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Author: Subject: Acetic anhydride or acetyl chloride, that is the question...
SplendidAcylation
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shocked.gif posted on 30-3-2024 at 06:29
Acetic anhydride or acetyl chloride, that is the question...


Hi,

I have some fairly simple questions about acetyl chloride and acetic anhydride...

I apologize in advance if these questions have been answered elsewhere, however I have UTFSE'd and found no satisfactory answers.


As far as I know, acetyl chloride reacts rather more rapidly than acetic anhydride; I attributed this to the fact that the chloride anion is a less nucleophilic leaving group than the acetate anion; Perhaps there is a more accurate explanation, but anyway, the main question is:

Are they interchangeable in the preparation of esters and amides?

I have seen many procedures that specify acetyl chloride, and many that specify acetic anhydride, and there is never an explanatory note saying anything along the lines of "Acetyl chloride/acetic anhydride can be used but the acyl halide will give better results" or anything of the kind.

Perhaps the most (in)famous use of acetic anhydride is in the acetylation of morphine to yield heroin.

In this case, one would imagine that acetyl chloride would substitute fine, however this is never discussed, and it even appears that AA is scheduled by the US DEA, and acetyl chloride is not!


So it seems as if there might be some significant differences of which I am unaware.

Although acetyl chloride is more electrophilic, it has a much lower boiling-point, which limits the temperature at which it can be refluxed, so I imagine this must somewhat cancel out the increased reactivity...

Would refluxing acetyl chloride at ~60c be more reactive than AA, refluxing at ~140c?



And a few questions regarding the acetyl chloride I have prepared myself.

I made it by the reaction between acetic acid and benzoyl chloride; It is a very volatile, highly fuming liquid.


I attempted an esterification reaction yesterday using acetyl chloride; I used triethylamine + DCM as the solvent, this was placed in an ice-bath and stirred, whereupon the acetyl chloride was added (prior to adding the alcohol of which the ester was to be prepared).

Immediately upon adding the AcCl, there was a "pop" due to rapid boiling, copious fumes, and white precpitate forming.

I suspect that the reaction taking place is the reaction between dissolved hydrogen chloride, in the AcCl, and the amine... Is this to be expected?

The reaction seemed rather too violent, given that only traces of hydrogen chloride should be present.


Whenever I open the bottle of acetyl chloride, voluminous fumes are produced; I wear a mask, but I can feel the warmth of hydrogen chloride dissolving my skin! :P

It is described as a "fuming liquid" however the degree to which it fumes just seems way too much, so I'm wondering if my product has too much dissolved HCl.



Finally, one other thing that has been bothering me;

I have, many times, attempted the preparation of Bohme's salt (similar to Eschenmoser's salt), the Mannich intermediate.

Every time I have failed to carry out a successful Mannich reaction, and I'm not yet sure why.

The prototypical reaction is between N,N,N,N-tetramethyldiaminomethane (an aminal) and acetyl chloride:


(CH3)2N-CH2-N(CH3)2 + AcCl --> (CH3)2N=CH2+Cl- + AcN(CH3)2


Typically, the aminal is dissolved in ether, whereupon the AcCl is added, to incipient precipitation of the Bohme's salt, but there is something that really bothers me, and I suspect might have contributed to my many failures:

If my acetyl chloride contains any dissolved HCl, this will surely protonate the aminal, forming a solid which will precipitate from the solution, and become unavailable for further reaction.

This would greatly diminish the yield of the Bohme's salt; I can find no reference to this potential problem, nor any mention that the acyl halide must be especially pure.

Am I missing something (perhaps the precipitated aminal salt would still react with dissolved AcCl?) or could this be a big problem?



Thanks in advance for reading my rambling post!

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[*] posted on 30-3-2024 at 07:58


Generally, acetic anhydride and acetyl chloride should be interchangeable for ester and amide formation. Acetic anhydride tends to be preferred because it is much more shelf stable and less unpleasant to work with than acetyl chloride. As you have observed, acetyl chloride is volatile and fumes a lot. Acetic anhydride does not.

It’s certainly odd that your AcCl would react violently with triethylamine in DCM. Perhaps you could stir your AcCl with some anhydrous potassium carbonate to neutralize excess HCl, then filter it and use the freshly filtered stuff quickly.




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[*] posted on 30-3-2024 at 11:52


AcCl can undergo an elimination reaction with triethylamine to give ketene. Luckily this is generally consumed as quickly as it is formed under these conditions. Ac2O does not react under these conditions. But now you know why pyridine is the preferred base for working with acyl chlorides :P



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[*] posted on 30-3-2024 at 13:48


Yes, I would not add AcCl to TEA, that is asking for side reactions. The normal prep for these reactions is to mix the TEA and alcohol, then add the AcCl dropwise or very slowly. Since Ac2O is less reactive, it can often be added much faster. Since AcCl can react with amines, even teriary ones, it is often not used for complex acylations, like morphine, which might react at the nitrogen as well as the phenol. There are even some reactions that utilize a harsh reagent like AcCl to remove a methyl group from a dimethylamino group.

So for many simple reactions, they are interchangable, but in general anhydrides are less reactive, but milder, which often can give better yields. But for some cases, the chloride is able to react when the anhydride is not reactive enough.

Also, I would rarely reflux a reaction like these, and the solvent would typically be what controls the boiling point. I would never run a reaction in anhydride at 140 C, its just too harsh. If the AcCl contains HCl, you could just distille it, which would remove some, or just add some TEA or pyridine to the substrate, before adding the AcCl, it will eventually soak up the HCl.
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[*] posted on 31-3-2024 at 05:47


Quote: Originally posted by clearly_not_atara  
AcCl can undergo an elimination reaction with triethylamine to give ketene. Luckily this is generally consumed as quickly as it is formed under these conditions. Ac2O does not react under these conditions. But now you know why pyridine is the preferred base for working with acyl chlorides :P
Ah, I was not aware of that. Good to know!



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[*] posted on 2-4-2024 at 04:08


Thanks for the replies everyone :)


Quote: Originally posted by Texium  
Generally, acetic anhydride and acetyl chloride should be interchangeable for ester and amide formation. Acetic anhydride tends to be preferred because it is much more shelf stable and less unpleasant to work with than acetyl chloride. As you have observed, acetyl chloride is volatile and fumes a lot. Acetic anhydride does not.

It’s certainly odd that your AcCl would react violently with triethylamine in DCM. Perhaps you could stir your AcCl with some anhydrous potassium carbonate to neutralize excess HCl, then filter it and use the freshly filtered stuff quickly.


Indeed, acetyl chloride is horrible to work with. Even with the appropriate mask, it isn't very satisfying to deal with, because it is difficult to suck it up with a pipette due to volatility, and the fumes make it hard to see what you're doing :P

Unfortunately I don't have enough to really do anything with, without significant losses; I will probably make some more first.





Quote: Originally posted by clearly_not_atara  
AcCl can undergo an elimination reaction with triethylamine to give ketene. Luckily this is generally consumed as quickly as it is formed under these conditions. Ac2O does not react under these conditions. But now you know why pyridine is the preferred base for working with acyl chlorides :P



:D Interesting! So pyridine is too weak a base to deprotonate the alpha carbon of acyl halides?

It looks like I will probably end up making some acetic anhydride and using that instead, or I could make some pyridine of course!

It definitely pays to be less lazy, and avoid taking Wikipedia at face-value:

"Triethylamine is commonly employed in organic synthesis as a base. For example, it is commonly used as a base during the preparation of esters and amides from acyl chlorides."

On the Wiki page for ketenes it does also say:

"Substituted ketenes can be prepared from acyl chlorides by an elimination reaction in which HCl is lost"



Quote: Originally posted by Dr.Bob  
Yes, I would not add AcCl to TEA, that is asking for side reactions. The normal prep for these reactions is to mix the TEA and alcohol, then add the AcCl dropwise or very slowly. Since Ac2O is less reactive, it can often be added much faster. Since AcCl can react with amines, even teriary ones, it is often not used for complex acylations, like morphine, which might react at the nitrogen as well as the phenol. There are even some reactions that utilize a harsh reagent like AcCl to remove a methyl group from a dimethylamino group.

So for many simple reactions, they are interchangable, but in general anhydrides are less reactive, but milder, which often can give better yields. But for some cases, the chloride is able to react when the anhydride is not reactive enough.

Also, I would rarely reflux a reaction like these, and the solvent would typically be what controls the boiling point. I would never run a reaction in anhydride at 140 C, its just too harsh. If the AcCl contains HCl, you could just distille it, which would remove some, or just add some TEA or pyridine to the substrate, before adding the AcCl, it will eventually soak up the HCl.


Thank-you, this is really useful!


I dissolved my alcohol in TEA, and then added the AcCl all at once, so probably not ideal.


The paper I am following suggests a 5-hour reflux at 140c in pyridine to acetylate the alcohol with the anhydride, which obviously indicates that the reaction is unusually slow...


I will probably make some more AcCl, and then convert it to Ac2O using an acetate salt.
Unfortunately I don't have any sodium acetate, and I'm reluctant to waste GAA to make some.

I do, however, have lithium acetate, so I'm hoping that it will work in place of sodium acetate... I don't see why not, since it is the acetate anion itself that is reacting as a nucleophile.



[Edited on 2-4-2024 by SplendidAcylation]
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[*] posted on 2-4-2024 at 05:34


The ketene formation is not a huge problem when it is consumed faster than it can dimerize as in an esterification. Because the trialkylamines catalyze ketene dimerization, it tends not to escape. See Org. React. vol III pp 124-5.

Note that triethylamine (pKaH+ ~10.5) is about 100000x as strong as pyridine (pKaH+ ~5.5).




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[*] posted on 2-4-2024 at 11:57


The AcCl should work, as long as the alcohol is present with the base first and then you add the AcCl slowly. Cooliong might be useful at first as well, depends on the scale and reactivity of the substrates. I would not try to convert the AcCl to the anhydride, as anhydride can only give 0.5 mol equivilant of the Ac product, as only half of the anhydride reacts.
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[*] posted on 3-4-2024 at 03:34


Quote: Originally posted by clearly_not_atara  
The ketene formation is not a huge problem when it is consumed faster than it can dimerize as in an esterification. Because the trialkylamines catalyze ketene dimerization, it tends not to escape. See Org. React. vol III pp 124-5.

Note that triethylamine (pKaH+ ~10.5) is about 100000x as strong as pyridine (pKaH+ ~5.5).


Interesting!

I attempted an esterification of isopropanol using my acetyl chloride in DCM + TEA, and the reaction mixture turned from clear to amber during the reaction; I then passed a current of air in to evaporate off the DCM, and added water, which resulted in the separation of a brown oil.

The oil was then dried by washing with CaCl2 solution, and I then attempted a boiling-point test... This confirmed the presence of isopropyl acetate (the pleasant smell was also an indicator) however once the ester had all boiled off, a viscous brown liquid remained... I attributed this to polymerization products of ketene, as you suggested, but who knows...

OH and another interesting thing!
When I added my acetyl chloride to the DCM + TEA + iPrOH mixture, white solids formed (as mentioned previously) and there was a bright pink colour at the boundary between the reaction mixture and the air.

It became brighter and more defined over time, however it disappeared upon stirring...

Are those the pKas of the conjugate acids? Interesting, quite a difference!



Quote: Originally posted by Dr.Bob  
The AcCl should work, as long as the alcohol is present with the base first and then you add the AcCl slowly. Cooliong might be useful at first as well, depends on the scale and reactivity of the substrates. I would not try to convert the AcCl to the anhydride, as anhydride can only give 0.5 mol equivilant of the Ac product, as only half of the anhydride reacts.



Thanks!

As for converting the AcCl to Ac2O, one of the acetyl groups will be coming from an acetate salt, which is of course much cheaper than the AcCl itself, so surely there shouldn't be any waste of AcCl?

AcCl + AcO- ---> Ac2O + Cl-
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[*] posted on 3-4-2024 at 07:40


I would advocate for converting to acetic anhydride. Not only will it be significantly easier to use, but it will be easier to store and last longer in storage too. And all of these conditions should contribute to higher yields and purity in the reactions you carry out with it.



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[*] posted on 6-4-2024 at 06:05
Success!


Quote: Originally posted by Texium  
I would advocate for converting to acetic anhydride. Not only will it be significantly easier to use, but it will be easier to store and last longer in storage too. And all of these conditions should contribute to higher yields and purity in the reactions you carry out with it.


Thanks Tex!

I took your advice and converted it to Ac2O.

Vogel reports a yield of 20g Ac2O using 20g of AcCl.

I used 17g of AcCl and obtained... *Drumroll*... 16.68g!


I collected the 130-140c fraction, which will be slightly less pure than the 135-140c fraction suggested by Vogel, but I was using a short-path distillation apparatus so I wasn't confident about discarding the lower-boiling fractions.

I used lithium acetate instead of sodium acetate.

The procedure was not without issues, but all in all relatively straight-forward; I will hopefully post a detailed write-up, since there isn't one here detailing this procedure.


I did a test by mixing a small amount of the anhydride with anhydrous isopropanol and allowing it to stand overnight.

The next day I added some NaHCO3 solution until the fizzing ceased, whereupon a cloudy, colourless ester layer appeared atop the aqueous phase :D

It smells pleasant and fruity as one would expect with isopropyl acetate.

It also looks nice and pure.
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