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Alice
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| Quote: | | Basicall, esterification of methanol with benzoic acid will work for any acidic catalyst. |
Agreed.
| Quote: | | The truth is: you don't need HClO4-SiO2 catalyst to get decent yields,... |
Agreed. Nobody has told anything different. The point about the immobilized acid was to make it reusable and separable by filtration. This might be
interesting for industrial applications but is somehow a waste of time for lab scale experiments.
| Quote: | | ...and the procedure for esterification of those particular reagents is wrong. You need to heat the reaction mixture to methanol reflux, and this is
the highest temperature you can reach. |
As I have already mentioned, the high concentration might lead to a sufficiently elevated boiling point. Furthermore the temperatures given are oil
bath temperatures.
Unfortunately I can't find any literature values, but another example is the boiling point of 25% NaOMe solution in Methanol which is 92 °C:
http://www.alfa.com/en/catalog/46585
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lullu
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A bit off topic but still quite an interesting read.
Only works for phenolic aldehydes but is totally OTC and safe.
Attachment: phpSHHQ12 (361kB)
This file has been downloaded 1170 times
[Edited on 12-5-2015 by lullu]
No idea whats wrong with the filename most likely too long
"O-Methylation of benzaldehyde derivatives by lignin specific caffeic acid 3-O-methyltransferase.pdf"
[Edited on 12-5-2015 by lullu]
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byko3y
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The reaction mixture (after an old dimethyl oxalate attempt) with hexane added to it finally separated after a long time. By heating it to 90°C I
separated soe oil, that seems to contain a lot of dimethyl oxalate, it probably contains some oxalic acid in it, because it partially solidifies
somewhere above 56°C, and completely solidifies at 56°C. Its weight is 10 g total, probably it has something some 7g of dimethyl oxalate, out of 50
g possible. I failed to extract more of it probably because of intensive emulsification, so I've managed to separate only 15 ml of hexane out of 40
ml.
So the yield is somewhere at 10-30%. Still such a yield is just a vaste of reagents, because you can get 70-80% using concentrated sulfuric acid.
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clearly_not_atara
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Not terrifically safe, but -- silver tosylate is soluble in organic solvents, such as THF. Silver bromide, however, is not. Additionally AgOTs
precipitates from aqueous salt metathesis of AgNO3 with NaOTs. See:
http://onlinelibrary.wiley.com/doi/10.1002/047084289X.rs030/...
https://www.alfa.com/en/catalog/L00307
Adding ice-cold liquid MeBr to a solution of AgOTs precipitates AgBr leaving MeOTs, which can be used at much higher temperatures (reflux!). Silver
can be reused by reduction and regeneration of the nitrate.
[Edited on 11-8-2015 by clearly_not_atara]
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byko3y
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MeBr is a good methylation agent by itself, most likely it can be used for high temperature methylation using an appropriate solvent (up to
110-120°C). And i'm pretty sure MeCl could methylate a lot of stubborn substrates, but there have been no reports on that yet.
Forgot the link http://www.sciencemadness.org/talk/viewthread.php?tid=10507&...
[Edited on 11-8-2015 by byko3y]
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dermolotov
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Now this is interesting. But if you're attempting to find an OTC methylating agent, wouldn't MeBr suffice?
I guess MeOTs would have the benefit of being solid at high temperatures. Tolulolsulphonic acid is reasonably "OTC", too!
That would be a better substitute for the methyl grignard reagent I was planning on using.
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clearly_not_atara
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MeBr is hard to store because of its volatility. If you're going to methylate more than one thing in your life -- and who isn't? -- is pays to have
something that doesn't boil when you take it out of the freezer.
IIRC the ethanesulfonate/methanesulfonate is more stable than the tosylate.
[Edited on 23-8-2015 by clearly_not_atara]
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byko3y
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I really like the idea of preparing the methylation agent right before usage in case of such an easy to make compound as MeBr (MeOH + H2SO4 + NaBr).
Otherwise you need to titrate your reagent (solid or liquid) after prolonged storage, because you have no idea about degree of hydrolysis.
Sodium methyl sulfate obviously is a relatively stable compound (it is not hydrolysed by water quantitatively, like dimethyl sulfate), as well as
monomethyl sulfates are weak methylation agents  Anisole can methylate sodium
sulfate, thus leading to approx 50% yield for NaMeSO4 + PhONa <-> PhOMe + Na2SO4, until we shift the equilibrium (btw, this is a way for
demethylation of methoxyarenes).
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dermolotov
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Quote: Originally posted by clearly_not_atara  | | MeBr is hard to store because of its volatility. If you're going to methylate more than one thing in your life -- and who isn't? -- is pays to have
something that doesn't boil when you take it out of the freezer. |
Quite fair. That's also why all the methylations i've done in academia have used iodomethane/methyliodide. probably for the fact that it's much less
volatile and doesn't actually need a solvent because of its (relatively) high boiling point!
Perhaps if you're going to go the inch to create Me-I, you might as well just take the mile and make Me-OTs for even better storage.
(However, maybe going the mile would be to make Mesylic Anhydride and adding it to methanol to produce Methyl Mesylate with a boiling point of
200degrees centigrade. But Mesylic Anhydride is some expensive stuff at $50 per 25g)
[Edited on 26-8-2015 by dermolotov]
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byko3y
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Ms2O + MeOH -> MMS + MsOH
Mesylic anhydride is hard to store, half of it converts int omesylic acid.
You can use mesyl chloride for the same purpose with almost quantitive yield of MMS. There's a thread about preparation of ethylsulfonyl chloride from
ethyl bromide. But anyway all those preparations need a hell lot of afford, and you need another alkylation agent.
Well, you could use waste gases from demethylation (MeCl, MeBr, MeI): absorb it with thiosulfate, chlorinate the adduct, thus obtaining mesyl
chloride, and there your methylation agent goes.
But I doubt anything can bit the ease of preparation and storage of alkali methyl sulfonate, methyl halides, and, drumroll... DMC.
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clearly_not_atara
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Sodium methyl carbonate can be produced from the reaction of CO2 with a solution of NaOH in methanol; see:
http://digital.library.okstate.edu/oas/oas_pdf/v23/p67_68.pd...
Perhaps this can be methylated with, e.g., MeBr? Or -- perhaps more usefully -- maybe the salt decomposes to NaOMe on heating?
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byko3y
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Sure you can alkylate the monoalkyl carbonate.
Applications of Phase Transfer Catalysis, 15. Phase Transfer Catalytic Preparation of Carbonic Esters Without the Use of Phosgene
Preparation of dialkyl carbonates via the phase-transfer-catalyzed alkylation of alkali metal carbonate and bicarbonate salts
But you need two steps anyway, and the last step requires high pressure vessel. Just like a lot of one step syntheses directly from CO2 and methanol
require high pressure. Pretty much the only easy way to make DMC for amateur chemist is via base-catalyzed transesterification of ethylene carbonate
with methanol. Preparation fo ethylene carbonate is posted somewhere on this board.
There are also much easier ways to produce sodium methoxide:
Production of sodium and potassium alkoxides (CaO) - US 4267396
Preparation of alkali metal alkoxides (K2CO3) - US 2278550
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clearly_not_atara
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I noticed that it should be possible to perform the Strecker sulfite slkylation and the Finkelstein reaction at the same time, using a solvent where
NaOMs (Ms = mesyl) is more soluble than NaCl, and probably using a PTC to solvate SO32- in said solvent. Ethanol is such a solvent, IIRC.
The Strecker: MeCl + SO32- >> MsO- + Cl-; this is basically irreversible.
The Finkelstein: MeCl + MsO- <<>> MeOMs + Cl-; this is reversible, but driven by the precipitation of NaCl.
Total reaction+ 2MeCl + Na2SO3 [PTC] >> MsOMe + 2NaCl
I think this is probably stronger than any safer methylating agent, and safer than any stronger methylating agent. MeCl is easy to make and is a
pretty good substrate for the Finkelstein, although it is a flammable gas.
EDIT: It appears that iodide salts catalyze the Strecker reaction, by way of the intermediate Finkelstein exchange MeCl + I- <> MeI + Cl-.
Copper also catalyzes the sulfite alkylation. It appears that phase-transfer catalysis is not required (but may still be useful).
[Edited on 25-5-2016 by clearly_not_atara]
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byko3y
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Methyl methylate is not safe, methyl tosylate is relatively safe for its power, because of low vapor pressure.
Why not use MeCl directly in the first place? You can make dimethyl oxalate by esterification of oxalic acid with methanol and sulfuric acid, but why
not use methyl sulfate? And so on.
As you might know, methylene chloride does not react with alcohols or phenols at room temperature. Neither methyl chloride does react with sodium
acetate at appreciable rate. So, basically, with MeCl + MsONa you have the same problems that you encounter when directly trying to methylate some
substrate (phenol, acid, alcohol, etc). So why you need the another step? To perform the final methylation at low temperature?
Most of the safe methylation agents require high temperature to act efficiently, and I see nothing wrong with this - you just need not to heat your
body above 70°C, because the methylation agent becomes toxic above that temperature.
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Eddygp
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Have you considered dimethyl carbonate?
there may be bugs in gfind
[ˌɛdidʒiˈpiː] IPA pronunciation for my Username |
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clearly_not_atara
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You make a really good point, I think, in saying "if methyl chloride can methylate MsO-, why can't it methylate the substrate?". And it seems you're
also right about MsO- being a poor nucleophile that won't directly react with MeCl at low temperatures.
However, MeCl in the presence of iodide is significantly more reactive, because iodide is both an excellent nucleophile (k = 5.0, compare 4.0 for HO-
and 2.7 for AcO-) and also an excellent leaving group.
One advantage is that you might be able to produce the sulfonate at a relatively low temperature, using iodide catalyst, and then use the sulfonate at
a higher temperature. This is convenient because it is much easier to trap methyl methanesulfonate than methyl bromide, since the latter is less
polar, unreactive at low temperatures, and gaseous under standard conditions. So preventing large amounts of MsOMe from being release should be much
easier than preventing MeX release for X = Cl,Br,I since it can be condensed and trapped, and actual reports of methylation with methyl iodide
indicate it's a highly unpleasant reagent to work with, especially if there's any sort of reflux going on. Releasing large amounts of methyl halide is
worth avoiding, especially when you consider that some nucleophiles in your body (cysteine) are way more reactive than acetate...
Anyway the methylation of salicylaldehyde and related phenols is a common topic of discussion, and while MeBr might do it at reflux, MeCl or Me2CO3 or
carboxylate esters won't donit at any temperature, so most people use MeI or Me2SO4. In this case, MsOMe fills an important hole.
The other advantage of sulfonates, although I'm less clear on this, is that their high degree of steric hindrance allows them to be used to make
tertiary amines with low amounts of quaternization. Methyl iodide, and presumably MeCl + I-, will quaternize amines easily. Carboxylate esters and DMC
by contrast tend to give amides or urethanes respectively. So again MsOMe gives a result not easily obtained otherwise.
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Chemi Pharma
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Dimethyl Carbonate is a very versatile methylating agent. Useful in many fields and the most important: is a low toxic reagent.
I attached a very interesting study of it's properties, reactions and mechanisms in the paper below.
Attachment: Dimethyl carbonate as Methylating Agent.pdf (407kB)
This file has been downloaded 715 times
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clearly_not_atara
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^ just for clarity, none of the examples in that paper deal with either aliphatic amines or salicylaldehyde.
EDIT: though I find no evidence on searching that sulfonates will not quaternize amines, and several references saying they will, so my intuition here
is unfounded. MsOMe's only advantage is that it can be used at reflux and the outgas is easy to trap.
[Edited on 27-5-2016 by clearly_not_atara]
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byko3y
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| Quote: Originally posted by clearly_not_atara | | However, MeCl in the presence of iodide is significantly more reactive, because iodide is both an excellent nucleophile (k = 5.0, compare 4.0 for HO-
and 2.7 for AcO-) and also an excellent leaving group. |
Any proofs? The numbers you are reffering to are
correct ( Nucleophile ), but they are all about attacking ionic nucleophiles, not about coavalent targets like methyl iodide or methyl chloride. It's hard
to tell more without particular substrates.
E.g., in non-protic solvent the iodide is weaker nucleophile than chloride, thus equilibrium MeCl + NaI <-> MeI + NaCl is shifted to the left,
making MeCl a main alkylating agent (look up books or articles for Sn2 nucleophilicity in different solvents).
MeCl is almost insoluble in protic solvents, while iodide catalyst does not work for non-protic. So I can't rationalize your words about sulfonate
intermediate. UPD: of course, alcohols can dissolve MeCl, so I'm wrong about "MeCl is almost insoluble in protic solvents", so MeCl+NaI alklation can
be performed in alcohol, yet it requires high temperature and/or long reaction time.
Once again, methyl methylate is as dangerous as methyl bromide and dillute dimethyl sulfate vapor (0.2 kPa MeOMs vs 0.5 kPa Me2SO4), while MeCl is a
relatively non-toxic substance.
| Quote: Originally posted by clearly_not_atara | | The other advantage of sulfonates, although I'm less clear on this, is that their high degree of steric hindrance allows them to be used to make
tertiary amines with low amounts of quaternization. |
This time I'll give you some proofs. Iodide(I) has ionic
radius of 2.06Å ( Ionic radius), while sulfate ion has radius ca 1.6Å, so it's approx 2.5Å for methyl sulfonate - not much higher than iodide, as you can see.
(Why Phosphorus and Sulfur form High-Energy Bonds?)
[Edited on 27-5-2016 by byko3y]
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clearly_not_atara
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| Quote: | | Any proofs? The numbers you are reffering to are correct ( Nucleophile ), but they are all about attacking ionic nucleophiles, not about coavalent
targets like methyl iodide or methyl chloride. It's hard to tell more without particular substrates. |
Here are three examples of iodide-catalyzed nucleophilic displacement:
http://www.sciencedirect.com/science/article/pii/00404039938...
https://www.google.com/patents/US3646147
http://pubs.acs.org/doi/abs/10.1021/jo01070a095
In fact the last paper mentions a reaction between allyl chloride and acetic acid at room temperature in the presence of KI.
| Quote: | | Methyl methylate [sic] is as dangerous as methyl bromide |
Boiling points:
MeBr - 5 C
MeOMs - 202 C
[Edited on 31-5-2016 by clearly_not_atara]
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byko3y
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They used up to stochiometric quantities
of iodide, and originally they had alkyl bromide, not alkyl chloride.
Here water is a solvent (protic solvent). It works well, as
I've said, but you need an autoclave, as you can see in the patent, otherwise methyl chloride will just fly away.
Sodium iodide in acetone is a Finkelstein reaction.
As far as I can see, you might be right about methyl mesylate, because exposure to 50 ppm ot if for a long period of time (many days) is dangerous
(tumors), while similar concentration of MeBr has similar danger, but MeOMs vapor pressure is significatly lower, and dimethyl sulfate have similar
effects somewhere at 2 ppm.
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clearly_not_atara
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You are aware that the only reaction in which I'm suggesting to use iodide takes place in ethanol, correct? :/
Your point is well-taken, but I'd just like to point out: the only prep on this forum demonstrating the successful methylation of an ortho-acyl phenol
uses the potentially explosive reaction of bromine with DMSO to make Me3SBr. So that's the bar I'm trying to lower.
The real interesting reaction is the O-methylation of 2-pyrrolidone, since this leads to a stable triazolylidene with 1,2-diphenylhydrazine. But I
doubt any safe reagent will achieve this.
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byko3y
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Reaction of amines with alkylators in ethanol is approx 80 times slower than in aprotic solvent, and reaction of ionic nucleophile
with alkylator is approx 300 times slower in protic solvent. Old procedures in alcohols recommend weeks as a reaction time, while modern methods with
aprotic solvents can do the same in a matter of hours.
| Quote: | | O-methylation of 2-pyrrolidone |
Oh really?
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clearly_not_atara
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2527449/figure/F...
Scheme 1, steps f, g, h. Converts 2-methoxy-1-pyrroline (O-methylated 2-pyrrolidone) derivatives to a triazolium NHC with 1. phenylhydrazine (23 C),
2. tri[m]ethyl orthoformate in MeOH (80 C). Surprisingly, this is milder than routes to the imidazoles, mostly because the intermediate hydrazamidine
is more stable than the alpha-aminoimine you would use to perform the same synthesis to make an imidazolium. As such, avoids obnoxious precursors like
glyoxal and carbon monoxide.
The methylation can be performed with refluxing dimethyl sulfate, or with Me3O+, or MeOTf. I don't know if any 2-methoxy-1-pyrrolines can be prepared
safely, but from there to NHC is almost too easy. The majority of Scheme 1 describes how to make this precursor from phenylalanine without
racemization.
[Edited on 2-6-2016 by clearly_not_atara]
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byko3y
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Amide O-methylation is more like dehydration than a usual methylation, because there's no nucleophile in amide. Me3O+, Me2SO4, COCl2 are usual (and
pretty much the only) reagents for this reaction, but not the MeOTf.
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