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Author: Subject: Possible OTC, 'safe' methylating agents
Alice
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[*] posted on 12-5-2015 at 08:58


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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[*] posted on 12-5-2015 at 09:33


A bit off topic but still quite an interesting read.
Only works for phenolic aldehydes but is totally OTC and safe.
:D


Attachment: phpSHHQ12 (361kB)
This file has been downloaded 657 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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[*] posted on 27-5-2015 at 16:20


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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[*] posted on 10-8-2015 at 17:36


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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[*] posted on 10-8-2015 at 19:09


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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[*] posted on 22-8-2015 at 08:43


Quote: Originally posted by clearly_not_atara  
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]


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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[*] posted on 23-8-2015 at 11:51


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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[*] posted on 23-8-2015 at 18:40


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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[*] posted on 26-8-2015 at 15:07


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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[*] posted on 27-8-2015 at 14:36


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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[*] posted on 30-8-2015 at 15:54


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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[*] posted on 30-8-2015 at 16:07


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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[*] posted on 25-5-2016 at 08:15


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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[*] posted on 25-5-2016 at 21:17


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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[*] posted on 26-5-2016 at 04:28


Have you considered dimethyl carbonate?



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clearly_not_atara
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[*] posted on 26-5-2016 at 10:46


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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[*] posted on 26-5-2016 at 11:39


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)
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[*] posted on 26-5-2016 at 12:33


^ 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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[*] posted on 26-5-2016 at 20:03


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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[*] posted on 30-5-2016 at 19:18


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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[*] posted on 31-5-2016 at 05:13


Quote:
http://www.sciencedirect.com/science/article/pii/00404039938...
They used up to stochiometric quantities of iodide, and originally they had alkyl bromide, not alkyl chloride.
Quote:
https://www.google.com/patents/US3646147
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.
Quote:
http://pubs.acs.org/doi/abs/10.1021/jo01070a095
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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[*] posted on 31-5-2016 at 10:27


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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[*] posted on 31-5-2016 at 19:17


Quote: Originally posted by clearly_not_atara  
You are aware that the only reaction in which I'm suggesting to use iodide takes place in ethanol, correct?
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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[*] posted on 2-6-2016 at 14:03


Quote:

Oh really?


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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[*] posted on 2-6-2016 at 19:31


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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