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All 24 posts Subject: Bromination difficulties Please login to post Down

Barium
(Hive Addict)
05-23-03 10:10
No 434934
      Bromination difficulties

When brominating eg. propiophenone with elementar bromine in DCM the reaction proceeds smoothly and rapidly with close to quantitative yields. When bromine is generated in situ using either a two-phase system of oxone/NaBr/DCM/water or H₂O₂/H₂SO₄/NaBr/DCM/water (with propiophenone present in the DCM phase) the reaction refuses to take place despite a reaction time of 20 hours at room temp.

Does someone have a explanation or theory why? frown

Sure it is no big problem handling and working with 500g free bromine but it would be much less of a hassle if it could be generated and used in situ.

Freaky

GC_MS
(Hive Addict)
05-23-03 11:27
No 434945
User Picture       DCM

You might want to use GAA as solvent. You can also try SPB instead of oxone. At least, it has proven to work in my lab (but not in a designer drug synthesis tongue ).

The faster you run, the quicker you die.

Barium
(Hive Addict)
05-27-03 09:03
No 435829
      No answer?

Doesen't anybody in the whole hive have a theory why it doesn't work? Not even a mod? shocked

Edit

The reaction doesn't work with GAA/NaBr/H₂SO₄/DCM/H₂O₂ either, but as soon as bromine is generated separately from NaBr/H₂SO₄/DCM/H₂O₂ and the DCM/Br₂ is added to GAA/propiophenone it runs smoothly. WHY?!

Freaky

Barium
(Hive Addict)
05-27-03 09:48
No 435834
      Never mind

I found the answer myself and it was actually quite simple crazy

Freaky

Bandil
(Hive Bee)
05-27-03 10:19
No 435836
      what was the answer then?

Please share your findings Barium :) What went wrong?

Cops are not there to help you, they're there to bust you.

Barium
(Hive Addict)
05-27-03 11:56
No 435853
      Water

Water fuck things up here. It can be tolerated to a certain point, but above about 30-40% water in the reaction mixture the reaction dies. What really puzzles me is that the two-phase systems doesn't work. mad

Freaky

Aurelius
(Hive Addict)
05-27-03 18:23
No 435903
      Barium

What's the pH of the mix with 30-40% water? just curious.

lugh
(Moderator)
05-28-03 01:16
No 435962
      Pressure Bromination Method

This improvised apparatus may bee helpful smile

The apparatus illustrated was used for brominating an organic compound, under pressure. At first an ordinary pressure-flask was used, equipped with a porcelain stopper and rubber gasket, as in a citrate of magnesia bottle. But it was suspected that the rubber gasket was being attacked by the bromine. to a pressure-bottle was desired in which nothing but glass would be exposed so the action of the hot bromine and reaction-mixture.
In the sectional view in Figure 1. A is a two-piece cylindrical aluminum box, shown in perspective in Figure 3, and originally intended as a shipping container for the wide-mouthed glass-stoppered bacteriological sample-bottle within. B and B are two wads of cotton. C is a Piece of muslin tied over the stopper and neck of the bottle with the string D (as shown in Figure 2). E is the reaction mixture. When the two halves of the box are screwed together, the wads of cotton are compressed and hold the stopper firmly in the bottle. A long string is then tied around the box, allowing it to be lowered into the steam-bath and to be removed when the desired length of time has elapsed.
The piece of cloth tied over the top of the bottle prevents the falling out of the stopper in case the box is inadvertently opened in an inverted position.

Chemistry is our Covalent Bond

Barium
(Hive Addict)
06-09-03 10:06
No 438810
      Smooth in situ bromination
(Rated as: excellent)

Example 1.

Arrange a gas generator and gas GAA with HBr to make a 40% solution. Dissolve 100 mmol propiophenone in some GAA and add 100 mmol HBr as the 40% HBr/GAA. With good stirring, add 100 mmol 30% H₂O₂ dropwise while keeping the temperature between 15 and 25°C. This gives a 90-97% yield of alpha-bromopropiophenone, which is as good yield as with a regular bromination.

But why not make use of the generated HBr formed in a regular bromination.

Example 2.

To 200 mmol propiophenone in 20 ml GAA add 100 mmol Br₂ dissolved in 20 ml GAA dropwise (use a pressure equalized addition funnel) with cooling to keep the temperature between 15-25°C. When all bromine has been added start adding 100 mmol H₂O₂ as a 30% solution while keeping the temperature in the same range.

The latter method makes use of all formed HBr by converting it to Br₂ again. Thus no bromine is wasted.

Freaky

Barium
(Hive Addict)
06-09-03 10:21
No 438813
      Amination quiz

I don't want to start a new thread for this so I carry on here instead.

When aminating e.g. alpha-bromopropiophenone with dimethylamine to N,N-dimethylcathinone all the methods I've found use slightly more than two moles amine/mol bromopropiophenone. One mol amine is used as acid scavenger and one mol amine replaces the bromine. But why don't use one mol NaHCO₃ as acid scavenger instead? I have UTFSE and searched all the patents I could find but no luck. To use a bicarbonate seems so obvious, but have I missed something even more obvious here?

Edit

Ok, of course the bicarbonate is too weak to liberate the amine from the amine hydrobromide also formed. K₂CO₃ should do the job though, but is it likely to hurt the bromopropiophenone? I was thinking along the line of adding bromopropiophenone to the amine dissolved toluene in the precense of saturated aqueous K₂CO₃.

Freaky

Aurelius
(Hive Addict)
06-09-03 13:24
No 438840
      Carbonates

you'll end up with some carbonate salts (just something to be aware of- not that it makes a huge difference)

Barium
(Hive Addict)
06-09-03 14:06
No 438845
      No carbonates

No carbonates will survive since the reaction between the bromoketone and amine produces HBr, and the post-reaction workup includes acidification with hydrochloric acid to separate the product from any remaining bromoketone.

Freaky

Aurelius
(Hive Addict)
06-09-03 22:39
No 438919
      Duh

I missed that very obvious item.

Act quickly or not at all.

Kinetic
(Hive Bee)
06-10-03 13:32
No 439058
      Carbonates and things
(Rated as: good idea!)

Since I feel slightly guilty for not trying to help out on your original question (for what my opinion is worth...), I'll try this one.

Firstly, congratualtions on the second in-situ bromination method, what an excellent idea! Just make sure to use enough GAA to dissolve the liberated HBr (I notice sometimes that some sneaks out towards the end). Also, when doing the bromination on ring-methoxy propiophenones, I tend to keep the temperature at 0^oC rather than 15-25^oC; when brominating 4-methoxypropiophenone without cooling, the solution turned black and the yield was lower than usual. I think this is because the liberated bromide ion is poorly solvated in GAA, making it a better nucleophile and more likely to cause demethylation.

I don't think potassium carbonate will cause too much damage to the bromoketone. Since it isn't a nucleophilic base like hydroxide, there won't be a tendancy for nucleophilic substitution, meaning less decomposition. A bee friend of mine washes his bromoketones with potassium carbonate during workup, so it can't be too unhealthy, although I stick to sodium bicarbonate. NaOH does an excellent job of destroying bromoketones and I suppose gives the appropriate hydroxy-ketone in a rather exothermic reaction.

Also, a patent which may come in useful for those who don't like working with bromoketones and want to aminate the propiophenone as is; the catch is the reaction of an amine with bromine. Make sure to keep the temperature low! The method is patented by Kamlet, but no yields are given: Patent US2155194. This could be a nice route to consider if we could find another suitable source of N⁺ instead of using toxic haloamines.

Aurelius
(Hive Addict)
06-10-03 15:51
No 439077
      US Pat 2155194 Alpha-alkylaminoacylophenones
(Rated as: excellent)

US Patent 2155194

Preparation of Alpha-Alkylaminoacylophenones

Abstract:

Alpha-alkylaminoacylophenones were prepared exclusively by halogenating and acylophenone and reacting the resultant halo-compound with an excess of alkylamine. Thus, in the preparation of alpha-methylaminopropiophenone, the common procedure involved the bromination of propiophenone and reacting the halo-compound with excess of methylamine. In this patent, alkyl-N-halogenated amines are generated in order to avoid formation and use of the alpha-halo compounds above, which are lachrymators and vesicants. It is also advantageous in that excess alkylamine is not required, thereby limiting over-alkylation of the nitrogen. It has been found that alpha-alkylaminoacylophenones may be obtained in one step by reacting an acylophenone with an alkyl-N-halogenated amines in a suitable solvent and in the presence of an alkaline substance.

CH₃NH₂ + NaOH + Br₂ а NaBr + CH₃NHBr

C₆H₅COCH₂R + R’ NHXà C₆H₅CO-CH-R-NH-R’+ HX

By the term “alkaline substance”, it is to be understood that the substance shall have an aqueous pH of higher value than the alkylaminoacylophenone being prepared. Such compounds include the hydroxides and carbonates of ammonia and the alkali metals, the oxides and hydroxides of the alkali-earth metals, the quat salt hydroxides and the alkylamines, proper.

Example Procedure:

A halogen (e.g. bromine) is added in small portions to a well-cooled aqueous or alcoholic solution of one mole of alkylamine and one mole of alkali-metal hydroxide (or two moles of alkylamine) until one mole of the halogen has been dissolved. The temperature of the solution must not exceed 10*C during this addition. One mole of acylophenone dissolved in a miscible solvent such as alcohol, is now added and the mixture is agitated at a temperature lower than 15*C while adding slowly a solution of one-mole-equivalent of an alkaline substance. After stirring for two hour, the reaction mix is neutralized to litmus with HCl acid, diluted with water and unreacted acylophenone is extracted with ether. From the aqueous residue ( which comprises a solution of alpha-methylaminopropiophenone hydrochloride) the free base may be obtained in the usual manner by alkalinization and extraction with an organic solvent.

Alternatively, an aqueous solution of alkyl-N-halo-amine and an alkaline substance (alkylamine) may be agitated with an acylophenone dissolved in a water-immiscible solvent, such as benzene, at a temperature not exceeding 25*C for two hours. By dissolving the reagents in mutually immiscible solvents, the strongly exothermic reaction is somewhat moderated and a simple means is provided for separating the final end-products of the reaction.

Example 1:

Bromine is added in small portions to a well-cooled solution of 35g of methylamine and 40g of caustic soda in one liter of 95% alcohol at –5*C until a total of 160g of (50.3ml) has been added. The temperature of the solution should never exceed 10*C during the addition. 135g of propiophenone is now added and the mixture is agitated while a cold solution of 40g of caustic soda in 50ml of water is added in a thin stream. After stirring for two hours at a temperature below 15*C, the alcohol is distilled off under vacuum and the residue is dissolved in two liters of 1N HCl acid. Unchanged propiophenone is extracted with two successive 250ml portions of ether and the residual acid-aqueous solution of alpha-methylaminopropiophenone HCl is neutralized to litmus with a concentrated solution of sodium carbonate. It may now submitted to reduction by hydrogenation at 3-4 atm in the presence of Pd/C, Pt/C or Raney Nickel.

Example 2:

Bromine is added to a well-cooled solution of 95g of methylamine in one liter of water at –5*C in small portions until a total of 160g (50.3ml) has been added. The temperature of the solution should never be allowed to exceed 10*C during the addition. 135g of propiophenone dissolved in one liter of benzene is now added and the mix is vigorously agitated for two hours with efficient external cooling to keep the temperature below 25*C. The components of the reaction mix are now allowed to stratify and the aqueous solution of methylamine hydrobromide is separated from the benzene solution alpha-methylaminopropiophenone. The latter is neutralized to litmus with a conc. alcoholic solution of hydrochloric acid and the crystalline precipitate that forms is removed by filtration. By solution in alcohol and reprecipitation with acetone, white crystals of alpha-methylaminopropiophenone hydrochloride that had; MP: 179*C.

Table 1

R / R’ / MP of HCl Salt in *C

H/Me/219
Do/Et/228
Me/Me/179
Do/Et/182
Do/n-Pro/182
Do/iso-Pro/212
Do/n-Butyl/159
Do/n-Amyl/154
Et/Me/191
Do/Et/196
n-Pro/Me/181

The products of these reactions can be catalytically hydrogenated to their respective ephedrines in near quantitative yields with Pt/C or Pd/C or Raney Nickel

Act quickly or not at all.

psychokitty
(«»)
11-12-04 17:24
No 541257
      Methanol works as bromination solvent

The reaction using oxone, NaBr, propiophenone in aqueous methanol works wonders at synthesizing a-bromopropiophenone: Post 360655 (Regis: "Products of the oxone reduction?", Chemistry Discourse)

But if you add all the sodium bromide at once, during the reflux phase of the reaction the bromine has a tendency to escape out the top of the condenser as it is very volatile.

My original thought was that after the a-bromopropiophenone was synthesized, the excess bromine could be neutralized, and the pH of the reaction brought to light basicity with the addition of sodium carbonate (bicarbonate causes a lot of foam).

Then, an amine (freebased) of some kind could be introduced
and the reaction could proceed via substitution.

This was tried with a cyclic amine, and during the course of 12 hours (overkill), a reaction occurred which after extraction and isolation, yielded a product which was not one of substitution at the a-carbon. Sooo, the reaction was proven to be somewhat viable but in no way was it optimized.

One of the big problems was with the amount of insoluble salts that were present. The byproducts of oxone oxidations and neutralizations are considerable and most are insoluble in the aqueous methanol mixture. Hence, the one experiment seemed to suggest that a one-pot reaction going from propiophenone to a-bromopropiophenone to a-whateveramine-propiophenone was indeed viable if the potentially excess oxone and bromine and whatever else could be neutralized. Isopropyl alcohol was used in the above reaction but who really knows if it worked. Sodium bisulfite or sodium sulfite could possibly be used to advantage as reducing agents but I'm not sure how they would react with the aminoketone products. Sodium carbonate was used as the base to achieve a lightly basic near neutrality mixture, and it was added very carefully until the fizzing stopped.

My thought, Barium, is that maybe H2O2 can be used in place of the oxone in this reaction. The byproduct of an oxidation using hydrogen peroxide is water. This would later on minimize the amount of byproducts in the mixture making it easier to move on to the secondary amination step.

A few questions:

1.) At minimum, how much water is present in the H2O2 oxidation of NaBr? Would it be less than that required for the oxone oxidation of NaBr used in the above-described propiophenone bromination reaction using methanol as a primary solvent?

2.) How much DCM or any other water-immiscible solvent is required to extract all of the bromine formed from H2O2 oxidation of NaBr? For the OTC operator without a hood, would this bee a very smelly and painful proceedure to carry out or does the DCM solvate the bromine well enough to eliminate such problems?

3.) How does your modified acetic acid bromination of propiophenone eliminate the hazards or working with lacrymatory a-bromopropiophenone?

4.) What about brominating in acetic acid per your method, adding a solvent with a higher bp than acetic acid, distilling off the excess acid, and then aminating afterwards? Do you think this would work?

NOTE: The bromination of a-bromopropiophenone using oxone/water/NaBr/methanol definitely works! When left alone for the required reflux time, the bromination took place, but upon return it was discovered that part of the reaction mixture had shot up and out of the top of the condenser, and was awash against a plastic protective backdrop that I had previously errected.

This reaction was performed on a 25g propiophenone scale, but nonetheless, that small bit of escaped a-bromopropiophenone was enough to make the room an unpleasant one in which to be. The solution to the problem was to open up the windows and air the place out (which took quite a long time to do).

What caused the minor mishap? I had a cheapie check valve attached between the hose leading from the condenser to the nearest open window. Through the course of the reaction, the internal plastic components of the check valve got fused (likely from the bromine vapor), thus causing a rise in pressure, which eventually caused the stopper at the top of the condenser to blow off, and via vacuum pressure, suck out some of the reaction flasks contents into the surrounding room. That's my theory, anyway.

Captain_America
(Über-Führer die Ironie)
11-12-04 17:33
No 541258
      i have had bad results brominating vanillin in

i have had bad results brominating vanillin in methanol.. but i generated br2 from kbr in situ, never tried adding elemental Br2 tho...

http://www.junkmusik.com/junkvideo.mov

Barium
(Heavyweight Chempion(eer))
11-14-04 00:20
No 541449
      Smoothest in situ bromination yet
(Rated as: excellent)

100 mmol Propiophenone
110 mmol NaBr
100 mmol H₂O₂, as a 30% aq solution
Hydrochloric acid

To a 250 ml two necked rb-flask equipped with a magnetic stirbar, thermometer and a addition funnel is added 100 mmol propiophenone, 110 mmol NaBr and 50 ml conc. hydrochloric acid. The stirring is started and 100 mmol hydrogen peroxide is added dropwise at a rate which never causes a distinct red color to the reaction mixture while the temperature is kept between 25-30 deg C. The addition takes about twenty minutes and it can be stopped a couple of times to check how quick the yellow color dissapears as a indicator of the speed of the reaction. At a temperature below 25 deg C the reaction takes a very long time but at between 25 and 30 dec C it is quite quick.

When all hydrogen peroxide has been added and the reaction mixture is colorless the alpha-bromopropiophenone is isolated by separation and washed once with water followed by one washing with a saturated NaCl solution. The yield is as good as with any bromination using elementar bromine.

The reaction can be viewed as:

H₂O₂ + 2H⁺ + 2Cl^- --> 2H₂O + Cl₂
Cl₂ + 2Br^- --> Br₂ + 2Cl^-
Ar-C(=O)-CH₂-CH₃ + Br₂ --> Ar-C(=O)-CH(Br)-CH₃ + H⁺ + Br^-
H₂O₂ + 2H⁺ + 2Br^- --> 2H₂O + Br₂

Severe Aztecoholic and President of Sooty's fanclub - Sooty for President!!

Captain_America
(Über-Führer die Ironie)
11-14-04 01:03
No 541454
      good work Ba..

Altho I'm not sure this reaction takes place: H₂O₂ + 2H⁺ + 2Cl^- --> 2H₂O + Cl₂

since chlorine is more powerful oxidizing agent than H2O2... i think h2o2 rather oxidize 2Br^- to Br2 directly.

will give vanillin bromination one more shot using H2O as solvent, i think it should bee perfect...

http://www.junkmusik.com/junkvideo.mov

psychokitty
(«»)
11-14-04 01:10
No 541456
      FANTASTIC!

Good going! That is definitely a very helpful write-up!

However . . . not to sound ungrateful, but I still have a few questions unanswered from my previous post and, most importantly, you haven't exactly indicated whether there's a way to perform an in situ amination after the completion of your bromination reaction. Can you foresee adding an amine directly to the reaction soup so that a substitution reaction can then occur? In your opinion, what kind of problems would such a "one-pot" synthesis entail?

Just looking to make this reaction as OTC and straight-through as possible as the isolation and the handling of lacrymatory a-bromopropiophenone is about as undesirable as can be.

Again, thank you very much, Barium.

EDIT:

One other question:

At the beginning of this thread, you indicated that you believed that the reaction would not occur while in the presence of too much water. Considering this, what do you think accounts for the success of your reaction? And what persuaded you to perform it without a solvent?

Saddam_Hussein
(Hive Bee)
11-14-04 01:11
No 541457
User Picture       bzzzt

HCl + H2O2 ---> HOCl + H2O
2KBr + HOCl ---> Br2 + KOH + KCl

President of the Iraqi Chemical Weapons of Mass Destruction Development Society

Barium
(Heavyweight Chempion(eer))
11-14-04 02:10
No 541468
      Nope

What you forget Captain and Saddam, is the huge excess of hydrochloric acid present. The mechanism you postulated is not valid in this acid enviroment. There is also very little bromide ions present since NaBr is not very soluble in hydrochloric acid. Therefore, chloride ions is oxidised to chlorine which immediately oxidises the few bromide ions present. How can I be sure that it isn't a simple chlorination of the propiophenone? Well, if the hydrogen peroxide addition is speeded up the reaction mixture turns red from bromine, and no chlorine escapes the setup.

Kitty:
Just siphone off the excess acid and you can perform the alkylation of any amine of your choice directly. About the nastiness of alpha-bromopropiophenone - Yes it is a nasty lachrymator. But keep it a bit below room temp when exposing it to the atmosphere and it won't make you cry. Well not too much anyway.

As long as the acid concentration doesn't fall below about 20% the reaction runs smoothly. This is just a wild guess from my side, but I think it has to to with the enol formation. In a acid of lower concentration the enol formation is simply too poor to make the reaction run.

I discovered this reaction possibility when I tried Br₃^- as bromination agent for propiophenone. I noticied that if the Br₃^- ion was generated in a enough acid enviroment the necessity of a co-solvent was eliminated.

Severe Aztecoholic and President of Sooty's fanclub - Sooty for President!!

psychokitty
(«»)
11-14-04 17:33
No 541527
      What comes first then?

Just siphone off the excess acid and you can perform the alkylation of any amine of your choice directly.

Should one add a co-solvent and then siphon off the aqueous layer or can the siphoning off be done with just the a-bromopropiophenone present as is? Btw, does the a-bromopropiophenone form a layer above or below the aqueous phase? Also, is it floating about all over the place in a haphazard manner or does it form a smooth easily separated layer? And after siphoning off the aqueous layer, is there any need to neutralize anything left behind (excess bromine, chlorine, HCl, H2O2, etc., etc.) before the addition of the amine or can one just proceed as is?

And my last question -- for now: Does one have to siphon off the aqueous layer in order to move on to the next amination step? All I'm asking is whether or not you believe that the byproducts in the aqueous phase could be neutralized to allow for the next amination step. Any suggestions regarding the feasibility of such a process are welcome.

Remember, my objective here is to avoid direct exposure to the lacrymatory a-bromopropiophenone, and siphoning off, lowering the temperature, and so on and so forth, do not guarantee that this will not happen. Not taking anything out of the flask and just dumping everything in, step by step -- correctly, of course -- is a much better way to go.

Seriously, we're almost there man in making this a one-pot straight-through synthesis. Please don't give up on me now . . .

Captain_America
(Über-Führer die Ironie)
11-14-04 17:57
No 541532
      What you forget Captain and Saddam, is the...

What you forget Captain and Saddam, is the huge excess of hydrochloric acid present.

I don't think the conc. of HCl matters, fill a test-tube with some konc. HCl and add H2O2, no chlorine will bee generated... But if you use things like KMnO4 (more powerful oxidizer than Cl2) chlorine will form... The role of HCl in your reaction is to provide H⁺ for the wanted equilibrium, so that Br2 instead of hypobromite forms, you might have used sulfuric equally well, might prove even better since it's an oxidizer in it's own right.

http://www.junkmusik.com/junkvideo.mov

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