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Author: Subject: Preparation of methyl tosylate, safe methylating agent
Klute
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Preparation of methyl tosylate, safe methylating agent

The most routinely used methylating agents, namely dimethyl sulfate (DMS) and methyl iodide (MeI), present significant health hazard, as both of them are very toxic.

Several safer substitutes exists, such as triemthylphosphate (TMP), sulfonate esters (RSO3Me), and dimethylcarbonate (DMC).

DMC usually requires harsh conditions to acheive methylation, TMP less so.

I have found commercial TMP to be very efficient in O-methylation of phenols ( Methylation of salicylaldehyde thread ), but have had disappointing results with certain N-methylation. There is very little information on the use of TMP for N-methylation of aliphatic amines in the litterature, so I decided on trying a new methylating agent, methyl tosylate (TsOMe)

p-toluenesulfonate esters are considered as safe, but efficient alkylating agents, on the same order of reactivity as alkyl iodides.

Theses esters can't be obtained by heating the acid with the desired alcohol, the usually preparation uses the sulfonyl chloride, a stable, white cristallin solid. Although tosyl chloride hydrolyzes to TsOH and HCl in presence of moisture, this reagent is much less prone to hydrolysis than acyl chlorides, and can be handled without protective atmosphere with minimal lose. TsCl is a cheap and available reagent, which can be used to form a variety of tosylates, for alkylation or displacements (halogen or azide swap, etc) purposes.

Preparation of methyl tosylate from tosyl chloride

I followed the OrgSyn procedure for methyl tosylate (see notes), at a 200mmol scale.

Reagents

The tosyl chloride, which is quite old, was used without any purification. It surely contained some TsOH. It was weighed and crushed to a fluid powder inside a home-made drybox, but this isn't mandatory, just avoids caking up and increases the lifespan of the reagent.

Technical methanol, not dried, and commercial 30% NaOH solution were used.

Procedure

In a 250mL 4-neck RBF, equipped with a condenser, a addition funnel, a thermometer and magnetic stirring, 50mL of technical methanol were charged ( ~1.2 mol, 6eq.). The flask was cooled in a cold water bath to 10°C.

38.13g (200 mmol) of TsCl were weighed into a dried pyrex container inside a dry box, and the caked-up lumps where broken down to a fine, fluid powder. The sulfonyl chloride was then added in portions over 5min to the stirred methanol, no heating occured. Stirring was set to obtain a well stirred suspesnion but avoid any splashing.

20.0mL of 30% NaOh solution (200mmol) were charged into the addtion funnel, and added dropwise (1dp/5sec)to the stirred suspension, keeping the temp between 20 and 25°C by occasionally adding ice to the water bath. There was a slight exothermic reaction.

As the addition continued, the reaction mixture became more viscous, and the white solid seemed to get thinner. When stirring was stopped, an oily layer formed at the bottom of the flask, along with the white solid.

The addition took about an hour, and the temp never exceeded 30°C. Some white solid remained unreacted (surely TsOH originally present in the reagent), and pH was slightly above 7.

the reaction mixture was left to stir for an hour at 15°C, then left to decant for another hour at the same temp.

50mL of water containing ~15g of NaCl was then added, causing immediate milkyness, and the colorless oil that sank to the bottom seperated. The aqueous was extarcted with 4x15 mL toluene. The extracts were washed with 50mL 5% K2CO3, 50mL water, and 50mL brine. the slightly milky solution was dried over K2CO3 for 30min, and the solvent removed under reduced pressure (at ~50°C) using a short vigreux, max vacuum applied for 15min to remove as much toluene as possible.

The viscous, pleasant-smelling ester weighed 32.77g (176 mmol, 87.99 % yield), and must contain some traces of toluene as it didn't solidify upon cooling to under 30°C.

This preparation is very easy, requires very little equipment and material, and can be done in a few hours. A workup avoiding the use of toluene could be usefull, I might try drowning the reaction medium in ice water next time, and filter out the solid.

I prefered on keeping the crude product, and using it pretty quickly, as distn requires tough vacuum (<10mmHg) to avoid decomposition. Apparently, the crude ester decomposes on standing after a few weeks.

High yeilds of this ester can be obtained, so it seems tosyl chloride is a very good alternative to dimethylsulfate or MeI, both health-wise and financially, if the chemist is willing to spend a few hours preparing the needed ester. Ther eaction can easily be performed on a large scale,a s suggested by the OrgSyn procedure, and the controlable exothermic reaction.

More accesable methods, not involving the sulfonyl chloride exist, like refluxing the anhydrous acid with excess trimethyl orthoformate, but high excess of this ester are required.

The acid can be recycled to the sulfonyl chloride with S2Cl2, but it's a dirty reaction, yielding a impur product. Otherwise, SOCl2, PCl5, etc are needed.

A better approach, for those that can't aquires TsCl, would be to prepare aliphatic sulfonyl chlorides by reacting alkyl halides and thiourea or thiosulfates, followed by aqueous chlorination of the intermediate adducts, and reacting these sulfonyl chlorides with the chosen alcohol.

Ullman (SM member) had the great idea of forming ethylsulfonyl chloride from the easily made ethyl halide and sodium thiosulfate, both very common products, and then reacting that with methanol, ethanol, etc.

Unfortuanly, aromatic sulfonyl chlorides cannot be prepared by this method.

I hope this post can sparkle some interest in these compounds and get people to try their preparation. Several references regarding the chlorination of isothioureas or Bunte salts (alkylthiosulfates) to sulfonyl chlorides are availble in the ref. forum.

[EDIT: Moved to Organic Chemistry]

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Sauron
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When you talk about TMP don't you mean trimethyl phosphite ((MeO)3P) rather than trimethyl phosphate ((MeO)3P=O) ?

The phosphite ester is a well known methylating reagent.

I do not recall the phosphate ester as an alkylating agent.

As for ethyl tosylate, it would be interesting to see if it can be substituted for diethyl sulfate in the N-alkylation of diphenylurea assisted by Et3BuN+Cl-. This is the non-phosgene route to enthyl centralite.

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Klute
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No, no, trimethyl phosphate, (CH3O)3PO. Indeed, the phosphites are also alkylating agents, but also act as nucleophiles IIRC.

These phosphate esters are less reactive than sulfate etsers, but their high bp ables higher reaction temps. At 50-60°C in DMF, TMP was as effective as MeI for O-alkylation of salicylaldehyde. There is one OrgSyn procedure employing TMP for dimethylation of certain anilines, and a article on the same subject (recently requested in the ref forum); apart from that, nothing else I could locate on N-alkylation.

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jon
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google n-alklylation and cesium you'll like it
jon
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you use an akly halide and a primary amine in dmf along with mol. seives and Cs(OH)II.H2O
the cesium base promotes mono alkylation over the susequent reactions, yeilds are in the 90's
Klute
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Indeed, I was well aware of this route but I have no cesium hydroxide and my supplier is closed until september, aswell as the lab, so I have to do with what I have at hand...

Have you tried this yourself? It would be a good alternative if this is first-hand yields. The HCHO/Zn procedure seemed very promising at first, but happened to be shit..

BTW, I think this discussion would be better placed in the monomethylation thread rather than here.

In any case, TsOME is much easier to handle than MeI or DMS, but does have an inconvenient: the form tosylate salt precipitates in large amounts as a very voluminous solid, making stirring very difficult depending on the solvent used (gel-like paste in THF, but crisatllin flakes in toluene), so larger amounts of solvents are required. I haevn't tried DMF yet, it's possible the salt is somewhat soluble in that solvent.

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Quantum_Dom
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Thank you so much Klute for such a brillant and thorough report. (J'apprécie énormément ton travail !)

Could you please, if possible, link me to a study where methyl tosylate has been used as a phenolic methylating agent ?

Should one just substitute methyl iodide to TsOME by adjusting the ratios and thats it ?

grind
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Tosylate esters are strong cancerogens, like most alkylating agents. They may have preparative advantages, but are not safer to your health than dimethyl sulfate or MeI.
Quantum_Dom
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 Quote: Originally posted by grind Tosylate esters are strong cancerogens, like most alkylating agents. They may have preparative advantages, but are not safer to your health than dimethyl sulfate or MeI.

Quantum_Dom
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Klute, I dont know if you were aware of the following procedure but I will post it for information purposes. It reports that sulfonic acids can be smoothly converted to their methyl and ethyl esters by reaction with trimethyl and triethyl orthoformate, respectively.

This could prove to be handy if one only has p-toluenesulfonic acid and not the chloride derivative.

A. A. Padmapriya, G. Just and N.G. Lewis
Synthetic Communications 15(12), 1057-1062 (1985)

Experimental

General Procedure

A solution of the sulfonic acid (200 mg) in trimethyl (or triethyl) orthoformate (2 mL) was either allowed to stir at room temperature for 14 h., or heated to ref lux for 30 min., under an atmosphere of nitrogen. The excess orthoformate was then removed under vacuum (0.5 mmHg) to give the corresponding methyl (or ethyl) ester. Where the solubility of the substrate was poor, the reagent was mixed with an equal volume of methanol, following which slow distillation over 1 h. gave the required ester in high yield.

[Edited on 31-12-2008 by Quantum_Dom]
sparkgap
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 Quote: A. A. Padmapriya, G. Just and N.G. Lewis Synthetic Communications 15(12), 1057-1062 (1985)

For those who want it.

sparky (~_~)

Attachment: estrsulfo.pdf (136kB)

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Quantum_Dom
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Very nice job spark

[Edited on 31-12-2008 by Quantum_Dom]
benzylchloride1
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Hello Klute, could yo post a procedure for making p-toluenesulfonyl chloride from p-toluenesulfonic acid and disulfur dichloride for those that cannot obtain tosyl chloride? I have been wanting some tosyl chloride for some time, I have plently of p-toluene sulfonic acid and disulfur dichloride. It would be interesting to try to optimize the tosyl chloride synthesis you mention and find a suitabl solvent to remove the tosyl chloride from impurities introduced by the synthesis.

Amateur NMR spectroscopist
Klute
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Hi benzylChloride,

I will have to search the procedure again, I didn't keep any info on it at the time.. Give me a day or two..

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Thanks klute, I appreciate this too.
jon
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Klute
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benzylchloride: Up to date I have still not found the patent that mentionned the sulfonic acid + S2Cl2 to form sulfonyl chloride.. Actually it was a patent describing more the purification of sulfonyl chlorides obtained by such method rather than the process itself, but it contained references, and the simple fact that a patent was filed specificly for products obtained via this method means it sufficiently used in the industry. I have spent several hours (!!) on many patent search engines with keywords like sulfonyl chloride purification sulfur dichloride, etc etc but have still not located it.. At the time I just read through it after random searching on sulfonyl chloride, and kept the reaction in a small mind box as a valid preparation without noting any info.. Useless now..

Jon, NaBH4 and formol gives mainly dimethylated amines, or statistical repartition of mono and dimethylated when formol is used in slightly less than molar proportions. Found it out in the lab.

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Nicodem
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 Quote: Originally posted by Klute benzylchloride: Up to date I have still not found the patent that mentionned the sulfonic acid + S2Cl2 to form sulfonyl chloride..

Maybe this one: DE499052?

The only other methods that could be suitable for amateurs are:
- heating PhCCl3 and TsOH at ~150°C to give PhCOCl and TsCl (CN101070295);
- treating TsOH with P4O10/KCl/n-Bu4NCl in MeCN (Bulletin of the Chemical Society of Japan, 56 (1983) 3813-3817; this is just a minor example, because the paper otherwise focuses on the reduction of arylsulfonic acids to diaryldisulfides with HI);

If you have an autoclave (for up to 10 bar at least!) you can try heating a solution of TsOH*H2O in 1,1,2-trichloroethene at 120-150°C. By theory this should give a mixture of TsCl, ClCH2COOH and ClCH2COCl. 1,1,2-trichloroethene (aka trichloroethylene) is a widely available solvent used as degreaser, a thinner to clean brushes, and for dry cleaning.

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zLo0nGz
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Dear Klute,

Can your method be used to prepare Isopropyl p-toluene sulfonate (Isopropyl tosylate) from p-toluene sulfonic acid and isopropyl alcohol (IPA)? Do you have any suggestion on how can this be performed? I have tried refluxing both chemicals with excess of IPA, temperature of 100-110oC, for 24 hours. Distill of the excess IPA and got a dark greenish semi-solid. Do you have any suggestion to purify this dark green semi-solid?

Nicodem
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 Quote: Originally posted by zLo0nGz Can your method be used to prepare Isopropyl p-toluene sulfonate (Isopropyl tosylate) from p-toluene sulfonic acid and isopropyl alcohol (IPA)? Do you have any suggestion on how can this be performed? I have tried refluxing both chemicals with excess of IPA, temperature of 100-110oC, for 24 hours.

How is refluxing of tosylic acid in isopropanol supposed to give isopropyl tosylate? That is not only impossible, but it is also not what Klute describes here. I think you misinterpreted something.
zLo0nGz
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Dear Nicodem,

Klute was describing about making methyl tosylate...in my case, isopropyl tosylate...now I have looked up in the internet...the only way that I could make isopropyl tosylate is by reacting tosyl chloride with IPA...however reaction of tosyl chloride with IPA gives HCl as by-product, a little risky eh...thats why I'm looking for a safer alternative to making isopropyl tosylate, the only way that I can think of is by reacting tosylic acid with IPA...or is there any other suggestions I could try?
mnick12
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HCl shoud be very easy to remove from you final product.

And if you dont want to use tosyl chloride there are other alternatives. Here is an article you may like, but I cant view the whole thing and I dont want to pay $30.00 to. http://pubs.acs.org/doi/pdf/10.1021/jo01185a005 . Maybe someone else has it, you could ask in references. Formula409 Hazard to Others Posts: 129 Registered: 13-12-2008 Member Is Offline Mood: No Mood  Quote: Originally posted by mnick12 HCl shoud be very easy to remove from you final product. And if you dont want to use tosyl chloride there are other alternatives. Here is an article you may like, but I cant view the whole thing and I dont want to pay$30.00 to. http://pubs.acs.org/doi/pdf/10.1021/jo01185a005 . Maybe someone else has it, you could ask in references.

See attached

Attachment: On Esters of p-toluenesulphonic acid.pdf (502kB)

zLo0nGz
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Thanks for the artical, Formula409...making isopropyl tosylate might not be an issue but the chemicals used are highly risky, e.g. pyridine and HCl...we are prohibited from using such chemicals for synthesis purpose as safety is our priority...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, i need varification...if it is true that by employing this method could produce isopropyl tosylate, is there any suggestion to purify it? I was thinking of solvent recrystalization method...
Nicodem
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 Quote: Originally posted by zLo0nGz ...making isopropyl tosylate might not be an issue but the chemicals used are highly risky, e.g. pyridine and HCl...we are prohibited from using such chemicals for synthesis purpose as safety is our priority...

I find that an insult to my profession, so you should think twice before posting such nonsense attempts at humiliation of chemists. Working with pyridine and HCl is bad, but working with isopropyl tosylate is OK? What a bunch of hypocrisy!
Besides, where have you seen that HCl is formed in the synthesis of isopropyl tosylate from isopropanol by using the here described method? The process Klute describes gives no HCl, just NaCl. Are prohibited to work with table salt as well?

 Quote: 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...

And where is a reference claiming such nonsense? How about doing some literature search before spreading misinformation over the internet?

 Quote: from theory it might be possible to produce isopropyl tosylate, i need varification...if it is true that by employing this method could produce isopropyl tosylate, is there any suggestion to purify it? I was thinking of solvent recrystalization method...

What theory? Have you even bothered checking the theory of esterification before making such a claim? Please explain how does the sulfonic group fit in that mechanism and how is it supposed to get protonated for the nucleophilic addition of the alcohol to occur. And now you are already asking on how to purify something that you don't even know what it is. Have you even bothered comparing it on TLC with the starting material?

…there is a human touch of the cultist “believer” in every theorist that he must struggle against as being unworthy of the scientist. Some of the greatest men of science have publicly repudiated a theory which earlier they hotly defended. In this lies their scientific temper, not in the scientific defense of the theory. - Weston La Barre (Ghost Dance, 1972)