[CKabes]

I'm trying to make a mixed anhydride using ethyl chloroformate. Upon addition of the acid chloride to the solution of my acid/triethylamine, the solution turns a lemonade-yellow and then quickly to a dark red. There really shouldn't be a color change in this reaction though, right? What's going on?



See attached reaction scheme that is more clear than the SMILES rendering.
Thanks for your thoughts.

[rolnor]

The color can come from very small amount of by-product. I would use pyridine instead of TEA. What are you going to use the anhydride for?

[Babcock_Hall]

Rolnor, What is the advantage of pyridine over TEA?

[CKabes]

Rolnor, in the same pot I treat the mixed anhydride with ammonia to make the primary amide.

[zuriel]

Would perhaps making the salt of your starting acid by stirring with 1 eq. KOH in ethanol, concentrating to dryness and then adding neat acetic anhydride help?

[rolnor]

Pyridine is a weaker base, maby there will be less colored by-products using it.
If you are having problems you could use some classic ways of peptide coupling agent and bubble trough amonia-gas? Do you monitor the reaction in someway, maby LC-MS?

[CKabes]

There are several reasons why I'm concerned about the use of pyridine:

1) Pyridine is difficult to remove compared to triethylamine because of its high boiling point
2) Pyridine catalyzes addition to acid chlorides, which may increase byproduct formation, if that is the reason for the color.

[wildfyr]

Pyridine can be easily removed with a copper sulfate wash

[pgk]

Coloration may mean nothing. Try to repeat the reaction under nitrogen (if you haven't already done).
But meanwhile, why don’t you isolate your reaction products, purify them and take their NMR and IR spectra? By-products might be interesting, too.

[zuriel]

If you feel your product is acid labile then I agree with wildfyr's suggestion: washing with a 10% aqueous copper sulphate solution is a great way to remove residual pyridine.

[rolnor]

CKabes, the structure you draw is an intermediate and will react with your acid to form the mixed anhydride. The pyridine will form pyridinium hydrochloride wich will be water soluble. Further I dont se anything wrong really with the use of triethylamine, maby you could use 1,0 eq. and do it cold, this can minimize colored by-product formation. I have used DPPA (diphenylphosphoryl azide) and TEA to form acyl azides of varius carboxylic acids, the acyl azide can then react with ammonia or amines etc.

[clarkstill]

Oxazolone formation from the adjacent NHBoc? You can push arrows and start to form conjugated/charged species that might be coloured.

As pgk says, in spite of the colour change, does the reaction actually produce product? My PhD supervisor used to say "a little colour goes a long way" - it could be there is a tiny amount of by-product and you're worrying needlessly.

I've never really made any primary amides - can you just do a normal coupling (DCC, HOBt) with ammonia? Or some ammonia equivalent? Like I say, I dont really know the area, but someone on here probably will.