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Author: Subject: Preparation of methyl tosylate, safe methylating agent
smuv
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[*] posted on 11-8-2010 at 22:36


Quote: Originally posted by zLo0nGz  
...therefore, simplest way is to react p-toluene sulfonic acid with IPA, similar to esterification process, distilling off the excess IPA and extracting out isopropyl tosylate...from theory it might be possible to produce isopropyl tosylate


The method you propose is in no way a preparative method for making isopropyl tosylate. The only thing you will recover other than your starting materials are propylene, water and maybe a trace of diisopropyl ether.




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[*] posted on 9-9-2010 at 04:02


Toluenesulfinic acid can be generated (per orgsyn) by reducing the TsOH with Zn, it can also be made by a number of other routes...(Review here) Including the reaction of toluene with SO2/AlCl3 to give only the p-toluenesulfinic acid. There is a paper around the place on the conversion of the sulfinic acids to the relevant sulfonyl chlorides/bromides

Apart from that, p-Toluenesulfonic acid can be esterified with alkyl orthoformates. Orthoformates can be made using chloroform and NaOH.

Attachment: Wu.etal.Production.of.p.Toluenesulfonic.Acid.by.Sulfonating.Toluene.with.Gaseous.Sulfur.Trioxide.pdf (91kB)
This file has been downloaded 719 times

Attachment: Tipson.On.Esters.of.p.Toluenesulfonic.Acid.pdf (992kB)
This file has been downloaded 575 times

Attachment: Walter.Notes.about.Orthoformic.Acid.Triethyl.Ester.Translated.pdf (437kB)
This file has been downloaded 1005 times

Attachment: Padmapriya.Just.Lewis.A.New.Method.for.the.Esterification.of.Sulphonic.Acids.pdf (238kB)
This file has been downloaded 623 times

[Edited on 9-9-2010 by un0me2]




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[*] posted on 9-9-2010 at 20:56


Another, maybe easier, route to sulfonyl chlorides could be the oxidation of thiols..
toluene sulfonyl chloride may not be easy unless you have p-bromotoluene laying around, buy other sulfonyl chlorides could be pretty simple and OTC. For example n-propyl bromide is otc as a major ingredient in certain cleaners. Then react it with thiourea to get the thiol, then oxidize with TCCA to the sulfonyl chloride... It still does look like a lot of effort compared to just making the appropriate alkyl halide and using that as an alkylating agent.

References for thiol oxidation: http://www.organic-chemistry.org/synthesis/O2S/sulfonylchlor...

Also, how much practical difference would there be between using methyl toluenesulfonate and say, methyl propanesulfonate, etc?
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[*] posted on 10-9-2012 at 05:48


Klute mentioned in the first post of this thread that p-toluenesulfonyl chloride may be made via p-toluenesulfonic acid and S2Cl2 and then struggled to find the reference where he saw it mentioned. Nicodem then mentioned that maybe DE499052 will help, and yes it's a very strong help indeed.

The patent follows this reaction:
2 C7H7SO3H + S + 2 Cl2 → 2 7H7SO2Cl + SO2 + 2 HCl.

I machine translated the patent but I need a member fluent in German and English to verify "my" translation. The pertinent section of the patent, in English follows:

Quote:

250 g of toluenesulfonic acid and 50 g of sulfur are suspended in carbon tetrachloride and treated with stirring with chlorine. The resultant heat development is prevented by external cooling. Sulfur gradually goes into solution under simultaneous escape of hydrogen chloride and sulfur dioxide. After completion of chlorine absorption water is added, partly in order to decompose excess sulfur chloride, and partly in order to remove dissolved hydrochloric acid and sulfurous acid. The carbon tetrachloride solution leaves behind after the evaporation of the solvent, 250 g of nearly pure sulfonic acid chloride, which corresponds to a yield of 90 per cent. Judging from pure p-toluenesulfonic acid, we obtain the p-toluenesulfonyl chloride, mp 68°.


That was machine translated from this part of the German patent:

Quote:

250 g Toluolsulfonsäure und 50 g Schwefel werden in Tetrachlorkohlenstoff aufgeschwemmt und unter Rühren mit Chlor behandelt. Die dabei auftretende Wärme, entwicklung wird durch äußere Kühlung unterbunden. Der Schwefel geht allmählich in Lösung unter gleichzeitigem Entweichen von Chlorwasserstoff und schwefliger Säure. Nach beendeter Chloraufnahme wird mit Wasser behandelt, einesteils um überschüssigen Chlorschwefel zu zersetzen, andernteils um gelöste Salzsäure und schweflige Säure zu entfernen. Die Tetrachlorkohlenstofflösung hinterläßt nach dem Verdampfen des Lösungsmittels 250 g fast reinen Sulfonsäurechlorids, was einer Ausbeute von 90 v. H. entspricht. Geht man von reiner p-Toluolsulfonsäure aus, so erhält man das p-Toluolsulfonsäurechlorid vom Schmelzpunkt 68°.



The original German pdf of DE499052:
Attachment: Process for the preparation of sulphonic acid halides (German) DE499052C.pdf (172kB)
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The complete machine translation of DE499052:
Attachment: Process for the preparation of sulphonic acid halides (machine translation).txt (4kB)
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benzylchloride1
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[*] posted on 23-9-2012 at 22:14


Thanks Nicodem and madcedar for the reference. This prep could be very useful to many on this forum, I wish this had been posted several years ago when I could not get p-toluenesulfonyl chloride. I have a lot of p-toluenesulfonyl chloride currently, but my source will probably not last for ever.



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[*] posted on 6-11-2013 at 11:02


The preparation according the German patent was tried. The first run was made with about 90g of dried p-TsOH (the flask was connected to vacuum for two hours and heated to about 150-180 degrees C). The acid was not much purified because of problems with recrystallization (any other way than gassing with HCl?).
Sulphur (19g) was added, and some CCl4 as solvent (50ml).
Chlorine gas was prepared from 120g TCCA and after drying with H2SO4 introduced into the mixture. The uptake was rapid, but the first hour almost nothing changed. To the end of the reaction, more HCl gas was produced. A little of sulfur remained at the bottom. Then water was added. This was a big mistake. A violent reaction started and almost all reaction mixture was ejected from the reflux condenser. Large HCl
gas clouds were produced too...Probably much unreacted sulphur chlorides was present.

Second try: Chloroform was used instead. 100g of dried TsOH (dark oil), 20g of sulfur, 150ml of chloroform. Chlorine from 120g of TCCA. The reaction proceeded very smoothly for about two and half hours, with little heating. This was checked with cold water bath. After ending of gas uptake, the mixture was orange-brown and cloudy from a little left over very fine sulphur. Water was again added carefully from a dropping funnel. Again, the reaction was very violent and produced much of heat. Cooling had to be applied. Orange liquid refluxed (sulphur chlorides?). After about one hour, 50ml of water was added, then more 150ml. Now the colour was sulphur yellow. Two layers formed, the lower was separated and filtered. The filtration proceeded very slowly. The resulting cloudy liquid should contain tosyl chloride and was stored for next steps.

Maybe there was only sulphur chlorides formed, and no TsOH reacted.

The smell of the reaction mixture was like the first attempt and the explanation is that the chloroform is chlorinated to CCl4. So it is better to use the tetrachloride directly, because it is unavoidable formed in this process.

The next try would be solvent-free.


Another possible methods - please correct if that is wrong:
p-TsOH and sodium metabisulphite or thiosulphate and chlorination (modification of the acetic anhydride patent, which replaces sulphur with an sulphur containing compound.
Na tosylate, S, Cl
Na tosylate, metabisulphite and chlorine. Should produce NaCl as byproduct. But all the products and reactants are solid, so maybe it will not work without an solvent.

Using of phosphorus trichloride and Na-tosylate (+ of course Cl2 gas) is possible and works (early commercial method) but is not preferred because P is needed.

---

The remaining liquid was removed the solvent on a water bath. The oily residue was dissolved in acetone and filtered. The solution was poured into water, and a dark bottom oily layer formed. It could be remains of the solvent, or a complete failure of this procedure.

Result: Nothing useful obtained.
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[*] posted on 6-11-2013 at 13:39


The method of Brown should work with this.

Attachment: An_Improved_Method_for_the_Preparation_of_Alkyl_Chlorides.pdf (869kB)
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[*] posted on 6-11-2013 at 14:16


@Nodream: If the TsOH goes into solution during the course of the reaction this is a good sign, as TsCl is soluble in chloroform and carbon tet. From here, I'd filter the reaction mixture to get rid of any excess sulfur, concentrate under reduced pressure to remove sulfur chlorides (why use excess sulfur anyway? Just use a stoichiometric amount?) and then take the (hopefully crystalline) residue up into chloroform and crystallise the TsCl with pet ether as per Armarego and Perrin.

In terms of purifying/drying the TsOH, I've found that distillation of the anhydrous acid (do the prep, and strip off the excess toluene under reduced pressure) under high vacuum (I recall 165-170*C at 0.5mbar) gave a pure white product. Its quite viscous and the atmospheric bp (extrapolated) is like 400+*C but it does work and it does give what appears to be very clean product. I will be repeating this properly at a later date. My motivation for the TsOH purification was also for this DE patent, and because I found the described methods of recrystallisation (gassing with HCl or adding 3x volumes of conc. HCl) worked quite poorly if the original material qas quite coloured (as mine was...).
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[*] posted on 6-11-2013 at 14:25


Quote: Originally posted by jon  
nabh4 and formalin read up


What does Jon have against references & links one wonders?




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[*] posted on 6-11-2013 at 22:56


The TsOH is soluble in chloroform too, so there was a homogenous clear solution with sulphur in it.Using an excess of S is suggested in the patent because the exhaust gases from the reaction (HCl and SO2) take an amount of sulfur chlorides with it. I observed this, the tube leading from the condenser to outside contained some yellow smelly liquid.

Unfortunately I have not a good vacuum source to vacuum distill the TsOH. Never had success with the HCl purification. The product is still coloured, much of the product remained in the mother liquors and the large scale work with HCl is a mess.

Hopefully the German patent without solvent will work too, I give a try. The suggest heating it a "little above room teperature", but it could be possible it needs to heat up to the melting point of p-TsCl to keep the mixture liquid. If it will work with crude TsOH, it would be the best option, because the separation of o- and p-TsCl is easier.
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[*] posted on 7-11-2013 at 13:28


Sorry, I was getting my wires crossed with the solubility. I've done the purification as per Perrin and Armarego and it works fine. Use of stoichiometric sulfur will prove less of a problem to the reaction as any unreacted TsOH is removed in the purification.
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[*] posted on 7-11-2013 at 17:16


Tosyl esters have been made from alcohols and tosyl chlorides. However I shouldn't suggested a method of converting carboxylic acids to acyl halides as a way of making sulfonyl halides. I still wonder whether N-chlorosuccinamide would work.

Attachment: jo00362a044.tosylation of alcohols.pdf (488kB)
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[Edited on 8-11-2013 by chemrox]




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[*] posted on 19-11-2013 at 10:43


Another failure.

110g of crude acid was dried by heating to about 180degC in a flask under vacuum. After some hours, the weight remained constant at 82g. Toluene, water and HCl was removed in this way. The patent states 0,5 mol ratio of sulphur to acid. This gives about 0,23 mol of S. 4 grams were used. Chlorine was prepared from 70g TCCA and 50ml conc. HCl - an excess of chlorine gas.

After heating the mixture to about 50degC it became liquid, of brown colour and with suspended S in it.

After the half of acid in the Cl2 generator was used, the S almost disappeared. Now the exhaust gases started to contain HCl and S chloride mist. This behavior was observed in the previous experiments too.

Maybe in the first phase S reacts with Cl2 and then with the TsOH? Almost all chlorine was absorbed, a little at the end escaped. The reaction mixture had a brown colour, with little S particles.

Water was added, the reaction was not much vigorous because the amount of S was only 4g to 20g in the experiments before. After it calmed down, more cold water was added. The mixture was of a brown-milky appearance. After filtering, almost nothing except some S remained on the filter. The filtrate was brown.

Some TsCl was produced because of the new strange smell of the post reaction mixture, which was identical to previous runs. It is different than sulphurous compounds or chlorine and very persistent.

TsCl is insoluble in water, so after diluting it should precipitate. This did not happened. Maybe bad luck with experiments or the patent is a bogus one.
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[*] posted on 21-11-2013 at 16:15


Won't TsCl be hydrolysed in your quench conditions, hot water?

Maybe if you quenched the opposite way, added your reaction mix to ice.
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[*] posted on 7-6-2014 at 23:01


The most facile preparation of methyl tosylate is from methyl orthoformate, reported here in 99% yield:

http://anonym.to/https://www.erowid.org/archive/rhodium/chem...

The synthesis of an orthoformate usually proceeds from an alkoxide and chloroform. In this case, we're often interested in methylating an o-formylphenol that had been prepared using magnesium methoxide.

It therefore seems reasonable to make trimethyl orthoformate from magnesium methoxide and chloroform! This can be the starting material for methyl tosylate by the literature route. It should be some advantage to reuse past work.

Mg(MeO)2 should be less reactive than alkali methoxides but still sufficiently ionic to make an orthoformate. It might be necessary to use higher temperatures and/or bromoform, which should be a little more reactive.

But, uh, has this been tried?

[Edited on 8-6-2014 by clearly_not_atara]

[Edited on 8-6-2014 by clearly_not_atara]
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[*] posted on 16-8-2014 at 03:13


Has anyone here used methyl p-toluenesulfonate successfully for an O-methylation and would like to share his experiences?
I found that although methyltosylate is often mentioned as an alternative reagent I did not find a lot of
actual reports on using it.

Most O-methylations on the board where done using DMF as a solvent, maybe someone could tell something about using it in DMSO or acetone? (or polyethylene glycol as far as I remember Nicodem used it, although I dont see how it can be used, it is quite similar regarding permittivity but certainly not aprotic, it wouldn't it be methylated too)?

[Edited on 16-8-2014 by lullu]

[Edited on 16-8-2014 by lullu]
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[*] posted on 21-11-2014 at 03:18


@lullu

In this thread http://chemistry.mdma.ch/hiveboard/novel/000417550.html
O-alkylations using esters of p-toluenesulfonic acid are described.
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[*] posted on 21-11-2014 at 08:29


Thank you haber, I should have mentioned these refs, I was too blind back then.
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[*] posted on 9-12-2014 at 00:30


From the link I posted above:

"Veratric aldehyde, 3-4-dimethoxybenzaldehyde
To 15.2 g vanillin (0.1 mol) a calculated amount of kalihydrat (probably KOH) was added and dissolved in 75 ml MeOH. 18 g methyl tosylate (0.1 mol) and heated on a water bath for 1.5 h to reflux. As soon as the the light yellow, clear solution starts boiling the potassium salt of methyl toluenesulfonic acid starts to precipitate. After 1.5 h everything is poured in about 300 ml of H2O. First there is a white emulsion which starts to separate a light yellow oil. The aqeuous solution and the oil is extracted exhaustive with Et2O, the organic phase is washed twice with 10 ml 5% aqeuous KOH to remove unreacted vanillin. The organic phase turns almost colourless, the alkaline solution is light yellow. The organic phase is washed with H2O, dried with freshly sulphate (probably MgSO4 or Na2SO4) and evaporated. The oily residue solidifies on cooling (melting point: 42-43°C).
Recrystallization from Et2O yields a white product. Yield: 13.8 g, 83% of theory.
The pooled basic solutions and wash water is acidified with 20% H2SO4 and extracted with Et2O. The organic phases are dried with Na2SO4 and treated as usally.
The yield of light yellow coloured vanillin (melting point: 81-82°C) is 2.5 g (increasing the yield to 99%) and it can be used without further purification."


I followed this preparation, except that I used DCM instead of Et2O in the workup.
The solid obtained had en melting point of ~78-80C, suggesting that the methylation had failed and I mainly recovered unreacted vanillin.

Have anyone else tried this reaction, or have some thoughts or suggestions about the preparation?
Would DMF be a more suitable solvent when alkylating phenolic aldehydes with alkyl tosylates?
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[*] posted on 9-12-2014 at 20:48


Typically, it is better to run these types of alkylations in polar aprotic solvents which would lead to the use of DMF or something similar (ie N-methylpyrrolidone). Acetone or MEK are less suitable in general. In my experience, when using an alkylating agent such as methyl tosylate or an alkyl chloride the addition of a small amount of sodium iodide as a catalytic "kicker" works wonders.

By the way, did you get the potassium tosylate preciptate in your experiment?

AvB
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[*] posted on 10-12-2014 at 11:06


Duo to ECHA, getting NMP in europe is getting harder nowadays.
NMP is still used in some paint strippers and hardeners but only as a very low percentage at least I never found one after reading a lot of MSDS.
DMF is always a bit of a struggle for the amateur chemist.

Has anyone experience with acetonitril and tosyl esters (vanillin solubility seems adequate)?

Maybe trying a melt-phase reaction with tosyl esters like they've done it here with TMP would be worth a try too?
https://www.erowid.org/archive/rhodium/chemistry/me3po4.html

[Edited on 10-12-2014 by lullu]
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[*] posted on 11-12-2014 at 00:23


Quote: Originally posted by AvBaeyer  
Typically, it is better to run these types of alkylations in polar aprotic solvents which would lead to the use of DMF or something similar (ie N-methylpyrrolidone). Acetone or MEK are less suitable in general. In my experience, when using an alkylating agent such as methyl tosylate or an alkyl chloride the addition of a small amount of sodium iodide as a catalytic "kicker" works wonders.

By the way, did you get the potassium tosylate preciptate in your experiment?

AvB

Thanks for your suggestions, I will try this with DMF instead.

About the potassium tosylate I think some of it precipitated, the reaction mixture were abit "cloudy" according to my lab notes.
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[*] posted on 14-12-2014 at 15:44


Yano... I've never considered this to be a good alternative to adding ethyl, propyl, etc groups on certain things.

Can I assume that any aprotic R- group can substitute the Methyl-?
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[*] posted on 25-11-2016 at 19:19


I would just like to point out that, while toluenesulfonyl chloride has been difficult for the amateur to buy in the past, HiMedia on Amazon is now selling 500 grams of it for around 30 dollars: https://www.amazon.com/HiMedia-GRM2486-500G-P-Toluenesulfony... . Although the shipping from this supplier takes a very long time, the products I have purchased from them have all been of good quality. Methyl iodide may no longer be a necessary evil for methylation!
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[*] posted on 30-11-2017 at 17:30
Some questions about the alternative ways?


I suppose that during the first step MeOH is converted into MeCl by adding SO2Cl2? Can I replace MeOH with MeI (or MeMgI) and let TsCl react with methyl iodide?

The theoretical alternative way is to add MeOH in pyridine as a solvent and let it react with TsCl, but I can’t any practical information (reaction time, temperature, other possible conditions about this particular reaction. Does anyone have experience with the pyridine/MeOH/TsCl method?

If TsCl is converted into TsOH over time then I can add TsCl to cold water and filter out the white precipitation (=TsOH). Next step is vacuum distillation to remove the water. Is that right?

In fact, I did try it out without any SO2Cl2 and right now I see a milky oily substance at the bottom of the flask and probably solid NaCl/TsOH. (picture will follow asap).

Can I purify this under vacuum to confirm that this fraction is methyl tosylate?
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