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AntPharm
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Methylation of phenols
I am currently in the process of devising a synthesis whereby I need to convert a phenol group to a MeO group. Reading through this excellent forum I
have found that this can be done using dimethyl sulphate but this is proving to be difficult to acquire. Does anyone know if it would it be possible
to make this in-situ using conc H2SO4 and MeOH at room temp? I would assume that a drying agent would remove the water produced and drive the rxn to
completion. I'm aware that this is pretty nasty stuff and if possible would like to make it in a dropping funnel (hence need to know if this would
happen spontaneously at RT).
If this proves to be a dead end, are there any other suggested methods that I might consider?
Two atoms on the way to school,
fell into one another's arms and made a molecule.
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vulture
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MeI and base is a pretty standard way to do this. Not so nasty as dimethylsulphate but not perfectly healthy either. But methylating something is
never healthy...
One shouldn't accept or resort to the mutilation of science to appease the mentally impaired.
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not_important
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Methyl tosalate - the methyl ester of p-toluenesulfonic acid is another methylating agent. Low vapour pressure, the resulting alkali salt of the acid
can be converted to the chloride (for making the Me ester) using the S-Br2 method.
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AntPharm
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Quote: Originally posted by vulture  | | MeI and base is a pretty standard way to do this. Not so nasty as dimethylsulphate but not perfectly healthy either. But methylating something is
never healthy... |
| Quote: Originally posted by not_important | Methyl tosalate - the methyl ester of p-toluenesulfonic acid is another methylating agent. Low vapour pressure, the resulting alkali salt of the acid
can be converted to the chloride (for making the Me ester) using the S-Br2 method.
|
Much appreciated tips but I'm not familiar with methyl tosalate and not been able to acquire MeI. If relevant safety precautions were taken, IYO do
you think the reagent (Me2SO4) would form easily at RT?
Two atoms on the way to school,
fell into one another's arms and made a molecule.
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Lambda-Eyde
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MeI is trivial to synthesize from methanol, phosphoric acid and an iodide salt. There's a write-up in the prepublication section, I believe.
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smuv
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what phenol?
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mr.crow
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There is already a thread using methyl bromide (a gas) and hydroquinone which is probably similar to what you have in mind
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entropy51
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There are several viable methods for O-methylations, but I don't think that is one of them. Most of the others have been discussed
on this forum and can be found by doing a search.
Most of the methods do however require the use of chemicals, and you seem to have some apprehension about using chemicals.
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AntPharm
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@Lambda-Eyde Thanks for that. Great simple method for MeI. Will be using that one 
@entropy51 I think you may have me wrong. It's not an apprehension of using chemicals, I am a chemistry graduate and have more than the average Joe's
experience. It's the availablility of some to the lay-chemist and more-so the long term health issues arising from working with carcinogens etc. in a
home lab. Thanks all for your help with my first post.
Speak again soon....
Two atoms on the way to school,
fell into one another's arms and made a molecule.
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Hexagon
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Reflux methanol and sulphamic acid, distill methanol, the remaining solid is ammonium methyl sulfate. Alternatively make sodium methyl sulfate by the
know process involving sodium bisulfate or sodium sulfate and sulfuric acid.
Neutralize the phenolic compound with an stechiometric ammount of NaOH (aq), add to this an excess of ammonium/sodium methyl sulfate. Relux for an
unspecified time (May be extract small aliquots and test for phenolics). When finished extract as usual.
Refs. on the methylation: U.S. Patent 2,490,842
May be not the highest yielding... but healthy 
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Vogelzang
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http://www.sciencemadness.org/talk/viewthread.php?tid=1261&a...
http://www.sciencemadness.org/talk/viewthread.php?tid=1261&a...
[Edited on 8-2-2011 by Vogelzang]
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Nicodem
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| Quote: Originally posted by AntPharm | | I am currently in the process of devising a synthesis whereby I need to convert a phenol group to a MeO group. Reading through this excellent forum I
have found that this can be done using dimethyl sulphate but this is proving to be difficult to acquire. |
As a new member, please note that the forum culture says to open referenceless threads only in Beginnings section. Saying you did a search without
providing a single reference or link to other threads makes you appear insincere (also because there already are threads on this or related topics
where you could have discussed your problem).
| Quote: | | Does anyone know if it would it be possible to make this in-situ using conc H2SO4 and MeOH at room temp? I would assume that a drying agent would
remove the water produced and drive the rxn to completion. |
Please give a reference to where the formation of dimethyl sulfate from H2SO4 in methanol is described. I'm not aware of such a reaction. Dissolving
H2SO4 in methanol gives an equilibrium with CH3OSO3H and H2O, this is well known and I have even posted the reference to the article giving the
equilibrium constant in one of the threads about methyl iodide synthesis. However, the so formed methylsulfuric acid is not easily transformed to
dimethyl sulfate. Generally it takes the thermolysis with vacuum distillation to convert it to the dimethyl ester.
PainKilla posted about some experiments with direct H2SO4 catalysed methylation of phenols with methanol, but the results were not really encouraging
as far as I remember (but read the thread nevertheless!). There are some similar reports of direct O-methylation of phenols with methanol using BF3 in
the literature (if I remember correctly), but most similar acid catalysed methylations give mainly C-methylated products (like in vapour phase over
solid acidic catalysts or when using AlCl3).
Regarding the dangers of using methyl iodide or dimethyl sulfate, the argument is pointless. Methyl iodide is dangerous if you use it outside the fume
hood (highly volatile!) while dimethyl sulfate is dangerous if you use it without personal protective equipment or clumsily (goes trough the skin
rapidly while causing burns!). Both are more or less equally carcinogenic. Personally, I'm more confident in using dimethyl sulfate, but that is
because once you have experience in using stinky compounds like thiols you never again fully believe in the power of the fume hood again. Both
reagents are more or less innocuous if treated with due respect.
[Edited on 8/2/2011 by Nicodem]
…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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Nicodem
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Recently madscientist pointed to an older thread where the product of Br2 reaction with dimethylsulfoxide (DMSO) is mentioned to be trimethylsulfonium bromide. I checked the
referred document which pointed further to a nonexistent Synthesis paper. It took me some time to find out the reference is erroneous and
that the paper was actually published in Journal für Praktische Chemie (see at the bottom). But the information was correct. The reaction
indeed gives Me3SBr as the main product which can thus be obtained pure with ease from relatively accessible starting materials. The onium salts like
Me3SBr are electrophilic methylating reagents and, among other nucleophilic substrates, they can also methylate phenols (and are not carcinogenic as
far as I know). So I thought to post this info in this recent thread.
We already had a discussion about methylation of phenols with onium salts, but the discussion was limited to the alkylation with ammonium salts which are less
reactive, however I remember that one of those papers had at least one reference to the use of sulfonium salts for this purpose.
Not only can Me3SBr be obtained from DMSO by its reaction with Br2, but the reaction of DMSO with some alkyl bromides like benzyl bromide or ethyl
bromoacetate is also applicable.
Trimethylsulfonium salts are also useful as reagents for the transformation of aldehydes and ketones to 2-alkyloxiranes and 2,2-dialkyloxiranes trough
the ylide addition to the carbonyl group followed by the concurrent nucleophilic substitution.
Preparations of Me3SBr:
From Acta Cryst. (1996) C52, 2580-2581:
(CH3)3SBr was prepared by the reaction between dimethyl
sulfoxide and ethyl bromoacetate (1.4:1). The reaction mixture
was kept in darkness and at room temperature. After 6d
the crystals were separated from the orange viscous solution
and treated with acetone. They were recrystallized from an
ether/methanol (1:1 ) solution.
From Bulletin of the Korean Chemical Society, 26 (2005) 1491-1492:
Typical procedure is as follows. A solution of benzyl bromide
(2.38 mL, 20 mmol) and dimethyl sulfoxide (10 mL) contained in
a round bottomed flask equipped with condenser was heated at 80
oC for 3 hours. When the reaction mixture was cooled to room
temperature, trimethylsulfonium bromide was precipitated which
was washed with acetone thoroughly. Recrystallization from
acetonitrile afforded colorless crystals. Yield 2.05 g (65%). mp
198-200 °C (dec). 1H NMR (DMSO-d6) δ 2.9 (s).
From Journal für Praktische Chemie, 312 (1970) 683–689:
…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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Paddywhacker
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That's very, very interesting, Nicodem.
Would somebody please translate the German. It cannot be cut&pasted into Babelfish, but it is only a short piece.
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vulture
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Translation:
To 234g (3 mol) of DMSO in a stirred vessel with a reflux cooler, 40g (0.025 mol0 of Br2 is added dropwise and the resultant solution is heated to
50C in a water bath until the red color has turned to light yellow (5 hours). The next day, the formed paraformaldehyde and dimethylsulfide are
distilled into a liquid air cooled trap under water aspirator vacuum and subsequently fractionated under atmospheric pressure. The mixture that
remains in the reaction flask is treated with 150mL of abs. isopropanol and cooled to 0C while stirring, upon which the trimethylsulfonium bromide
precipitates as crystals.
The next part discusses the analysis of the supernatant which remains after filtration of the trimethylsulfonium bromide.
One shouldn't accept or resort to the mutilation of science to appease the mentally impaired.
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Paddywhacker
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Talking of O-methylating agents, dimethylformamide dimethyl acetal, CAS 4637-24-5, is used to methylate carboxylic acids and phenols for
derivatization for gas chromatography. It is said to be very fast and efficient.
It isn't as OTC as DMF and methanol, but I wonder if it can be made from those by Dean-Stark or molecular sieve in Soxhlet. The only prep I've seen
involves dimethyl sulfate, and I wouldn't wish that onto an amateur chemist.
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Fleaker
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So how comparable is trimethylsulfonium bromide to say, CH3I?
The scary thing about Vulture's translation is the dimethylsulfide produced--it stinks and it will have to be scrubbed/oxidized.
Neither flask nor beaker.
"Kid, you don't even know just what you don't know. "
--The Dark Lord Sauron
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Nicodem
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Paddywhacker, DMFDMA methylates only exceptionally and it does so trough the Me2N<sup>+</sup>=CH-OMe cation which forms after protonation
and MeOH elimination. This however does not form in the basic media required for the deprotonation of most phenols (their pKa is generally from 9 to
10). Therefore DMFDMA does methylate carboxylic acids and sometimes it even leads to some methylation of very acidic methylene groups as a side
reaction (instead of cleanly introducing the =CH-NMe2 group). But in my opinion with phenols it could utmost just O-formylate them unless under some
unusual conditions or using very acidic phenols as substrates (like nitrophenols).
Also, you can not prepare DMFDMA from DMF and methanol as if you would be preparing normal acetals - you do need dimethyl sulfate or some other
methylating reagent.
| Quote: Originally posted by Fleaker | So how comparable is trimethylsulfonium bromide to say, CH3I?
The scary thing about Vulture's translation is the dimethylsulfide produced--it stinks and it will have to be scrubbed/oxidized.
|
The electrophilicity of sulfonium salts is much lower than that of the corresponding alkyl iodides. I would estimate that Me3SBr requires heating
somewhere between 50 to 100 °C for the methylation of phenols to take place with K2CO3 as base in a moderately polar aprotic solvent. I would try
with reflux in acetone, THF, MEK or acetonitrile to start with. Toluene might be inappropriate due to solubility issues, but I would not rule it out
without trying (it seems to work with Me4NCl according to the article cited in the other thread, even though this is nearly totally insoluble in it -
glyme and ethyl acetate also worked well). Other nucleophiles of comparable strength, like amines, imides or active methylene groups can probably be
methylated at similar conditions. However, I have not done a literature search on the topic (I'm sure that those interested will do that on their
own). I'm only aware of the above mentioned reference where phenyldimethylsulfonium salts methylate phenols already at room temperature with K2CO3 in
acetone, CH2Cl2 or similar solvents, but the aryldialkylsulfonium salts are more electrophilic due to the electronic effects of the aryl group.
The dimethyl sulfide stench is not the problem only during the preparation of Me3SBr (anyway it goes in the sink trough the aspirator during the
reaction mixture concentration step), it is much more of a problem during the methylation as it is de facto the leaving group and thus one equivalent
of it forms during the methylation reaction. It is not very toxic on small scale experiments, but it is highly unpleasant and the reaction should be
done in a fume hood or outdoor (bevare of the neighbours!). I think most of Me2S can be captured by absorption in ice cold acetone. In any case, the
choice is between risking cancer by using dimethyl sulfate and MeI, or unpleasant stench. To me Me2S does not smell terribly bad (nearly not as bad as
mercaptans), but some people are more sensitive to its stench. Of course, for methylations in general I would always prefer dimethyl sulfate as it is
cheap and very effective, but for the average amateur Me3SBr is much more accessible as the reagents required to prepare it are easily acquired (DMSO)
or made from OTC stuff (Br2).
PS: I like the idea of using methylsulfonium salts as methylating reagents mostly because it sounds so "back to the roots" chemistry - these are the
compounds that all living creatures use for electrophilic methylations in their organisms (e.g., S-methylmethionine).
[Edited on 13/2/2011 by Nicodem]
…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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vulture
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| Quote: |
To me Me2S does not smell terribly bad (nearly not as bad as mercaptans), |
Whoa Nicodem, you must have an exceptionally strong stomach. I remember an oxidation in our lab which used DMSO as the oxidant, the stench was
unbearable and remained for days, despite full fumehood operation.
One shouldn't accept or resort to the mutilation of science to appease the mentally impaired.
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ScienceSquirrel
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I don't find dimethyl sulfide that bad, thiols are a lot worse in my opinion.
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Fleaker
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@Nicodem
Thanks for the explanation as always. I agree that dimethyl sulfate is preferable to about any other methylating agent if one is working with phenols.
It is very quick and it is *very* cheap and relatively easy to synthesize for the well-equipped amateur (although I would recommend everyone against
it). It is also very poisonous, but I find that its lower vapour pressure than CH3I makes it safer; ideally, all manipulation would be done in the
fume hood, but this is optimistic for most amateurs. After reading about Klute's experience with trimethyl phosphate (TMP), I'm very interested in
that reagent.
Neither flask nor beaker.
"Kid, you don't even know just what you don't know. "
--The Dark Lord Sauron
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Nicodem
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| Quote: Originally posted by vulture | | Whoa Nicodem, you must have an exceptionally strong stomach. I remember an oxidation in our lab which used DMSO as the oxidant, the stench was
unbearable and remained for days, despite full fumehood operation. |
I think I know what stench you talk about, but I think there is more to Me2S to blame in those cases. For example, if you do a Kornblum oxidation with
DMSO, the dimethyl sulfide is not the only stinky stuff that forms. I worked with reagent grade Me2S and it does not stink as bad as the reaction
mixture from Kornblum oxidations (or Swern's). Me2S is a perfectly manageable liquid provided that you use it straight from the freezer (with a bp of
only 37 °C you don't want to use it at room temperature where its volatility becomes too much of a hassle). It's stench does not linger at all and it
does not contaminate objects. At the risk of sounding like a pervert, I can even say that there is a component of its smell that I find pleasant.
While mercaptans are something completely different and totally nauseating.
| Quote: Originally posted by Fleaker | | After reading about Klute's experience with trimethyl phosphate (TMP), I'm very interested in that reagent. |
Yes, I agree, trimethyl phosphate is a good alternative. It is still toxic, quite less efficient and more expensive that dimethyl sulfate, but at
least it is not as hazardous in my opinion. Otherwise, generally those that can buy trimethyl phosphate can also buy dimethyl sulfate. But if someone
was determined to make any of these two at a home lab I would strongly suggest to choose trimethyl phosphate from P2O5 rather than dimethyl sulfate
from NaHSO4 (for which, one mistake can cost a life later on). However, I would say that, for the averagely equipped amateur, methyl bromide as per
PainKilla's method is a way more suitable alternative to both of these.
…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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Magic Muzzlet
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I use trimethyl phosphate for a lot of methylations but always in DMF or solventless. Can it be used in aq. alkali? I cannot find info online about
aqueous usage, and I do not want to pay for articles. The only example is on the rhodium page where it is used to methylate Hydroquinone to
1,4-dimethoxybenzene in aq NaOH.
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Nicodem
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Dimethyl sulfate can be used in aq. NaOH without any problems as it reacts with the phenoxide much faster than it hydrolyses. I would tend to think
that trimethyl phosphate would be somewhat less efficient in water as it reacts slower and thus more of it could succumb to side reactions (but since
it is also less reactive...). So, I would say there are good chances you can use it in water, but use a higher excess of it and monitor the pH to add
more NaOH when needed (or just use excess Na2CO3 as a base and buffer).
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smuv
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One thing to remember, despite what everyone seems to say about methylating agents (probably without any research backing it up), is that methyl
bromide is not a potent carcinogen (if a carcinogen at all). In rodents it was not found to be carcinogenic, in humans there are conflicting reports.
Generally, with MeBr found to be carcinogenic with cancer rates just a tad above statistical significance.
Anyways, read about whatever methylating agent you use. Don't listen to word of mouth, do research.
But in the end, its probably going to be the solvents and lifestyle choices that give most chemists cancer (as if you can pinpoint the causes of
carcinogenisis).
Edit: About trimethylsulfonium bromide, the problem is you need a shitload of bromine to make reasonable amounts of the methylating agent. Other than
that, its pretty interesting (mostly because I am scratching my head trying to figure out the mechanism of this).
[Edited on 2-14-2011 by smuv]
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