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JJay
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Preparation of Dimethyl Sulfate Discussion
I've been looking at dimethyl sulfate recently. As a methylation agent, it has some attractive properties: It's cheap and effective. While it can't be
used to make Grignards directly, dimethyl sulfate is said to react with potassium iodide to make methyl iodide in high yield.
I haven't read many reliable reports where hobbyists said they made dimethyl sulfate successfully. I don't think it's particularly hard to make, but
it's extremely toxic and carcinogenic, and most references suggest methods requiring reagents that are hard to obtain. While some old procedures
suggest that a fume hood is not required for handling it, Vogel wrote, "The vapour is highly poisonous and the substance should only be used in a fume
cupboard with a good draught. The liquid itself is readily
absorbed through the skin, with toxic results."
I recently ran across a simple procedure to make methyl sulfuric acid. It doesn't require anything exotic. Vacuum distillation of methylsulfuric acid produces dimethyl
sulfate. I think calcium carbonate would work OK instead of barium carbonate if making dimethyl sulfate.
| Quote: |
A general method of obtaining methyl and ethyl sulphates is to treat the alcohols with concentrated sulphuric acid or with chlorosulphonic acid. The
first method is convenient, but since the reaction is a reversible one it does not give the theoretical yield.
For the methyl hydrogen sulphate, 1 part by weight of methyl alcohol is mixed with 2 parts of strong sulphuric acid, and the mixture kept warm for
some hours. It is then diluted with water, and barium carbonate added in excess, to neutralise the free acids. After filtration from the barium
sulphate and excess of carbonate, the filtrate, which contains the barium salt of methyl hydrogen sulphate, is evaporated to a conveniently small
bulk, and treated with just sufficient sulphuric acid to precipitate all the barium as sulphate, and then again filtered. An aqueous solution of the
free methyl sulphuric acid is thus obtained, which can now be evaporated in a vacuum over strong sulphuric acid.
Methyl hydrogen sulphate is an oily liquid, which does not solidify on cooling to - 30°. On distillation, it decomposes into dimethyl sulphate and
sulphuric acid.
Dimethyl sulphate, (CH3),SO4, is made by distilling monomethyl sulphate in a vacuum. To obtain a good yield, the monomethyl compound should be free
from water and other impurities. It need not, however, be separately prepared. A mixture of 25 kilos. of sulphuric anhydride with 10 kilos. of nearly
absolute methyl alcohol is made, the temperature being kept below 0°, and preferably between - 5° and - 10°. The mixture is then distilled in
vacuo. An almost theoretical yield of 19 kilos. can be obtained.
Alternatively, 100 parts of chlorosulphonic acid are run into 27 parts of methyl alcohol at a temperature of - 10° to - 15°, care being taken that
the liquids are well mixed, and moisture excluded. The mixture is then distilled in a vacuum 4 (20 mm.; the temperature being about 140°). Yield,
about 80 per cent. of the theoretical.
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I understand that dimethyl sulfate is very toxic and carcinogenic, but it has a fairly high boiling point. Are there any easier ways to make it? Is
there any reason it shouldn't be handled with regular lab gear (nitrile gloves, lab coat, etc.) in a fume hood?
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Metacelsus
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I have used dimethyl sulfate before, under the conditions you describe (gloves, lab coat, etc. in a fume hood). I believe it is safer than methyl
iodide due to its lower volatility. When using it, I would recommend keeping a beaker of ammonia solution on hand so that any spills can be
immediately quenched.
I would be hesitant to prepare dimethyl sulfate on a large scale in a home setting. If there were to be an accident, the results would be quite bad.
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Tsjerk
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Calcium carbonate should work.
Here they do it without either calcium or barium.
https://www.slideshare.net/mobile/NikolayMasin/dimethyl-sulf...
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S.C. Wack
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Get BaCO3 from a ceramics supplier if nothing else (expect sulfide) and don't look back. BaSO4 is heavy, does the job right, and is easily regenerated
by boiling with baking soda.
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JJay
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That's really interesting. I can't seem to download the presentation, but that procedure looks really easy. I am curious about why the reported yield
is so low... but the reagents are cheap. The references given in the presentation don't seem to relate directly to the procedure. Does it work? I
will say that I've found that the high yields of US 3047604 are hard to reproduce, but it does work to some extent....
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JJay
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Quote: Originally posted by Metacelsus  | I have used dimethyl sulfate before, under the conditions you describe (gloves, lab coat, etc. in a fume hood). I believe it is safer than methyl
iodide due to its lower volatility. When using it, I would recommend keeping a beaker of ammonia solution on hand so that any spills can be
immediately quenched.
I would be hesitant to prepare dimethyl sulfate on a large scale in a home setting. If there were to be an accident, the results would be quite bad.
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Keeping ammonia solution ready for quenching spills is a good idea.
I would be reluctant to prepare it on a large scale at home as well. I don't think it's more dangerous than chlorine or bromine, though....
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Loptr
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| Quote: Originally posted by JJay | | Quote: Originally posted by Metacelsus | I have used dimethyl sulfate before, under the conditions you describe (gloves, lab coat, etc. in a fume hood). I believe it is safer than methyl
iodide due to its lower volatility. When using it, I would recommend keeping a beaker of ammonia solution on hand so that any spills can be
immediately quenched.
I would be hesitant to prepare dimethyl sulfate on a large scale in a home setting. If there were to be an accident, the results would be quite bad.
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Keeping ammonia solution ready for quenching spills is a good idea.
I would be reluctant to prepare it on a large scale at home as well. I don't think it's more dangerous than chlorine or bromine, though....
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I would have to disagree with the implications of that statement. The halogens smack you across the face to make their presence known, while dimethyl
sulfate is just a smell. With chlorine I have to get out of the area because it hurts. I am not sure about the toxicity comparison, but I know that I
would likely have more exposure with dimethyl sulfate than chlorine.
"Question everything generally thought to be obvious." - Dieter Rams
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JJay
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Bromine and chlorine have strong and offensive odors, and dimethyl sulfate has little odor. Bromine has an IDLH level of about 1/3 that of dimethyl
sulfate and an OSHA PEL at about 1/10. Chlorine has IDLH and PEL levels that are comparable to dimethyl sulfate's. But chlorine is a gas, and bromine
is a volatile liquid boiling at 59 C. Dimethyl sulfate boils at 188 C.
I would say that the outlet of the vacuum pump should be inside the fume hood during preparation (along with scrubbers and traps). There should be
absolutely no detectable odor. A respirator should be available. People who are not aware of the risks should be kept away when dimethyl sulfate is
being prepared or is in use.
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AvBaeyer
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From a safety perspective, I cannot understand why anyone would want to make dimethyl sulfate in a home/amateur laboratory setting using the
procedures initially described above. The material is just too dangerous. Methyl iodide is far easier to make and though not the safest of reagents it
can be used with appropriate caution. Moreover, when using methyl iodide for a methylation, the iodide can be easily recovered as iodine from the
work-up solutions. An alternative is methyl p-toluensulfonate which can be easily prepared following Org Syn procedures. It requires no distillation
or follow on purification before use and is relatively non-volatile. It is my go-to methylation reagent, especially when used with a small amount of
iodide catalyst. At least in the US, the now ready availability of p-toluenesulfonyl chloride makes methyl p-toluenesulfonate (as well as other
esters) the reagent of choice. Just my nickels worth.
AvB
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JJay
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I can't get 85% phosphoric acid, for one. I don't think I can get p-toluenesulfonyl chloride either.
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Magpie
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85% phosphoric acid is available through Duda Diesel.
The single most important condition for a successful synthesis is good mixing - Nicodem
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JJay
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They won't ship it to my location.
Edit: Actually, they will ship it to my location if I buy it directly off of the company website, but shipping costs far exceed the price of the
product.
[Edited on 12-9-2018 by JJay]
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Magpie
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I have seen 85% phosphoric acid sold at brewing supply stores. It is also available through Amazon, some with free shipping:
https://www.amazon.com/s?k=85+phosphoric+acid&hvadid=143...
[Edited on 12-9-2018 by Magpie]
The single most important condition for a successful synthesis is good mixing - Nicodem
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JJay
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I've looked for it. It's not quite inaccessible, but shipping is expensive. A lot of methylations are lower yielding with methyl iodide than with
dimethyl sulfate. Synthesis of methyl iodide with dimethyl sulfate seems to be highest yielding method....
I'm not quite sure why it is regarded as so dangerous. It's dangerous, sure, but I've handled more dangerous things.
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zed
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My buddy Dr.Death, used to work with Dimethylsulfate on occasion.
Claimed it was a lovely way to methylate yer innards, with the bonus of releasing H2SO4 into your delicate lung tissues.
Trimethylphosphate appears to be a nice methylating agent, but the literature doesn't provide a lot of convenient preparations. Not very volatile,
and phosphoric acid, just doesn't pack the same scorch factor that H2SO4 does.
P-TolueneSulfonylChloride? I'll look into it. Methyl prep? I assume you mean this one? http://www.orgsyn.org/demo.aspx?prep=CV1P0145
Well, not dirt cheap. But, available on Amazon. https://www.amazon.com/HiMedia-GRM2486-500G-P-Toluenesulfony...
Thank you AvBaeyer.
[Edited on 12-9-2018 by zed]
[Edited on 12-9-2018 by zed]
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JJay
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I could probably get that to work just fine for methylations, but I have no idea what the yields would be. I've never bought from HiMedia before.
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JJay
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After researching the topic a bit, it looks like I could actually make some methyl tosylate with materials I have on hand (I'd use methyl orthoformate
and toluenesulfonic acid, both of which I would have to prepare), but I think making and using dimethyl sulfate would be a lot less work, and there is
a lot more literature on it. I suspect dimethyl sulfate methylates in higher yields, and I think it's more versatile. Data on the toxicity of methyl
tosylate is a bit sparse.
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Metacelsus
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For methylation of phenols, dimethyl sulfate gives quantitative yields. I don't know about other methylating agents (tosylate / phosphate).
If you can get trimethyl orthoformate, you might be able to use that as a weak methylating agent.
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AvBaeyer
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As I mentioned I use methyl p-tosylate as my reagent of choice. For example, I have methylated acetaminophen, vanillin, and ethylvanillin with
isolated yields of >90% on a 0.1 mole scale. The reactions are run in acetone using 50% excess potassium carbonate and 10 mole% NaI or KI as
catalyst. The reaction is run at 50-55 C in a closed system for 24 hrs. The reaction time is arbitrary as the phenol is largely bound to the potassium
carbonate so the disappearance of phenol cannot be conveniently followed by TLC.
I have yet to have a bad product from HiMedia - the tosyl chloride is fine. Also, the free shipping makes HiMedia products excellent bargains.
Trimethyl phospate is a poor alkylation agent by itself. However, when iodide catalysis is used it is quite good since the active methylation agent is
methyl iodide.
BTW- Trimethylorthoformate is available from HiMedia if one wants to methylate p-toluenesulfonic acid. There is a least one paper on this that I know
of. I am not aware of any direct phenolic methylation with trimethylorthoformate.
AvB
[Edited on 12-9-2018 by AvBaeyer]
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Pumukli
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Would methyl bisulfate work for e.g. methylating phenols? I read that methylations with DMS can be tailored to use both methyls of the reagent so I
assume methyl-H-sulfate could be used too.
Its synthesis seems to be fairly simple, it's inexpensive, and probably more forgiving than the other (DMS, MeI) big-gun methylating agents.
Depending on the substrate I'd probably run a few trials to evaluate its effectiveness.
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JJay
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I'm pretty sure that it would work to some extent for methylating phenols, but I don't think it works without heat and an extended reaction time, and
the yields look like they would be lousy. Assuming that the first methyl group methylates quantitatively, the second methyl group would only methylate
in something like 45% yield on the remaining phenol here: http://www.orgsyn.org/demo.aspx?prep=CV1P0058
I wouldn't recommend it.
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Loptr
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Trimethylsulfonium bromide and its use for the methylation of phenols
http://www.sciencemadness.org/talk/viewthread.php?tid=15704
[Edited on 12-9-2018 by Loptr]
"Question everything generally thought to be obvious." - Dieter Rams
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clearly_not_atara
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| Quote: | I am not aware of any direct phenolic methylation with trimethylorthoformate.
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After extensive searching one time I did find a paper which methylates phenols with MeO3Me. However, this occurs at several atmospheres and well above
100 C, only on activated phenols. It probably isn't practical.
For phenols tetramethylammonium salts may be worth considering. Trimethylamine hydrochloride is a lot easier to synthesize than you think:
http://www.orgsyn.org/demo.aspx?prep=CV1P0531
The other methylating agent that always sticks in my head are the mixed methyl-alkyl carbonates, which preferentially transfer methyl. Dimethyl
carbonate boils too low to be used for methylation at atmospheric pressure, but methyl octyl carbonate should work fine. I wonder if you could make it
from methyl carbamate like this:
MeOCONH2 + C8H17OH + [cat. ZnO] >> MeOCO(OC8H17) + NH3 (g)
[Edited on 12-9-2018 by clearly_not_atara]
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Pumukli
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These tetraalkyl-ammoniums seems interesting, but how could you reach tetramethylammonium from trimethylamine? :-)
Wouldn't you need something like MeI first? :-)
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clearly_not_atara
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You can make Me4NBr from MeBr + Me3N; the former compound is much easier to handle and store because MeBr boils at 5 C. If it weren't for the low
boiling point of methyl bromide, there would never have been any discussions on methylating agents in the first place -- alkylations with every other
group just use the bromides.
You can also make Me4NBr from MeBr + NH3, but this is highly impractical because ammonia boils extremely low, four times as much bromide is required,
and you need a catalytic base. If you start with trimethylamine no base is required (because no H atoms are displaced) and the reagents are liquid at
0 C. So having an easy synthesis of trimethylamine makes Me4N+ much more accessible.
EDIT:
Dimethyl sulfone, widely sold as a health supplement), is cleaved to methyl sulfinate by a Birch reduction:
https://pubs.acs.org/doi/abs/10.1021/ja01496a050?journalCode...
Oxidation of the resulting methyl sulfinate with bromine should yield the corresponding sulfonyl bromide, from which the methyl ester is available.
Although... I am a little unclear on the safety of this one. Methyl methanesulfonate?
For phenol methylation specifically, I wonder if you can't use sulfonyl halides to perform it "in reverse" by forming the aryl sulfonate and rxn with
sodium methoxide.
[Edited on 13-9-2018 by clearly_not_atara]
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