[Qfbale]

someone has worked with EDC or DCC?
I'm trying to amidate a natural product that has a carboxylic acid.
What kind of amines used better? I dont have N-hydrosuccinimide
Is more convenient to use nitrogen atmosphere?

[phth]

I would be asking myself is can a diimide react with water in the atmosphere? No: ok.  Yes: inert atmosphere.  How can EDC simplify the workup?

[Qfbale]

Thank you,

I will start to work with carbodiimides, and I have three questions:
I have seen that the DCC and EDC are carboxylic acid´s activating agents, and I want to transform a carboxylic acid to amide.
1. Which carbodiimide would help me better?
2. Is the nitrogen  atm okay?
3. What kind of amines recommend me to use?

[phth]

You do need a catalyst like DMAP or HOBt.  It really depends on what you got on hand to use DCC/EDC.  EDC can be removed with water but depends on the structure of your product/starting material can be removed by doing a separation with water.  This simplifies things if your target is not souble in water or at a certian pH.  Carbodiimides have been around since the 1960's. But you probably get higher results using more modern methods like T3P: http://www.organic-chemistry.org/abstracts/lit3/412.shtm or  NHC: http://www.organic-chemistry.org/abstracts/literature/899.shtm  etc.  heres a  longer list http://www.organic-chemistry.org/synthesis/C1N/amides.shtm

[clarkstill]

You do need a catalyst like DMAP or HOBt.

Be careful, yes DMAP is a nucleophilic catalyst, but this isn't the primary role of HOBt in peptide coupling. It is added stoichiometrically to react rapidly from the carboxylate-carbodiimide isourea adduct to prevent side reactions including formation of the N-acylurea. So, while the arrows you draw are the same as with DMAP, HOBt is actually added to lower the reactivity of the intermediate towards side reactions, rather than to accelerate the overall reaction as with DMAP.

[clarkstill]

And in answer to the OP's question, my first set of conditions would be to use DCC and DIPEA in DCM or DMF. Both primary and secondary amines work reasonably well if they aren't especially hindered, and if the amine is cheap you can just use it in excess and not bother with the DIPEA. I would avoid anilines, as these are much less reactive and don't couple well. EDC does help the work-up as it allows you to remove the dicyclohexylurea, but until you make your product you won't know if this is a problem anyway - often the DCC by-product is easily removed by chromatography. Also, be careful using DCC - it is a sensitizer, so wear gloves and use in a fumehood. There are horror stories of people so sensitive to it that they can't enter a lab where it has been used - this would be a career death sentence if you work on peptide chemistry!

In addition to the reactivity I just described, using HOBt can also prevent epimerization of the amino acid during coupling, so if you're not using it you should check whether this has happened, either by optical rotation, HPLC or by checking for diastereomers if there are >1 stereogenic centre.

Hope this helps.

[phth]

And in answer to the OP's question, my first set of conditions would be to use DCC and DIPEA in DCM or DMF. Both primary and secondary amines work reasonably well if they aren't especially hindered, and if the amine is cheap you can just use it in excess and not bother with the DIPEA. I would avoid anilines, as these are much less reactive and don't couple well. EDC does help the work-up as it allows you to remove the dicyclohexylurea, but until you make your product you won't know if this is a problem anyway - often the DCC by-product is easily removed by chromatography. Also, be careful using DCC - it is a sensitizer, so wear gloves and use in a fumehood. There are horror stories of people so sensitive to it that they can't enter a lab where it has been used - this would be a career death sentence if you work on peptide chemistry!

In addition to the reactivity I just described, using HOBt can also prevent epimerization of the amino acid during coupling, so if you're not using it you should check whether this has happened, either by optical rotation, HPLC or by checking for diastereomers if there are >1 stereogenic centre.

Hope this helps.

To add to what you're saying T3P is more effective than HOBt, HOAt, HATU, DCC, EDC... T3P yielding no detectable epimerization under certian cases, and less than the rest.  In addition, this reaction the authors(see the link above) were able to carry out the reaction on a 20kg scale meaning that all they had to do was filter and wash with water.  It's worth a read IMO. And it works for hindered anilines such as 2,6-dimethylaniline 99% yield.

[clarkstill]

Never used it before, but that looks very good indeed!

[Dan]

I've thought about T3P before, it does look great, but it's not cheap.

I like EEDQ.

[phth]

Dan, do you have a reference for EEDQ?

[Dan]

Dan, do you have a reference for EEDQ?

Nothing specific on hand, but here is a review that should have some info and references:

Chem. Soc. Rev., 2009, 38, 606-631

Great reagent. Just amine + acid + EEDQ. No extra base required, no witches brew of additives and catalysts, byproducts are quinoline and ethanol. Racemisation/epimerisation is low, and you don't need to protect alcohol functions - it's quite commonly used in med chem to couple p-aminobenzyl alcohol (a self immolative spacer group) to amino acids and peptides.

[TheMantis]

Why don't you just convert the carboxylic acid to an acid chloride, followed by a classic amidation reaction or a modified schotten-baumann reaction.