Bromination of Safrole
Reagents
100 mmol (16.21g) safrole
210 mmol (21.58g) NaBr
190 mmol (19.00g/10.33mL 98% conc.) H2SO4
40mL (38.43g) GAA (solvent)

Procedure
The reaction flask was charged with H2SO4 (190mmol) and chilled to 0C.  The GAA was added as such as rate that the temperature was kept below 5C.  The NaBr was then added portion-wise over five minutes.  The flask took on a tangerine orange appearance.  Once the addition was complete (exothermic), the safrole was added at a rate which maintained the previous temperature.  After the addition a brown/green color was noted, along with a thin deposit of what was assumed to be NaBr on the sides of the flask. Noxious fumes were evolved, the author would suggest sniffing them to get high.  The flask was left to stir on an ice bath for 24 hours.

Note: the safrole was not purifed or distilled from the sassafras oil.  According to the original author the phenolic compounds in the oil help to quench free radical side reactions. The oil known to be 89% safrole.


3 hrs - the flask has progressed to a black/purple color

I look forward on both of your experiments!

Bromosafrole workup
The solution was removed from the freezer, where it had frozen (shocking).  Upon warming two layers were noticed: an upper layer which was lighter and a dark purple almost black lower layer.  Due to stirring, the salts on the bottom of the flask had taken on a purple shade as well.  The solution was decanted into a sep funnel and 2x volume of water was added.  The organic layer was drained and set aside.  The aqueous layer was then extracted twice with dichloromethane.
After extraction the organic layers had a green/gray color.

The combined extracts were then washed once with water (the water took on a vinegar-like odor), once with sodium bicarb (there was very little evolution of CO2), and once with brine.  After the workup, the product had a considerable green character, though not brown as noted by the original author.  The solvent was removed under reduced pressure and the the product stored.  TLC forthcoming.

Note: A more extensive work up was suggested by jon, but due to time constraints it was not used.  Another reaction will be tested using his workup shortly.

I guess its hard to convey sarcasm over the internet.  The astute observer would notice that I added H2SO4 and brought it to 0C THEN added AcOH (instead of adding AcOh -> 0C -> H2SO4) because this way colligative effects will prevent the solution from freezing in an icebath.

that's funny i  never had a problem getting it to separate.

yes sniffing those fumes do get you high.
 a very high hospital bill on a respirator very expensive

I can't remember where but I recall seing something say if you saw orange you had Br2 - i'm not 100% positive on that, but I remember thinking I'd add the sulfuric more slowly next time. 

I also found this old thread at the hive where Rhodium explains a method for removing the Br2.

 

Re: OTC MDMA is now easy and cheap!!   Bookmark  Reply     

Acidify a concentrated NaBr (or KBr) solution with H2SO4, thereby getting aqueous HBr. Add H2O2 of any available concentration to oxidize the Hbr to Br2. You now have a dark red solution consisting of many things, but only the bromine is soluble in organic solvents like DCM, so just extract it from the aqueous phase.

It is a byzantine route to dry HBr you propose, but it is indeed creative.

Salat

Yay for butterfingers.  Dropped and shattered one of the flasks (Reaction #1).  Interestingly though Rxn #2 has darkened significantly.  It had been kept at RT, but when this was noticed the flask was flushed with argon and is now sitting in a fridge.  TLC should be done tomorrow, will be taken against safrole for comparison.

HBr is clear or slightly yellow if there's a little Br present. The redder it is the more free Br there is.

in  the case of allybenzenes 14 hours yeilded 70% conversion and it maxed out to 93% at 24 hours so somewhere between those timeframes is the (mol/unit time) curve.
if all your trying to do is be antagonistic i see no purpose in discussing this further

good to know this is an exothermic reaction though, in the future i will know that cooling will accelerate things.

in  the case of allybenzenes 14 hours yeilded 70% conversion and it maxed out to 93% at 24 hours so somewhere between those timeframes is the (mol/unit time) curve.
if all your trying to do is be antagonistic i see no purpose in discussing this further

good to know this is an exothermic reaction though, in the future i will know that cooling will accelerate things.

Honestly, I wasn't trying to be antagonistic. I thought you had a research paper with the hydrohalogenation reaction kinetics of safrole + HBr.

WizardX: you're confusing reaction kinetics (which is based on activation energy) with reaction thermodynamics (which is based on the change in gibbs free energy).

Sedit: that's a pretty interesting claim, can you provide any references?
dG = dH - TdS  Increasing the temperature of a reaction significantly can increase the T/\S term to the point that the forward reaction is no longer spontaneous.  Just because a reaction is exothermic does not always necessarily make it spontaneous.

And the rate of the reaction is determined by the magnitude of the activation energy, not the overall change in energy.  The overall change in energy determines the equilibrium.  The data you provided was the over all change in energy, not the AE

Certainly true, the reaction is dependent upon a number of factors.  But the arrhenius equation tells us that there is a relationship between the rate constant and the activation energy:

It also suggests a logarithmic relationship between the reaction rate constant and the temperature.

Activation energy can be thought of as the height of the potential barrier (sometimes called the energy barrier) separating two minima of potential energy (of the reactants and products of a reaction). For a chemical reaction to proceed at a reasonable rate, there should exist an appreciable number of molecules with energy equal to or greater than the activation energy.

http://en.wikipedia.org/wiki/Activation_energy

minima of potential energy (of the reactants and products of a reaction)

---

The rate of a reaction depends on the temperature at which it is run. As the temperature increases, the molecules move faster and therefore collide more frequently. The molecules also carry more kinetic energy. Thus, the proportion of collisions that can overcome the activation energy for the reaction increases with temperature.

http://chemed.chem.purdue.edu/genchem/topicreview/bp/ch22/activate.html

---

The hydrohalogenation reaction of safrole + HBr reactants at 0-1 oC react slowly over a period of 24 hours. At this 0-1 oC temperature, the activation energy is enough to break the bonds of the reactants, BUT the rate of the reaction is slow, requiring approx 24 hours for the hydrohalogenation reaction to complete 90%+ conversion.

At 0-1 oC temperature, the activation energy required for the cleaverage of the methylenedioxy ring with HX (X = Br or I) is inadequate, or negligible, thus the reaction rate is zero, or ultra slow.

The only relationship I've seen in the lab or read about in my gen chem book was the one mentioned by jon.  As I pointed out, the Arrhenius equation dictates a logarithmic relationship between temp and reaction rate.  I distinctly remember gen chem two lab where we graphed k against time and the relationship definitely was not a doubling in the reaction rate for a 50% inc in temp.

dG = dH - TdS 


can you define the equation i remeber this vaugely from chem 1
delta gibb's free energy = delta enthalpy - (what is T and d?) i know S is entropy

T and S aren't terms in this equation btw

wizard you are dead on about the rate of hydrohalogenation being 24 hours.

That is one of the fundamental thermodynamic relations.  The d(variable) is the differential change in that property.  Use of this equation and related equations is really Thermo 2 information, which is based on highly idealized situations.  In real life the complexity of these organic reactions are based on a lot of other things.  Based on reactor geometry and type, reaction kinetics and such. 

that relationship, and the other related ones, are some of the most fundamental building blocks of understanding thermo.

Reasearch Thermodynamic Web if you're more curious.

Actual high level organic chemistry like this cannot be explained with such basic thermo
relations.

EDIT:mostly used for multi component vapor liquid equilibrium, and very interesting stuff.

Looking forward to the results!

Found these writeups laying around, seems to have a nice level of detail to them.  The stuff about lighting in the Finkelstein writeup probably applies to the Bromination too.

Bromination with HBr in GAA

RATIOS

2:1 NaBr/KBr to oil
0.5:1 H2SO4 (actually, just a hair less than equimolar)
?:1 GAA (see METHOD for determination)

METHOD

To determine how much GAA is needed, you must first compute the mass of HBr required based on the 2:1 molar ratio.  The mass of GAA is equal to the mass of HBr for a 50% concentration.  Remember to account for GAA’s density when determining volume.

Charge a flask with a stir bar, the GAA, and with vigorous stirring add the bromide in doses.    This is to prevent overloading/stalling the stirbar, which is a real pain to restart.  A pan or other container needs to be placed on the stirrer, under the flask, so a water/ice mix may conveniently be added without disturbing the stirring.

When all the bromide has been added, fill the pan under the flask with a water/ice mixture, and give the contents some time to begin cooling.  Take care not to OVER-COOL or the GAA will freeze!

Now add the sulfuric, being mindful that unless the flask is stoppered in some way, HBr gas will fume off vigorously.  Do this addition SLOWLY (like drop-wise) so the generated HBr has time to dissolve in the GAA.  The cooling helps reduce gas loss, so add the sulfuric in a measured way to keep the temp (and fumes) down.

When all has been combined and the solution has cooled about as much as it’s going to, firmly stopper the flask (tape the stopper in to be certain!), wrap in Al foil or otherwise place in a light-tight container.  Place the entirety into the fridge for a day or so.

WORK-UP

While the flask contents are still cold (like RIGHT AFTER you get it out of the fridge!), carefully decant the acid layer from the solids (salts).  Add only enough water to the salts in the flask to fully dissolve them, then extract once using a chlorinated solvent.  Discard the dissolved salt solution. 

The trick is to add EXACTLY enough water to solvate the salts… this minimizes the amount of water that dissolves in the solvent and saves a wash step.

Add one to two volumes of water (the colder, the better) to the acid you decanted at the beginning.  This will crash the bromo out of solution.  Add the chlorinated solvent used to extract the salts (above) to the water layer you just created to extract any bromo that might have been left behind.  Drain off the non-polar and add it to the bromo that fell out.  Extract the aqueous solution once more, but use about half as much solvent.  Add separated extract to the bromo.

To the now isolated bromo, add an equal volume of water and neutralize using bicarb.  You’re done when the bicarb no longer fizzes when added.  Separate the bottom (non-polar) layer and discard the top (aqueous) one.  Wash the non-polar layer with water and then with brine. 

Finally, distill off the solvent AT THE LOWEST PRACTICAL TEMPERATURE.  Temps much above ambient can adversely affect the bromo, so a vacuum is mandatory.

---

Finkelstein Conversion of Bromosafrole to Iodosafrole

RATIOS

1:1.1 Br to KI
n/a    Acetone (anh) – sufficient to ensure good mixing during stirring

METHOD

First, ELIMINATE all sources of UV or really bright lights (like flourescents, halogens, sunlight) before you expose the bromo. 

Weigh out the KI so it’s just a bit more than equimolar with the bromo compound you’re processing.  My suggestion is a 10% excess.  Since KI is hygroscopic and this reaction doesn’t like water, dry the KI as much as possible.  This will also skew the weight, so dehydrate before weighing. 

Place the bromo and a stir-bar in a suitably sized flask (RB recommended), add a bit of acetone and begin stirring.  Adjust stirring so the bromo is well agitated; add acetone if needed.

Now add the iodide, in small portions, being careful not to stall the stir bar.  Add acetone and/or adjust the stirring to maintain through agitation.  Leave it to stir vigorously for 30 minutes to an hour in a water/ice bath to keep it cool.

When the time is up, remove the acetone being ESPECIALLY careful to not heat the (now) iodo much above R.T.  Iodo is very easily decomposed by heat and energetic photons (like UV).

WORK-UP

At this point, you should have your iodo in the flask mixed with (what is now mostly) potassium bromide.  Isolate the iodo with an anhydrous solvent in which neither the bromide nor the iodide salts are soluble (but the iodo compound is).  BTW, the salts ARE soluble in acetone, which is why we had to get it out of the mix.  IPA would be a good choice, especially if you’re going to aminate your iodo next.

---

Noticed the discussion of time for prep of bromo and this evening I came across this bit from Weygand and Hilgetag (1972 ed).

In laboratory practice addition of HBr is usually effected in glacial acetic
acid at 0-15°, or HBr is led into the undiluted olefin or a solution thereof in
CHCI3 at about —20°. Volatile olefins are left for several days in a bomb-tube,
higher-boiling ones for about 24 h in normal apparatus.

So it may be that you need to leave it in a pipe bomb if it is one of the lower boiling point oils, but 24 hours is plenty for safrole IMLE.

Because the hydrogen adds to the double bond and the more stable secondary carbocation forms, nucleophilic bromide ion then bonds to it.... You should pick up an organic chem book, will answer all these basic questions for you. Displacement reaction? It's an addition reaction, just read an OC book.

Are you going to be giving this a try, if so good luck. Those molar ratios seem about right. Im not sure where you got the 2.2 ratio of oil to KI. The KI is used to substitute the bromine for an iodine in bromosafrole. Thhe Finkelstein reaction requires just a slight molar excess of NaI. Use a 1:1.1 molar ratio of bromosafrole to NaI dissolved in dry acetone. Stir it for an hour or two and you should have almost quantitative conversion.

Check out salats writeup on the previous page. She has it laid out nice and clear. How do you plan on aminating the iodosafrole? I haven't tested it but I think there might be easier ways than drying to gas methylamine into dry IPA.

I don't see any reason why it wouldn't work to dissolve dry Methylamine.HCl in anhydrous IPA. Triethylamine, a nonnucleophilic base can then be added to the ice cold IPA to deprotonate methylamine, forming an dry, concentrated, solution of methylamine freebase in IPA?

I'm not sure if the methylamine will stay in solution once it is freebased, but I imagine it would as long as the alcohol is kept cold. Its something to test out anyways if you have those chems available. Good luck.

Edit:
Just found something similar discussed on the rhodium archive

Treatment of carbonyl compds with methylamine hydrochloride, NEt3 and Ti(IV) isopropoxide, followed by in situ Na borohydride redn. and straightforward aq. work-up, affords clean products in good to excellent yields. An equimolar mixture of methylamine hydrochloride and triethylamine is used as the mathylamine equivalent. This alleviates the use of excess gaseous methylamine.

A mixture of methylamine hydrochloride and triethylamine has been employed as the source of nucleophilic methylamine. The method conveniently avoids the use of gaseous methylamine, however, the overall reaction was slow.
https://www.erowid.org/archive/rhodium/chemistry/redamin.titanium.html

A source of nucleophilic methylamine which avoids the inconvenience of gaseous methylamine is exactly what we want.

Edit 2:
It appears that mephedrone is commercial synthesised from the 2-bromo starting material. Below is a writeup from the literature of the amination being carried out with MeNH2.HCl and Et3NH3 in DCM. The yields are are around 70% from the hydrobromide salt in this case. I don't see any reason why iodosafrole would not result in a greater yield. Also the author doesn't use an excess of methylamine which would help improve yield.

The title compound was prepared using the method reported by Camilleri et al. [9] with the following modifications: to a suspension of (±)-4 -methyl-2-bromopropiophenone (4.54 g, 20 mmol) and methylamine hydrochloride (1.35 g, 20 mmol) in dichloromethane (40 mL) was added triethylamine (5.58 mL, 40 mmol). The mixture was stirred at room temperature overnight and then acidified (pH ? 1) with 6 M hydrochloric acid (50 mL). The aqueous layer was washed with dichloromethane (3 × 50 mL), basified (pH ? 10) with 5 M sodium hydroxide (circa. 100 mL) and then re-extracted with dichloromethane (3 × 50 mL). The combined organic fractions were dried (MgSO4 ) and concentrated in vacuo to give a viscous yellow oil. The oil was dissolved in isopropanol (4 mL), treated with hydrochloric acid (3 M solution in butanol, 10 mL) and stirred at room temperature for 1 h. The mixture was diluted with diethyl ether (150 mL) and stirred to reveal
a pale yellow solid (circa. 30 min). The crude product was filtered, washed with diethyl ether and recrystallised from acetone to give (±)-4 -methylmethcathinone hydrochloride (1.09 g, 51.2%
from 2) as a colourless powder.

Synthesis, full chemical characterisation and development of validated methods for the quantification of (+/-)-4 '-methylmethcathinone (mephedrone) : a new "legal high".
Santali, Eman Y. ; Cadogan, Anna-Karina ; Daeid, Niamh Nic ; Savage, Kathleen A. ; Sutcliffe, Oliver B..
Journal of Pharmaceutical and Biomedical Analysis, Vol. 56, No. 2, 10.09.2011, p. 246-255.
DOI: 10.1016/j.jpba.2011.05.022

Thank you Polonium!

I am just curious. The lack of satisfactory writeups makes me reluctant to give it a try. I have very limited resources and only a little knowledge so who knows

The amination would be with NH3 (NH4Cl + NaOH + trap) gassed in dry IPA(tone/dry ice bath).

Hi lugh,

I already know these threads and others scattered around the net.
Where I said "satisfactory writeups" I should have said "happy ending writeups". I regret the lack of precision in my writings generated by my linguistic deficiencies.

In other words, I have not found examples where newbies like me end up getting what they want.

Anyway thanks for reply and info.

HI all!!!!
The last night i was dreaming about "the Jon method".
6 gr of oil was bad brominated, then the finkelstein swap was made and finally the iodo compound was aminated under Delepine.
The yield was so bad, but for the first time I product!!! 
.................................
The end results from the effort applied

Damned i just lost the full reply when automatically getting logged out!

In other words, I have not found examples where newbies like me end up getting what they want.

Anyway thanks for reply and info.

It is because they usually dont when they need to be spoon fed 
I have not said you do, but you have to become more than just a newbee to actually have success, that involves you could answer some questions after looking for them yourself, and this is the effort that it takes to achieve what you want.

Bright star's writeup gives you a good idea of the level of effort it takes to achieve what you want.

Totally agreed

I have read everything i could get my hands on, nobody to ask, no one to talk about, and useing actual organic chemistry books borrowed from the library, and rhodiums archive too to get a look into both sides of praticing chemistry.
It could have made me able to compare what is bullshit and what is not, to success when i dreamed for the very first unbelievable time after nearly a year of theory (but i like the theoretic part as well and you should too).
Eventually, when i had a two year enduring training as a chemisty laboratory assistant a few years ago I possibly was able to do everything for the pratical part at the start of it because i have learned and teached it myself, that made me to realise how far I really got into it.
Actually I think to have such a forum behind his back would have made it a lot harder to start successful 

But back on topic:
The delepine reaction suffers from steric hinderance? But this contributes to the large molecule that hexamine is, I guess? Because delepine-alike reactions with an amine do not as you said so this is probably the case.

Polonium: Wouldnt water/heat be created in reacting triethylamine with methylamine.hcl`? Then i guess this route wouldnt be viable.

HOw would one go about that reaction?

Cold IPA-->Methylamine.hcl--->Triethylamine ( in situ freebase Meam) ?

Best practical Sn2 writeup I've seen

thank you!

My only concern would be the KCl byproduct...

Sorry methanol is absolut non-otc to get here but if concentrated ethanolic lye is used in a good ice-bath and slow addition this one is covered;D
anyway, i prefer to use pre-dried denatured ethanol with maybe 1% H2O left, which dissolves like ~3,5 mol NaOH in a liter,thats like 150gram or such, maybe an option if its more easily avaible? Ethanol has to be warmed a bit to get the NaOH to dissolve complete. I usually would saturate it simply, warm up to get it in, and then cool it under 20°C, let stand one day undisturbed where it is around 20°Celsius, and then simply decant from everything thats left if there was anything.
just remember if you use it saturated that a few milliliter of this saturated ethanolic lye can free some few liter methylamine-gas from dried salt if spilled around.
Always remember the stronger caustic material is added to the lesser, not otherwise round if one has to do so, to avoid it from reacting violent
 
And the sulfate/carbonate mixture (2 part sulfate, 1 carbonate) is only useful for the alcoholic freebase solution, as it helps drying especially for alkaline material. was from both anhydrous salt mixed just because i thought i wont hurt anyway so why not then?

i just guessed that triethylamine is a less strong base (pkB=3,25), but it actually just a tiny bit stronger than methylamine with a pkB=3,38, so my assumption was wrong and this would indeed work.
sorry for that mistake

While triethylamine is commonly employed in organic synthesis as a base, and other applications, I would NOT consider it as a reagent to freebase methylamine.HCl

The cost, compared to NaOH or KOH and, the hazard (Explosive limits, exposure) isn't justified.

Its not about cost its about being able to free the methylamine without the creation of H₂O.

I recall a thread in the hive archives where Rhodium advocated the triethylamine method.  The way Rhodium spoke about it sounded to me like an Aspie who has solved a problem and as a result is no longer interested in any other methods.

I did a quick search but can't find the thread right this moment and can't spend any more time on it.  I'm knee deep in packing lab glassware in hopes of finally moving.  Perhaps someone else knows the thread.

Quote from: Wizard X on June 25, 2012, 12:55:38 AM

While triethylamine is commonly employed in organic synthesis as a base, and other applications, I would NOT consider it as a reagent to freebase methylamine.HCl

The cost, compared to NaOH or KOH and, the hazard (Explosive limits, exposure) isn't justified.

Its not about cost its about being able to free the methylamine without the creation of H₂O.

Please read and understand Dissolution (chemistry). http://en.wikipedia.org/wiki/Dissolution_(chemistry)

ipa is definitely the secret here

ok thx for the info it was new to me. but my opinion wont change, better make some cool nitroalcohol with it for norephedrine production

Salat

What specifically prevents one from using KI, GAA, & H2SO4 as reagents with Safrole to arrive at Iodosafrole. Why the extra step?
It is commonly known that one can arrive at Iodosafrole using NaI, and it would seem that the Iodide is all we're concerned with.