as a heat sink such that there is more time to react, should the reaction suddenly sustain itself and then some. Having said all that, a second attempt by me would avoid the hassle and just use acetone as solvent.

[Fig. 6] Addition of potassium carbonate to crude diether

[Fig. 7] 30 minutes after DMS addition

[Fig. 8] 1:15 into the reaction

[Fig. 9] (1:38) Sudden increase in reaction vigor

[Fig. 10] (1:52) Immediate aftermath

[Fig. 11] Reaction mixture following complete water addition

On the following day, 50 mL of water was used to dilute the mixture, which resulted in the separation of three distinct phases; a layer of mostly solid sulfate accumulated at the bottom of the flask, whereas the buff, water-insoluble crude product floated to the top, leaving a pale salmon-colored suspension between the two. The mixture was vacuum filtered, and most of the salmon-buff top layer of the cake was scraped into a beaker where it was dissolved in 10 mL of DCM. The remaining solids were transferred to a second beaker and stirred with three consecutive 10 mL portions of DCM; the last of these was used to rinse the Büchner funnel and to extract the aqueous filtrate, which was then extracted with one or two more such portions. The organic extracts were pooled and washed with 10 mL of 10% aqueous NaOH, which gave rise to an emulsion that was resolved by a few additional grams of water.

The solvent was removed by first distilling the mixture under atmospheric pressure, followed by some moments under vacuum, and then by magnetically stirring the residue under a steady discharge of argon. The oily, amber residue was cooled down close to 0°C in the hopes of observing solidification, but there was none. 10 mL of heptane was added to give a solution with a light dusting of insolubles in it. The solid impurity was removed via filtration through a dense ball of cotton, which was then rinsed using a dash of fresh heptane. The solution was evaporated to dryness at room temperature, resulting in 6.67 g of a surprisingly hard, amber, crystalline solid with a phenolic, slightly woody, earthy (not moldy), medicinal, artificial strawberry odor subtly hinting at vanilla. After melting the solid in a 50°C oven, 6.62 g remained, and had a melting point of 42.3–48.5°C

The 6.62 g of crude product was recrystallized from 19.1 g of 78.5% MeOH to obtain 5.7 g of crystals with the appearance of Himalayan rock salt and a melting point of 51.1–52.3°C. A second recrystallization from 15.9 g of the solvent gave 5.26 g of material with less discoloration, no odor, and a slightly higher melting point of 51.7–53.0°C; this is what was used in the subsequent formylation.

An impure residue from evaporating the mother liquors was rinsed with 3 mL of ice-cold isopropanol to afford 0.98 g of a reddish material which was recrystallized from 2.74 g of 81% MeOH but neglected such that it evaporated nearly to dryness. Most of the impure liquor was removed by pressing the material between folded paper towels, yielding 0.86 g of dull-brown crystals — for an unexciting total yield of no more than 45.5%, based on phloroglucinol.

[0]: According to literature, the 1,3,5-trimethoxybenzene can be purified through steam distillation; despite reports of the neutral C-alkylated side products also coming over with steam, it would be interesting to see the results from attempting its isolation directly from the reaction mixture in this way.

[Fig. 12] Reaction mixture following overnight stirring

[Fig. 13] Dilution with water

[Fig. 14] Vacuum filtration

[Fig. 15] Evaporating solution of crude product in heptanes

[Fig. 16] Crystalline evaporation residue

[Fig. 17] First recrystallization

[Fig. 18] Recrystallized product

[Fig. 19] Second recrystallization

[c4] 2,4,6-trimethoxybenzaldehyde
196.20 g/mol
316.37 g/mol (bisulfite adduct; potassium salt)

A deviation from the PiHKAL procedure, this experiment substitutes N,N-dimethylformamide for N-methylformamide, because the latter is reported to produce dramatically inferior yields of an impure product. [1] [2] Indeed, just as originally reported by the Hyperlab member _hest, [3] this modification gave excellent results.

[1]: PiHKAL: #162 TMA-6.
[2]: (Hyperlab) amethyst: TMA-6.
[3]: (Hyperlab) _hest: Synt of 2,4,6-trimethoxybenzaldehyde.

Experiment 1
In a round 50 mL reaction flask, 1,3,5-trimethoxybenzene (5.00 g, 29.7 mmol) was dissolved in 20 mL of DMF. A stir bar was added, and the mixture was set up in a stationary ice bath over a stirrer. A pasteur pipette was driven through a thermometer adapter to suspended it above the magnetically agitated mixture; through this, there was gradually injected phosphoryl trichloride (4.87g, 31.8 mmol) at a fluctuating dropwise pace over 40 minutes. [1] Two hours after completing the addition, the now-orange mixture was removed from the bath, whose temperature of 9°C it shared. Stirring was resumed for 2.5 hours at 24°C.

[1]: This arrangement served as an improvised way of limiting air exchange inside the flask (to protect the POCl3) in lieu of an appropriately sized addition funnel, and worked passably: the opening was otherwise airtight, which necessitated the application of some pressure from the dropper in hand; hence, a thin bypass through the O-ring would have been shrewd. On the other hand, the consequences of simply alternating a stopper instead might have been negligible.

[Fig. 20] Discolored 1,3,5-TMB dissolving in DMF

[Fig. 21] Reaction apparatus

[Fig. 22] Claret hue evolving from initial additions

[Fig. 23] Reaction mixture following removal from bath

Approximately 150 mL of cool, clean, well-stirred water from the tap was prepared in a 250 mL beaker; the contents of the reaction flask were then added to this in <10 minutes using a dropper, causing the temperature of the mixture to rise to ~30°C before gradually cooling down again. A sudden onset of precipitation was observed after 20 minutes. The mixture was allowed another 8 hours of stirring (in the dark, although this is probably not important) prior to a vacuum filtration to separate the solids, which were rinsed with six 10 mL portions of water and air-dried to obtain 5.26 grams (90.2%) of a delightfully pink, [1] crystalline solid melting at 119.5–120.5°C.

[1]: The pink hue seems to have almost completely faded away over time, doing so much faster, initially.

[Fig. 24] Post-reaction mixture being added to water

[Fig. 25] Completed quenching mixture after some minutes of stirring

[Fig. 26] Quenching mixture after 35 minutes of stirring

[Fig. 27] Mixture prior to vacuum filtration

[Fig. 28] 1,3,5-trimethoxybenzaldehyde

This at last concludes the benzaldehyde portion of my quest for the corresponding phenethylamines!
As for what's next, I'm pleased to announce that I have made some progress on the remainder as well: Having decided (in light of some initial failures which had fascinating implications) that it would be apt to learn more about the condensation and subsequent reduction in order to minimize the further waste of precious starting materials, I was able to prepare all of the intended nitrostyrenes, which are currently pending reduction as I'm figuring out the copper-catalyzed process that I quite prefer over the alternatives at my disposal. I feel like I'm finally getting close to where I want to be, although a good deal of work still remains to be done; but I do believe that it'll all be worth it.

Whoever you are, whenever you are: thank you for making it here !

AvBaeyer - 6-11-2023 at 20:41


Indeed, a very masterful exposition on a complicated problem. I wondered about how you were going to pull everything together. Thank you for the kind acknowledgment. However, it is the first time that anything I have done has been called "awesome"! I am simply happy to know that I was able to help a bit.

Your experimental write up is excellent. Good luck on your remaining synthesis pathways - keep us posted.


Dr.Bob - 7-11-2023 at 10:33

Beautiful writeup, I wish any of the papers I try to follow was as thorough, detailed and had photos. You might want to break the pieces into chunks (maybe one post per step) for easier reading, but the photos and details are great.

walruslover69 - 7-11-2023 at 11:12

Amazing Right up!

I had some some trouble with the further reduction step. Tried a few procedures that never seemed to work for unknown reasons, Eventually I found a procedure using nickel chloride and sodium borohydride. I believe it generates nickel nanoparticles that actually act with the hydrogen to carry on the reaction. I can dig up my procedure.

Quieraña - 11-12-2023 at 16:39

I said it before, and I'll say it again: I've read and loved pihkal and no where I have read yet that triacetoxybenzaldehyde has been used to make triacetoxyphenethylamine, or what have you. I'm excited at the prospect of more phenethylamines that could be entheogens.

Edit: sorry, didn't know I posted about this in the same forum twice. That being said, there could be 2,5 diacetoxy, even simple acetone derivatives. Jeez, what else can we throw in the bunch?

[Edited on 12-12-2023 by Quieraña]

Now I see there's even a thioacetoxybenzaldehyde. Crazy a whole other book waiting to be written. That substance line.. hmm.

[Edited on 12-12-2023 by Quieraña]