Sciencemadness Discussion Board

Possible OTC, 'safe' methylating agents

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Formula409 - 13-12-2008 at 06:48

Greetings.

After reading the literature available on the Hive and the journals, it appears that methyl esters of carboxylic acids are able to function as methylating agents with reasonable yield (/chemistrydiscourse/000463170.html). The author of the post specifically mentions a journal article which shows that methyl, and other esters of oxalic acid alkylate aromatics quite well. This article is attached and a synthesis of the compound can be found here: http://www.orgsyn.org/orgsyn/orgsyn/prepContent.asp?prep=cv2... . The main advantage of dimethyl oxalate over compounds such as DMS and TMP are its easy availability and low toxicity, with it not having any large warnings on the MSDS and it being a powder, preventing one's DNA getting methylated when one tries to move the compound into the reaction vessel.

ning then proposes that methyl esters of other carboxylic acids found around the home (citric, tartaric) should be able to perform the same function. It appears that nobody else has attempted to study these as I am having a hard time just finding basic data regarding the properties of these compounds let alone their methylating powers!

Does anybody have any information to contribute regarding this? I am all for giving it a go, but my knowledge of methylation and designing synthesises is lacking. What would be a good, legal substrates to asses the effectiveness of each agent on?

It would be great if others could perhaps have a go at preparing methyl esters of both tartaric and citric acids, or even oxalic acid and seeing whether they work! I will be able to attempt a synthesis of all three (with pics) using Fischer Esterification within the next few days if all goes well.

Formula409.

[Edited on 13-12-2008 by Formula409]

[Edited on 13-12-2008 by Formula409]

Attachment: dimethyloxalate.pdf (684kB)
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Nicodem - 13-12-2008 at 08:46

The oxalic acid methyl and ethyl esters work because the monoalkyl oxalate is almost a good leaving group. Compare the pKa1 of oxalic acid and that of other common carboxylic acids like acetic or citric (the pKa of acids generally strongly correlates to their leaving group ability in S<sub>N</sub>2 reactions. Though esters of weak acids like carbonates, formates, acetates and phthalates have been reported to alkylate phenols at extreme conditions (only most simple phenolic substrates can thus be used), the mechanism was found to be different (not S<sub>N</sub>2). Of these only dimethyl carbonate is useful for preparative reactions.
As far as oxalates as alkylating reagents and home chemistry, you can find an example of ethylation of a simple phenol (eugenol) using diethyl oxalate and K2CO3 at the Hyperlab forum. I do not know if that procedure would work for phenols substituted with more sensitive functional groups as it is done under quite harsh conditions. Obviously since the reaction is a simple S<sub>N</sub>2 substitution, the methyl oxalate should react at considerably milder conditions since the reactivity of RX goes in the direction MeX > EtX > i-PrX (where X is a leaving group). Often the difference in reactivity between MeX and EtX is of order of few magnitudes.

Klute - 14-12-2008 at 09:01

Although this obviously is a interesting subject, I think it is very limited in scope. Like Nicodem said, only very few, thermicly stable phenols have been alkylated, most of the time in medium to mediocre yields, by very high temps. Under such conditions, even hydrogenosulfates seem as efficient and easily made.

I think other esters have much more potential, trimethylphosphate can be regarded as safe (as a chemical can be), and quite efficient for phenols, can be used around 80°C which is more than suitable for medium-sensitive phenol substrates.

Alkyl sulfonates are easily made at home, and seem very promising. Ullmann (the meber) reported very nice yields using ethane sulfonates. Tosyl chloride, although a bit less easily accesable, is a very quick and easy way to tosylates, which prove to be very good O- or N-alkylating agents .

MeBr is very easily made, and can be used in a way that prevents any exposure. Yields reported by Painkilla seem to be very satisfying.

Feel free to report back any results you can obtain with alkyl oxalates, these esters can be regarded as reagents for other reactions too (formation of b-keto esters here, here, here, and here.
(lots of other examples available)

It can also be used in a indole squeleton synthesis from o-nitrotoluene here.

I think there are far more possibilities in condensation reactions than in O-alkylations.

Nicodem - 15-12-2008 at 00:35

Nevertheless, dimethyl- or diethyloxalates are relatively common chemicals and some may have less troubles obtaining these than the more common reagents. Of course, if you have to buy a methylation or ethylation reagent then you better buy an efficient one. I would also not bother with esterifying oxalic acid just to prepare these oxalates, but it is always nice to have a wider spectrum of reagents that can be used by home chemists. Too bad that harsh conditions are required, but a reflux in DMF and K2CO3 as base is actually something that several simple phenols can withstand without troubles and I have to thank Formula409 for sharing the attached paper now that I finally read it.

Formula409 - 15-12-2008 at 00:53

Thank you for your responses. I should be able to post up a synthesis tomorrow hopefully. Just a quick question, though, what purpose does the DMF serve in the methylation reaction? Is it just used as a solvent that will not react with the agent as it cannot be further methylated? Can it be substituted with DMSO? I will have to purchase some (long wait) if I cannot find a suitable substitute.

Formula409.

[Edited on 15-12-2008 by Formula409]

Nicodem - 15-12-2008 at 02:03

DMF is a dipolar solvent which serves many purposes in the reaction (to solvate the K2CO3 in order for it to deprotonate the phenol; S<sub>N</sub>2 reactions run faster in polar solvents; it is a solvent that does not solvate the nucleophile and thus makes it more reactive...). DMF can be O-methylated thus forming the MeO-CH=N<sup>+</sup>Me<sub>2</sub> species which can also O-methylate either the phenoxide or monomethyl oxalate anions (thus making this irrelevant). However, at such temperature using DMSO may not be a good idea since it can also get O-methylated but to a species that decompose to formaldehyde and dimethylsulfide (this is the reason why alkylations are generally not done in DMSO at temperatures higher than 100°C). Instead of DMF you can use any equivalent solvent: NMP, dimethyl- or diethylacetamide, sulfolane, tetramethylurea (expensive!) and so on. You can also use a less polar solvent like diglyme or polyethyleneglycol. Or you can just do the reaction solventless like in the example described at the Hyperlab forum (I could post a direct link, but I'm not sure their administrator would like this, so find it yourself - it is in the " The eugenoloids / Эвгенолоиды" thread which is currently on the 11th page of the forum).

Formula409 - 18-12-2008 at 19:22

Ok, have obtained NMP. Going to try methylating a phenolic benzaldehyde with dimethyl oxalate both solventless and in NMP which I get time. A TON of my equipment broke yesterday which will prevent me doing anything until I purchase more when the suppliers re-open after Christmas.

Formula409.

[Edited on 10-19-2009 by Polverone]

Ebao-lu - 19-12-2008 at 00:00

Actually, CHO(and other EWG-groups) in o,p-positions to OH make it less active, and in case of such weak alkylators like dimethyl oxalate it may be critical. If the experiment fails, try to prolong the time of reaction and/or increase the temperature.

detritus - 19-12-2008 at 01:21

@Nicodem,

I looked but could not find the hyperlab article you mentioned. Forum link sent me to a website placeholder..? Do you have a link or a cut/paste you can sharing?

Mush - 19-4-2015 at 05:51

1, The Alkylation of Phenols with Dialkyl Oxalate. III. n-Propylation, n-Butylation and Isoamylation

Yoshiaki Sakakibara

Nippon kagaku zassi Vol. 82(1961) No. 3

2,
The Alkylation of Phenols by Means of Oxalate. II. The Methylation and the Ethylation of Phenols

Yoshiaki SAKAKIBARA

Nippon kagaku zassi Vol. 81(1960) No. 3

Science reports of the Yokohama National University. Section 1, Mathematics, physics, chemistry 19 ,p32-47,1972
3, Allylation of Phenols (with diallyl oxalate)

http://kamome.lib.ynu.ac.jp/dspace/simple-search?query=Yoshi...

4, N-Methylation and N-Ethylation of Aniline

http://kamome.lib.ynu.ac.jp/dspace/simple-search?query=Yoshi...

5, n-Octylation of Phenols (with di-n-octyl-oxalate)

http://kamome.lib.ynu.ac.jp/dspace/simple-search?query=Yoshi...




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[Edited on 19-4-2015 by Mush]

byko3y - 19-4-2015 at 06:54

Nein, nicht understandu, neither word. Can anyone at least quote the conditions and yields for the methylation via dimethyl oxalate? Because google translate doesn't help to undarstand what paper says: "Death in the previous report yu "as a firewood seems alkylating agent
Oxalic acid dimethicone". The problem is a bad characters recognition in the original document.
At hive people mentioned that the method gives really low yields.
Btw, does the next article at the end of 2, Nippon kagaku zassi Vol. 81(1960) No. 3 81_495.pdf tell about amination of alcohol via imide?
For some reason there's not much said about dimethyl carbonate, while it is a relatively ease to synthesize via ethylene carbonate and further transesterification with methanol via basic catalyst like NaOH or K3PO4.
The stumbling-stone of the methylation with carboxylic acid ester is that phenols prefer to give acid-phenol ester rather than the alkyl-phenol one. Same difficulty exist while methylating with dimethylcarbonate, and the solution is heat to at least 150°C driving away CO2. As you may understand, you can't get rid of the oxalate, so the same trick doesn't work for dimethyloxalate.
UPD: oops, looks like the OP article (dimethyloxalate.pdf) has a translated description of substrates and yields. So the yield for phenol o-methylation is almost 80%.
Here's an article in english describing the mechanism and a picture from Houben-Weyl which is actually the same as in the paper, but is easier to read.
As you may notice, the actual mechanism is not a transesterification, and you can't use any other solvent except formic secondary amides (which is DMF in most cases).

Dimethyloxalate alkylation.png - 23kB

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[Edited on 19-4-2015 by byko3y]

Mush - 19-4-2015 at 13:05

Qing-hua. C.; Ju-xian. L.; Lan-gui. C.; Xue-wen. 2. Acta Chimica Sinica 1981,39,263

THE ALKYLATION OF PHENOLIC HYDROXYL GROUP IN BERBAMINE
CHEN QING-HUA, LU JU-XIAN, CHEN LAN-GUI, ZHAO XUE-WEN
Institute of Hygiene, Chinese Academy of Medical Sciences, Beijing

Abstract A method concerning the selective alkylation of phenolic group in berbamine by means of dialkyl oxalate was reported. We succeeded in preparing methyl, ethyl and iso-propyl ethers of berbamine without N-alkylation by treating sodium berbaminate with the corresponding dialkyl oxalates.

Sorry, this paper is written in Chinese. :(

Thanks for that scheme! Here is the article what the book referes to.
(176) Anomalous ether formation in attempts to transesterify oxalate esters with phenoxides
Edward E. Smissman, Michael D. Corbett, Samir. El-Antably, Kathryn C. Kroboth
JOC, 1972, pp 3944–3945

DOI: 10.1021/jo00797a040

Attachment: THE ALKYLATION OF PHENOLIC HYDROXYL GROUP IN BERBAMINE.pdf (2.5MB)
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[Edited on 19-4-2015 by Mush]

byko3y - 19-4-2015 at 14:43

I dunno how to tell ya but... it's the same paper as I posted. Look at the file size.
Trying to translate the first procedure from the chinese paper:
"1. Dimethyl oxalate ester method: 50 ml of anhydrous methanol in a dry three-necked flask, 0.46 g (0.02 mol) of sodium metal mole, 12.2 g (0,02 mol) small polyamine was added after the completion of action , heated and stirred to dissolve.
The methanol was evaporated, 60 ml of toluene, 10 ml of toluene was distilled off, coolish, ester was added 4.7 g of oxalic acid dimethyl [11], (0.04 mol), heated at reflux for 3 hours identified by thin layer chromatography, about 75% the amine was converted to ether small bi. Was extracted with 2% hydrochloric acid, then with 2% potassium hydroxide aqueous solution was basified to ph 10, deposited precipitate was filtered, the precipitate washed with water until neutral, 60C and dried to give 9.4 g of a white powder , yield 75.5% acetone was purified by recrystallization or column, you can get 4.7 grams of fine granular colorless crystals, mp 180 ~ 182 ° С, the yield of 37%;. Specific rotation [a] 15D + 150 ° (c. 0.89, chloroform); Rf value Rf0.83 ([3] reported that the melting point of 182 ~ 183 ° С (acetone); specific rotation [a] 20D + 151 ° (c 0.85, chloroform))"
So they've got 75% crude yield using NaOMe and dimethyl oxalate. I can't see the DMF there in fact, nowhere in the article.

UPD: Forgot to link a nice article about dimethyl oxalate preparation:
"Protic Acid Immobilized on Solid Support as an Extremely Efficient Recyclable Catalyst System for a Direct and Atom Economical Esterification of Carboxylic Acids with Alcohols"
A. K. Chakraborti, B. Singh, S. V. Chankeshwara, A. R. Patel, J. Org. Chem., 2009, 74, 5967-5974.
DOI: 10.1021/jo900614s
http://www.organic-chemistry.org/abstracts/lit2/638.shtm
At the official page you can freely download a supporting information file containing the procedure ( this one http://pubs.acs.org/doi/suppl/10.1021/jo900614s/suppl_file/j... )
Briefly: HClO4 on silica gel powder (obtained by adding HClO4 to a silica gel in Et2O, evaporating the ether and then heating for 3 days at 100 C in vacuum) can be used to catalyze the esterification of a hell lot of alcohols and acids. To perform the reaction you need to just mix everything (acid, alcohol and catalyst) and stir few hours until it's done.
The orgsyn procedure gives lower yield and requires some nasty method to separate the ester. Though I don't know if the HClO4 catalyst is applicable to dimethyl oxalate.

[Edited on 19-4-2015 by byko3y]

clearly_not_atara - 19-4-2015 at 20:34

I wonder if you couldn't find some sort of drying agent that would let you esterify methanol and toluenesulfonic acid. It's possible to get TsOMe by reacting TsOH with a methyl orthoester which can be produced from methanol and acetonitrile. Maybe you could do the same thing with methyl carbamate: MeOCONH2 + 2TsOH >> MeOTs + CO2 + NH4OTs

For methyl orthoacetate see the attachment on preparing orthoesters from nitriles and alcohols. Acetonitrile, of course.

Then TsOH + Et(OMe)3 >> TsOMe + MeOH + AcOMe:

https://www.erowid.org/archive/rhodium/chemistry/sulfonic.es... (I am being a little optimistic that orthoacetate will behave like orthoformate...)

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[Edited on 20-4-2015 by clearly_not_atara]

byko3y - 19-4-2015 at 23:00

What will hydrolyze the methyl carbamate? At the left side you have an amide, at the right side there are acid and ammonia.
Methyl tosylate is OTC if you can get toluenesulfonic acid and either acetonitrile or sodium methoxide + chloroform, which looks more OTC to me, though longer to perform.
And yes, orthoacetate is almost the same as orthoformate. Orthoformate is employed commonly because it can be cheaply made industrialy using mentioned sodium alkoxide + chloroform, while acetonitrile by itself costs a lot.

clearly_not_atara - 20-4-2015 at 07:36

Quote: Originally posted by byko3y  
What will hydrolyze the methyl carbamate? At the left side you have an amide, at the right side there are acid and ammonia.


Henry Louis le Châtelier, of course. MsOH transesterifies to give methyl mesylate and carbamic acid HO2CNH2, although the equilibrium is in favor of methyl carbamate, and carbamic acid decomposes to CO2 and NH3. We have to hope MsOMe doesn't react with NH4OMs, which normally only happens under basic conditions / high temps. Water shouldn't be necessary.

Also, methanesulfonic acid or ethanesulfonic acid makes more sense because those are liquids. Ethanesulfonic acid can be had from EtBr + Na2SO3 (Strecker sulfite alkylation).


[Edited on 20-4-2015 by clearly_not_atara]

byko3y - 20-4-2015 at 09:06

Quote: Originally posted by clearly_not_atara  
MsOH transesterifies to give methyl mesylate and carbamic acid HO2CNH2

No, it would not. I see no reason for tosyl to attack the ester oxygen, even if it's converted into oxonium. Water can easily hydrolize this but not the tosyl. Remember that tosyl is a good leaving group, so you will have a hard time trying to attach it to anything.
Although the tosyl could have attacked the carbonic acid carbon, but again the tosyl s a good leaving group.
Toluenesulfonic, methane- and ethanesulfonic acids have pretty similar functional properties.

clearly_not_atara - 20-4-2015 at 20:04

You're forgetting that it's an equilibrium.

MsOH + MeOCONH2 <<<< > MsOMe + HOCONH2 (maybe the left is favored by 10^5?)

HOCONH2 >>>> CO2 + NH2 (incalculably huge; MsOH's affinity for ammonia makes this irreversible)

Everything is assisted by using an excess of MsOH. Now, maybe carbamic acid is stabilized somehow, or maybe MsOMe reacts with NH2 regardless, but it conceivable.

byko3y - 20-4-2015 at 22:19

Carbamic acid has pka close to acetic acid. So basicall it's MsOH + MeOAc <-> MsOMe + HOAc, with equilibrium strongly to the left, because MsOMe is highly electron deficient and HOAc is electron sufficient. I want to emphasize that the mixture on the right side is not slightly acidic, but strongly acidic because the MsOMe is a lewis acid in fact with the oxygen positively charged.
Decomposition product of carbamates should be close to urea's ones (cyanuric acid, ammelide and ammeline http://www.sciencedirect.com/science/article/pii/S0040603104... )
I like the idea of driving the equilibrium by evaporating the reactants, but I don't think it's possible here.
Actually, toluenesulfonic acid is a good transesterification catalyst for converting dimethyl carbonate into diphenylcarbonate ( http://www.sciencedirect.com/science/article/pii/S1566736710... ), though in this reaction amount of methyl tosylate is close to zero.

Dimethyl oxalate decarbonylation to dimethyl carbonate

byko3y - 1-5-2015 at 03:27

US4544507 - alkoxides
US5973184 - alkali carbonates
(also CN 1113852)
428px-DMC_from_DMO.svg.png - 4kB

[Edited on 1-5-2015 by byko3y]

byko3y - 11-5-2015 at 10:51

I've tried esterification of oxalic acid via HClO4-SiO2 as the article http://pubs.acs.org/doi/abs/10.1021/jo900614s says, and I'd say it's ludicrous. My first suspicion aroused after reading about esterification of methanol at 60-80°C in an open reactor.
And truly, the goddamn methanol just flew away. 1-5% yield of dimethyl oxalate is what I've got. I used oxalic acid dyhidrate, but what is the point of the catalyst which doesn't help to get rid of water?
I'm starting to feel like I can ignore every article written by indian "researchers".
There's a nice review of esterification reactions
http://www.hindawi.com/journals/isrn/2012/142857/
and basing on it I can say that a sulfuric acid is a best catalyst you can pick for fisher esterification of oxalic acid. In fact, you can use a plain oxalic acid as a catalyst, though you will need a lot of time to reach equilibrium. Actually, you can use almost any lewis or bronster acid, like HCl, NaHSO4, BF3, SnCl2, etc.
But the main problem with the dimethyl oxalate is that it's the only case when you can't dehydrate the reaction mixture easily. You can use carbodiimides for that, or thionyl chloride and product of its reaction with silica gel (so-called silica chloride and methoxyl silica gel), or maybe polyphosphoric acid, but the authors of orgsyn article use sulfuric acid for dehydration: 0.64 mole of H2SO4 per 1 mole of oxalic acid and 2.5 moles of methanol, this is clearly not just a catalyst, but a dehydration agent. And if you use too much of sulfuric acid - your mixture will become viscous and it becomes harder to separate the product.
This rises some questions:
- would it be easier to use monomethyl sulfate directly instead of using oxalate as alkyl carrier?
- in case of phosphoric acid as a dehydration agent (polyphosphoric/P2O5), we have n-methyl-phosphates as intermediates ( e.g. US4133838 ); maybe it's better to avoid the dimethyloxalate and go strait to the trimethyl phosphate?
As far as I can see, dimethyloxalate is viable in case you produce it from something like methanol and CO on palladium catalyst, which is clearly not OTC. And within OTC constraints every route to dimethyloxalate lies through some methylation agent.

Alice - 12-5-2015 at 03:46

Quote: Originally posted by byko3y  
I've tried esterification of oxalic acid via HClO4-SiO2 as the article http://pubs.acs.org/doi/abs/10.1021/jo900614s says, and I'd say it's ludicrous.


The examples given in the paper are about equimolar mixtures of methanol and benzoic acid. If I got it right, you have used 2 parts water, 1 part oxalic acid, and 2 parts methanol. So you didn't do what the paper says but something different.

Quote:
My first suspicion aroused after reading about esterification of methanol at 60-80°C in an open reactor.And truly, the goddamn methanol just flew away. 1-5% yield of dimethyl oxalate is what I've got.


By an open reactor you mean non pressurized with reflux?
Maybe the boiling point of methanol is elevated due to the highly concentrated mixture with benzoic acid, so it doesn't fly away. If a diacid is used as the substrate the molality of the methanol mixture is only half compared to a monoacid.

Quote:
I used oxalic acid dyhidrate, but what is the point of the catalyst which doesn't help to get rid of water?


Maybe one equivalent of water can get adsorbed by the silica effectively, which does not mean more water could get absorbed equally well.

byko3y - 12-5-2015 at 04:47

Alice, I did 10 g of SiO2 + 1.75g of HClO4 (17.5 mmol, almost 2% by methanol) catalyst for 55 g of oxalic acid dyhydrate (0.45 mole) and 32 g of methanol (1.0 mole). After reaction, an ether extract gave me something that can be called traces of ester.
I did put a simple reflux condenser on it, and obviously it did not pressurize the vessel, and probably some amount of methanol was left in the reaction mixture, but it's not enough to make any decent yield.
Methanol-benzoic acid mixture is zeotropic, as well as benzoic acid-water. You can keep the mixture on reflux without methanol flying away, ut you won't be able to reach 80°C because it starts bumping as crazy, and again your methanol will be out of reaction in the reflux condenser all the time.
If you use a strong acid, like nitrobenzoic or oxalic, then the equilibrium is shifted to acid+alcohol, while for ethanol and acetic acid equilibrium constant is like [ester]*[water] / [alcohol]*[acid] = 4. And this is why dialkyl oxalates are used for alkylation - they can easily give away the alkyl group.
Silica gel absorbs 0.2g/g (0.1 mole of water for my case) at room temperature, which is far even from absorbing water of esterification water.
It's okay, I was performing bulshit researches in my college and writing reports about them. It's just sad that indian researches are forced to publish their articles in magazines like tetrahedron or synlett.

Alice - 12-5-2015 at 06:33

Thank you for mentioning the equilibrium issue. But this means that an esterification reaction where water is not removed sufficiently (like the one you tried here) is a bad idea with strong acids like oxalic acid. The authors didn't show the reaction for oxalic acid anyway.

Comparing the amount of catalyst you used with the amount the authors used shows some difference:

Paper example:

50 mmol n-octanol -> 1 g catalyst ("1%")
For 1 mol n-octanol -> 20 g catalyst

Your example:

1 mol methanol -> 10 g SiO2 + 1.75 g HClO4

So you have used another catalyst composition. Let's see what is the difference in catalyst preparation:

Paper:

23.75 g SiO2 + HClO4 1.25 g (12.5 mmol)

You:

10 g SiO2 + 1.75 g HClO4 (17.5 mmol)

The factor of HCLO4 content is 3.3 between yours and the catalyst described in literature.

If you like to perform the reaction like stated in literature with "2 %" you would have to use 40 g of catalyst for 1 mol methanol.

I didn't search for a value of SiO2 water adsorption, so thanks for delivering one. This speaks against water removal as a major driving force but it might still contribute to some degree especially if the equilibrium is already on the product side.

I think your experiment is not suitable to make any judgements about this publication. Unless an experiment is performed according to one of the literature examples I remain undecided. :)


[Edited on 12-5-2015 by Alice]

byko3y - 12-5-2015 at 08:00

Basicall, esterification of methanol with benzoic acid will work for any acidic catalyst. The truth is: you don't need HClO4-SiO2 catalyst to get decent yields, 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.
I want to emphasize that the stochiometric amount of methanol is 0.7 mmol, so I was very close to the article conditions in that regard.
http://pubs.rsc.org/en/Content/ArticleLanding/2003/CC/b30417... - The original "research" on the catalyst. First, the authors (which are all the same people as with other article) used aqueous HClO4 and it worked well (for Ac2O acylation, lol). There's neither rationalization nor experimental data on stochiometric of the HClO4-SiO2 catalyst, they just used the only perchloric acid loading all over their works. Basically, you can add aqueous HClO4 and the reaction should work too, though in the esterification article the authors never compared free and supported acids.
First and foremost difference of my conditions and article conditions - I've used a hydrated reagent. But what is the point of the catalyst, if a catalytic amount of sulfuric acid can give you the same results?

Alice - 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

lullu - 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


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[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]

byko3y - 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.

clearly_not_atara - 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]

byko3y - 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]

dermolotov - 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.

clearly_not_atara - 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]

byko3y - 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).

dermolotov - 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]

byko3y - 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.

clearly_not_atara - 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?

byko3y - 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

clearly_not_atara - 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]

byko3y - 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.

Eddygp - 26-5-2016 at 04:28

Have you considered dimethyl carbonate?

clearly_not_atara - 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.

Chemi Pharma - 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)
This file has been downloaded 508 times

clearly_not_atara - 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]

byko3y - 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]

clearly_not_atara - 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]

byko3y - 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.

clearly_not_atara - 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.

byko3y - 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?

clearly_not_atara - 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]

byko3y - 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.

clearly_not_atara - 21-9-2018 at 11:47

Recently Loptr posted about the catalytic tosylation of alcohols with CoCl2:

https://www.sciencemadness.org/whisper/viewthread.php?tid=91...

However, a careful reading of the paper he attached shows only tosylations of secondary alcohols, and indeed, the paper claims that the reaction prefers to tosylate secondary rather than primary alcohols. But the paper references an earlier paper, using Fe3+ on montmorillonite as a heterogeneous catalyst for tosylation of primary alcohols with TsOH.

That paper, "Montmorillonite Clay Catalyzed Tosylation of Alcohols and Selective Monotosylation of Diols with p-Toluenesulfonic Acid: An Enviro-Economic Route", is attached. In fact, this paper claims the preparation of methyl tosylate in 82% yield:

MeOH + TsOH [ClCH2CH2Cl, Fe3+/montmorillonite clay, reflux, 3 hours] >> MeOTs + H2O

When I discussed the CoCl2 paper on another forum, there were some concerns that the results might not replicate. The following points were raised:

- TsO- is a good leaving group

- The researchers are from India

- The paper was published in Tetrahedron Letters

In response to the first point, I want to point out that the reaction of triflic acid and alcohols produces some yield of alkyl triflates with no catalyst:

https://en.wikipedia.org/wiki/Triflic_acid#Organic_chemistry

We know catalysts cannot change an equilibrium, only cause it to be reached, so the role of the catalyst is irrelevant when considering the reaction energetics. The equilibrium:

MeOH2+ + TsO- >> << TsOMe + H2O

does not at first seem to lean right, but if you complete the equation:

MeOH2+ + TsO- + TsOH >> << TsOMe + H2O + TsOH >> << TsOMe + TsO- + H3O+

you can then understand why TsOMe is produced. H3O+ (pKa -1.6) is a weaker acid than MeOH2+ (pKa -2.5), so the reaction is actually driven forward by the basicity of water, or alternatively, by the affinity of TsOH for H2O. It is therefore clear that using an excess of toluenesulfonic acid should help drive the reaction to completion.

In response to "the researchers are from India", this paper actually comes from two very distinguished researchers who both have h-indexes over 50:

https://scholar.google.com/citations?user=R1MxH_EAAAAJ&h...
https://scholar.google.com/citations?user=XgHcVy0AAAAJ&h...

The ICT Mumbai where Prof. Kantam works is one of the top 20 universities in India. So I think these guys are better than your standard-issue Indian researchers.

As for TetLet, I can't defend it, but the paper got cited 56 times without any complaints, which is a good sign. Overall, the method definitely warrants further investigation, particularly since montmorillonite and aqueous FeCl3 are OTC. Amazon reviews laud the effectiveness of montmorillonite for "detoxification from chemtrails", so as usual, crazy people keep us in business.

Intriguingly, the paper also claims the preparation of 1-tosyloxy-2-propanol from propylene glycol by the same method.

The preparation of the catalyst is as follows:

"K10 montmorillonite purchased from Fluka was used as
such. The chemical composition of this starting material
(main elements) is SiO2, 67.6; Al2O3, 14.6; Fe2O3, 2.9;
MgO, 1.8. Metal-exchanged montmorillonite:22 to 1 L of
1 M aqueous metal chloride solution, 80 g of K10 montmorillonite was added. Stirring was maintained for
16–30 h in order to saturate the exchange capacity of K10
montmorillonite. The clay suspension was centrifuged and
the supernatant solution was discarded. The clay catalyst
was washed each time with fresh distilled water until free
of chloride ions as indicated by AgNO3 test. The catalyst
was dried overnight in an oven at 1208C and finely ground in
a mortar."


Attachment: choudary2000.pdf (161kB)
This file has been downloaded 383 times

[Edited on 22-9-2018 by clearly_not_atara]

AvBaeyer - 23-9-2018 at 01:12

clearly-not-atara:
You obviously did not read the paper very carefully. The paper reports high yields of primary benzylic and allylic alcohols and even a modest yield of a normal aliphatic primary alcohol which is very clearly shown in Table 2. How could you miss that? Indeed secondary aliphatic alcohols appear to be selected for over primary ones but not to complete exclusion. Please try to be a bit more thorough.

AvB

clearly_not_atara - 23-9-2018 at 10:39

Quote: Originally posted by AvBaeyer  
clearly-not-atara:
You obviously did not read the paper very carefully. The paper reports high yields of primary benzylic and allylic alcohols and even a modest yield of a normal aliphatic primary alcohol which is very clearly shown in Table 2. How could you miss that? Indeed secondary aliphatic alcohols appear to be selected for over primary ones but not to complete exclusion. Please try to be a bit more thorough.

AvB
My bad, I missed entry 5 in Table 2. I wouldn't normally count allylic and benzylic alcohols as analogous to methanol.

But really my point in posting was to argue that these reactions are plausible despite the fact that the papers are from Indian researchers and published in Tetrahedron Letters. I was originally going to write the same post defending the first paper, but in the other paper methyl tosylate was actually synthesized, so of course it seemed more appropriate here.

People didn't seem as impressed by Loptr's post as I thought they would be, because discussions of methylating agents usually end with no good answers. I thought maybe nobody was interested in the reaction because they didn't think it would work, but after thinking about it and reading other related literature, I wanted to argue that it will work.

Loptr - 23-9-2018 at 12:23

I started looking for more articles discussing catalytic tosylation and discovered this has been discussed before The Hive by psyloxy. I am not sure what ever came of it.

https://the-hive.archive.erowid.org/forum/showflat/Cat-/Numb...
https://chemistry.mdma.ch/hiveboard/chemistrydiscourse/00050...

Another Indian/Tetrahedron paper, except this time using silicon tetrachloride. There is mention of reaction with MeOH getting an 87% yield.
An efficient and selective tosylation of alcohols with p-toluenesulfonic acid
https://www.sciencedirect.com/science/article/pii/S004040390...

Attachment: das2004.pdf (250kB)
This file has been downloaded 676 times

Another one that I have found uses ZrCl4 as catalyst.

Greene's Protective Groups in Organic Synthesis also mentions these three methods. YMMV.



[Edited on 24-9-2018 by Loptr]

tosylation_greenes-protective-groups_mention.png - 95kB

Loptr - 25-9-2018 at 05:25

Reaction of Carboxylic Acid Esters with p-Toluenesulfonic Acid



pTsOH_transesterification.png - 88kB

Attachment: nitta1985.pdf (742kB)
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clearly_not_atara - 25-9-2018 at 09:26

^now that is awesome!

The paper made me wonder if methyl carbamate (bp 177 C) could be used instead of dimethyl carbonate (bp 90 C) since the latter's low boiling point was blamed for a low yield. In both cases, the acid decomposes upon cleavage:

MeO2CNH2 + 2 TsOH >> MeOTs + CO2 + NH4OTs

The amine should not be alkylated as long as the reaction mixture is not basified in situ -- ammonium tosylate can be washed away with cold water, which should not dissolve MeOTs.

It's my understanding that methyl carbamate is actually produced more easily from methanol + urea than DMC. The first NH2 comes off more easily than the second. Methyl carbamate might also be produced from the reaction MeOH + NaOCN + acid, as long as that reaction can be performed safely -- isocyanic acid is a little scary, but NaOCN is very easy to make.

Loptr - 25-9-2018 at 09:50

Methyl tosylate seems to be a very useful reagent. I am finding a treasure trove of interesting reactions.

Nickel-Catalyzed Reductive Methylation of Alkyl Halides and Acid Chlorides with Methyl p-Tosylate
https://pubs.acs.org/doi/10.1021/ol502682q

methyl-tosylate_acid-chloride_alkylation.png - 52kB

Attachment: Nickel-Catalyzed Reductive Methylation of Alkyl Halides and Acid Chlorides with Methyl p-Tosylate.pdf (479kB)
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[Edited on 25-9-2018 by Loptr]

byko3y - 25-9-2018 at 13:52

That's a modification of reaction known for at least thirty years:
https://doi.org/10.1016/S0040-4039(00)81952-8 - Metallic nickel: A coupling reagent of benzyl halides and acyl halides to yield benzyl ketones
https://dx.doi.org/10.1021/jo00209a006 - Metallic nickel-mediated synthesis of ketones by the reaction of benzylic, allylic, vinylic, and pentafluorophenyl halides with acid halides

monolithic - 25-9-2018 at 15:40

Are these reagents any more "OTC" or safer than dimethyl carbonate or trimethyl phosphate?

clearly_not_atara - 25-9-2018 at 15:53

Everything in this thread is more OTC than trimethyl phosphate. Given an arbitrary compound containing "methyl", it's probably more OTC than methyl phosphate. (MeO)3PO is made exclusively from the reaction of alcohols with phosphoryl chloride, which is highly restricted because it's an LSD precursor.

The OTC synthesis of dimethyl carbonate is believed to be fully achievable, but AFAICT it has never been performed. Dimethyl carbonate also requires pressure for methylation, so while it is safe to handle, it is less safe and not convenient to use.

In general methylating agents are not sold to the public, for obvious reasons. I would say that these direct esterifications of toluenesulfonic acid are the most promising development I've ever seen in methylation reactions in amateur chemistry -- although, to be fair, nobody has tried it yet.

Methyl tosylate is certain to be highly carcinogenic if ingested, but it has a very low vapor pressure, so most of us believe it is much safer than other strong methylating agents. Methyl phosphate and carbonate are much less reactive and therefore safer, although (MeO)3PO is probably a carcinogen.

monolithic - 25-9-2018 at 18:24

I think dimethyl carbonate is being phased in as a VOC compliant solvent, so it is OTC, in a way. You can purchase a liter of it on Amazon right now.

Loptr - 25-9-2018 at 18:26

Quote: Originally posted by monolithic  
I think dimethyl carbonate is being phased in as a VOC compliant solvent, so it is OTC, in a way. You can purchase a liter of it on Amazon right now.


I am still confused why you said trimethyl phosphate was OTC. You can't make the phosphate esters from phosphoric acid.

clearly_not_atara - 25-9-2018 at 19:22

Quote: Originally posted by monolithic  
I think dimethyl carbonate is being phased in as a VOC compliant solvent, so it is OTC, in a way. You can purchase a liter of it on Amazon right now.
That makes it an awful lot easier to use the methyl tosylate procedure Loptr just posted.

Although, being that DMC is volatile, organic, and degrades to methanol, which as we all know causes blindness, I'm curious why it's considered to be VOC compliant? Is it really considered safer than acetone or something? I know it's a battery electrolyte, but I'm pretty sure that methyl ethyl carbonate "MEC" is preferred due to some sort of weird electrical properties.

monolithic - 25-9-2018 at 21:33

Quote: Originally posted by Loptr  
Quote: Originally posted by monolithic  
I think dimethyl carbonate is being phased in as a VOC compliant solvent, so it is OTC, in a way. You can purchase a liter of it on Amazon right now.


I am still confused why you said trimethyl phosphate was OTC. You can't make the phosphate esters from phosphoric acid.


I thought I remembered reading a "somewhat" straightforward preparation of trimethyl phosphate, but I'm clearly wrong.

Loptr - 26-9-2018 at 06:58

Quote: Originally posted by monolithic  
Quote: Originally posted by Loptr  
Quote: Originally posted by monolithic  
I think dimethyl carbonate is being phased in as a VOC compliant solvent, so it is OTC, in a way. You can purchase a liter of it on Amazon right now.


I am still confused why you said trimethyl phosphate was OTC. You can't make the phosphate esters from phosphoric acid.


I thought I remembered reading a "somewhat" straightforward preparation of trimethyl phosphate, but I'm clearly wrong.


I thought you were going to have an OTC source for it! What a let down! :(

deep_dreamer - 6-10-2018 at 02:07

It seems that trimethyl phosphate may also be produced by reacting P2O5 with MeOH, yield about 35%. I have originally found the procedure as a german translation on LambdaSyn, but this seems to be a copy of the original writeup:

https://chemistry.mdma.ch/hiveboard/rhodium/me3po4.html

monolithic - 6-10-2018 at 04:46

Quote: Originally posted by deep_dreamer  
It seems that trimethyl phosphate may also be produced by reacting P2O5 with MeOH, yield about 35%. I have originally found the procedure as a german translation on LambdaSyn, but this seems to be a copy of the original writeup:

https://chemistry.mdma.ch/hiveboard/rhodium/me3po4.html


I believe this is what I was thinking about, although P2O5 isn't very OTC. :D

clearly_not_atara - 8-10-2018 at 09:55

Apparently aluminium phosphate decomposes to P2O5? People in the old thread couldn't find a use for P2O5, but Magpie reported that the reaction was noticeable at 1000 C:

http://www.sciencemadness.org/talk/viewthread.php?tid=12694

Aluminium metaphosphate has been described and it might decompose sooner:

https://www.americanelements.com/aluminum-metaphosphate-1377...

but I've no idea how to make it. Nickel sulfate is used in the sulfur-iodine process as a precursor to SO3, so Ni3(PO4)2 or a nickel polyphosphate might also be a good choice.

zed - 16-10-2018 at 12:29

P2O5?

Well, you probably can't buy it at Ace hardware, but some pyrotechnics suppliers might have it.

It isn't restricted (I don't think); it's just a fussy reagent that must be handled carefully.

Available on both Ebay and Amazon, at an outrageous price.....
But, cheaper elsewhere.

https://www.ebay.com/itm/Phosphorus-pentoxide-99-5-Analytica...

[Edited on 16-10-2018 by zed]

[Edited on 16-10-2018 by zed]

[Edited on 16-10-2018 by zed]

Loptr - 16-10-2018 at 12:35

Quote: Originally posted by zed  
P2O5?

Well, you probably can't buy it at Ace hardware, but some pyrotechnics suppliers might have it.

It isn't restricted (I don't think); it's just a fussy reagent must be handled carefully.

Available on both Ebay and Amazon, at an outrageous price.....https://www.ebay.com/itm/Phosphorus-pentoxide-99-5-Analytical-Reagent-ACS/273326700570?hash=item3fa38a781a:g:fJUAAOSwc~NbNQ0H:rk:1:pf:0
But, cheaper elsewhere.

[Edited on 16-10-2018 by zed]


I never understood why a pyrotechnic supply would have it.

zed - 16-10-2018 at 13:00

Possibly because weird science people like us, might like to buy some (maybe a lot), and the business owners would make money thereby?

"Bobby you're ten years old now, and you are working, so I guess that makes you a man. As long as you have the money, I guess I can sell you a pound of Potassium Cyanide, if you say you need it. None of my business what you do with it, but be careful. OK?" " Huh? You would like shot of whisky for the road?" "Sure..... I guess so, but that will be an extra 10 cents!"

clearly_not_atara - 16-10-2018 at 13:35

Quote: Originally posted by Loptr  

I never understood why a pyrotechnic supply would have it.

If I were to guess, it probably increases the sensitivity of some oxidizers, like nitrates and perchlorates, by producing the corresponding anhydrides N2O5 and Cl2O7, both highly unstable.

Is this good stuff or no?

itsafineday - 14-2-2019 at 13:06



IMG_20190214_155746.jpg - 375kB

mayko - 14-2-2019 at 13:45

It's probably good for phosphorus-depleted soil, but it's not actually a bag of phosphorus pentoxide. The MSDS lists the ingredients as mostly calcium phosphates:
http://www.kochfertilizer.com/pdf/KFB_TSP_GHS_EN_09Nov2012.p...

The analysis label probably reports the content in terms of P2O5 because of the analytical technique used, in the same way that bleach concentration is sometimes reported in terms of elemental chlorine. If you can figure out that technique, it might help you find a path to P2O5.

Tsjerk - 14-2-2019 at 14:05

Quote: Originally posted by itsafineday  




0-45-0 just tells you how much P by weight there is in the fertilizer. Nothing more, nothing less.

itsafineday - 14-2-2019 at 15:23

Doh! I am such and eeeeediot :) and good at wasting money in this hobby.

TGSpecialist1 - 17-2-2019 at 21:55

I wonder if it would be possible to make dimethyl carbonate by dissolving magnesium in methanol, bubbling dry CO2 through it to make magnesium methyl carbonate, distilling to dryness, then cracking it with heat to dimethyl carbonate and magnesium carbonate.

clearly_not_atara - 21-2-2019 at 16:43

You know, I keep trying to think of a problem with that and I can't. It does seem like it would work better if you could obtain metallic calcium, just based on analogy to similar reactions, but Mg should be fine I guess.

Chemi Pharma - 26-2-2019 at 11:13

I have a patent teaching how to produce (DMC) Dimeyhyl Carbonate without the use of Phosgen. They use just Dimethyl oxalate (easy to produce. See here at Doug's Lab You Tube vídeo: https://www.youtube.com/watch?v=imtSH3OAdKE) and Sodium Methoxide at 100ºC.

The Patent is attached:

Attachment: Dimethyl carbonate from dimethyl oxalate and sodium methoxide.pdf (269kB)
This file has been downloaded 314 times

starlight_ - 27-2-2019 at 12:08

That’s a very interesting post by Chemi Pharma on preparation of dimethyl carbonate.

Is an autoclave necessary to do this do you think, or could the DMC be distilled off as it is formed by heating up reactants in standard rbf? (Obviously CO would have to be vented or scrubbed).

Chemi Pharma - 27-2-2019 at 20:12

The Patent say that the temperature of the batch needs to stay between 50-150ºC. cause this I think an autoclave use is not mandatory. I'd rather heat the batch with a water bath (90-100ºC) at reflux. DMC has a boiling point of 90ºC, then it could be refluxed during the 1,25 hours needed, while CO escapes on the top of the column.

monolithic - 8-4-2019 at 17:16

I may have found a very OTC source of dimethyl carbonate: Savogran Heavy Duty SuperStrip (non-DCM). The MSDS shows the following, by weight:

45-50% dimethyl carbonate (MP 3C, BP 90C)
30-35% 1,3-dioxolane (MP -95C, BP 75C)
15-20% methanol (MP -98C, BP 65C)

It seems to sell for about $16/quart at the big orange hardware store.

wakatutu - 8-4-2019 at 22:54

https://images.homedepot-static.com/catalog/pdfImages/da/da1...
savogran super strip (dcm-free)


https://images.homedepot-static.com/catalog/pdfImages/b2/b29...
savogran super strip dcm-free (CA)

The second one has methyl acetate, and its warning section says "Inhalation of Vapor May Cause Death" whereas the warning on the first one simply says inhalation causes dizziness and stuff like that.

I'm not 100% whether it's canada or california that has the methyl acetate version.

Great find, monolithic!

clearly_not_atara - 17-4-2019 at 16:07

So I had a sudden realization.

Orthoesters are produced by reacting a nitrile with an alcohol in the presence of acid:

MeCN + 3 MeOH + H+ >> NH4+ + Et(OMe)3

Alkyl sulfonates are produced by reacting a sulfonic acid with an orthoester:

Et(OMe)3 + TsOH >> TsOMe + AcOMe + MeOH

Soooo... why can't these reactions happen in the same flask?

3 MeOH + 2 TsOH + MeCN >> TsOMe + NH4OTs + AcOMe + MeOH

The obvious objection is that ammonia will react with methyl tosylate. But with excess acid, there should be no ammonia present, only ammonium, which is not nucleophilic. Correspondingly, the rxn mixture cannot be neutralized; MeOTs must be distilled off directly. That should be fine, since MeOTs should be much more volatile than TsOH or ammonium tosylate but much less volatile than methanol or methyl acetate; i.e., no "azeotropes".

AvBaeyer - 17-4-2019 at 16:57

Where is the reference to converting nitriles to orthoesters? Without that the above is just pointless bs.

AvB

clearly_not_atara - 17-4-2019 at 22:09

It’s the Pinner reaction. But apparently HCl is required. However, the basic idea still has merit. If you perform the classic Pinner rxn to get the methyl acetimidate, you can use the anion metathesis here to convert it to the tosylate:

https://arca.unive.it/retrieve/handle/10278/38060/28512/c3gc...

Then adding methanol, heat, more TsOH should work. I guess this ultimately just replaces distilling the orthoester with solvent extraction of the alkyl imidate. But hey, it’s easier...

(Don’t use excess methanol in the imidate formation, it forms emulsions.)

Loptr - 18-4-2019 at 18:04

This sort of reminds me of the synthesis of acetamidine starting from acetonitrile. The intermediate alkyl imitate reacts with excess ammonia form the imidine.

http://www.orgsyn.org/demo.aspx?prep=CV1P0005

monolithic - 20-4-2019 at 21:00

Quote: Originally posted by wakatutu  
https://images.homedepot-static.com/catalog/pdfImages/da/da1...
savogran super strip (dcm-free)


https://images.homedepot-static.com/catalog/pdfImages/b2/b29...
savogran super strip dcm-free (CA)

The second one has methyl acetate, and its warning section says "Inhalation of Vapor May Cause Death" whereas the warning on the first one simply says inhalation causes dizziness and stuff like that.

I'm not 100% whether it's canada or california that has the methyl acetate version.

Great find, monolithic!


I didn't realize that, but yes it appears the California compliant models do not contain DMC and instead contain methyl acetate. You can see the model numbers here: https://savogran.com/removers.html :)

monolithic - 10-2-2020 at 17:50

Slightly off topic, slightly on topic: any thoughts on whether dimethyl carbonate could be used to make diglyme from diethylene glycol? Apparently dimethyl carbonate can work under mild conditions, see http://www.sciencemadness.org/talk/viewthread.php?tid=22370 I wonder how it would fair with a slight excess of K2CO3 in a solventless environment of diethylene glycol. Reflux at 100-125 C and then fractionally distill the diglyme (BP 162 C) from unreacted diethylene glycol (BP 245 C) and 2-(2-Methoxyethoxy)ethanol (BP 194 C)?

clearly_not_atara - 10-2-2020 at 18:18

I think it could probably work, diglyme's protons are both relatively acidic by alcohol standards if methoxyethanol is any indication, and alkoxides are pretty strong nucleophiles. Carbonate is already known to make methoxide effectively.

That's a pretty clever idea ngl

monolithic - 10-2-2020 at 18:57

Quote: Originally posted by clearly_not_atara  
I think it could probably work, diglyme's protons are both relatively acidic by alcohol standards if methoxyethanol is any indication, and alkoxides are pretty strong nucleophiles. Carbonate is already known to make methoxide effectively.

That's a pretty clever idea ngl


Diethylene glycol is the major constituent (>99%) of some sterno style fuels like https://blazeproducts.com/wp-content/themes/blaze-products/a... or https://www.webstaurantstore.com/choice-6-hour-wick-chafing-... . Might have to try the reaction. :)

[Edited on 2-11-2020 by monolithic]

wakatutu - 14-2-2020 at 10:28

I'd like to add to this discussion that I've put in the money and effort to buy a couple gallons of the new paint stripper, vacuum distill the dimethyl carbonate from it, and then run the vac distillation a couple more times to remove DMSO and a nasty smelling amine compound.

Overall I got a pretty decent amount of dimethyl carbonate from this.

I ran a couple experiments to determine the usefulness of such a compound. I am not impressed! Some literature claims that methylation won't take place at 900C and that you have to get the mixture up to around 130 degrees, and some literature claims good yields with some compounds at 90 degrees using TBAB and K2CO3.

I tried 8 hours at 90 degrees with huge excess of DMC, good amount (about .5 molar relative to substrate) of TBAB, and 3.3x molar amount of potassium carbonate. The result: I was able to get about 3-5% yield of the methylated compound, but mostly just got my initial compound back.

Probably conditions could be altered and more experiments should be done, but I was not impressed with all the effort and expense leading to such a crappy yield. The substance was protocatechualdehyde. The 3% yield was the fully methylated veratraldehyde. In the recovered starting material, there was no vanillin or isovanillin. I thought it was weird that the only material that was methylated at all was methylated twice.

horribilis - 14-2-2020 at 13:50

Quote: Originally posted by wakatutu  
I'd like to add to this discussion that I've put in the money and effort to buy a couple gallons of the new paint stripper, vacuum distill the dimethyl carbonate from it, and then run the vac distillation a couple more times to remove DMSO and a nasty smelling amine compound.

Overall I got a pretty decent amount of dimethyl carbonate from this.

I ran a couple experiments to determine the usefulness of such a compound. I am not impressed! Some literature claims that methylation won't take place at 900C and that you have to get the mixture up to around 130 degrees, and some literature claims good yields with some compounds at 90 degrees using TBAB and K2CO3.

I tried 8 hours at 90 degrees with huge excess of DMC, good amount (about .5 molar relative to substrate) of TBAB, and 3.3x molar amount of potassium carbonate. The result: I was able to get about 3-5% yield of the methylated compound, but mostly just got my initial compound back.

Probably conditions could be altered and more experiments should be done, but I was not impressed with all the effort and expense leading to such a crappy yield. The substance was protocatechualdehyde. The 3% yield was the fully methylated veratraldehyde. In the recovered starting material, there was no vanillin or isovanillin. I thought it was weird that the only material that was methylated at all was methylated twice.


Your temperature is too low and your reaction time is too short. You didn't mention what solvent you used. The solvent has to be a high boiling polar, aprotic solvent otherwise your DMC will boil off. See the below procedure -- DMF is proven to work. I imagine DMSO, NMP, and propylene carbonate would also work. An inert atmosphere may be required, or at least a protected atmosphere (flushed and sealed with an oil bubbler.) I've also heard that attempting o-methylation on two hydroxy groups is more difficult than a single hydroxy group, regardless of reaction time and excess of methylation agent. Once you improve temperature, solvent, reaction time, etc. you may consider recycling your unreacting starting material (separated from reaction mixture with dilute base wash) and give it another run.

Some supplemental reading on gentler methylation agents which might give some helpful information about reaction conditions:

US4453017 (TMP but discussion on solvent is relevant)
US6326501B1 (pay attention to the section on temperatures)
https://www.sciencemadness.org/whisper/viewthread.php?tid=22...

Quote:
20.15 g of syringaldehyde, 100 ml of dry DMF (technical grade, fractionally distilled once under vacuum and stored over 3 A molecular sieves), 11.71 g of anhydrous K2CO3 (anhydrous photography grade, ground by mortar and pestle and dried for 1 hour at 300 C), 6.10 g of TBAB, and 22 ml of dimethyl carbonate (technical grade, fractionally distilled once and stored over 3 A molecular sieves) were added to a 500 ml 3-neck round bottom flask equipped with a condenser, pressure equalizing addition funnel, thermometer, and magnetic stirring. The addition funnel was charged with an additional 22 ml of DMC. The apparatus was sealed from atmosphere by leading a hose adapter on the head of the condenser to a small beaker filled with mineral oil. A latex balloon septum was fitted to the head of the addition funnel and the apparatus was gently purged for 10 seconds with a nitrogen wine preserver, and then the septum was very quickly replaced with a stopper. Stirring was initiated and the reaction mixture was brought to a gentle reflux between 120 – 130 C. The DMC within the addition funnel was added in several small portions in the first 3 hours of reflux. From the initiation of reflux, the reaction was allowed to proceed for approximately 20 hours. A light brown/caramel reaction mixture was observed. The reaction mixture, while still hot, was poured into 200 ml of room temperature water. The solution turned a clear orange-red and no precipitation was observed. The mixture was allowed to cool to room temperature, accelerated by the use of a refrigerator. A milky precipitate was then observed, and so another 600 ml of water was added, the total volume now being approximately 1000 ml. Precipitation was observed immediately and the beaker was placed in a freezer for 1 hour. Large amounts of crystals were observed, which were vacuum filtered for approximately 5 minutes. The light beige colored filtrate was discarded and the delicate mass of crystals, off-white and slightly beige in appearance, were dissolved in 100 ml of ethyl acetate and transferred to a separatory funnel. The crude product was then washed with 2 x 50 ml of 5% w/w NaOH, 2 x 50 ml water, and 2 x 50 ml brine. At the conclusion of the washings, approximately 80 ml of a yellow liquid was collected, dried over MgSO4, and evaporated under gentle vacuum to yield 15.39 g (71% yield) of a crude 3,4,5-trimethoxybenzaldehyde as a light beige solid.

24.20 g syringaldehyde, 120 ml DMF, 14.02 g K2CO3, 7.30 g TBAB, and 27 ml DMC was combined in the previously described apparatus. The addition funnel was charged with an additional 27 ml of DMC. The apparatus was protected from atmosphere and purged as before. The mixture was heated, with stirring, to a gentle reflux between 120 – 130 C. Additional DMC was added at the rate of one drop every 3-6 seconds once reflux was reached. Total reflux time was 14 hours. The reaction mixture, still hot, was quenched with 200 ml room temperature water. The mixture was allowed to cool to room temperature with aid of a refrigerator. Upon cooling, milky precipitate was noted. The mixture was then diluted with more water to the 1000 ml line, and the precipitate appeared more defined and crystalline, as in the previous trial. The mixture was placed into a freezer for 1 hour and the large volume of crystals was vacuum filtered for 5 minutes. The solids were dissolved in 100 ml of ethyl acetate and the workup was performed as before: 2 x 50 ml 5% w/w NaOH, 2 x 50 ml water, 2 x 50 ml brine. The yellow liquid was dried over MgSO4 and evaporated under gentle vacuum to yield 17.74 g (68% yield) of a crude 3,4,5-trimethoxybenzaldehyde as a light beige solid.

The outputs of both trials were combined, total mass of 33.09 g after accounting for some minor losses, and a short path vacuum distillation apparatus was set up. Because the product is a solid well above room temperature (lit. MP 73 C), it was a motherfucker to vacuum distill. The reaction flask and vertical section of the short path apparatus, except for small viewing ports, were wrapped in aluminum foil and the flask was heated over an oil bath with maximum stirring. The distillate rose up the vertical section of the still head but would repeatedly stall, and so the apparatus was brought up to temperature with a 750-watt heat gun. (Use metal keck clips so they don't melt.) The 3,4,5-trimethoxybenzaldehyde distilled at approximately 140 C, although it was hard to pinpoint an exact temperature due to the output of the heat gun. A small amount of dark brown/orange liquid which did not solidify at room temperature was left behind in the reaction flask. Total mass of recovered product was 29.75 g (90% recovery) as a snow-white amorphous mass which was stored in an air-tight container in a freezer, to protect against any potential degradation to 3,4,5-trimethoxybenzoic acid.



[Edited on 14-2-2020 by horribilis]

monolithic - 14-2-2020 at 15:05

Quote: Originally posted by horribilis  
Quote: Originally posted by wakatutu  
I'd like to add to this discussion that I've put in the money and effort to buy a couple gallons of the new paint stripper, vacuum distill the dimethyl carbonate from it, and then run the vac distillation a couple more times to remove DMSO and a nasty smelling amine compound.

Overall I got a pretty decent amount of dimethyl carbonate from this.

I ran a couple experiments to determine the usefulness of such a compound. I am not impressed! Some literature claims that methylation won't take place at 900C and that you have to get the mixture up to around 130 degrees, and some literature claims good yields with some compounds at 90 degrees using TBAB and K2CO3.

I tried 8 hours at 90 degrees with huge excess of DMC, good amount (about .5 molar relative to substrate) of TBAB, and 3.3x molar amount of potassium carbonate. The result: I was able to get about 3-5% yield of the methylated compound, but mostly just got my initial compound back.

Probably conditions could be altered and more experiments should be done, but I was not impressed with all the effort and expense leading to such a crappy yield. The substance was protocatechualdehyde. The 3% yield was the fully methylated veratraldehyde. In the recovered starting material, there was no vanillin or isovanillin. I thought it was weird that the only material that was methylated at all was methylated twice.


Your temperature is too low and your reaction time is too short. You didn't mention what solvent you used. The solvent has to be a high boiling polar, aprotic solvent otherwise your DMC will boil off. See the below procedure -- DMF is proven to work. I imagine DMSO, NMP, and propylene carbonate would also work. An inert atmosphere may be required, or at least a protected atmosphere (flushed and sealed with an oil bubbler.) I've also heard that attempting o-methylation on two hydroxy groups is more difficult than a single hydroxy group, regardless of reaction time and excess of methylation agent. Once you improve temperature, solvent, reaction time, etc. you may consider recycling your unreacting starting material (separated from reaction mixture with dilute base wash) and give it another run.

Some supplemental reading on gentler methylation agents which might give some helpful information about reaction conditions:

US4453017 (TMP but discussion on solvent is relevant)
US6326501B1 (pay attention to the section on temperatures)
https://www.sciencemadness.org/whisper/viewthread.php?tid=22...


[Edited on 14-2-2020 by horribilis]


Any thoughts on dimethyl carbonate working in a solventless environment (diethylene glycol)?

clearly_not_atara - 15-2-2020 at 07:59

wakatutu: Do you mean that you started with 3,4-dihydroxybenzaldehyde? It's helpful to explain the precise conditions used.

Overall, solventless DMC is not very good. DMC itself is not very polar; its dipole moment is lower than ethyl acetate. For making diglyme it shouldn't be a problem because the alkoxide is a really strong nucleophile, but you do run a risk of transesterification instead of methylation. Ideally it is always used with a highly polar solvent which will promote SN2 reactions. DMSO or PC8 would seem ideal because their dipole moments are very high.

With DMC and a catechol I wonder if you might accidentally produce the cyclic carbonate. That would be a problem.

For high-yielding methylation of difficult substrates, transesterifying DMC with TsOH gives TsOMe, which methylates many otherwise weak nucleophiles.

[Edited on 15-2-2020 by clearly_not_atara]

monolithic - 15-2-2020 at 12:35

***Never mind, misunderstood!

[Edited on 2-15-2020 by monolithic]

wakatutu - 15-2-2020 at 15:10

I used 3,4-dihydroxybenzaldehyde and only used DMC as its own reaction solvent. I was working with information from a paper published around 2001 for the optimization of reaction conditions for methylating vanillin and eugenol. I have also tried the transesterification with DMC and p-toluenesulfonic acid, which resulted in a very poor yield of methyl tosylate. However, I have had some pretty hefty difficulties arriving at p-TsOH of decent purity, so I haven't put a lot of time into that route.

clearly_not_atara - 16-2-2020 at 07:55

Yeah, TsOH synthesis is conceptually simple but technically difficult. TsOH must be in excess for the reaction to proceed, as noted on the last page.

It would be nice to have a simpler route to sulfonic acids, but that doesn't seem to exist.

AvBaeyer - 16-2-2020 at 19:52

I suggest that dimethyl oxalate be explored as an easy to obtain methylation reagent in the home lab setting. It has been shown to alkylate phenols among other functionalities. It operates by a novel mechanism not available to dimethyl carbonate (DMC) in a manner which precludes the transesterification problem associated with DMC. Furthermore, dimethyl oxalate is easily accesssible.

I have posted some references for relating to dimethyl oxalate.

Also there is a review on DMC chemistry.

I apologize if I am going over plowed ground in this series of posts.

AvB

Attachment: DImethyl Oxalate OrgSyn cv2p0414.pdf (126kB)
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Attachment: Alkylation with Oxalic Esters. Scope and Mechanism..pdf (684kB)
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Attachment: 1799-Anomalous-ether-formation-in-attempts-to-transesterify-oxalate-esters-with-phenoxides807f.pdf (293kB)
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Attachment: The Chemistry of Dimethyl Carbonate Accts C Res 35_706_2002.pdf (229kB)
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clearly_not_atara - 16-2-2020 at 21:35

Earlier byok3y tried the Orgsyn prep of Me2C2O4 using oxalic acid dihydrate, but it failed. It seems like you need to use anhydrous oxalic acid. So what is missing here is a way to prepare anhydrous oxalic acid.

As for the properties of Me2C2O4, I really don't know, but for salicylaldehyde and other resistant phenols I'd use a 2x molar excess.

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