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]