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Author: Subject: question an N-acetylation of aniline, using aspirin
Jor
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[*] posted on 18-1-2009 at 08:13
question an N-acetylation of aniline, using aspirin


Last 2 days, I have tried this reaction again, using a readily available, potential N-acetylating agent: aspirin.

A few question remain.

This is what I did:

Weighed out 2,05 grams of pure acetylsalicylic acid and put this in a test-tube.
http://i405.photobucket.com/albums/pp133/Joris12345/P1090822...

I next added 2,5mL of colorless aniline, and heated the test-tube for 20 minutes at 110-120C. After 20 minutes, the reaction mixture looks like this:
http://i405.photobucket.com/albums/pp133/Joris12345/P1090831...
The brown coloration is due to oxidised aniline by oxygen. Aniline is was colorless, but at this temperature, the coloration is very rapid.

I cooled down to about 60C and dissolved everything in about 16mL of ethyl acetate.

I next washed with 15mL of saturated bicarbonate, followed by a wash with 1M HCl. Both washings looked the same:
http://i405.photobucket.com/albums/pp133/Joris12345/P1090840...

Next the solvent was evaporated (it was ca. 5-10C)

This left about 1,5g of dry, brownish beautiful crystals:
http://i405.photobucket.com/albums/pp133/Joris12345/P1090857...

I added some to a hot NaOH-solution. Droplets were formed. I first though that this was the hydrolysis product of acetanilide, aniline, but colling down gives about the same volume of brown solid again (???) .
I also added a small spatula of acetylsalicylic acid to the same concentration NaOH-solution, and all very quickly dissolved.

I next took about 0,7-0,75g of the brown solid and added 13-14ml of water. Next the liquid was heated to 90C. Most had dissolved, but to my surprise there was very dark brown liquid on the bottom, wich did not seem to dissolve after addition of more water, and heating again.
http://i405.photobucket.com/albums/pp133/Joris12345/P1090859...

Next 125mg of activated charcoal was added, and it was heated for 1 more minute, followed by filtering.

The filtering was hard, as I have a plastic funnel and normal filter paper and also no vaccuum, so I couldn't filter hot. I therefore filtered in 3 steps, small amounts at a time.

The filtrate quickly became a white suspension, suspected acetanilide crystals.

The other 0,7-0,8g of the crude product was dissolved in 10mL ethyl acetate and 125mg of AC was added. I am leaving this to stand for a few hours.

My question is: what is the brown liquid, when recrystallising. Acetanilide is supposed to melt at 113-114C, the crude product (or at least a part of it) melted at 70-90C in the hot water...

And does 1 wash with sat bicarbonate remove al (acetyl)salicylic acid? I shaked very vigorously, until no more gas evolution. Maybe it was too cold? (5-10C).
I also shaked very vigorously with 1M HCl, so the unknown brown liquid can't be aniline right?

I cannot test for presence of (Acetyl)salicylic acid in the crude brown product at the moment. My thought was to dissolve some crude product in NaOH-solution, decant, and add excess HCl to the solution. This would precitipate out any (acetyl)salicylic acid present. BUT, I already used up all my crude product, I have nothing left!!!

Any thoughts?
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not_important
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[*] posted on 18-1-2009 at 09:31


Consider this - you have an amide RCONHAr' and a carboxylic acid AcCO2H mixed together and heated above the boiling point of RCO2H. Can you be sure that

RCONHAr' + ArCO2H <=> RCO2h + ArCONHAr'

doesn't occur?
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[*] posted on 18-1-2009 at 11:29


Do you have a reference for this?

Simply cooking up aniline in an excess of acetic acid will provide acetanilide.

What was your source for Acetylsalicylic acid? was it a pill extraction? if so they usually contain waxes.




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[*] posted on 18-1-2009 at 11:54


Are you sure heating GAA with aniline will give acetanilide? I thought only formic acid would do that.

The aspirin was synthesised from pure, farmacy-grade salicylic acid, reagent grade acetic anhydride and P.A Merck phosphoric acid. So don't worry it's impure ;)

Wonder why I did not use straight anhydride? Well I wanted to try if this works, to provide an alternative acetylating agent, instead of the hard to get AcCl and Ac2O.
And I was too lazy to go to the farmacy, buy aspirin, and purify it, while I had a liter (well 900mL) of anhydride at hand.

I have no reference, I did this for my school project, when I was still very unskilled in chemistry. I only came with the idea to use aspirin as an acetylating agent, all the other ideas are from Nicodem.
I don't think there are any references on this, it might be useful for a home chemist, but industrially or in labs, everyone would use AcCl or Ac2O.

Not_important. I'm not sure if that reaction does not occur. But during the heating. I only have seen SOME bubbles, and they were probably just water, because the graduated cylinder I used for measuring aniline was still a bit wet.
Even if ArCONHAr' was formed, this can't be the liquid encountered during recrystallisation, because that even has a higher meting point than acetanilide.
BUT, I have performed in the fume hood, so I would have smelled the acetic acid if formed, but not now as it is all sucked away.
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[*] posted on 18-1-2009 at 12:01


Look up acetanilide in vogel's Practical organic chemistry. The yield is good.

If you want to further pursue this, you should probably use a healthy excess of aspirin relative to aniline, as I don't see a huge driving force for this reaction.




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[*] posted on 19-1-2009 at 00:59


Jor, you are doing the reaction in a non-synthetically oriented way. That is, you use excess aniline instead of a slight excess aspirin. You should consider that salicylic acid is the other reaction product and being a carboxylic acid it can easily react with excess aniline particularly if you heat above 100°C (ammonium and particularly anilinium carboxylates can be dehydrated to amides by heating to 120-170°C). I suggest you to use a 25% excess aspirin and not heat above 100°C (the reaction mixture should be liquid at this temperature since aniline is liquid and acetanilde has a close enough mp to dissolve salicylic acid in an eutectic). Therefore try with a boiling water bath. The reaction should easily proceed already at about 50°C in my opinion (for example, plain phenyl acetate is a relatively good N-acylating reagent while p-nitrophenyl acetate approaches the reactivity of acid anhydrides - aspirin should therefore be somewhere in between in reactivity). The only point in heating it to a higher temperature is because you do it solventless, but still do not exaggerate more then necessary.
After you optimize it, you can try it on some aliphatic amine if you have any.
Otherwise you did a nice job.

PS: Linking to the previous thread would be a good idea since I doubt all members ever followed it.




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[*] posted on 20-1-2009 at 14:36


Sorry for the late reply.

I have only a small amount of salicylic acid (5g) left, and i'd like to keep that for other purposes.

This means I eirther have to buy some acetylsalicylic acid from my supplier, or do the purification process.

Anyway, I don't have the money at the moment, as I'm doing a very large glassware buy and some chemicals (25g CsCl, 10g luminol, 10g lithium, 25g NaBH4, and some others for 35 EUR :D ).

I will just heat it with a boiling water bath when i have the stuff. Also excess aspirin.

I have one aliphatic diamine, ethylenediamine. I have used that for making some complex copper and nickel salts.

[Edited on 20-1-2009 by Jor]
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[*] posted on 5-2-2009 at 00:52


I'm afraid ethylenediamine is not appropriate since the resulting N,N'-diacetylethylenediamine is too water soluble and this would require a reaction work up maybe too complicated for your liking.
When I'll have the time (and when I'll finally remember to buy some aspirin) I'll give it a try on aniline as well as benzylamine or some other aliphatic amine and follow the reaction with HPLC to see at which temperature it starts.

PS: The off topic discussion on the role of pyridine, Et3N or other such bases in the N-acylation with acyl chlorides has been split off to a separate thread: http://sciencemadness.org/talk/viewthread.php?tid=11778




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[*] posted on 10-3-2009 at 06:16


The topic of this thread is the continuation of the thread "acetylsalicylic acid".

I finally remembered to buy some aspirin…

Anyway, here is a simple test of the reaction between acetyl salicylic acid and aniline.

To a stirred solution of 235 mg of aniline (2.5 mmol) in 30 mL of acetonitrile was added a 500 mg pill of aspirin (Bayer, cca. 2.77 mmol), which took about 5 min to dissolve, leaving only a tiny amount of insoluble solids from pill binders. The temperature of the reaction mixture was 22°C and samples were taken from time to time to monitor the progress of the reaction with a HPLC (70% acetonirile mobile phase, an old defective C-18 Nucleosil column, and UV detector at 254 nm).

The formation of a small amount of acetanilide (the product) was evident already at the first HPLC measurement. However it took almost 3 h of stirring at room temperature for the peak of acetanilide to reach approximately the area of the aniline peak (starting material).* This means it would take about 24 h at room temperature for the reaction to complete. The reaction mixture was therefore heated with a heat-gun to boil (~79°C) and immediately left cooling to room temperature. This time the reaction went almost to completition. The area ratio of acetanilide : aniline was about 80 : 20, indicating a 10 min reflux would be enough for a quantitative conversion.

In conclusion, aspirin is quite reactive for N-acylation of aniline, the reaction takes place slowly at room temperature but very rapidly at acetonitrile reflux temperature.
I will try the same with benzylamine next time to see how it works on aliphatic amines.

* The UV absorption of acetanilide and aniline are not identical, so that for example, a 1 : 1 area ratio in HPLC does not necessarily mean a 1 : 1 molar ratio.




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[*] posted on 11-3-2009 at 13:50


Very good job Nicodem. I'm sorry I haven't yet had the time to do it myself. I have yet been doing other projects, that interest me more. But my interests shift all the time so when I'm in the mood again, I will buy some aspirin! :P

Maybe acetonitril should be substituted. If this would be a method for OTC acetylation, it should work without MeCN, as that is hard to get, hard and expensive to make in large amounts (acetamide with P4O10), and if you can buy it is hard now, as there is a world shortage :D

You did this with HPLC at home? :o
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[*] posted on 12-3-2009 at 07:25


I'm sure ethyl acetate would work similarly well. Isopropanol or ethanol might also be fine. I'll try with ethanol next time.
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[*] posted on 15-3-2009 at 03:40


Nicodem, it would seem that asprin might be an acetylation catalyst, sort of like DMAP. Would that be worth an experiment?
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[*] posted on 16-3-2009 at 00:03


Quote:
Originally posted by Paddywhacker
Nicodem, it would seem that asprin might be an acetylation catalyst, sort of like DMAP. Would that be worth an experiment?

I'm afraid I do not understand. What do you mean by aspirin as acetylation catalyst? There is absolutely nothing in common between DMAP and aspirin. Me and Jor are trying to evaluate the use of aspirin as N-acetylation reagent. Maybe you missed the point of the tread. You should read the thread linked above where Jor describes his experiments.




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[*] posted on 16-3-2009 at 11:29


Quote:
Originally posted by Nicodem
Quote:
Originally posted by Paddywhacker
Nicodem, it would seem that asprin might be an acetylation catalyst, sort of like DMAP. Would that be worth an experiment?

I'm afraid I do not understand. What do you mean by aspirin as acetylation catalyst? There is absolutely nothing in common between DMAP and aspirin. Me and Jor are trying to evaluate the use of aspirin as N-acetylation reagent. Maybe you missed the point of the tread. You should read the thread linked above where Jor describes his experiments.

No need to be condescending, Nicodem.

I posit that acetylsalicylate could act as a useful catalyst if it is a faster acetylating agent than acetic anhydride and can be reconstituted by acetylation from acetic anhydride as fast as it is consumed.

So the question is, is Asprin plus acetic anhydride (with or without pyridine or other base) a better N-acetylator than the same mix without Asprin?

I would have thought that extending your work from a batch scenario to its possibilities as a catalyst would have been obvious.
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[*] posted on 16-3-2009 at 14:53


I would have thought that aspirin would be a slower acetylating agent than acetic anhydride simply because of the comparative reactivity between an acid anhydride and an ester. I could be wrong, but it seems incrediably unlikely that aspirin will acetylate anything faster than acetic anhydride itself, thus ruling out its "possible" use as an acetylating catalyst.

As seen by Jor's results upthread, 110-120C for 20 minutes is pretty harsh conditions compared to those required for acetic anhydride. I also suspect that the reaction may be in equilibrium, and the only thing that drives it is the formation of the more stable amide compared to the ester (acetanilide c.f. acetylsalicylic acid). I expect that trying to acetylate anything other than an amine with aspirin will fail to produce decent (if any) yields, for the reason just stated (hence Jor's correct thread title "N-acetylation ...")
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[*] posted on 16-3-2009 at 15:16


Ofcourse acetic anhydride is better. The whole reason this method might be interesting for some is that acetic anhydride is very hard to get, because of it's illicit uses.
And it is not easy to prepare, you need some exotic reagents like acetyl chloride, sulfur chlorides (of I remember right) or highly toxic ketene.

So this might be a good, safe and cheap, OTC alternative for acetic anhydride as an N-acetylating agent.

And yes, I used some harsh conditions, but as stated by Nicodem, I should have carried it out at lower temperatures, and in other molar ratios.
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[*] posted on 16-3-2009 at 15:32


Yes Jor. The point of my post was to tell that acetylsalicylic would not catalyse acetylation reactions as Paddywacker had suggested is possible.
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[*] posted on 16-3-2009 at 15:49


Sorry, I missed Paddywackers post. I already found your post a bit weird, because I did not read Paddywacker's post :P
Now I understand what you were saying.

Yes indeed, it would be extremely unlikely aspirin could act as a catalyst. Acetic anhydride is far more reactive.
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[*] posted on 16-3-2009 at 21:24


Quote:
Originally posted by Jor
Sorry, I missed Paddywackers post. I already found your post a bit weird, because I did not read Paddywacker's post :P
Now I understand what you were saying.

Yes indeed, it would be extremely unlikely aspirin could act as a catalyst. Acetic anhydride is far more reactive.


Is it for sure? Asprin acetylates cyclooxiginase-1 in platelets under psysiological conditions.

In the reactions that we are considering the ferr carboxylic acid could be expected to play a part in recruiting the amine nitrogen for the acetyl group to attack.

Until you have elucidated the reaction mechanism and measured it's kinetics then you are speculating. Speculating rather unimaginatively in my opinion. Widen your horizons.... or do some tests.

Your initial premise and its testing and confirmation by Nicodem shows imaginative thinking. Don't sink down into the mud after that one effort. Pick up your bedroll and run.
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[*] posted on 16-3-2009 at 23:57


Paddywhacker, I must admit that I still do not understand your reasoning. Salicylic acid and other phenols in general are much more difficult to O-acetylate with acetic anhydride than anilines or aliphatic amines. Before even a couple of % of the phenol would get acylated all of the aniline/amine would already be turned to acetanilide/amide. Phenols are not so easy to O-acetylate, even primary alcohols react faster with acetic anhydrides. The only phenol acetates that could be of electrophylicity comparable to acetic anhydrides would be the acetyl esters of nitrophenols. For example, p-nitrophenyl acetate is a relatively strong acetylating reagent, yet still weaker than acetic anhydride (which actually makes it useful for selective acylations for which it is generally used). I bet picric acetate would be a stronger acylating reagent, but it is not something you can come by in your nearest pharmacy.
A catalyst like DMAP works by forming an intermediate which when protonated becomes more electrophilic than the acylating reagent itself, therefore reacting with the substrate faster. A compound that reacts with the acylating reagent slower than the substrate and in addition forms a product that itself is a much weaker acylating reagent, can not act as a catalyst.
To make things clearer, you can check the electrophilicity of carboxylic acid derivatives (as found in organic chemistry school books):
RCO-X (X=halogen) > RCO-O-COR > RCO-OAr > RCO-OR > RCO-NR2 > RCO-OH > RCO-O-




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[*] posted on 18-3-2009 at 13:09


Yeah, I think that too, which is why I qualified my supposition with "it ... can be reconstituted ... as fast as it is consumed"

It seems unlikely, but should be testable by adding a catalytic amount of acetylsalycilate to an anhydride-based acetylation reaction and following the kinetics roughly via TLC.
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[*] posted on 12-5-2010 at 01:19


It seems that asprin's ability as a transacetylator is out there ...
http://www.justice.gov/dea/programs/forensicsci/microgram/jo...
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[*] posted on 13-6-2013 at 21:51


Thank you for your great work Nicodem and Jor. May I ask what the yield is for this reaction? I'm thinking of eventually using it as part of a larger project I have in mind (I have to purchase a decent amount of equipment first).
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[*] posted on 14-6-2013 at 11:55


The yield for Jor's solventless attempt is given in the first post. I didn't notice any other preparative example being reported. The reaction should be cleaner by using a proper solvent, conversion monitoring and improved work-up.
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[*] posted on 14-6-2013 at 17:53


Ah, my understanding was that you had also performed this reaction. Or was it for monitoring purposes only? Perhaps the oxidation can be mitigated by adding zinc dust, as per Vogel, resulting in a better yield.

[Edited on 15-6-2013 by amazingchemistry]
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