Sciencemadness Discussion Board - Aromatic bromination with NBS

Aromatic bromination with NBS

KidCurry - 4-8-2005 at 01:07

From an old post on The Hive:

Quote:

From a bottle that was labeled as "ricuarte's 2,4-dimethoxyphenylethylamine HCl" there was 5 gram (23 mmol) dissolved into 35 ml GAA.

To this mixture was added 4,9 gram (28 mmol) NBS which caused the solution to turn deeply red.

After covering the RBF with foil and placing a stopper on the flask the whole was stirred for 30 minutes. The precipated crystaline mass was filtered off and washed twice with ethyl acetate, another wash with H2O caused the solids to dissolve, the pH was adjusted to > 11 and the organic layer was extracted with 3x 30 ml EtO2, after removal of the solvents the residual oil was dissolved in 20 ml IPA and the solution was neutralized with dry HCl in IPA. The solids that formed where washed once with EtO2 and filtered to provide a crop of white crystals weighing 5,38 gram.

An attemp to recrystalize the solids from IPA/Toluene (10ml ipa:5ml Toluene / gram) did not dissolve all sollids, even the addition of more IPA caused the solution to stay turbid. After allowing the solution to slowly cool down to RT the whole was refrigerated overnight providing 4,86 gram of what is beleived 4-bromo-2,4-dimethoxyphenylethylamine HCl (71 %) with a mp of 235-237°C, a marquis reagent test gave a a dark green spot.

Tried out. Dissolved freebase (not salt) in GAA, added NBS and stirred for 30 minutes. Nothing, stirred for another hour, nothing. Stirred it overnight, nothing. So, is 30 minutes actually a typo for 30 hours? All other posts I've seen with NBS bromination mentions a reaction time of atleast 4-12 hours. What would be a wise approach now? Maybe apply some heat and wait atleast another 12 hours? If no solids appear do an A/B extraction?

transformer - 4-8-2005 at 06:25

What substrate did you use? 30 minutes was not a typo, if no solids apear try an a/b.

[Edited on 4-8-2005 by samsung]

KidCurry - 4-8-2005 at 06:40

2C-H, from Al/Hg reduction of 2,5-DMNS (not distilled). Unknowned amoumt, but was assumed to be about 5-6g. Dissolved in 50ml GAA.
Some isopropanol might have slipped in since I didn't want to burn the phenethylamine when stripping the IPA off.
I tried starting the reaction with heat, but still no solids. Did you recrystallise your NBS before use? I will have to wait to do an a/b for a few days, do you thinks it's ok?

[Edited on 4-8-2005 by KidCurry]

enima - 4-8-2005 at 08:48

distill/recrystallize your amine first, get a known amount before you brominate. You will have product of higher purity and will know the exact amount of bromine to use.

The yields on brominations are generally higher if the starting compound is of high purity.

KidCurry - 4-8-2005 at 08:51

Yes, I know but perfect yield was really not an issue here and I didn't have the possibility to A/B the amine or distill it at the moment so I just proceeded rather than waited. Dirty 2C-H have been known to brominate fine before so..
(But maybe I have to pay for my lazyness now

)

[Edited on 4-8-2005 by KidCurry]

KidCurry - 4-8-2005 at 10:43

Took out a few milliliters and evaporated in a small beaker. The question is if this is 2C-B.HBr and succinimide, just NBS or something completely else.

EDIT: The addition of some GAA dissolved almost all formed crystals, except maybe 1mg (really small amount) and since 2C-B.HBr is supposed to be insoluble in GAA:
1) Bromination failed.
2) Freebase of 2C-B was the product.

Why?
Hm.

[Edited on 4-8-2005 by KidCurry]

hmm.jpg - 136kB

KidCurry - 4-8-2005 at 11:16

More woes:
Added a few drops of water to see if everything dissolved, but instead I got this mess. What the hell has happened here?

goo.jpg - 109kB

enima - 4-8-2005 at 12:37

How pure was your nitroethene/nitrostyrene before the Al/Hg reduction. NBS brominations are fairly easy.

KidCurry - 4-8-2005 at 12:41

Well, it was pure (I think). Recrystallised from IPA. Long fine needles, coloured intensly orange. Should a NBS bromination in GAA form the hydrobromide salt? If not, the product might be in solution and an A/B workup is in order.

The result of the reduction can be seen here: http://www.sciencemadness.org/talk/viewthread.php?action=att...

This was what was dissolved in GAA, together with NBS.

There's basically three "errors" possible:
1) A few ml's of IPA still left from the reduction.
2) I calculated a 1.5 molar excess of NBS assuming the weight of nitrostyrene was 5-6g. Maybe it was too much?
3) NBS wasn't recrystallised before use (as someone advised in a post on The Hive). Yellowish powder.

Don't know how this will affect things. But if bromination took place, and the HBr salt was the product it COULD dissolve in the IPA left in the mix. BUT, it's a maximum of 10ml's and that would probably not dissolve more than a gram of 2C-B (?). So, where's the rest of it?

EDIT: Basified a small amount of the solution, and it resulted in a brown mixture with some not very cool blackish insolubles (same as seen in the last picture). In other words, I'm probably fucked.

[Edited on 4-8-2005 by KidCurry]

transformer - 4-8-2005 at 17:24

If the freebase or 2,5-dimethoxy acetate gets brominated at the 4th position at all instead of forming some n-bromo compound then chances are good that the 2c-b in the post reaction will contain a lot of different salts from which i guess the more GAA soluble 2c-b acetate is the most abundant.

Try to use the hydrochloride salt next time, im not sure exactly how soluble 2c-b acetate is in GAA but rumor says 2c-b hcl is pretty insoluble in RT GAA and don't skip on the a/b here, good luck!

Quote:

Originally posted by KidCurry
Well, it was pure (I think). Recrystallised from IPA. Long fine needles, coloured intensly orange. Should a NBS bromination in GAA form the hydrobromide salt? If not, the product might be in solution and an A/B workup is in order.

The result of the reduction can be seen here: http://www.sciencemadness.org/talk/viewthread.php?action=att...

This was what was dissolved in GAA, together with NBS.

There's basically three "errors" possible:
1) A few ml's of IPA still left from the reduction.
2) I calculated a 1.5 molar excess of NBS assuming the weight of nitrostyrene was 5-6g. Maybe it was too much?
3) NBS wasn't recrystallised before use (as someone advised in a post on The Hive). Yellowish powder.

Don't know how this will affect things. But if bromination took place, and the HBr salt was the product it COULD dissolve in the IPA left in the mix. BUT, it's a maximum of 10ml's and that would probably not dissolve more than a gram of 2C-B (?). So, where's the rest of it?

EDIT: Basified a small amount of the solution, and it resulted in a brown mixture with some not very cool blackish insolubles (same as seen in the last picture). In other words, I'm probably fucked.

[Edited on 4-8-2005 by KidCurry]

Sandmeyer - 5-8-2005 at 11:19

Bromine (Br2) is the brominating agent when you use NBS -- only in this case it is slowly formed in situ, unsing NBS hence pose no difference from 'oridnary' bromine bromination.

epck - 5-8-2005 at 11:52

As per normal I am slightly confused by the mechanism by which the reaction is proceding. According to my OChem book the rxn procedes through benzyl radical intermediate step and produces Br2 which, as Sandmeyer pointed out, does the actual bromination. However, in the mechanism in my book the akyl side chain is bromonated at the benzylic position. For example, propylbenzene->(1-bromopropyl)benzene.

So what causes the difference in bromine position? Does the presence of the methoxy groups stabilize the intermediate needed produce the 4-bromo? Is it because there is a ethylamine instead of a alkane? Does the GAA catalyze this reaction? I seem to remember reading about using perchloric acid to catalyze a similar reaction but I wouldn't think GAA would do this.

KidCurry - 5-8-2005 at 12:19

Sandmeyer: If that is the case, wouldn't the bromination in GAA result in the HBr-salt falling out as a solid?

Sandmeyer - 5-8-2005 at 13:42

Quote:

Originally posted by epck
As per normal I am slightly confused by the mechanism by which the reaction is proceding. According to my OChem book the rxn procedes through benzyl radical intermediate step and produces Br2 which, as Sandmeyer pointed out, does the actual bromination. However, in the mechanism in my book the akyl side chain is bromonated at the benzylic position. For example, propylbenzene->(1-bromopropyl)benzene.

Mechanism, picture from http://www.brynmawr.edu/Acads/Chem/mnerzsto/bettermechanism....

It simply works by providing small concentrations of Br2, small concentration of HBr is enough to protonate the amide and thereby get the reaction going, then every addition produce some HBr which liberate more Br2. HBr is also produced in the ring-bromination step.

[Edited on 6-8-2005 by Sandmeyer]

epck - 5-8-2005 at 13:51

That part of the mechanism was understood. Sorry I wasn't clearer on my question. The unclear bit was why the Br ended up on the benzene ring instead of on the number one carbon on the ethylamine as my OChem book indicated it should.

After some reading (which I should have done in the first place) I think it is the presence of the methoxy groups which directs the Br to the fourth position. Pretty sure, I think.

Sandmeyer -thank you very much.

KidCurry - 8-8-2005 at 06:18

Ok. Decided to do the A/B today.
Basification left a mess, and cleaning it up sucked. Extracted with 3x30ml xylene which was dried with KOH and then gassed with HCl. Became very happy when something started to fall out, became pretty sad when filtering and saw that the crystals were chocolaty brown(!). Washed with xylene but did not get rid of coloration. Drying now, which actually makes it turn into very tan brown/off-white. Who knows what it is, most probably not 2C-B tho.

KidCurry - 8-8-2005 at 06:19

Picture of product, while still wet:

prod.jpg - 57kB

Sandmeyer - 8-8-2005 at 07:04

will you try the product for activity?

I think NBS is a good bromination alternative to elemental bromine which at leat I can't purchase where I live :mad:

. I hope you get the reaction to work and report when fully done.

KidCurry - 8-8-2005 at 07:08

Maybe, depending on how it looks after complete drying and recrystallisation from IPA (but it's probably not more than 500-1000mg in there, so if it really is 2C-B the yield was crap).

I have no problems aquiring bromine, but I really like to avoid it if I can. Will try the bromination again when I find the time, but on the hydrochloride salt instead of the unpurified freebase.

[Edited on 8-8-2005 by KidCurry]

xwinorb - 9-8-2005 at 12:14

Hey Kid Curry :

SWIX has sucessfully made 2C-B. Interested in helping and learning more about bromination. What he did :

Purchased 100 g 2,5-DMBA.

Henry condensation with AmAc yielded 40 g nitrstyrene from 50 g 2,5-DMBA.

Zinc-HCl reduction yielded aprox 24 g 2C-H.HCl.

Distilled with short path to get 20 g 2C-H.HCl

Tried to brominate with ammonium bromide and H2O2 in AcOH. This one failed, SWIX thinks becasue the bromination is via BrOH, not Br2.

Next tried to purchase NBS, but was unable to.

Then tried Chromic bromination, with less water ( just enough to dissolve NaBr ) and dripped in all at once. Over freebase on AcOH ( did it once on the HCl salt, but looks dirtier and lower yielding, I suggest not to try it on the HCl salt but on the freebase ).

As soon as dripped in the Br2 solution, temperature went to 50 C, then slowly back to RT. Basified, with ice cooling, slowly. Noticed oily layer on top. Extracted with toluene. Dripped in HCl till xtals no longer forming. Added about 2X cool water, filtered ( don't wash filter, it clogs ).

Got enough 2C-B to distill it. Long, slow distillation, vacuum degrading a lot. Is it typical ?

The best part of this procedure is the reduction, easy, nice clean, got 65 % and 55 % yields. I guess only vitride will give more, IF you cook it well.

One question, how bad is to have all the Br2 all at once ? I tried to drip it in, but it forms solids and clogs the adition funnel.

enima - 9-8-2005 at 12:19

Nice, what proceedure did u use for the zn/hcl reduction?

becareful with that bromination if temps get to high you'll end up with more 6-bromo impurity.

HBr + H2O2 in gaa works pretty well.

Zinc reduction

xwinorb - 9-8-2005 at 12:51

To enima : SWIX used a modified Leminger reduction. Search the archived old Hive, easy to find. If you cannot find it I will PM you or post it. Hinted to him by Sunlight form the old Hive.

xwinorb - 9-8-2005 at 13:11

Forgot to say, never tried to brominate more than 5 g at once, usually did 3 g. Main reason, there is a lot of AcOH to basify.

Nicodem - 9-8-2005 at 14:04

Just wanted to correct a small confusion from the posts above.

Quote:

The question is if this is 2C-B.HBr and succinimide, just NBS or something completely else.

Should a NBS bromination in GAA form the hydrobromide salt?

When brominating with NBS you can not get the hydrobromide salt. If the reaction works at all you can only obtain the brominated 2C-H as the acetate which is probably soluble in acetic acid and succinamide. When using Br2 an equal amount of HBr also forms hence leading to the hydrobromide salt.
I would expect the use of 2C-H×HCl prevents the formation of N-bromo 2C-H side product which can oxidatively decompose. If the amine is protected by protonation with a stronger acid (than acetic, like HCl) this side reaction is less likely. When using Br2 the N-bromo compound does not form much, since for any consumed Br2, a HBr forms and this reacts with bromoamines to restore Br2 and the amine (it’s an equilibrium) until all the Br2 gets consumed by the ring bromination of the substrate. The more acidic environment brought by the hydrochloride salt also favors the electrophylic bromination.
Hence using the hydrochloride salt instead of the free base in the bromination with NBS is not only a matter of convenience but it is highly favorable.

KidCurry - 9-8-2005 at 14:38

Nicodem: But if NBS bromination works by liberating small amounts of Br2, why does not HBr form? And the formed preticipate that samsung got in his bromination, would it be the hydrochloride salt or succinimide? If it is the wanted product, is it just possible to filter it off, wash and recrystallise, or should an A/B extraction be done?

And thanks to everyone else for their input!
The bromination will be tried out again, on the HCl-salt, but it will take some time (all 2C-H went up in smoke).

[Edited on 9-8-2005 by KidCurry]

Brominating the HCl salt instead of freebase.

xwinorb - 9-8-2005 at 15:12

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.

KidCurry - 10-8-2005 at 00:13

xwinorb: But you didn't brominate with NBS, when using Br2 it's recommended to use the freebase.

Nicodem - 10-8-2005 at 09:50

Quote:

Nicodem: But if NBS bromination works by liberating small amounts of Br2, why does not HBr form?

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

KidCurry - 11-8-2005 at 00:37

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.

xwinorb - 11-8-2005 at 21:34

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.

Sandmeyer - 13-10-2005 at 13:19

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

gonzo - 30-3-2009 at 08:06

Your post has been removed on referral. Pending deletion.

[Edited on 31-3-2009 by Ramiel]

Ramiel - 30-3-2009 at 20:18

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

xwinorb - 3-1-2010 at 18:25

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.

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.

Nicodem - 4-1-2010 at 03:13

Quote:

Before that I had also one failure when trying to brominate the HCl salt in AcOH. The reaction did not started, nothing happened.

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).

xwinorb - 4-1-2010 at 21:43

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]

Klute - 5-1-2010 at 14:42

Does the N-bromoamines problem occur when using bromine?

DJF90 - 5-1-2010 at 15:14

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.

A bit more info

xwinorb - 5-1-2010 at 19:45

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.

Nicodem - 6-1-2010 at 00:21

Quote: Originally posted by Klute

Does the N-bromoamines problem occur when using bromine?

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.

Klute - 6-1-2010 at 03:18

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?

xwinorb - 6-1-2010 at 08:34

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.

DJF90 - 6-1-2010 at 11:36

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.

turd - 6-1-2010 at 13:37

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?

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]

xwinorb - 6-1-2010 at 17:59

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.

Nicodem - 7-1-2010 at 00:49

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:

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.

voidwalker - 14-9-2010 at 00:08

any reason for why n-iodosuccinimide could not be used in the same manner on 2c-h freebase?

Chainhit222 - 18-9-2010 at 15:38

why not do this shit
http://www.erowid.org/archive/rhodium/chemistry/nxs.html

Methyl.Magic - 27-9-2010 at 07:18

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.

kjar - 13-4-2012 at 14:01

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..

Quote:

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]

Nicodem - 14-4-2012 at 00:18

Quote: Originally posted by kjar

Aqueous bromination of 2c-h yielded nothing under reflux immediately. After 24 hours dirty crystals were apparent. Not the best method.

Do you mind posting the experimental so that we can discuss the issue with more specifics? How did you monitor the conversion?

Any crystals that precipitated under reflux conditions certainly could not be the 4-bromo-2,5-dimethoxyphenetylamine.HCl because this is well soluble in warm water (in fact, water or diluted aq. HCl is the solvent of choice for its recrystallization). Even at room temperature it can takes from minutes to hours for the crystallization to start (this is from pure water, so it should take longer with reagents leftovers). Reflux is also improper for such a reaction. The reaction should either proceed at room temperature or it would not proceed with satisfying selectivity at higher temperatures. Brominating such nucleophilic substrates at elevated temperatures is thus not a recommended solution to improve kinetics as you loose on selectivity. When bromoimides are used as the brominating reagents, the addition of an acid as a catalyst generally improves the reaction kinetics (for a hydrochloride as a substrate, as you apparently already were aware, HCl is best in order not to introduce foreign anions). This is all I can comment in general without you giving the experimental details.

There are a couple successful and good yielding aqueous brominations (dibrominations even!) of related substrates posted at the Hyperlab forum, so water is definitively a possible solvent, but it might not work for just any brominating reagent and will certainly not work equally well for just any substrate. In this regard, I don't remember seeing 2,5-dimethoxyphenetylamine.HCl among the examples there. However, examples of this substrate hydrochloride bromination in its acetic acid solutions are plentiful, either with bromine or NBS (there is a dedicated thread for this topic at the Hyperlab).

kjar - 14-4-2012 at 11:30

Yeah, I respect your wisdom and it should WORK right? But, no. Reflux was tried nothing happened. No reflux, nothing happened. Both were let set for 24 hours. Crystals did form, but they were minor and very dirty and the aqueos solution just remained black like the bromination never completed. Other brominations have always proceeded from an orange to clearish upon completion. In DCM it is stellar.

Weird, huh? Since I the water based crystals weren't tested for activity I have no if the reaction was completed, but since all the bromine remained in the solution it seemed I do not have high hopes for it's success. Thanks for the advice, it opened up new avenues of experimentation.

Nicodem - 14-4-2012 at 11:50

Is there any reasons on why you don't share the experimental? I mean, you don't even say what did not work and I would at least like to know what we talk about and what the conclusions are based upon.

ctrade - 22-3-2013 at 11:58

The original procedure has always worked fine for me with the hydrochloride salt of the amine. Almost immediate precipitation of crystalline mass. Antoncho posts what works.

What I am having a problem with is the use of N-Iodosuccinimide on the same substrate. Using the same procedure as Antonchos on first page except with an equivalent amount of NIS nothing has precipitated after an hour of stirring and solution is still extremely red.

I am also trying the same procedure with the substitution of 2-propanol and a small amount of HCL for the acetic acid. Solution is orange immediately after mixing in the NIS. I will update this post after stirring for an hour.

Anyone had success with NIS or NCS on this subtrate?

ctrade - 24-3-2013 at 11:13

5 grams (23mmol) of 2,4-dimethoxyphenylethylamine HCL was dissolved in 35ml GAA and 6.3g (28mmol) N-iodosuccinimide was added to the mixture which caused the solution to turn deeply red.

Watchglass was placed on top of beaker and stirred for 30 minutes. No precipitation and solution still deeply red.

Stirred overnight, still no precipitation and solution still deeply red.

Solution quenched with sodium metabisulfite and stirred for 30 minutes. Solution turns light yellow. Solution basified slowly with 40% aqueous NaOH, color of solution turns brownish/greenish.

Toluene is added and solution is stirred, nasty green emulsion is formed. Toluene seperated cleanly after a little stirring and waiting and is slightly yellow. Toluene is seperated and solution is extracted twice more with toluene. Organic phases have been pooled together and are light yellow.

2.5g of 2,4-dimethoxyphenylethylamine HCL was dissolved in 20ml IPA and 5ml HCL was added. 3.15g N-iodosuccinimide was added to the mixture and after a minute of stirring, solution turned from slight yellow to deep red.

Watchglass was placed on top of beaker and solution stirred for 30 minutes. No precipitation, solution still deep red.

Stirred overnight, still no precipitation and solution still deep red.

Solution quenched with sodium metabisulfite and stirred for 30 minutes. Solution turns light yellow. Solution basified slowly with 40% aqueous NaOH. Solution turns light brown and NaCl precipitates.

Toluene is added and solution is stirred. Toluene layer dissolved some IPA and takes on a slight green color. Toluene is washed with water and separated, water returned to original solution. Solution is extracted twice more and organic phases pooled. Toluene is colored light yellow.

This is where I'm at currently.

Workup will be washes with water followed by brine. Then IPA/HCl solution will be added to the toluene in hopes of precipitation. If this doesn't work I will pass dry HCl gas into the toluene instead.

EDIT: It looks like the expected product in salt form is quite insoluble in water. Maybe I will instead back extract with dilute HCl from the Toluene, neutralize, and chill to induce crystallization.

Any advice or personal experiences would be appreciated.

[Edited on 24-3-2013 by ctrade]

ctrade - 24-3-2013 at 13:03

I guess I will answer myself. N-iodosuccinimide will not work as stated in my previous post. In order for the iodination to occur electrophilic iodine I+ must be in solution, not I2.

Tomorrow I will dissolve my substrate and potassium iodide in aqueous alcohol and slowly drip in bleach. Stir for 30 minutes, quench with bisulfite, and acidify with dilute HCl. Product should precipitate followed by recrystallization from water. I'll post experimental when done.

oblivionbubble - 12-3-2023 at 15:31

What would happen if instead of HCl, product to be brominated in GAA, existed as an oxalate?