Analyzing acid chlorides ?

My conditons were either reflux in neat SOCl₂ or reflux in toluene with 4eq. of SOCl₂. Im getting the amide using mixed anhydride and also from chloride but my conversion to amide is rather low (aprox. 30% for chloride and 50 for anhydride). Its decent as a start but I would like to find general procedure that would allow me to make those amides in higher yields and more important, with no racemization of the substrate.
Thanks for help, im gonna take a short break from this and come back to it next week I gues I will end with those coupling reagents anyway :-D

What are your next steps or substrate?

For instance, in the past I have made 4-chloro picolinoyl chloride from picolonic acid and although the acid chloride was more or less isoable I quenched with methanol to be sure I was dichlorinating (authentic deschloro ester made with a small sample of TMS-diazomethane)...?

What are your reaction conditions? Forming an acid chloride is fairly straightforward, I don't think testing for it is necessary. Just add your amine and check for product. If you're dying to make sure you've converted it all, maybe go to an intermediate like an NHS ester which is ready to react in amide bond formation but stable enough to isolate and analyze by TLC.

I didn't have good experiences with T3P and CDI isn't the best way to go for mixed anhydride substitution. I've used EDC a ton of times for peptide couplings and it's both inexpensive and easy to use. HATU is another one that works well, but slightly more expensive than EDC.

I think the chloride is reactive but the acid is not. I got my amide with 50% conversion while rest of the mixture was shown to be the starting material. Indeed it was HPLC analysis so thre could be chloride left that hydrolized during the analysis but the reaction went on for 24 hrs so I think that the chloride is formed slowly (its reaction should be fast )

COCl2 neat or in solvent? I might try that

Quote from:

I think the chloride is reactive but the acid is not. I got my amide with 50% conversion while rest of the mixture was shown to be the starting material. Indeed it was HPLC analysis so thre could be chloride left that hydrolized during the analysis but the reaction went on for 24 hrs so I think that the chloride is formed slowly (its reaction should be fast )

COCl2 neat or in solvent? I might try that

In THF. Oxalyl chloride [(COCl)2] is far too reactive to use neat. That is also something I liked about it. You could use it virtually stoichiometrically. Again, I advocate using a catalytic amount of DMF to form an acid chloride. I don't know if anyone still uses Fieser and Fieser, but it was in there. It works.

I have had modest success making amides from the 4-nitrophenylesters (it is slow).  IIUC pentafluorophenylesters have also been used, but I have had problems with this group in a different context.

Checked and Aldrich got it, its dimethylaminopropylethyl carbodiimide.

sjb: my next step is making an amide. Im trying more routes but in general nothing works at reasonable conditions. I see the amide in HPLC but it usualy requires high temperatures to form (using T3P or CDI) and since I want to make amides with chiral amines (amino acids), im worried that at those conditions those amines would racemize. Chloride seems like the best option but I want to be sure that my acid is completely converted into chloride.

I dont realy want to use DCC because It might be hard to remove completely but might give it a go too

Assuming that rapid hydrolysis or reaction with the silica itself is the problem, what about reversed phase TLC plates?  One might still have the problem of finding an unreactive mobile phase, however.

Since I don't know the structures and the results further cloud the issue, this is a bit challenging. Way back when I was doing reactions in the lab, one of my favorite methods was oxalyl chloride with a drop of DMF. Gas evolution showed the reaction was progressing. I usually didn't analyse my acid chloride, but if I did, I usually just took in IR spectrum. In some cases, I reacted it further, for example with methanol or ammonia.

If the acid chloride is unreactive, then I'm surprised you cannot analyze it directly or that it has been able to form some by-product.

Isnt there a variation of DCC with aminogroups so you can wash with a little acid after reaction? I dont remember exact structure on that reagent, sorry. Acidchlorides on TLC are not good, as you have discovered.

It seems that i confirmed my chloride with NMR, im waiting till my starting material is measured in CDCl3 to confirm but it seems that the raction was completed and it just takes more than 24hrs to make the amide. Which is fine I guess. Thanks for suggestions and help guys