[Robanada]

If you don't want to read the details of my life story, skip ahead to the next bold part. That's my real question.

Hi guys, this is my first post in the forum- I'm looking forward to participating in this community, as I very much enjoy Chemistry, and that's why it's my major. I volunteer in a research lab, working on making protein modulators for specific proteins. I'm not allowed to talk very much about it, but there you go- it's organic synthesis.

It's actually been quite a while since I've had an organic chemistry course, and I have a problem:
I'm protecting an alcohol with an ester, and then performing a friedel crafts acylation on the parent molecule. This gives me an ester and a ketone in my target molecule. I only had about 50% yield- leaving me with a large quantity of acid chloride. I need to get rid of it, and for some reason, washing with water doesn't wash it out. My instructor said that some acid chlorides are resistant to water washing. (TLC shows that it remains the acid chloride rather than becoming the carboxylic acid.)

I didn't want to run a column, because I'm doing several reactions in parallel, which would mean running like 7 columns. So I thought maybe I could attack the acid chloride with a water soluble nucleophile that is less reactive than a chloride, but more reactive than the ester-- so that I don't end up actually decomposing my product. I remember that acid chlorides are more reactive than anhydrides, which are more reactive than sulfonic esters, which are in turn more reactive than esters, and ketones and aldehydes, etc... The point of this is that the  nucleophile that I attach to the unreacted acid chloride would then lend water solubility to this new acyl compound.

So I thought of selecting an anhydride because it would not destroy my ester, but it would indeed attack the acid chloride. Then I could simply wash off the new acyl compound, leaving my product in the organic layer. The problem I saw with this is that my anhydride might decompose into alcohols, which I have already found not to be water soluble (the rest of the molecule is too greasy, i suppose). So the question at the heart of this is: will an anhydride decompose into two alcohols under neutral conditions? Or does a base need to be present to pluck off the hydrogen from the water molecule that attacks the acyl carbon?
Ultimately, the compounds would probably be in the separatory funnel for a few minutes.

I suppose I could also use a sulfonic ester, but I've never actually used one before. Can anyone recommend a water soluble one? My initial thought was nitro groups because they're so polar, but then I realized the nitrogen would act as a nucleophile as well, and would mess up the product. Then I thought maybe some alcohols would help, for their hydrogen bonding business. Phosphate maybe?

[dunno260]

An anhydride isn't going to act as a nucleophile for the acid chloride.  Both species are electrophiles.

You should be able to decompose your acid chloride using some mild base or acid.  It shouldn't affect the ester of your parent molecule unless its some protecting group that is particullarly prone to acidic or basic environments.  Something like a sodium bicarbonate or sodium carbonate wash (might have to stir for a bit in the flask) would be ideal.

The acid chloride might be hydrolyzing slowly also because it isn't soluble in water especially if the organic solvent is something like dichloromethane or hexane that doesn't dissolve much water.

If you are looking for some nucleophile to use to lend water solubility to your molecule I would think some nucleophilic amino acid might work.  Something like serine or cysteine might work to create an ester or thioester with a very hydrophilic group (zwitterion of the amino acid).

[Doc Oc]

I'm very skeptical that your acid chloride has survived a water wash, they will decompose into a smoky HCl mess if they're even exposed to ambient humidity (open a bottle of fresh acetyl chloride and you'll know what I mean).

One thing about TLC is that you can't make quantitative judgments on anything unless you've already run that TLC and know exactly what goes where.  I've had a few instances where I spotted a reaction and saw only starting material.  So in frustration I purified that spot and discovered it was my product.

As to what could be happening, how did you get rid of the metal salt from the FC reaction?  Some metals can be exceptionally stubborn and difficult to remove (I had trouble getting the aluminum out of my LiAlH₄ reactions for a while).

[Robanada]

An anhydride isn't going to act as a nucleophile for the acid chloride.  Both species are electrophiles.

You should be able to decompose your acid chloride using some mild base or acid.  It shouldn't affect the ester of your parent molecule unless its some protecting group that is particullarly prone to acidic or basic environments.  Something like a sodium bicarbonate or sodium carbonate wash (might have to stir for a bit in the flask) would be ideal.

The acid chloride might be hydrolyzing slowly also because it isn't soluble in water especially if the organic solvent is something like dichloromethane or hexane that doesn't dissolve much water.

If you are looking for some nucleophile to use to lend water solubility to your molecule I would think some nucleophilic amino acid might work.  Something like serine or cysteine might work to create an ester or thioester with a very hydrophilic group (zwitterion of the amino acid).

I'm sorry, you're right. I meant I should attack it with a carboxylic acid to make an anhydride.

The mild acid/base scares me, because I've done some of this chemistry before, and I did deprotect the alcohol (cleave the ester) with sodium bicarbonate. I feel like treating my molecule like a newborn baby, haha.

That's a good point with the water solubility though- I'll try that tomorrow. I did shake it pretty vigorously in a separatory funnel, so I thought that would be enough. I guess not?

I thought about an amino acid as well, but the problem there is that the nitrogen scares me. I think the nitrogen would also attack the ester in my product, and the starting material and product would be both washed away. Maybe I should draw something in chemdraw so that it'll be easier for everyone.

I'm very skeptical that your acid chloride has survived a water wash, they will decompose into a smoky HCl mess if they're even exposed to ambient humidity (open a bottle of fresh acetyl chloride and you'll know what I mean).

One thing about TLC is that you can't make quantitative judgments on anything unless you've already run that TLC and know exactly what goes where.  I've had a few instances where I spotted a reaction and saw only starting material.  So in frustration I purified that spot and discovered it was my product.

As to what could be happening, how did you get rid of the metal salt from the FC reaction?  Some metals can be exceptionally stubborn and difficult to remove (I had trouble getting the aluminum out of my LiAlH₄ reactions for a while).

I was surprised, too, to be honest with you, but TLC showed a difference in Rf between the acid chloride and the alcohol to be ~0.7 in 10% Ethyl Acetate/Hexanes.
I would be surprised if the acid chloride ran with the product on the TLC- they have fairly different Rf values.
We do have an HPLC and a chromatotron in another lab, maybe I should try to resolve that spot on those.

I just washed the AlCl₃ out with water when I was trying to get rid of the acid chloride.




I'm bringing up some more of the ester- I'm not sure what you'd call it. The molecule in the FC acylation that gets acylated? I'm going to try the reaction again tomorrow.


Edit: I thought it would be easier if I attached a sketch:

[nox]

Have you tried protecting the alcohol (I'm assuming it's the phenol you're trying to protect) with other protecting groups? If for some reason you have to use an ester, I recommend protecting it as the t-butyl ester. These things are quite resistant to base, and it will definitely survive a bicarb wash. To remove it just throw in some moderately strong acid (TFA/TsOH/10% HCl) and it's gone.

Nitrogen nucleophiles are not compatible with unstablized carbonyls (aldehyde/ketone), so yes that's definitely a bad idea.

[Robanada]

Have you tried protecting the alcohol (I'm assuming it's the phenol you're trying to protect) with other protecting groups? If for some reason you have to use an ester, I recommend protecting it as the t-butyl ester. These things are quite resistant to base, and it will definitely survive a bicarb wash. To remove it just throw in some moderately strong acid (TFA/TsOH/10% HCl) and it's gone.

Nitrogen nucleophiles are not compatible with unstablized carbonyls (aldehyde/ketone), so yes that's definitely a bad idea.

Hmm, good idea- I'll definitely look into it. Yeah, it's the phenol I'm protecting. I considered using MOM or MEM, but we didn't have either in the lab, so I thought I'd try the ester first. I didn't consider t-BOC, because in my book on protecting groups I have a big note saying "Difficult to deprotect," haha. I need to check the literature and see if the acid will damage the molecule elsewhere. Thanks!

[nox]

Actually t-Boc is used for protecting amines as carbamates, I personally haven't heard of it being used to protect alcohols (you'd make an organic carbonate rather than an ester).

To make a t-butyl ester, just use t-butyl acid chloride. You'll most likely find it under the name "pivaloyl chloride" or "trimethylacetyl chloride".

Also you might also consider protecting the phenol as a silyl ether.

[Robanada]

Actually t-Boc is used for protecting amines as carbamates, I personally haven't heard of it being used to protect alcohols (you'd make an organic carbonate rather than an ester).

To make a t-butyl ester, just use t-butyl acid chloride. You'll most likely find it under the name "pivaloyl chloride" or "trimethylacetyl chloride".

Also you might also consider protecting the phenol as a silyl ether.

Oh, well that would be because I'm an undergraudate and don't know what I'm talking about. =p Thanks for setting me straight. I'm assuming it wouldn't be available in the acid chloride, most likely? I'd probably have to generate it in situ?

You think a TBS ether would work? I was afraid to use a TMS ether because of its liability to hydrolysis and column chromatography.

[nox]

Pivaloyl chloride is available commercially, and plenty cheap.

The TBS ether should survive an aqueous workup and column.

[Robanada]

Awesome, thanks!
Right now, I protected the phenol by forming phenyl acetate- hoping that when I cleave the ester, it'll form acetic acid. I was hoping that acetic acid would wash out in an aqueous workup (I'll find out later, I suppose). I've never used pivalic acid- I suppose it's just as soluble in water? What would be the advantage of using pivatoyl chloride instead of acetic anhydride to protect it?

I didn't answer your question about if I had to protect it with an ester. The answer is no, I don't need to use an ester per se, I just thought that it would be easy enough to deprotect (I also have a ketone elsewhere in the molecule that could be susceptible to harsher conditions) when the time came.

[dunno260]

TBS groups are fairly robust.  They will survive most moderately acidic and basic workups and most silyl groups can be removed fairly gently using some source of fluoride ion.

t-butyl esters have the advantage of being more acid stable and more resistant to nucleophilic attack than acetates.  You should still be able to remove a t-butyl ester in the presence of a ketone though.  Though the pivalic acid is going to be less water soluble than acetic acid, you should be able to easilly wash both away in a sodium bicarb wash.

I still think that you can use something like 1N HCl or 1N NaOH over 15 minutes or so to quickly quench your acid chloride and have your acetate group come out unscathed.  Both will eventually deprotect the groups, but time is a factor here as well.  Also what solvent are you using when you are quenching the reaction.  If its a solvent like DCM or chloroform were water doesn't "mix" well then you can have issues with quenching.  I have done workups with water/hexane mixtures to remove stuff from the hexanes layer and not had it done with hours of vigorous stirring.  Change the organic layer to a 50/50 mix with ether and its done in minutes. 

[Robanada]

TBS groups are fairly robust.  They will survive most moderately acidic and basic workups and most silyl groups can be removed fairly gently using some source of fluoride ion.

t-butyl esters have the advantage of being more acid stable and more resistant to nucleophilic attack than acetates.  You should still be able to remove a t-butyl ester in the presence of a ketone though.  Though the pivalic acid is going to be less water soluble than acetic acid, you should be able to easilly wash both away in a sodium bicarb wash.

I still think that you can use something like 1N HCl or 1N NaOH over 15 minutes or so to quickly quench your acid chloride and have your acetate group come out unscathed.  Both will eventually deprotect the groups, but time is a factor here as well.  Also what solvent are you using when you are quenching the reaction.  If its a solvent like DCM or chloroform were water doesn't "mix" well then you can have issues with quenching.  I have done workups with water/hexane mixtures to remove stuff from the hexanes layer and not had it done with hours of vigorous stirring.  Change the organic layer to a 50/50 mix with ether and its done in minutes. 

Hmm, sounds like a plan to me!

The solvent is DCM right now, maybe I should try your 50% mixture. 50% ether/water? or 50% ether/hexane? Could THF work, too? I hate working with ether- I had a bad experience the first time I used it (fume hood was out of commission at the time)

[orgopete]

It is always difficult to suggest an answer to a synthesis question and bordering on irrational for a problem without detail. None the less, I'll give my opinion. I shall presume the acid chloride is an aromatic one as they are less reactive than alkyl chlorides as someone suggested about acetyl chloride. I concede this same reactivity profile may be working against you in the work-up. That is, the acetate may be more reactive than the aroyl chloride, but I don't know this. Excess reagents and kinetics my give this as an apparent result.

This is not a solution, but my expectations. Hydrochloric acid is used to wash out the AlCl3. If excess bicarbonate were added to remove the HCl, a big excess of reagent is common and could cleave the acetate, especially if you washed to pH 8. I cannot say the rate of acetate and aroyl chloride cleavage are exactly the same, but I think it would be unexpected to find they had the exact same rates. If water were used to wash out the HCl (several), most of the HCl can be washed out this way. At this point, only the stoichiometric excess of aroyl chloride should be present. If a stoichiometric amount of bicarbonate were added (or NaOH, titrate it), then if the acetate were cleaved faster, it would cleave before the aroyl chloride or visa versa (my guess).

Without knowing the purpose, if the acetate came off during the acylation reaction, I'd just put it back on if that is what I wanted. If not, then you are already one step ahead. You are more than one if you are considering using other protecting groups. I am presuming you are protecting to get the phenol back.