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xwinorb
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Brominating the HCl salt instead of freebase.
I have tried once to brominate the HCl salt instead of the free base as I have mentioned before. Same technique. Noticed the following :
1) The temperature did NOT went up to 50 C like it allways did whne brominating the freebase. It stayed at RT. What does this mean ?
2) The yield and color of the final 2C-B.HCl looked worse than when brominating the freebase.
Sorry, I am the first to say I don't know enough organic chemistry to try to understand why, this is only what I have noticed. After that I
decided to keep brominating the freebase and not the HCl salt.
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KidCurry
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xwinorb: But you didn't brominate with NBS, when using Br2 it's recommended to use the freebase.
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Nicodem
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| Quote: |
Nicodem: But if NBS bromination works by liberating small amounts of Br2, why does not HBr form?
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This is why:
NBS + HBr <=> succinimide + Br2
Any trace of HBr that forms from any traces of Br2 is just a trace and nothing more. It only contributes to the formation of further traces of Br2
according to the above equation. Besides the theoretic explanation of the electrophylic substitution on the aromatic ring with NBS does not need to
call for Br2 as the brominating reagent. NBS itself is electrophylic in protic and more so in acidic media. Furthermore very electrophylic species
like AcOBr form in equlibrium concentration from NBS in acetic acid. When the hydrochloride salt of 2C-H is used even more reactive electrophyles like
BrCl probably form (again in equilibrium concentration).
But anyway, you could simply write down the equation for the bromination with NBS and you would notice that there is no HBr formed:
NBS + 2C-H => succinimide + 2C-B
While with Br2:
Br2 + 2C-H => HBr + 2C-B
…there is a human touch of the cultist “believer” in every theorist that he must struggle against as being
unworthy of the scientist. Some of the greatest men of science have publicly repudiated a theory which earlier they hotly defended. In this lies their
scientific temper, not in the scientific defense of the theory. - Weston La Barre (Ghost Dance, 1972)
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KidCurry
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Thanks!
Will keep you updated on the bromination, but it will probably not be done in atleast a few weeks. Tried to synthesise some new 2C-H yesterday, but
was tired and everything just went wrong (ie, I screwed up). Don't think I can recover any product, and I'm out of some important solvents
etc I n eed to do another batch and I'm also pretty much out of money. This project has costed me way too much already, so it will have to wait
some time.  Next time I will probably do the reduction with Zn/HCl, seems easier in
some ways even though it takes more time.
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xwinorb
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To KidCurry :
I good point to take a break is after filtering out the zinc, after main reaction, before workup. Then one has 2C-H.HCl in alcohol plus water, can be
kept for a while ( I keep it in the refrigerator just in case, do the workup next day ) whithout problems.
Keep us posted, I think you will have no problems with the reduction, I would like to know how well it brominated with NBS.
Good luck,
XW.
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Sandmeyer
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A few references can be found in March Fifth in case someone is still interested in the NBS vs. Br2 bromination mechanism, see discussion starting on
page 927 (pdf) in the below link, or page 911 in the hardcopy.
http://rapidshare.de/files/965524/March_5th_ocr.rar.html
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gonzo
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Your post has been removed on referral. Pending deletion.
[Edited on 31-3-2009 by Ramiel]
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Ramiel
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This whole thread irks me, and if it were up to me it would've been nuked from orbit just to be sure.
Gonzo, your post crossed the line into transparent drug manufacture, spoonfeeding, double-posting, unscientific stream-of-consciousness rubbish, I'm
afraid.
I'll be keeping a close eye to make sure the rules aren't inadvertently broken again, please abide by them 
Caveat Orator
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xwinorb
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I have just finished brominating 3 g of the same substrate previously mentioned in this thread, I did not used NBS. This is the fourth time in a row I
have success, good quality also, final product almost white.
After some minor technique changes, my yields have been ( for the fourth times I mentioned ) ALLWAYS above 60 %, my last one was 68 %. Without using
bromine, it is generated in situ. Using NaBr + H2SO4 + H2O2 added to freebase in AcOH.
By stark contrast, I have had three failures in a row while trying to improve things by using NBS. The quoted text below is the procedure I have
followed, it is an old thread from The Hive, named "bromination with NBS". The quoted text is by slappy.
| Quote: |
There is no need to use Perchloric Acid as a catalyst. Just do it like I said and it will work. 1-1.1 eq. NBS (DBDMH works better sometimes) in MeCN,
stir at R.T. for 12 hours. Partition between DCM and water, and a couple successive water washes to remove the succinimide.
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Well, I don't think this works as stated. Tried it twice, both with the yellow ( non-crystalized ) NBS and also after re-xtalizing it from boiling
water and drying. The re-xtalized NBS was nice, white, clear, and dry.
I used 0.5 g and 1 g of the starting substrate respectively, zero yield for both. Seems to make a lot of red tar only.
Before that I had also one failure when trying to brominate the HCl salt in AcOH. The reaction did not started, nothing happened.
I have the impression from a few references and comments I have seen that maybe N-bromination is an issue with NBS in MeCN. Looks like using NBS it is
not the best way to brominate the above substance. And also even using AcOH as the solvent, NBS yield and quality are not as good as the alternate
method.
If I doing anything wrong, please feel free to post or PM me.
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Nicodem
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| Quote: | | Before that I had also one failure when trying to brominate the HCl salt in AcOH. The reaction did not started, nothing happened.
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This is not an appropriate forum for such discussions and if you would have followed a certain more appropriate forum you would have noticed that,
contrary to your claims, it is possible to brominate the hydrochloride of your substrate with NBS in acetic acid without problems. Since the
theoretical aspects of the chemistry in this thread are of interest to a wider public, I can only say that it is unlikely that the bromination of
2,5-dimethoxyphenylethylamine with NBS in acetonitrile would go smoothly because in any case the first step of the reaction would be N-bromination
which in neutral conditions does not exclusively go further to ring bromination (N-bromoamines are not particularly electrophilic in neutral media -
much less than NBS at least). This means other pathways might prevail instead (meaning tar-like products, etc.). Something similar is to be expected
even when using acetic acid as solvent (glacial AcOH is not acidic enough to protect the amine because the acetate anion is a relatively strong base
in anhydrous acetic acid).
However, bromination of 2,5-dimethoxyphenylethylamine hydrochloride with NBS in acetonitrile as described in the quoted text should give the ring
brominated product without problems (provided solubility is not an issue). Here the amine is well protected by protonation, so that N-bromination can
not occur as easily. In this respect acetonitrile is just as appropriate an solvent for brominations with NBS, as is acetic acid or water (even though
optimal water is rarely used for electrophilic brominations with NBS because most substrates are insoluble in it - this is however not the case for
2,5-dimethoxyphenylethylamine hydrochloride which is well soluble in water).
…there is a human touch of the cultist “believer” in every theorist that he must struggle against as being
unworthy of the scientist. Some of the greatest men of science have publicly repudiated a theory which earlier they hotly defended. In this lies their
scientific temper, not in the scientific defense of the theory. - Weston La Barre (Ghost Dance, 1972)
Read the The ScienceMadness Guidelines!
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xwinorb
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Nicodem : I am not saying brominating the hydrochloride in AcOH with NBS will not work, it does. But, I got lower yields and quallity than with the
other technique.
I think I brominated the HCl salt with NBS in AcOH some 3 times, then once it completely failed to start, no idea why.
After that I tried again the other method, with some minor changes to the proportions of the three agents used to make the bromine in situ, and then
yield and quality jumped up. Kind of accidental though.
Then I found the refered thread and tried it because it is reported to yield 90 %. As I said above it does not work.
Tried again the referred alternate method, got my best yield ever at 68 %.
Many thanks for your comments.
Note : I have not tried the HCl salt with NBS in MeCN though.
[Edited on 5-1-2010 by xwinorb]
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Klute
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Does the N-bromoamines problem occur when using bromine?
\"You can battle with a demon, you can embrace a demon; what the hell can you do with a fucking spiritual computer?\"
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DJF90
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Classically (and I'm sure there are many examples of this) carbon tetrachloride is used as the solvent for NBS brominations. One such reason
is that the succinimide byproduct is insoluble in this solvent, making purification just that little bit easier.
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xwinorb
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A bit more info
Case anyone is interested, my best results were using 1.5 eq. of NaBr and H2SO4, and using 3 eq. of H2O2. The slight excess of H2O2 seems to help with
yields and quality. Two hours reaction time more than enough.
I think I will still try the HCl salt in MeCN, but I can't do it so soon, maybe in one month or two. Just to make sure.
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Nicodem
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No. With Br2 the reaction with amines is R-NH2 + Br2 <=> R-NHBr + HBr. So, as you see, there is no problem with the bromoamines decomposing,
because the equilibrium is leaned toward left and no considerable N-bromoamine decomposition can occur (provided the aromatic ring is nucleophilic
enough for its bromination to compete, so to consume all the R-NHBr and Br2 rapidly enough - which is the case in regard to the discussed substrate).
N-Bromination can only become a problem in a medium where N-bromoamines are thermodynamically favoured as reaction intermediates and are not
electrophilic enough to react further (in neutral or basic media).
Quote: Originally posted by DJF90  | | Classically (and I'm sure there are many examples of this) carbon tetrachloride is used as the solvent for NBS brominations. One such reason
is that the succinimide byproduct is insoluble in this solvent, making purification just that little bit easier. |
Certainly not. NBS in CCl4 is hardly electrophilic. You need a polar solvent to increase the electrophilic character of any N-haloimide (NBS, NCS,
NIS, TCCA, dihalohydantoins...) for them to perform electrophilic aromatic substitutions. If this is not enough then an acid is used to increase their
reactivity (H2SO4, HClO4, AlCl3, etc.). With NBS the most common solvents employed are acetonitrile, acetic acid, DMF, methanol and water. It is only
when one wishes to suppress the electrophilic character of NBS, in order to favour the radical pathway, when CCl4 is used (not just this, but also
because CCl4 is inert toward radicals). NBS in CCl4 is traditionally only used for benzylic and allylic halogenations (Wohl-Ziegler reaction) which are however not related to the discussed topic (except for the reagent used).
| Quote: Originally posted by xwinorb | | Case anyone is interested, my best results were using 1.5 eq. of NaBr and H2SO4, and using 3 eq. of H2O2. The slight excess of H2O2 seems to help with
yields and quality. Two hours reaction time more than enough. |
This is analogous to a method described a year or two ago on a certain other forum. There, KBrO3 was used (instead of H2O2). If I remember correctly a
solution of KBrO3(aq) was slowly added to a solution of a certain phenylethylamine hydrochloride and KBr in water acidified with H2SO4 while stirring
on an ice bath. However, it was a different substrate. I don't know if that forum is still active, though.
…there is a human touch of the cultist “believer” in every theorist that he must struggle against as being
unworthy of the scientist. Some of the greatest men of science have publicly repudiated a theory which earlier they hotly defended. In this lies their
scientific temper, not in the scientific defense of the theory. - Weston La Barre (Ghost Dance, 1972)
Read the The ScienceMadness Guidelines!
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Klute
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Thanks for the explanation, Nicodem.
I take it using Br2 and the HCl salt will be even more efficient because no haloamines can form, and the HCl salt precipitates when brominated..
I wonder why this technique isn't more discussed? Why go the the hassle of basifying, extracting the amine freebase, distilling the solvant, and
dissolving in acetic acid, when simply adding the HCl salt (commonly formed to purify the unbrominated amine) to GAA then dripping Br2 can be done?
\"You can battle with a demon, you can embrace a demon; what the hell can you do with a fucking spiritual computer?\"
-Alice Parr
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xwinorb
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Klute : I think if you use Br2 in AcOH it is better for yield and quality to brominate the freebase and not the HCl salt. I have tried it once and did
not liked the results. I think all recipes for brominating 2C-H with Br2 in AcOH do use the freebase and not the HCl salt.
For brominating with NBS it is prefered to use the HCl salt though. Already discussed in this thread.
Again thanks to Nicodem for posting his comments on the mechanism of the NBS bromination. Very interesting.
One more thing, I think maybe the technique that slappy posted on The Hive work for other substances, but maybe does not work for amines due to the
mentioned problems.
In that same Hive thread other users were specifically talking about 2C-H though. I think it is possible slappy never used if for 2C-H.
He is not specific either about using the freebase or the HCl salt.
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DJF90
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Nicodem: Sorry, there seems to have been a misunderstanding. What I was saying was in relation to the radical bromination; I hadn't read enough of the
thread to know that we're talking about electrophilic bromination here. My apologies.
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turd
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| Quote: Originally posted by xwinorb | | Case anyone is interested, my best results were using 1.5 eq. of NaBr and H2SO4, and using 3 eq. of H2O2. The slight excess of H2O2 seems to help with
yields and quality. |
I don't know if the "slight" was tongue-in-cheek or an euphemism, but I think the total reaction is:
H+ + Br- + H2O2 + Ar-H ---> 2H2O + Ar-Br
So 3 eq. of H2O2 is actually a threefold excess relative to the limiting reagent or a twofold excess relative to the bromide. That's quite a lot.
| Quote: | | I wonder why this technique isn't more discussed? Why go the the hassle of basifying, extracting the amine freebase, distilling the solvant, and
dissolving in acetic acid, when simply adding the HCl salt (commonly formed to purify the unbrominated amine) to GAA then dripping Br2 can be done?
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Well, when making amines I usually end up with the distilled freebase. And making the salt often is a surprisingly lossy process (maybe I should
ponder on that one time). So it's seems just practical to use the freebase.
But I guess the real reason is, as so often, inertia. Someone tried it, it worked and that's it. New things are only tried if the need arises, i.e. a
precursor is not available anymore.
[Edited on 6-1-2010 by turd]
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xwinorb
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turd :
Here is how this came out : I started experimenting using the technique posted by Chromic, only withouth water.
Reason I choose to do that, more similar to Shulgin's, that is, Br2 in AcOH.
Chromic uses everything at 1.2 eq. I got low yields and dirty product initially. Yields around 40 %. I experimented changing the ratio, used 1.5 and
1.9 of everything. Yields up, but still browninsh output. Best ratio seemed to be 1.5, choose this one.
Once, by accident, useed double the 1.5 ammount of H2O2, and got good yields and quality. Tried it again, same thing.
Everytime I used the ratios as above I got more than 60 % and clean product, w/o having to distill it. Dry it, one or two acetone washes, that's it.
Even before the washes it is quite clean. The washes remove ( I guess ) some residual water, excess HCl ( I drip HCl in toluene to xtalize ) and
impurities.
Some of the final product passes through the filter, don't waste it. I use to recover the acetone + product and to re-filter or let it sink, then
pipette out the top acetone.
2C-B.HCl seems to have a low solubility in acetone, but DRY IT before the acetone washes.
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Nicodem
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| Quote: Originally posted by Klute | | I take it using Br2 and the HCl salt will be even more efficient because no haloamines can form, and the HCl salt precipitates when brominated..
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I doubt you would get any precipitate of a pure hydrochloride from acetic acid. Most likely you would get a mixture of chloride/bromide salts.
Besides, it is wasteful to just filter the precipitate, because a lot of product surely remains dissolved in the reaction mixture. From what I read,
the hydrochloride is soluble in many organic solvents. It is well soluble in alcohols and relatively soluble in acetone and ethyl acetate.
If I would be given a project to optimize this halogenation I would most likely opt to perform the bromination of the substrate as the hydrochloride
in aqueous solution with NBS (or dibromohydantoin). Since the hydrobromide of the product has a low solubility in cold water it would crystallize out
(some HCl can be added to reduce the solubility), while the succinimide remains in solution. The product, crude
2-(4-bromo-2,5-dimethoxyphenyl)ethylamine hydrochloride, is then recrystallized from water. This would be quite a "green" method. Not a drop of an
organic solvents used and the succinimide side product can even be isolated. But this amine is for some strange reason listed as illegal to make and
posses where I live, so I think I will never get such a project. Instead I always only get some stupid contracts to optimize the synthesis of legal
drugs (I was told that these are more profitable). Xwinorb can consider himself lucky to live in a country where such a synthesis is not considered as
breaking the law (or so I hope for his own sake).
| Quote: | | I wonder why this technique isn't more discussed? Why go the the hassle of basifying, extracting the amine freebase, distilling the solvant, and
dissolving in acetic acid, when simply adding the HCl salt (commonly formed to purify the unbrominated amine) to GAA then dripping Br2 can be done?
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Because that is the original procedure published in the scientific literature by Shulgin et al. As you might have noticed over the years, there is
very little initiative for innovations. Most people that are motivated for such a synthesis don't even have a basic grasp of theory. So how could they
ever develop anything new? Those that have a grasp of theory rather choose to make new and legal drugs. If you are intelligent enough to understand
theory then you are also intelligent enough to avoid unnecessarily breaking the law.
…there is a human touch of the cultist “believer” in every theorist that he must struggle against as being
unworthy of the scientist. Some of the greatest men of science have publicly repudiated a theory which earlier they hotly defended. In this lies their
scientific temper, not in the scientific defense of the theory. - Weston La Barre (Ghost Dance, 1972)
Read the The ScienceMadness Guidelines!
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voidwalker
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any reason for why n-iodosuccinimide could not be used in the same manner on 2c-h freebase?
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Chainhit222
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why not do this shit
http://www.erowid.org/archive/rhodium/chemistry/nxs.html
The practice of storing bottles of milk or beer in laboratory refrigerators is to be strongly condemned encouraged
-Vogels Textbook of Practical Organic Chemistry
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Methyl.Magic
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You can make a solution of Br2 in DCM : Dissolve some bromide in water, add an acid and an oxidising agent such as BrO3- or H2O2. Extract the water
solution with DCM, then dry it. Pipette out x ml of the solution, add an excess or KI and titrate with know concentration of thiosulfate solution to
know how much Br2 x ml of the solution contains. As soon as you know the concentration of the solution you can use it on the key substrate.
2,5-dimethoxyphenehtylamine HCl has a strangely good solubility in Et2O and DCM. You can dissolve it into DCM and do the bromination on the
hydrochloride. It will avoid N- and o- bromination side reaction.
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kjar
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| Quote: Originally posted by Nicodem | | Quote: Originally posted by Klute | | I take it using Br2 and the HCl salt will be even more efficient because no haloamines can form, and the HCl salt precipitates when brominated..
|
I doubt you would get any precipitate of a pure hydrochloride from acetic acid. Most likely you would get a mixture of chloride/bromide salts.
Besides, it is wasteful to just filter the precipitate, because a lot of product surely remains dissolved in the reaction mixture. From what I read,
the hydrochloride is soluble in many organic solvents. It is well soluble in alcohols and relatively soluble in acetone and ethyl acetate.
If I would be given a project to optimize this halogenation I would most likely opt to perform the bromination of the substrate as the hydrochloride
in aqueous solution with NBS (or dibromohydantoin). Since the hydrobromide of the product has a low solubility in cold water it would crystallize out
(some HCl can be added to reduce the solubility), while the succinimide remains in solution. The product, crude
2-(4-bromo-2,5-dimethoxyphenyl)ethylamine hydrochloride, is then recrystallized from water. This would be quite a "green" method. Not a drop of an
organic solvents used and the succinimide side product can even be isolated. But this amine is for some strange reason listed as illegal to make and
posses where I live, so I think I will never get such a project. Instead I always only get some stupid contracts to optimize the synthesis of legal
drugs (I was told that these are more profitable). Xwinorb can consider himself lucky to live in a country where such a synthesis is not considered as
breaking the law (or so I hope for his own sake).
| Quote: | | I wonder why this technique isn't more discussed? Why go the the hassle of basifying, extracting the amine freebase, distilling the solvant, and
dissolving in acetic acid, when simply adding the HCl salt (commonly formed to purify the unbrominated amine) to GAA then dripping Br2 can be done?
|
Because that is the original procedure published in the scientific literature by Shulgin et al. As you might have noticed over the years, there is
very little initiative for innovations. Most people that are motivated for such a synthesis don't even have a basic grasp of theory. So how could they
ever develop anything new? Those that have a grasp of theory rather choose to make new and legal drugs. If you are intelligent enough to understand
theory then you are also intelligent enough to avoid unnecessarily breaking the law. |
Aqueous bromination of 2c-h yielded nothing under reflux immediately. After 24 hours dirty crystals were apparent. Not the best method.
2c-h hcl and NBS in DCM w/addition HCL form crystals immediately. Keep mixing, light heat. Chill. Filter. Wash with ice cold water.
[Edited on 13-4-2012 by kjar]
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