nimgoldman
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Blanc Chloromethylation - Removing BCME from Product
It is well known that Blanc chloromethylation produces a highly carcinogenic bis(chloromethyl) ether (BCME).
The compound can be easily neutralized by dilute aqueous ammonia [1, 2] but the chloromethylated products such as benzyl chloride, heliotropyl
chloride and such will hydrolyze into an acid and alcohol under such conditions.
Many chloromethylations are designed to be biphasic, while the product migrates into the organic phase, increasing yield. Unfortunately BCME is
soluble in wide range of organic solvents, and it migrates along with the product, contaminating it.
The only ideas I have so far:
1) separate BCME and the product by frac. distillation (under a fume hood), then destroy BCME separately - DANGEROUS
2) use the crude product in the next synthetic step (e.g. aldehyde synthesis) - the next intermediate might not be sensitive to aqueous alkali and we
may remove BCME there
3) let the chloromethyl compound hydrolyze into an acid and alcohol, make the aq. solution basic with ammonia (to destroy BCME), extract the alcohol
and convert it back to methyl chloride with conc. HCl - this however adds more steps to the synthesis
I am surprised that none of the patents and books I've gone through mentioned how to deal with BCME, how to separate it from the chloromethyl compound
etc.
Here is one synthesis from the Br. Pat. 1 538 214:
| Quote: | (a) Paraformaldehyde (4.5 g, 0.15 mole) was suspended at O °C in saturated aqueous hydrogen chloride (20 ml). MDOB (12.2 g, 0.1 mole) was added and
the reaction mixture stirred between 17° and 20 °C with a slow stream of hydrogen chloride passing through the mixture. Stirring was continued for
1.5 hours when almost all the MDOB
had disappeared. The mixture, composed mainly of heliotropyl chloride together with some bischloromethyl-methylenedioxybenzene and MDOB was separated,
the aqueous layer extracted twice with 10 mL portions of methylene chloride and the total organic layer evaporated at 30°-35°C in vacuo.
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Could it be possible that BCME reacted with the MDOB (methylenedioxybenzene), forming the bischloromethyl-methylenedioxybenzene, thus neutralizing
itself ?
| Quote: | [1] Lunn, George, and Eric B. Sansone. Destruction of hazardous chemicals in the laboratory. John Wiley & Sons, 2012. p. 211 - Haloethers
[2] Alvarez, M., and R. T. Rosen. "Formation and decomposition of Bis (Chloromethyl) ether in aqueous media." International Journal of Environmental
Analytical Chemistry 4.3 (1976): 241-246. |
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Tsjerk
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The bischloro-methylenedioxybenzene is a side product from which was methylated twice. The oxygens on the ring are activating and promote a second
methylation.
Is there really no alkaline step downstream of your reaction? It Isa minor side product, just leave it in there. How where planning on seperating the
bischloromethyl side product in the first place?
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clearly_not_atara
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Since I can all but guarantee that your intention with your chloromethylated arene is to convert to the aldehyde, one way to neutralize BCME at workup
is to add excess hexamine immediately, forming the quaternary salts from both chloromethylbenzodioxole and BCME. Reflux at neutral pH should then
induce the Sommelet reaction, converting CMBD to the aldehyde and BCME to formate.
Also, the more likely double alkylation product is the annoying bis(benzodioxolyl)methane you can get.
[Edited on 04-20-1969 by clearly_not_atara]
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nimgoldman
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Quote: Originally posted by Tsjerk  | | Is there really no alkaline step downstream of your reaction? It Isa minor side product, just leave it in there. How where planning on seperating the
bischloromethyl side product in the first place? |
The problem is I need to isolate the benzyl chloride (or another respective chloromethylated compound) as I am investigating several different
reactions and thus I need it relatively pure to calculate yields.
For example, I am going to try oxidation of benzyl chloride with copper(II) nitrate or similar mild oxidizing agent:
https://www.prepchem.com/synthesis-of-benzaldehyde/
From the abstract of "Formation and Decomposition of Bis(chloromethyl) Ether in Aqueous Media" (document attached):
| Quote: | | In this study, it is shown that the compound formsrapidly in a chloromethylatingmedium (HC1-HCHOZnC12) at low levels (100 ppm) and attains a fairly
steady concentration of 300-500 ppm. Methods for destroying BCME are discused.including the rates of destruction in homogeneous and heterogeneous
media. Although BCME is considered reactive, it is not readily decomposed by water or aqueous base because of its low solubility. In homogeneous media
such as MeOH-H20. the rate of hydrolysis is much faster. The reaction of BCME with aqueous ammonia is very fast and a reaction path to
hexamethylenetetramine is suggested. |
The interesting finding is that BCME mixes with water and hydrolyses by adding MeOH to 50% concentration, so maybe just adding enough alcohol (other,
less toxic, alcohols might work too) will be sufficient. The rxn mixture will be stirred for few hours to allow BCME to hydrolyze. The alcohol will
then be fractionally distilled from the rxn mixture and the chloromethyl compound extracted in organic solvent.
I am not sure what happens to the excess formaldehyde. Is it progressively consumed by reacting with HCl? How come formaldehyde is not extracted with
the product?
Another possible route has been already mentioned, that is to hydrolyze benzyl chloride to benzyl alcohol, then making the soln. alkaline with NH3.
This will destroy BCME rapidly. Re-acidifying the soln. with HCl will form benzyl chloride again, now free of BCME (hopefully). This assumes all the
formaldehyde is consumed of course. I am not sure if this will work at all though... perhaps the benzyl alcohol should be first extracted to remove
the ammonium and other ions.
As a safety measure, the reactor will be connected to a nitrogen tank and a scrubber (wash bottle with ammonia soln.). After the reaction, the
apparatus will be flushed with nitrogen, moving all the vaporized BCME through the scrubber. The reaction should ideally run under inert gas anyway
(according to the patent).
| Quote: Originally posted by clearly_not_atara | | Since I can all but guarantee that your intention with your chloromethylated arene is to convert to the aldehyde, one way to neutralize BCME at workup
is to add excess hexamine |
This is just one of the synthetic routes I am going to explore. Having a sample of pure benzyl chloride (or piperonyl chloride or other species) will
be neat to be able to calculate stoichiometry, yields and such.
NOTE: I know the chloromethyl- compound is hazardous, being moisture-sensitive, lachrymatory, and should be stored under inert atmosphere in a
freezer. Fortunately I can provide that. All the work is being done in a fume hood.
In the mentioned patent (see attachment), they do not purify the intermediates apart form simple workup and go by the following route:
1,3-benzodioxole -> piperonyl acetate -> piperonyl alcohol -> piperonyl aldehyde
So yes there is an alkaline step in the synthesis (base-catalysed hydrolysis of piperonyl acetate - I think). But this is just a one particular paper.
Others do not perform such step at all and e.g. oxidise the chloromethyl derivative directly.
The benxodioxole seems not to participate in the reactions and comes out unchanged, which is why they seem not to bother with purification of the
intermediates in the patent.
Attachment: PROCESS FOR SYNTHESIZING HELIOTROPINE AND ITS DERIVATIVES.pdf (623kB)
This file has been downloaded 299 times
Attachment: Formation and Decomposition of Bis(chloromethyl) Ether in Aqueous Media.pdf (289kB)
This file has been downloaded 329 times
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Tsjerk
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I'm pretty sure your problem will not be benzodioxole but over alkylated product, as the benzodioxole is pretty insensitive and will be lost during
some workup later on, but the over alkylated will product will have the exact same functional groups as your target compound... If you insist on
having a pure start product you will have to vacuum fractionate or do column chromatography.
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nimgoldman
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Didn't you mean *sensitive* ?
Of course I plan to fractionally distill the chloromethyl intermediate, or at least distill off the unreacted benzodioxole. I just need to get rid of
BCME first since I don't wan't to distill it at all (risk).
Unfortunately, even evaporating the DCM extract with the product will give off some BCME fumes. Maybe I could connect the rotavap or distillation
apparatus to a washbottle with cold 50% MeOH and some strong base, then shake the distilled DCM with ammonia soln. to clean it...
I understand it looks paranoid, but I heard a rumours about amateur chemists getting skin carcinomas from the compound and I would really like to
avoid that at all cost.
[Edited on 23-1-2020 by nimgoldman]
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karlos³
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Do it like atara said, just use excessive hexamine for the sommelet reaction, that minimises exposure to the BCME completely.
You can then separate the products resulting from that without risk of exposure.
Honestly, you really sound somewhat paranoid, but your measurements aren't really good, you did the same with the copper based reduction method, it
just adds to the effort without making sense to steer away from the traditional workup.
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Tsjerk
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No, not compared to the compounds you are trying to make. You do realize the chloromethylation conditions are harsh and brutal right? I don't think
your yields will be great, and you will get a ton of over-alkylation. You wonder where the 50% excess formaldehyde is going? Up in air (formaldehyde,
carcinogenic , gaseous, not nice). That together with the HCl (gaseous, even less nice) and that while you are fuming your BCME as well
What were you worring about again?
[Edited on 23-1-2020 by Tsjerk]
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clearly_not_atara
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It's possible that zinc metal will reduce BCME in preference to piperonyl chloride. However, it's merely possible.
[Edited on 04-20-1969 by clearly_not_atara]
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nimgoldman
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There was probably some standard way how they dealt with BCME in the industry, when Blanc chloromethylations were used... but unfortunately I haven't
found any info on that.
So far the most practical way (for an amateur chemist) seems to be to perform the reaction in water, then hydrolyze the chloromethyl to alcohol,
separate the unreacted material, reform the chloromethyl with acid and extract it.
The yield will be probably low, maybe 35-40% instead of 50% reported by the patent, or higher as with biphasic substrate and PTC, but better have
slightly lower yield than deal with BCME...
Perhaps isolating the benzyl/piperonyl alcohol is more beneficial as it is easier to store and not irritating.
I will investigate more about the removal of BCME from the rxn mixture though...
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