[Cultivator]

Hi,
I need to synthesize a compound which looks like: Cl-(C=O)-(CH2)x-COBn. (acyl chloride of a dicarboxylic acid monoester)
(where x>10)
I obtained the monobenzylated precursor (pure) from previous step and used it in a 1:2 ratio with SOCl2 in CH2Cl2 solvent with dry (air atmosphere) reflux for ~1-2 hours.

The reaction mixture was slightly yellowish at first, and over time became darker brown/orange, transparent.

Later the rxn mixture was evaporated to yeild a viscous oily substance. Since I had no idea of how to purify this vulnerable compound, I reacted it with the desired alkyl alcohol to obtain an ester on the other side.

The problem is the following:
1) The ester product is contaminated with the same dark brown liquid, which makes it impossible to crystallize. This yellow/brown liquid can be separated by column, but it is unfavorable.

2) I am trying to understand where does this product come from in the first step of reaction and whether it can be avoided.

Does anyone have any idea of how to treat the reactants in order to avoid this side reaction?

What is the origin of that brown/orange oily impurity?

It should be noted that the impurity is more polar than the desired product but not water soluble. Slightly soluble in Hexane (not enough to purify)/soluble in MeOH etc.

Thanks for any help

[Sam (NG)]

Have you got any proton/carbon NMR and mass spec data?  Thionyl chloride reacts producing HCl.  HCl can in theory hydrolyse esters.  The resulting acids and alcohols can react with more thionyl chloride (seeing as you have an excess) producing benzyl chloride (from the benzyl alcohol produced by the hydrolysis) and acid chlorides.  Then you put in an alcohol that can react with either your desired acid chloride or the one that you formed from the hydrolysis and subsequent activation with thionyl chloride.  So you'll end up with a mess.

If I were you, I would start with the dicarboxylic acid, react with two equivalents of thionyl chloride, then add benzyl alcohol dropwise to the solution of diacid chloride, exactly one equivalent, use high dilution.  Then you can add in the other alcohol that you want to use for esterification.

Having just read back through this, I'm not sure if my method would create the ester the correct way around at the benzyl side.  Is that a benzyl ether, benzyl ester or benzoate ester?  If you could draw your structures using a structure drawing software, that would be helpful.

[edit] Which are you trying to make, A, B or C from the image attached?

[Cultivator]

- this compound is the expected compound from SOCl2 step

I know from  TLC/HPLC of the second step reaction mixture that I am getting 3 compounds in the mixture, ~70% of it is the diester (after reaction with long chain ester-alcohol), the rest is something else. I assume one of the 3 is the coloured impurity which was there from the 1st step..

I thought about what you said, to make a diacyl chloride and then reacting it with 1/2 benzyl alcohol and 1/2 other ester-alcohol. I think that if something happens to the benzylated side, it will happen here too, the HCl is still being generated.

Can a benzyl react with SO2? is it coloured?


What about nitrogen atmosphere in the SOCl2 step?

[blind]

When you made the acid chloride, did you add a base (such as triethylamine)? It would precipitate out when HCl is produced, forming triethylammonium hydrochloride.

The other compounds could be the monocarboxylic acid, since you're doing it under air atmosphere.  What did you mean by "dry air atmosphere"?

Also, is the acid chloride your final product? If not, you could just make it in-situ, and not worry about isolating it.

[Cultivator]

No, I did not use base in the acid chloride production step. I used base in the next step in reaction of the acyl chloride with an alcohol.

Do you mean decarboxylation is going on in some rate? (By dry air atmosphere I meantthat the system is dry of water in the atmosphere but I didn't use N2 atmosphere).

Acid chloride is not my final product as I react it with an alcohol later, to make a diester. I do not understand your last statement about making it in-situ and not worrying about impurities.

[blind]

Sorry, had my reaction order wrong, you did not need a base for making the acid chloride.

No, I didn't mean decarboxylation, that shouldn't be an issue.  Also I doubt it'll react with SO2, since that leaves the system as a gas.

What I meant by "in situ" was to make the acid chloride with thionyl chloride, then directly add an alcohol to make the ester, then purify.  How did you know the system was free of water in the atmosphere?

[Sam (NG)]

it will happen here too, the HCl is still being generated.

What about nitrogen atmosphere in the SOCl2 step?

Yes, but in the esterification step, you use Et₃N to mop up the HCl generated, where as you don't during the acid chloride synthesis.

I carry out all my reactions with thionyl chloride and acid chlorides under Argon.

[Arctic-Nation]

Working under an inert atmosphere would be better indeed.

My primary concern, however, is that the benzyloxy group might be quite acid sensitive, resulting in the formation of alpha-chlorotoluene and a new carboxylic acid, which would consequently be reacted to an acid chloride and finally a new ester. You could check for such a compound on HPLC.

[Cultivator]

My primary concern, however, is that the benzyloxy group might be quite acid sensitive, resulting in the formation of alpha-chlorotoluene

This is why base can be used in this step too

[Sam (NG)]

My primary concern, however, is that the benzyloxy group might be quite acid sensitive, resulting in the formation of alpha-chlorotoluene

This is why base can be used in this step too

Careful, if you add base to anything with thionyl chloride in, it's going to go wild.  Make sure you're cooling it.

[Cultivator]

You add base to the mixture where there is a reagent that you want to react SOCl2.

One thing is that Pyridine at least catches HCl and precipitates out. Later it is better not to filter it out and continue to next step. If it may do something bad in the next step, it should probably be avoided.

Why is DMF sometimes being used as a catalyst in thionyl chloride reaction?

[Cultivator]

And I did not observe anything exploding when I did it on hot medium, also refluxed it a bit untill no more gas evolution.
Is it good to do SOCl2 rxns in cold environment to avoid oxidation? (if there is oxidation indeed - the browning of medium)

[Sam (NG)]

I generally do my thionyl chloride reactions at 40 - 80 degrees with no problem whatsoever.  Try to avoid going over the boiling point of thionyl chloride as it decomposes.  I used triethylamine, not pyridine for my reactions, that's why it was more aggressive.

Reason that DMF catalyses the reaction is that it forms a highly electrophilic cationic intermediate according to CGWW:

[edit]  That should be -H⁺ over the arrow in the mech. as in -HCl.

[Cultivator]

I wonder whether this activated DMF species is stable as a chloride salt, it could be helpful to preactivate it prior to acil chloride production and later make it chlorinate the acid by itself... Is it possible?

[Sam (NG)]

I wonder whether this activated DMF species is stable as a chloride salt, it could be helpful to preactivate it prior to acil chloride production and later make it chlorinate the acid by itself... Is it possible?

There's no point, the reaction is catalytic in DMF so you only need a small amount and the second part of the reaction involving formation of the acid chloride still involves production of HCl so essentially carries the same risks as the reaction without DMF.