Sciencemadness Discussion Board

Procedure of tosylation of p-aminochlorobenzene

JAVA - 23-10-2014 at 11:01

Hi guys,
I have performed the synthesis of p-aminochlorobenzene a couple of months ago. The problem is that this aromatic amine becomes yellow (and then red) in a alkaline medium. I did store this amine in concentrated HCl and that was a clever idea.

My idea is to use sodiumbicarbonate or sodiumcarbonate to neutralize the HCl and extract the freebase in EtOAc several times.

After the purification process I would distilling off p-aminochlorobenzene under reduced pressure.

However, I think the last step isn't necessary since both p-aminochlorobenzene and TsCl are soluble in EtOAc. My question is: does this work ?

The reaction times of amine tosylation ranging from 1 hour to 16 hours (see references), is this a straightforward reaction that reacts spontaneously under reflux ?

Also, some chemists say that the end product hydrolysed quickly with moisture in the air but according to a german chemist these tosylated amines are fairly stable.

What about the storage of these compounds and how long can I store them ?


References about the reaction time:
Tosylation of amines
Procedure of the tosylation of aromatic amines

ScreenHunter_307 Oct. 23 20.16.jpg - 36kB

Java

AvBaeyer - 23-10-2014 at 18:33

Java,
You want to run a very simple Schotten-Bauman reaction. It's described in most every sophomore college org chem lab manual. Read and learn! In a nutshell. you can take your amine HCl solution, make it to about pH 13 with NaOH and shake the resulting mixture with a 10% molar excess of Tos-Cl. No organic solvent is needed. Add additional NaOH during the shaking process to keep the pH above 11 or so. As the reaction proceeds, the tosyl amide should dissolve in the aqueous layer. When the rection is complete (pH is stable and basic), acidify and filter off your tosylamide. Purify as you see fit.

Your tosylamide should be stable indefinetely. Your particular tosyl amide will be extremely difficult to hydrolyze.
AvB

JAVA - 24-10-2014 at 05:59

Quote: Originally posted by AvBaeyer  
you can take your amine HCl solution, make it to about pH 13 with NaOH and shake the resulting mixture with a 10% molar excess of Tos-Cl. No organic solvent is needed.
AvB


But tosyl chloride reacts with water (hydrolysis), I can read it everywhere. That's no problem ?

Secondly, p-aminochlorobenzene is a solid amine that is insoluble in water. Without organic solvent I should mix 2 solids and shake them. That doesn't make sense.

The stability is yet another big problem since p-aminochlorobenzene becomes yellow if you don't use a inert atmosphere or a vacuum source.

I guess that nothing will happen except a rapid hydrolysis of tosyl chloride to the corresponding acid and a side reaction like aniline in air, but way faster.

Nicodem - 24-10-2014 at 07:38

Quote: Originally posted by JAVA  
But tosyl chloride reacts with water (hydrolysis), I can read it everywhere. That's no problem ?

No, it is no problem, especially not with tosyl chloride. The Schotten-Baumann reaction is commonly used for the sulfonations of anilines or other amines. I also used it for tosylation or anilines. That acid chlorides or anhydrides hydrolyse is more or less irrelevant by itself, what matters is the difference in the nucleophilicity between the substrate and the chloride/anhydride.
The Schotten-Baumann synthesis of your product is in DOI: 10.1002/cber.19560890832.
Quote:
Secondly, p-aminochlorobenzene is a solid amine that is insoluble in water. Without organic solvent I should mix 2 solids and shake them. That doesn't make sense.

Both reactants have some significant solubility in water. I would personally first prefer using water with some THF, acetone, 2-propanol or acetonitrile (4 : 1) and Na2CO3 as the base, but that's probably because I'm not too adventurous when I try a new reaction the first time. Though, I think it might work exactly as AvBaeyer suggested it. Note also that under the Schotten-Baumann conditions, the yield depends on the excess of the acid chloride and base.
Quote:
The stability is yet another big problem since p-aminochlorobenzene becomes yellow if you don't use a inert atmosphere or a vacuum source.

That is irrelevant. Coloration will not affect yields and has negligible effect on purity.
Quote:
I guess that nothing will happen except a rapid hydrolysis of tosyl chloride to the corresponding acid and a side reaction like aniline in air, but way faster.

The hydrolysis of tosyl chloride is notoriously slow and any reaction of aniline with air is negligible.

However, there is something I don't understand. If you are so concerned about doing it right the first time, why don't you used a published procedure? What's wrong with the procedure in DOI: 10.1016/j.tet.2003.08.006 or DOI: 10.1039/C3CC40858B or any of the other reasonable examples? I think there are even literature reports where an aniline and tosyl chloride are just mixed together, slowly heated up to release the HCl, and you are left with a crude, perhaps just needing a recrystallization. Just don't do it on a large scale.

DJF90 - 24-10-2014 at 08:43

I've done tosylation of 2-iodoaniline before using pyridine as solvent. It worked ok but purification was a pain. To re-attempt the synthesis now, I would certainly use schotten baumann conditions. I've used that reaction to tosylate a primary alcohol (DCM solutions of substrate and TsCl, aq NaOH with a little BnEt3NCl added as PTC), I've selectively N-acylated a 3-hydroxypyrrolidine with an aromatic acid chloride (THF/40% K2CO3 solution), and several other successful reactions I don't remember well enough to cite.

The one time it did not work for me was in atttempting to N-acylate a phenylhydroxylamine with benzoyl chloride. This was later attributed to too fast an addition rate and inadequate stirring, leading to a slight build up of HCl which effected the bamberger rearrangement to give the 4-aminophenol.

And as an old friend used to say; "colour doesn't weigh much"

[Edited on 24-10-2014 by DJF90]

JAVA - 25-10-2014 at 12:48

I'll try it out, I don't suspect any problems actually. Stirring it just at r.t. for one hour is enough ? Heating might cause hydrolysis of the product, right?

Final question is what solvent is well suited to remove the excess TsOH ?
Java

DJF90 - 26-10-2014 at 01:46

It should partition nicely into the aqueous phase. At end of reaction (check by TLC/NMR/any other suitable method) separate the phases and wash the organics with a portion of water. Check pH is near neutral, otherwise wash again with water. Then just concentrate under reduced pressure to afford your crude product (DCM dissolves very little water and forms an azeotrope). I'd suggest trying to recrystallise from (aq.) ethanol - this gave me lovely colourless plates

JAVA - 26-10-2014 at 04:44

Thank you DJF90 for the post reaction. In diluted hydrochloric acid the majority of the p-aminochlorobenzene was dissolved indeed. After adding aq. sodium carbonate till pH 9 the free base was released as white powder while stirring at rt.

After addition of a slight excess of TsCl (pH 9) and stirring for 1 hour a brownish water insoluble chewing gum like compound did appear at the bottom of the RB flask.

Now... the post-reaction ;)
Java

DJF90 - 26-10-2014 at 22:54

Why didn't you use an organic solvent like I had suggested... likely would have avoided any gum, and provided a cleaner reaction.

JAVA - 27-10-2014 at 03:51

It wasn't actually a sticky compound, before the post-reaction (still in the RB flask) it did look like a gum.

During the purification I isolated a crude brownish powder. I did dry that solid mass after washing it with water (3 times). The end product is very soluble in pure EtOH and it looks a bit like whiskey at the moment.

I used a excess (220 mL) EtOH because I have time enough to wait untill the N-(4-chlorophenyl)-4-methylbenzenesulfonamide is visible as a crystalline mass (th. mp. 120°C).

I did use 7,6 g p-aminochlorobenzene as limiting reagent.

No idea why the organic solvent is needed during the tosylation ?
I don't have a PTC to bring it into the DCM layer. Also, I didn't simply had any THF/Et2O during the experiment. Amines might react with acetone so I didn't trust that and it's just a experiment.

DJF90 - 27-10-2014 at 05:55

Thats a fairly unconventional way of (re)crystallising your product. Personally, I'd dissolve in minimal hot ethanol, add water until a hazyness persists, then add a little more ethanol to give a clear solution again. Then allow it to cool slowly to RT (or lower, if required).

Toluene is another very successful solvent for Schotten Baumann reactions. I'm not absolutely sure that the PTC is required, and have always added some for good measure. It doesn't complicate the workup, and would do more good than harm.

JAVA - 27-10-2014 at 07:23

I did already try to dissolve p-aminochlorobenzene in toluene, but the needle-shaped crystals quickly became yellow as well as the toluene.

Now I do understand what went wrong: p-aminochlorobenzene is soluble in diluted HCl but the freebase is a white solid and doesn't dissolve in the aqueous phase. TsCl is soluble in water and might react faster with the hydroxide ions present. That is the reason why you did add THF: to dissolve both TsCl and p-aminochlorobenzene so that they are able to react.



Unfortunately, after adding just a little bit cold EtOH (less then 20 mL) everything did dissolve, including the brown solid and suddenly a bloodred solution was obtained.

Now I'm just curious whether I can remove the colored impurities from the end products. If there wasn't a tosylation then I'm still able to isolate the unreacted p-aminochlorobenzene or if the "AvBaeyer procedure" did work I might end with the desired N-(4-chlorophenyl)-4-methylbenzenesulfonamide.

JAVA - 15-11-2014 at 11:04

Quote: Originally posted by DJF90  
It should partition nicely into the aqueous phase. At end of reaction (check by TLC/NMR/any other suitable method) separate the phases and wash the organics with a portion of water. Check pH is near neutral, otherwise wash again with water. Then just concentrate under reduced pressure to afford your crude product (DCM dissolves very little water and forms an azeotrope). I'd suggest trying to recrystallise from (aq.) ethanol - this gave me lovely colourless plates


Do you have a IR spectrum of the lovely colourless plates, I see them on the wall and it looks like lovely colourless sodium chloride crystals.

I suppose the organics are still in the EtOH.
What might be the structure of the brownish coloured product?

btw:
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