Author Topic: 2,5-DMA bromination issues  (Read 7367 times)

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  • Guest
2,5-DMA bromination issues
« on: April 10, 2004, 01:26:00 AM »


  • Guest
N-bromo-DOB troubles?
« Reply #1 on: April 10, 2004, 02:07:00 AM »
This was basified with sodium hydroxide, which made everything totally brown-black immeditaly??

It looks to me that you did not eliminate the excess bromine thoroughly enough. Bromine forms a bromoamine from DOB when NaOH is added (amines and bromine react very fast in basic medium). The bromoamines are usualy from orange to dark-brown-red colored. Not everything is lost though. Try to thorougly wash its DCM solution with aqueus sulphite or ascorbic acid. This should regenerate the amine (if it did not decompose already :( -probably not ;) ).


  • Guest
Perhaps an improved workup would be to wash a...
« Reply #2 on: April 10, 2004, 04:37:00 AM »
Perhaps an improved workup would be to wash a few times with DCM and then add some sulphite to neutralize the excess bromine? Then the mess can be basified and extracted?



  • Guest
Alternative cause
« Reply #3 on: April 10, 2004, 06:05:00 AM »
It seems a little strange that your DCM washes didn't remove the extra bromine from the aqueous solution, especially as the aqueous phase was only a very pale colour before basification. An observation I made when brominating 4-methoxypropiophenone to the corresponding bromoketone in GAA may provide an alternative explanation:

Bear in mind that the HBr liberated as the reaction proceeds is also an effective demethylating agent, especially in solvents such as GAA, in which the bromide ion is less well solvated than in water, and thus more nucleophilic. O-demethylation will leave you with phenol derivatives which are sensitive to base. The likelihood of this occuring seems to incease dramatically with temperature.

Any amphetamine with a ring hydroxy substituent will remain both O- and N-protonated under acidic conditions and stay in the aqueous layer, and will not be extracted by the DCM. However as soon as you add a strong base such as sodium hydroxide you'll deprotonate the phenol (and the nitrogen of course), leaving you with a black mess of 'freebase' which is likely to be soluble in water.

This phenomenon has been noticed several times when working up Friedel-Crafts acylations of aryl ethers, and gave a good guide to the expected outcome of the reaction. Using the standard AlCl3/acid chloride in DCM at ~0-10oC, the base washing during workup of a benzodioxole acylation gave a hideous black mess from which no product was obtained; with a 4-bromo-2,5-dimethoxybenzene acylation only the initial base washes turned brown/black; with benzene, toluene, and indane acylation workups however, there was essentially no discolouration during base washes.

Shulgin uses something similar this to his advantage to make tweetios; taken from the synthesis of



These [aqueous NaOH] washes, after combination and acidification, were extracted with 3x75mL CH2Cl2 and the extracts washed once with saturated NaHCO3. Removal of the solvent under vacuum provided 28.3g of 2-hydroxy-5-methoxyacetophenone as yellow crystals which, on recrystallization from 2 volumes of boiling MeOH and air drying, provided 21.3g of product with a mp of 49-49.5°C. Ethylation of this material serves as the starting point for the synthesis of 2CE-5ETO.

For a little more information on the suspected HBr demethylation, see the second paragraph of

Post 439058

(Kinetic: "Carbonates and things", Chemistry Discourse).

What temperature did you run the reaction at? If this does turn out to be the problem, running the reaction at a lower temperature should help in future.


  • Guest
« Reply #4 on: April 10, 2004, 03:40:00 PM »
Add some dithionite first (after pouring the GAA out over ice) this will remove the bromine. NaOH and bromine turns' into hyboromite. And there is no reason to use more than 1,1 mol bromine, I'm sure that it's the bromine who is the troublemaker.


  • Guest
J. Med. Chem.17, 1100-1111 (1974)
« Reply #5 on: May 05, 2004, 10:19:00 PM »
From the VERY interesting article:

Structure-Activity Relationships in Psychotomimetic Phenylalkylamines
F. A. B. Aldous, B. C. Barrass, K. Brewster, D. A. Buxton, D. M. Green, R. M. Pinder, P. Rich, M. Skeels, and K. J. Tutt

J. Med. Chem., 1974, Vol. 17, pp. 1100-1111 (1974)


A study has been made of the relationship between the structure of phenylalkylamines and potential correlates of their psychotomimetic activity. Optimum activity is associated with (a) an isopropylamine side chain, with a R-(-) configuration at the carbon atom a to the amino group, and (b) 2,5-dimethoxy substitution, together with an alkyl or halo group at position 4 that is probably limited in bulk to n-propyl or bromo. The activity of compounds in producing hyperthermia in rabbits provides good quantitative correlation with reported psychotomimetic activities in man.

(You'll like this one if you don't already have it - includes some new active substituted 2-phenylcyclopropylamines like DMCPA in pihkal)

Also more importantly, this article shows us a bunch of stuff that would be inactive - so we don't waste time on them. For instance 1-phenyl-3-aminobutanes, and 2,5-dimethoxy-4-methylphenyl-[CH(Me)CH2NH2, C(Me2)CH2NH2, CH(Me)CH(Me)NH2, CH2CH(Me)NHMe, CH2CH(Me)NHEt]. Yes, they are ALL inactive.

Okay, back to the DOB bromination. Bandil, maybe you should pretend to try this...

4-Bromo-2,5-dimethoxyphenylisopropylamine Hydrobromide
To a solution of 2,5-dimethoxyamphetamine (1.5 g) in glacial AcOH (7.5 ml) was added a 50% solution of HBr in glacial AcOH (1.25 g), and to this mixture at 0-5C was added a solution of Br2 (1.23 g) in glacial AcOH (10 ml). The reaction mixture was stirred for 3 hr at room temperature and concentrated in vacuo, and the residue was recrystallized from EtOAc. mp 145-146C, Yield: 70%.

Or if you want DOC...

4-Chloro-2,5-dimethoxyphenylisopropylamine Hydrochloride
Dry HCl was passed into a solution of 2,5-dimethoxyamphetamine (2.64 g) in glacial AcOH (15 ml) until 0.4 g had been absorbed. To this stirred solution at 0-5C was added a solution of Cl2 (0.9 g) in glacial AcOH (15 ml), the whole mixture was stirred at room temperature for 5 hr. Concentration in vacuo, and recrystallization from EtOAc gave impure product, which was purified by further recrystallization from 2-propanol-Et2O. mp 187-188C, recrystallized from Acetone/EtOH, Yield: 50%.

The DOC made from the above reaction and used in the evaluations was nearly identical in potency to DOB. Both being active in the 0.062 mg/kg range, with DOC being metabolized faster than DOB. So if you're worried about polychlorination effecting potency, don't, because the resulting compound is just as active.


  • Guest
DOC, et. al.
« Reply #6 on: May 05, 2004, 10:31:00 PM »
That article has been posted in

Post 459981

(Rhodium: "Synthesis of DOM optical isomers", Methods Discourse)

Read this article regarding impurities in DOC synthesized via liquid chlorine: