Sciencemadness Discussion Board

Preparation of methyl tosylate, safe methylating agent

Klute - 11-8-2008 at 04:32

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.






Comments

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]

Sauron - 11-8-2008 at 11:41

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.

Klute - 11-8-2008 at 12:58

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.

jon - 13-8-2008 at 18:10

google n-alklylation and cesium you'll like it

jon - 13-8-2008 at 18:13

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 - 13-8-2008 at 20:14

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.

Quantum_Dom - 28-12-2008 at 18:44

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 ?

Many thanks in advance !

grind - 30-12-2008 at 02:47

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 - 30-12-2008 at 15:54

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.


Life is a deadly disease.:)

Quantum_Dom - 31-12-2008 at 07:59

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.


****Update****** Sorry, I just read in your post that you already knew about it. I should be more careful !!!*****

[Edited on 31-12-2008 by Quantum_Dom]

sparkgap - 31-12-2008 at 08:12

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)
This file has been downloaded 2173 times

Quantum_Dom - 31-12-2008 at 08:35

Very nice job spark :D






[Edited on 31-12-2008 by Quantum_Dom]

benzylchloride1 - 16-8-2009 at 21:27

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.

Klute - 19-8-2009 at 02:07

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..

DJF90 - 19-8-2009 at 12:01

Thanks klute, I appreciate this too.

jon - 14-10-2009 at 22:38

nabh4 and formalin read up

Klute - 15-10-2009 at 12:17

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.

Nicodem - 16-10-2009 at 00:06

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.

zLo0nGz - 8-8-2010 at 23:23

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?

Thanks in advance.

Nicodem - 9-8-2010 at 14:57

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 - 9-8-2010 at 17:22

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 - 9-8-2010 at 18:27

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 - 9-8-2010 at 20:42

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)
This file has been downloaded 1466 times

zLo0nGz - 9-8-2010 at 21:33

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 - 9-8-2010 at 23:59

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?

smuv - 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.

un0me2 - 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 1254 times

Attachment: Tipson.On.Esters.of.p.Toluenesulfonic.Acid.pdf (992kB)
This file has been downloaded 911 times

Attachment: Walter.Notes.about.Orthoformic.Acid.Triethyl.Ester.Translated.pdf (437kB)
This file has been downloaded 1544 times

Attachment: Padmapriya.Just.Lewis.A.New.Method.for.the.Esterification.of.Sulphonic.Acids.pdf (238kB)
This file has been downloaded 1008 times

[Edited on 9-9-2010 by un0me2]

497 - 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?

madcedar - 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 &rarr; 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)
This file has been downloaded 856 times

The complete machine translation of DE499052:
Attachment: Process for the preparation of sulphonic acid halides (machine translation).txt (4kB)
This file has been downloaded 1977 times

benzylchloride1 - 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.

no_dream - 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.

chemrox - 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)
This file has been downloaded 822 times

DJF90 - 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...).

chemrox - 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?

no_dream - 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.

DJF90 - 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.

chemrox - 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)
This file has been downloaded 743 times

[Edited on 8-11-2013 by chemrox]

no_dream - 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.

Paddywhacker - 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.

clearly_not_atara - 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]

lullu - 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]

Haber - 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.

lullu - 21-11-2014 at 08:29

Thank you haber, I should have mentioned these refs, I was too blind back then.

Haber - 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?

AvBaeyer - 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

lullu - 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]

Haber - 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.

dermolotov - 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-?

Cryolite. - 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!

Some questions about the alternative ways?

KiWiki - 30-11-2017 at 17:30

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?

clearly_not_atara - 30-11-2017 at 19:36

I don't know what planet you live on where methylmagnesium iodide is easier to work with than methanol, but no, you can't do that. Also, TsOH is water-soluble, while TsCl is not, but tosyl chloride slowly reacts with water. Sulfuryl chloride is not a dehydrating agent and will not convert alcohols to chlorides; rather, it oxidizes them.

What "alternative" method of making methyl tosylate are you trying to perform, exactly?

KiWiki - 30-11-2017 at 23:06

Thank you, this makes sense...
The only alternative pathway that remains is the pyridine/MeOH/TsCl pathway. This seems to work in theory.

I have read the entire procedure. Vacuum is not a option as methyl tosylate decompose over 5 mBar.

The good news is that I see indeed a white oil at the bottom of the flask. I think that this compound is methyl tosylate....


Experiment.JPG - 489kB

AvBaeyer - 1-12-2017 at 19:16

If you have methanol and tosyl chloride why not just follow the Org Syn procedure described at the very beginning of this thread? Making methyl tosylate by that procedure is borderline trivial and works every time. No need to distill or otherwise purify the product.

AvB

KiWiki - 2-12-2017 at 13:52

Interesting, thank you!
If I click on the old link “Org. Synthesis” then I see a lot of subjects but I can’t find the right procedure. What vol., yr., p., (sub)version OR just the title of this particular subject?

Thanks in advance!

DJF90 - 2-12-2017 at 13:54

http://orgsyn.org/demo.aspx?prep=cv1p0145

See note 4.

clearly_not_atara - 7-12-2017 at 19:35

On the topic of sulfonyl chlorides, they can be obtained by the reaction of anilines with sodium nitrite followed by sulfur dioxide in AcOH containing HCl, the reaction proceeding most effectively for electron-deficient anilines. The procedure is described in Orgsyn:

http://www.orgsyn.org/demo.aspx?prep=CV7P0508

I can think of a few anilines which are OTC and might be suitable for the procedure, most notably benzocaine, aka ethyl para-aminobenzoate, but also 3-aminopyridine, from the Hofmann degradation of nicotinamide, and 4-amino-2,5-dimethylpyrimidine, from the reduction of thiamin. I am a little unsure of how the use of heterocycles affects the formation of sulfonyl halides, but usually pyridine and pyrimidine behave like electron-deficient benzene in aromatic substitutions. Unsubstituted aniline works as well, with lower yield. Para-trifluoromethylaniline might be obtained by rxn of para-chlorobenzotrifluoride, an ink solvent, with ammonia, though I'm not clear on the details of such a rxn.

This reaction is considered a special case of the Meerwein arylation with diazonium ions, where the substrate is sulfur dioxide. A modification by Prinsen using dioxane as the solvent claims increased yields on less activated anilines; attached.

Attachment: prinsen1965.pdf (296kB)
This file has been downloaded 376 times

KiWiki - 16-12-2017 at 00:24

Note 4 seems the same procedure however this complete reaction will take about 8 to 10 hours, not just 4 hours as mentioned by Klute.

First step: Purification of TsCl
Dissolve crude TsCl in bz/tol, wash the organic phase with 5% NaOH to remove TsOH. Dry it over MgSO4 and filter the organic phase again over MgSO4. Remove the toluene completly by vacuum destillation. Dissolve the solid pure TsCl in DCM (heating required).

After evaporation of DCM the EXACT amount of pure TsCl is necessary to calculate the equimolar amount of 25% NaOH solution.

Because MeOH acts as both solvent and reagens, it’s unimportant to calculate the exact molar ratio of this. Instead use MeOH in excess (follow the procedure)

Once this reaction is running for hours, you still have a destillation apparatus to start another reaction. I strongly recommend to don’t waste your time to sit down all the time.


Improvements (second run):

1. Use equimolar amounts of NaOH and TsCl. The only way to do that is to purify TsCl, this takes about 2-3 hours.

2. Once you reach the first neutral point then not all your NaOH is consumed as this reaction proceeds further and continues to release HCl from unreacted TsCl. Measure the pH every 20 minutes or so and stay adding dropwise 25% NaOH as the reaction continues untill all your 25% NaOH is consumed.