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Chemistry Forums for Students => Organic Chemistry Forum => Topic started by: dkhoo on September 21, 2011, 01:44:56 PM

Title: Tosylate Synthesis
Post by: dkhoo 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 ?
Title: Re: Tosylate Synthesis
Post by: opsomath 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.
Title: Re: Tosylate Synthesis
Post by: BobfromNC 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
Title: Re: Tosylate Synthesis
Post by: the.khemist.ds 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
Title: Re: Tosylate Synthesis
Post by: dkhoo 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.
Title: Re: Tosylate Synthesis
Post by: orgopete 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.
Title: Re: Tosylate Synthesis
Post by: OC pro 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.

Title: Re: Tosylate Synthesis
Post by: opsomath 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.
Title: Re: Tosylate Synthesis
Post by: OC pro 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
Title: Re: Tosylate Synthesis
Post by: Nosterius 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.
Title: Re: Tosylate Synthesis
Post by: opsomath 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.
Title: Re: Tosylate Synthesis
Post by: Doc Oc 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.
Title: Re: Tosylate Synthesis
Post by: dkhoo 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 ?
Title: Re: Tosylate Synthesis
Post by: opsomath 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?
Title: Re: Tosylate Synthesis
Post by: OC pro 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.   
Title: Re: Tosylate Synthesis
Post by: orgopete on September 23, 2011, 08:08:26 AM
Don't use chloroform or dichloromethane. i used a procedure to isolate an amino acid from its hydrochloride salt by treating with triethylamine and extracting the triethylamine hydrochloride out with dichloromethane. While the reaction would work, it will retain too much of the salt. Use an ether.

Isn't benzene a regulated carcinogen?
Title: Re: Tosylate Synthesis
Post by: nox on September 23, 2011, 11:34:22 AM
I tosylate my indoles in DCM with 3 equiv of KOH at room temperature. Reaction works beautifully and is done in 30 minutes. Only issue is TsCl co-elutes with my product so if I have to be very precise with how much TsCl I use. Eventually I found that 1.03 equiv is enough, and with this I am able to regularly obtain ~95% yields.
Title: Re: Tosylate Synthesis
Post by: OC pro on September 23, 2011, 02:18:22 PM
Here in Germany benzene is regulated but we can buy it. It is not that bad as many people may think.
Co-elution of TsCl and tosylated compound happens somehow often. I also made the experience several times.
Title: Re: Tosylate Synthesis
Post by: orgopete on September 25, 2011, 11:20:02 AM
Okay, I was only referring to using DCM with triethylamine. I agree with NOX about KOH, no problem.

Re: benzene is regulated, but not that bad.
This statement suggests the regulators erred. I don't know how toxic it is or isn't. It is found fairly commonly. None the less, why wouldn't you use toluene instead? I would, if I needed to use benzene in this example.
Title: Re: Tosylate Synthesis
Post by: opsomath on September 25, 2011, 01:02:52 PM
Quote
This statement suggests the regulators erred.

Yes, it does, and she is probably right. Benzene is one of the most useful solvents. It is brilliantly effective for crystallization of nonpolar materials and is considerably easier to remove than toluene. It is also stable towards free radical oxidation, a handy property in many reactions which also means that you don't have to worry as much about the purity of an old bottle.

Its regulatory and hazard treatment is disproportionately severe compared to many other common compounds such as aniline or phenol. It should be used in the hood and disposed of in a sealed waste container, but that's most solvents.
Title: Re: Tosylate Synthesis
Post by: OC pro on September 25, 2011, 02:23:19 PM
Totally agree with opsomath.
Just for your info guys: according to the newest investigations chloroform is a mutagenic and cancerogenic substance. Moreover, 1,4-dioxane is now also classified as toxic. That´s why we have to store it now in special cabinets.
Title: Re: Tosylate Synthesis
Post by: fledarmus on September 27, 2011, 10:28:04 AM
The real difference between benzene and toluene in biological terms is that the body can metabolize toluene and get rid of it, while benzene tends to accumulate. The methyl group on toluene gives the body a handle for oxidation and elimination. Consequently, there is no level of benzene exposure which is considered "safe" - any exposure will accumulate until enough is present to cause damage.

I think the bad reputation of benzene was caused by the very clear association between exposure and various leukemias. Benzene was widely regarded as a harmless solvent before this link was established, and was widely used as a solvent and even for hand-washing to remove oils in many industries. Consequently, a lot of people were affected. Benzene is now very difficult for me to get and use even in a research lab in drug discovery, and if we can replace it with anything else to run our reactions, we will.
Title: Re: Tosylate Synthesis
Post by: OC pro on September 28, 2011, 11:12:58 AM
@fledarmus:

In fact, benzene gets almost completely metabolized. The highly reactive benzene epoxide (cytochrome P 450 oxidases) yields hydroxybenzenes (phenol, hydroquinone...) which decompose into reactive oxygen species (radicals?). These specimen cause oxidative DNA damage. radicals?). These specimen cause oxidative DNA damage. radicals?). These specimen cause oxidative DNA damage.
Moreover, its flat architecture enables it to intercalate into DNA.

And of course, one should avoid to work with this stuff.
Title: Re: Tosylate Synthesis
Post by: fledarmus on September 28, 2011, 02:55:06 PM
Thanks for the corrections OC pro - rereading my post, it does appear that I overstated the case.

The distinction I intended to make was that most of the toluene that enters the body is readily oxidized by the CYP450 enzymes in the liver to form innocuous glucoronides that are rapidly excreted. The body can efficiently clear toluene from its system. This metabolic pathway is not available to benzene. Instead, any benzene that is metabolized goes through a much slower pathway involving direct oxidation of the benzene ring, leading, as OC pro pointed out, to highly reactive oxygenated species that are not excreted and are particularly adept at causing DNA damage. The body will slowly clear the benzene out, but it is removed unchanged, and the longer it is present, the more likely it is to undergo this alternative metabolic pathway and cause damage.

Toluene, due to the stabilizing effect of the methyl group, would be expected to undergo this second metabolic pathway even better than benzene, except that it is so rapidly cleared by the first metabolic pathway.
Title: Re: Tosylate Synthesis
Post by: Honclbrif on September 28, 2011, 04:28:45 PM
I always thought that was a pretty rude thing that the liver did with benzene, making it even worse and all.
Title: Re: Tosylate Synthesis
Post by: helenn on October 14, 2011, 08:11:58 AM
Going back to the original topic, I have done this reaction a number of times recently on scales of up to 15 g and consistently acheived >95% yield. I add TsCl to the alcohol in pyridine in ice, then stir overnight at room temperature. Add ether and filter off the pyridine Cl salt, wash the ether filtrate with HCl, water NaHCO3 and water, dry and evaporate the organic layer to give clean product.
ref: tetrahedron asymmetry, 1995, 1181