Brominating 2CH HCl directly worked without a snag

[SpicyBrown]

There has been a lot of discussion on the Hive about this topic in the past, and although many people have suggested that it should work fine, nobody has actually stated outright whether or not it does. SWIM would like to let everybody know that it does in fact work fine, although SWIM wouldn't personally take credit for this. Big thanks goes to Vaaguh for verifying that this worked before SWIM went ahead and tried it himself.

About 0.55g of grayish-white (not the cleanest stuff you ever saw) 2CH HCl was placed in a small beaker and swirled with about 2mL glacial HOAc. Not everything dissolved at first.  About 1mL of glacial HOAc with about 0.5g Br2 dissolved in it was then added, and all remaining solids dissolved. The beaker was covered with foil and swirled, the contents began to heat up noticeably. Within about 10 minutes, everything was a tan slush.

The contents of the beaker were allowed to return to room temp, and the foil was removed as SWIM coughed and choked on HBr fumes.... The contents were then triturated with anhydrous ethyl acetate until all color disappeared. SWIM once read a long time ago that somebody thought ethyl acetate was an ideal solvent for cleaning up the tan 2CB HBr formed from the bromination, and they were VERY right! Without any extensive cleaning procedures, only trituration with anhydrous ethyl acetate, SWIM managed to get about 0.60g of pure white, fluffy 2CB HBr.

SpicyBrown

[Rhodium]

Who is "Vaaguh", and where did you find the reference to cleanup with ethyl acetate? The above procedure would be great if it works as stated, but it looks somewhat too simple to be true.

One well-founded point of critique is that your product isn't 2C-B.HBr, but rather an unknown mixture of 2C-B.HCl and 2C-B.HBr, because you introduced one molar amount of HCl through the 2C-H salt. This will result in the actual 2C-B content in a given weight of your product mixture, as the HBr salt is 20% heavier than the HCl. Having a salt mixture also complicates further purification, should it be needed.

[Edited to fix the typo catched by SB below]

[SpicyBrown]

Who is "Vaaguh", and where did you find the reference to cleanup with ethyl acetate? The above procedure would be great if it works as stated, but it looks somewhat too simple to be true.

Well, Vaaguh is a person here at the Hive, see recent post

Post 384994

(Vaaguh: "directly brominating 2c-h hcl", Methods Discourse).

SWIM looked around and found the mention of ethyl acetate in Beaker's method for making 2CB. SWIM should have looked at it again first before making the comment up there in the first post, because he now realizes that Beaker was talking about cleaning the post-bromination tar (bromination here with NaBr/H2O2) by partitioning between water and EtOAc, which is different than what SWIM did.. This is where SWIM got the idea though, and none the less, SWIM triturated the tan solid from the bromination repeatedly (it took 4 or so triturations) until all hints of any brown color disappeared. After allowing the solid to dry for an extended period of time under a heat lamp, no traces of bromine or HBr were detectable by the nose either. SWIM may have a chance soon to run an NMR on the product and look for other residual impurities.

One well-founded point of critique is that your product isn't 2C-B.HBr, but rather an unknown mixture of 2C-H.HCl and 2C-H.HBr

SWIM assumes you meant 2C-B and not 2C-H, right? SWIM considered this possibility but wasn't entirely sure if it would be the case. Suppose the only way to fully remedy that would be to do an acid/base and form entirely the HCl salt or HBr salt in the end.

SWIM just tried placing a small amount, perhaps 5mg or so of the product on a watch glass. With a bit of agitation, it dissolved completely in a few drops of room temperature diH2O. Is 2CB HCl completely insoluble in water, or is there a partial solubility? SWIM would have expected only some of the product to dissolve with the water-insoluble HCl salt present, although it could be possible that the spatula-tip SWIM grabbed just happened to be only the HBr salt.

SWIM could send a picture of the final product after only triturating if you wanted to see what it looked like.

SpicyBrown

[Rhodium]

Yes, of course i meant 2C-B (I have now corrected the typo), and I must have spelled "Vaaguh" wrong in TFSE too.

If you say five triturations was needed to remove the color, then I'm more inclined to believe you, but there is of course a difference between white and white. I would VERY much welcome a purity estimation made by NMR, HPLC, GC or whatever, as even if your crystals are clean on the outside, they may still contain occluded impurities if you haven't performed a recrystallization. Wouldn't it actually be easier to rinse the crude salt with some ethyl acetate on the buchner funnel, and then recrystallize it from MeCN/IPA/MeOH (or whatever suitable solvent) instead of triturating it five times?

2C-B.HCl is not completely insoluble in water, just very slightly soluble compared to most HCl salts. Why don't you freebase 2C-H.HCl before dissolving it in GAA, thereby eliminating all doubts about the identity of the product? I also strongly believe that you will minimize byproduct formation if all of the 2C-H is in solution before the addition of bromine.

As it is right now, the only way to be fully sure about the salt-form you have is to A/B and precipitate the HCl salt, as you correctly assume.

[Antoncho]

So many coincidences lately - that 4-OH-indole synth for one thing

And it just happens that this salt-bromination topic is currently being discussed at HyperLab  The results thus far:

a) It turns out that SpicyBrown is quite correct and HCl-salt bromination might even work actually BETTER than bromination of acetate. Experimentational confirmation has been done by Vitsh; also i have a russian article that describes this proc. in all details and varieties (but alas, w/out specifying yields....)

b) Another point of interest from that article: if one brominates HCl salt of 4-OH-3-MeO-PEA (one that you'd get from straight vanillin) then the product  is 5-Br ('mescalinic' pattern); when one brominates hydrosulfate (*HSO4) salt, one gets 6-Br product! Brominating w/out solvt gives a mixtr of isomers.

Can anyone explain, WHY and WHAT makes the difference? Please?

And, most importantly, what implications it might have in case of 2C-H?

c) Bromination is performed with dioxane*Br2 in the article, so that should work w/2C-H as well (and, probably, better than straight bromine).

d) To get 2C-B*HCl there's no need to make freebase from it, just add HCl to sat. aq. soln of hydrobromide salt. (Established by Fomalhaut&Dionket).


Feel free to ask questions if needed.

Antoncho

[Rhodium]

Antoncho: Interesting! Could you just state for the protocol the journal/volume/page/year?

What solvent is used for the anomalous bromination?

My only guess (being remote) is that if the HSO₄^- salt is used, it disproportionates to "(amine)₂SO₄" and sulfuric acid, the latter protonating the phenolic group on the PEA, making R-OH go R-O⁺H₂ - an electron-withdrawing group (which thus is meta-directing, favoring 6-bromination), which instead of the electron-donating hydroxyl group one would expect to find on the molecule (and which would be ortho-directing, favoring 5-substitution).

[Antoncho]

Could you just state for the protocol the journal/volume/page/year?

Sure.

Zhur. Obsch. Khimii (Journal of General Chemistry) 28; 12; p. 3320 (1958)

http://chembook.narod.ru/other_articles/article17.djv

The article was found and uploaded by Diafrag of HyperLab.

What solvent is used for the anomalous bromination?

Always AcOH. What is interesting, the rxn is performed as follows:



1. 3-MeO-4-OH-5-Br-PEA.

To the solution (note the word 'solution')of 6.24g 3-MeO-4-OH-PEA*HCl in 40 mls AcOH at 70 C there's added w/stirring 7.55 g dioxane*Br₂ and the solvent is removed in vacuo.(looks like bromination happens on the fly)

The residue is treated w/20mls EtOAc and left standing at 0 C for 72hrs. Precipitated HCl salt is filtered, dissolved in 10mls water and neutralized w/aq. ammonia. The freebase is washed w/water (30mls) (hey, although they don't state the yield, looks like it was decent - judging by the amt's of the solvts used!).

Colorless crystals, sol. in xylene and bromobenzene w/heating. Mp 169.5-170 C (from m-xylene)



2. 3-MeO-4-OH-6-Br-PEA.

To a solution of 2g 3-MeO-4-OH-PEA*HSO₄ in 20mls GAA there's added 1.87g dioxane*Br₂ with stirring over 2-3 mins. The solvt removed in vacuo, mixed w/20mls EtOAc, left at 0 C for 3 days, filtered, dissolved in water, basified w/NH₄OH. (Evrything as in the prev. rxn).

Yield - 58,8% M.p. - 187-189 C.




sulfuric acid, the latter protonating the phenolic group on the PEA, making R-OH go R-O+H2

Wow! That's wild - never knew it was possible (may i ask you: how easily does phenol bind a proton and in what other rxns such things happen? Phenol ether demethylations, maybee?)



Antoncho

[Osmium]

Ph-O⁺H₂ is analogous to water being protonated forming H₃O⁺.

> how easily does phenol bind a proton

Not too easily. Ph-O⁺H₂ is a strong acid and its concentration should be rather low, unless the other acid where that proton came from is much stronger.

> and in what other rxns such things happen?

It should happen in all reactions which use an excess of strong acids together with phenols.

> Phenol ether demethylations, maybee?

Yes, definitely. That's why only very strong acids like HI or HBr will work for this reaction (even though I still believe that eugenol can indeed be cleaved by H2SO4 and everyone else keeps ignoring me      )

Another example is solubility of diethylether in water. When you acidify the water with a strong acid, e.g. HCl or H2SO4, the solubility of the ether will be much higher since it becomes protonated and carries a positive charge.

[SpicyBrown]

I would VERY much welcome a purity estimation made by NMR, HPLC, GC or whatever, as even if your crystals are clean on the outside, they may still contain occluded impurities if you haven't performed a recrystallization.

Rhodium, SWIM will perform TLC's and obtain an NMR spectra within the next week, the results will be posted here. Does anybody know of a good solvent system to use for TLC on the HCl/HBr salts of 2CB? Also, would anybody expect the salt to be soluble in CDCl3? SWIM has deuterated DMSO at his disposal for NMR's as well, but it's sort of a commodity next to the CDCl3. Also, does anybody have an NMR spectra from confirmed 2CB for comparison?

d) To get 2C-B*HCl there's no need to make freebase from it, just add HCl to sat. aq. soln of hydrobromide salt. (Established by Fomalhaut&Dionket).

Antoncho, this sounds a lot more convienent then doing the usual acid/base. Is the idea then to make a saturated aq. solution of the HBr salt, add HCl dropwise and the 2CB HCl will spontaneously crystalize from the saturated solution?

SpicyBrown

[pHarmacist]

As it's a salt (ionic compound) you'll have to use DMSO for NMR. Why not make the NMR analysis before crystallisation? Then you can use CDCl3 to dissolve the freebase. You could use trial and error on that particular NMR-spectra intrepretation, it's not an awfully complicated substance. Or you can just post the results and the hive can verify them.

[SpicyBrown]

As it's a salt (ionic compound) you'll have to use DMSO for NMR.

That's what SWIM figured.

Why not make the NMR analysis before crystallisation?

That's exactly what SWIM planned on doing, SWIM's eager to see how clean this is w/o the recrystalization.

SWIM has a lot of experience with NMR spectra of protected or free amines, but never runs spectra on salts of amines. How will the amine being ionic effect the spectra? Will the amine's proton peak show an additional hydrogen? Will it not show up at all, or in a different place (although amines usually have crazy wide ranges anyway)?

SpicyBrown

[yellium]

If you UTFSE with 'NMR of 2c-b' you'll find a post from yours truly giving NMR data on 2cb and other goodies.

There's even a mass spectrum of 2c-b in that thread.

[pHarmacist]

That's exactly what SWIM planned on doing, SWIM's eager to see how clean this is w/o the recrystalization.

There are other methods to assure purity, NMR is mostly for the structure elucidation (spell check).


SWIM has a lot of experience with NMR spectra of protected or free amines, but never runs spectra on salts of amines. How will the amine being ionic effect the spectra? Will the amine's proton peak show an additional hydrogen? Will it not show up at all, or in a different place (although amines usually have crazy wide ranges anyway)?


Its even better to protonate amine by as you did during the crystallisation. In order to avoid intermolecular proton exchange, or at least push the equilibrium towards the quart amonium ion so that it slows down. The methylene group (alpha carbon) will thus have 3 neighbors (from the protonated amine). You should expect the amine betwean 1 and 3 ppm, I think.

[pHarmacist]

There is allready an NMR analysis/interpretation of 2cb as well freebase as salt, it can be found here:

Post 298778

(karel: "2CB NMR", Methods Discourse)

[pHarmacist]

Since we got both MS and NMR spectra for 2CB, why don't you provide us with IR spectra for it. If you've got accscess to NMR I'm sure that you've got to a IR machine as well.

[Rhodium]

The IR peaks can be found in

Post 298949

(Rhodium: "Analytical profile of 2C-B", Methods Discourse).

[SpicyBrown]

Shit! SWIM prep'd an NMR sample today in D2O, only to find out that a power outage over the winter break has downed our NMR for the time being. Will eventually get the spectra, but not now. It took a week and a half to get it fixed last time something similar happened, putting a bit of a halt on a fair deal of research..

Oh well, a bit of the product was however recrystalized, 23mg produced an incredibly ass-kicking experience..

SpicyBrown

[SPISSHAK]

how did you get the 2,5 dimethoxy phenethylamine to start with?
Off the shelf at your university?
PM me and tell me what school I need to enroll in .

[SpicyBrown]

how did you get the 2,5 dimethoxy phenethylamine to start with?
Off the shelf at your university?
PM me and tell me what school I need to enroll in

Hehe, no not off the shelf, it was painstakingly made from 2,5-dimethoxybenzaldehyde by condensation with nitromethane by refluxing in the presence of ammonium acetate for 3 hours. The resulting nitrostyrene was reduced directly to 2CH using NaBH4 and in-situ generated Ni2B (From NiCl2-2H2O and NaBH4) in methanol at room temperature.

Making the nitrostyrene is easy, trying to reduce it produced a lot of tar. 6.4g of starting nitrostyrene yielded almost 1g of 2CH HCl. Another attempt on a little over 3g of nitrostyrene seemed to pretty much fail all together, but the procedure was stupidly changed a bit by SWIM. SWIM is currently looking into other methods, and very soon will try reducing the double bond on the nitrostyrene with NaBH4 via Barium's method in EtOAc/EtOH followed by reduction of the nitro group by activated zinc and formic acid. Praying the tar monster doesn't visit SWIM any more. Would consider CTH with Pd/C, but commercial Pd/C is hard for SWIM to come by and the limited amount SWIM has is reserved for other endeavours.

-SpicyBrown

[yellium]

The EDDA method for producing nitrostyrenes is easier and has better yields. UTFSE for 'edda'.