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Topic: Tosylate Synthesis  (Read 23383 times)

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Offline dkhoo

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Tosylate Synthesis
« on: September 21, 2011, 01:44:56 PM »
I tried a lot of times trying to synthesising this tosylate in a high yield but I failed.  I only managed to get about 40% yield only whereas it is reported to be able to achieve 80%-90% yield.

The following procedures were applied.
1.  TsCl was charged with anhydrous sodium carbonate in a mortar.  The alcohol was then added.  The mixture was grinded for 10 mins.
2.  Powdered KOH was added to remove extra TsCl [Very exothermic reaction] followed by addition of few drops of tertiary alcohol.
3.  The resulting mixture was extracted using diethyl ether. Extraction being carried out by adding diethyl ether into the mixture followed by gravitational filtration using funnel. [ I wonder this extraction method is effective].  The unwanted solids were discarded.
4.  The resulted solution was heated to concentrate it.  Hot n-hexane was then added to crystallize the crude product.
5.  The mixture was then placed into an ice bath.  White solid formed but in low yield.

Reference: Chemoselective and scalable preparation of alkyl tosylates under solvent-free conditions.
 by Foad Kazemi, Ahmad Massah and Mohammad Javaherian.

Anyone tried this type of reaction before?  How to increase the % of yield ?

Offline opsomath

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Re: Tosylate Synthesis
« Reply #1 on: September 21, 2011, 01:49:29 PM »
I would skip the KOH addition, it may be hydrolyzing your product, and instead remove the TsCl another way during the workup. You may have trouble with the ether extraction if it isn't thoroughly mixed with your crude.

Why are you dead-set on the solvent-free process? I have had great results with a slight excess of TsCl with pyridine in THF.

Offline BobfromNC

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Re: Tosylate Synthesis
« Reply #2 on: September 21, 2011, 02:35:16 PM »
Even with dry reaction, you might need to extract the solids multiple times to get all of the product out.  Extractions of dry materials are slow and poor yielding in some cases.   That would be my first guess as to low yield.  I also agree that hydrolysis of TsCl might cause side reactions, but not sure of it. 

I have to agree that in some cases solvent reactions are more easily reproduced, but partly because the details are usually give clearly.  In the case of a no solvent reaction, there may be factors that are not clearly described, like how well the compounds were ground, how hard they mixed, how long, etc.

Bob

Offline the.khemist.ds

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Re: Tosylate Synthesis
« Reply #3 on: September 21, 2011, 05:08:52 PM »
dkhoo,

I think it would be worthwhile to make it clear whether your goal is to synthesis the particular product, or to use that particular methodology, as this will allow people to give you the most suitable response.

Dave

Offline dkhoo

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Re: Tosylate Synthesis
« Reply #4 on: September 21, 2011, 07:47:28 PM »
1.  At first, I tried using pyridine as the solvent but it is difficult to totally remove the pyridine via rotary evaporator as I fear some products might be lost during this process.  Besides, pyridine has some strange odour.

2.  My objective is to synthesis the particular product.  It would be best if I can do it using this solvent-free method but I am willing go try any other useful methods suggested.

3.  Besides, this solvent-free method is faster compared to the reflux method using pyridine which takes days.

Offline orgopete

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Re: Tosylate Synthesis
« Reply #5 on: September 22, 2011, 07:54:30 AM »
It hasn't been made clear why the yield is low. Has all of the starting material been converted to the tosylate? Has some of the product been lost? For all we know, the reaction has only proceeded to 50%. Increasing the time or mixing could change that.
Author of a multi-tiered example based workbook for learning organic chemistry mechanisms.

Offline OC pro

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Re: Tosylate Synthesis
« Reply #6 on: September 22, 2011, 02:39:39 PM »
1.  At first, I tried using pyridine as the solvent but it is difficult to totally remove the pyridine via rotary evaporator as I fear some products might be lost during this process.  Besides, pyridine has some strange odour.

2.  My objective is to synthesis the particular product.  It would be best if I can do it using this solvent-free method but I am willing go try any other useful methods suggested.

3.  Besides, this solvent-free method is faster compared to the reflux method using pyridine which takes days.

Your arguments are lame.
1.: Yes of course pyridine has an unpleasant smell but that is CHEMISTRY!!! If you cannot stand this go for another field. There is much more terrible stinky stuff outside. Removal of pyridine via rotavap is not difficult. Moreover, loss of material will not occur.
2. In my experience, solvent-free syntheses are crap, they don´t work well and give bad reproducibility.
3. The pyridine reflux method takes several days? I have a big doubt. Tosylation in pyridine is very fast. The reactions are often performed under ice-cooling.


Offline opsomath

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Re: Tosylate Synthesis
« Reply #7 on: September 22, 2011, 02:58:02 PM »
OC pro. Calm down. It's pretty clear the OP isn't a native English speaker and isn't particularly experienced with organic chemistry, or he would know that the rotovap is fine in this case. There's no need to belittle OP.

However I agree with OC Pro's statements about chemistry. The tosylation in solvent should only take an hour or two at most, use thin-layer chromatography to monitor the reaction. Triethylamine can be used in place of pyridine if you are having trouble getting rid of the pyridine; if you use a nonpolar solvent like DCM or THF, most of the amine will come out as a salt anyway and you can just filter it off.

Offline OC pro

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Re: Tosylate Synthesis
« Reply #8 on: September 22, 2011, 03:02:19 PM »
Sorry, but my little son here (3 weeks old) drives me a bit insane. And when I have to read "pyridine smells bad" in combination with the term "solvent-free chemistry (terrible invention)" it drives me crazy *argh*.
Ok...back to topic.  ::)

Here is my suggestion:

Dissolve the alcohol in dichloromethane and cool the reaction in an ice-bath. Add 1.5equiv. triethylamine and then 1.1equiv. TsCl. Stir for 1h at room temperature and the job should be done.
And please...forget about solvent-free chemistry. Organic chemistry lives from it´s rich solvents. There is nothing better than performing an extraction after a successful reaction. ;D

Offline Nosterius

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Re: Tosylate Synthesis
« Reply #9 on: September 22, 2011, 03:18:35 PM »
Also, if for an unexpected reason, the tosylation occurs too slowly, you can try adding a catalytic amount of DMAP. However, if greatly catalyzes the reaction and you need an ice-bath to keep the reaction running at a reasonable rate... I've seen a reaction mixture come out of a round-bottom flask upon adding a spatula tip of DMAP...

If you want to keep a "green chemistry/solvent free" approach, there are exemples in the litterature of tosylation reaction using TsCl in water, with sodium carbonate as a base.

Offline opsomath

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Re: Tosylate Synthesis
« Reply #10 on: September 22, 2011, 03:18:46 PM »
Congrats on the little one! I had a non-sleeper myself, he's 1.8yrs old now and I am still catching up on sleep. Hope you have some good family or friends around as a support network.

I did precisely one solvent-free synthesis ever, and it worked okay. It was a condensation of the enolate of some acetylpyridine derivative with some benzaldehyde derivative, and you were supposed to grind them in a mortar with NaOH. The acetylpyridine smelled exactly like Doritos. I still can't eat doritos.

We wound up going to a different procedure, but that one did actually work.

Offline Doc Oc

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Re: Tosylate Synthesis
« Reply #11 on: September 22, 2011, 07:46:51 PM »
One sticking point I had with tosylation was the potential for E2 elimination, which I believe could also prove problematic with this substrate.  But I agree that it should take nowhere near several days, I typically couldn't stop mine fast enough.  By the time I saw the tosylated product by TLC it was already starting to eliminate to the alkene.  This usually took less than an hour.

Offline dkhoo

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Re: Tosylate Synthesis
« Reply #12 on: September 22, 2011, 09:03:26 PM »
Thank you all for the advise.  I have one question, can dichloromethane be replaced with THF or Choloroform ?

Offline opsomath

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Re: Tosylate Synthesis
« Reply #13 on: September 22, 2011, 09:13:56 PM »
I believe that the first time I used this procedure, I used THF. You may wind up with a little more amine salt (pyridinium hydrochloride or triethylammonium chloride) in your crude product than you would otherwise.

Chloroform, I don't know. Guys?

Offline OC pro

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Re: Tosylate Synthesis
« Reply #14 on: September 23, 2011, 04:33:33 AM »
Chloroform, benzene, toluene, acetonitril, dioxane...

Everything should work. To avoid elimination one can stir at 0 - 5°C. But I don´t see a prob here.   

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