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Benignium
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A foray into phenethylamines of the Shulgin kind
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.
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karlos³
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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? 
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
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!
Here: https://www.thevespiary.org/talk/index.php?topic=16739.msg54...
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.
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mr_bovinejony
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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
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Opylation
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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
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Benignium
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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".
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arkoma
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nice to see a discussion of these molecules and their chemistry without any "moral" histrionics
"We believe the knowledge and cultural heritage of mankind should be accessible to all people around the world, regardless of their wealth, social
status, nationality, citizenship, etc" z-lib
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symboom
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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]
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Texium
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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.
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arkoma
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well said ^^^^
"We believe the knowledge and cultural heritage of mankind should be accessible to all people around the world, regardless of their wealth, social
status, nationality, citizenship, etc" z-lib
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Opylation
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[Edited on 24-5-2021 by Opylation]
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njl
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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?
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Links?
Reflux condenser?? I barely know her!
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karlos³
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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.
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njl
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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.
Reflux condenser?? I barely know her!
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Newton2.0
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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]
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mr_bovinejony
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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
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Newton2.0
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@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]
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mr_bovinejony
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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
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Newton2.0
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Oh man, I will have to check that out! That is extremely cool
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mr_bovinejony
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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.
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laserlisa
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Nice pictures OP!
OP performed a variant of the Cu/borohydride reduction where the original procedure is posted here http://www.sciencemadness.org/talk/viewthread.php?tid=84596
Im curious about your contributions though if you dont mind sharing!
[Edited on 25-5-2021 by laserlisa]
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karlos³
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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:
| Quote: |
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]
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Oxy
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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
Benignium, very nice report (as usual)!
[Edited on 25-5-2021 by Oxy]
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karlos³
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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]
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Benignium
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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:
2C-H
2C-B
June-July 2021:
2,5-DMA
2C-C
DOI #1
DOI #2
DOC
DOB #1
March-April 2022:
DOI purification
DOC purification
DOB purification
DON
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.
Recrystallizations
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)
1-(2,5-dimethoxyphenyl)-2-nitropropene
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
Purification
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
Reduction
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.
Work-up
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
N-chlorosuccinimide
~20 minutes after adding acid catalyst
At 24 hours
At 48 hours
At 72 hours
At 72 hours, 30 minutes
Work-up
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
Work-up
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.
Work-up
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
Work-up
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
Work-up
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
Purification
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 (SWGDRUG.org). 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
Work-up
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
Purification
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
Work-up
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
Purification
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
Work-up
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
Purification
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
Work-up
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
Purification
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]
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timescale
Harmless
Posts: 21
Registered: 12-9-2021
Location: USA
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Mood: Neurotic
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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.
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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.
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?
Est-il une beauté aussi belle que le rêve ?
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