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Nicodem
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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.
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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).
…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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kjar
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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.
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Nicodem
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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.
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ctrade
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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?
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ctrade
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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]
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ctrade
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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.
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oblivionbubble
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What would happen if instead of HCl, product to be brominated in GAA, existed as an oxalate?
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