Like others have mentioned, DMAP is easy to remove by washing the crude mixture with 2N HCl, unless your product is basic in nature (in fact, since you usually use the catalytic amount of DMAP in combination with Et3N, acidic wash is a part of the standard work-up procedure).

Speaking of DCC/DCU contamination, I think that the bigger problem is the removing of N-acyl urea, the notorious by-product of almost any carbodiimide mediated esterifications. This by-product is much harder to remove than DCC or DCU because it is is usually very close in properties to your desired compound. You may consider using other esterification protocol.

DMAP is easy to remove by dilute acid wash if your ester does not contain basic functions. DCC derived urea is a little nasty. Bur it's not very soluble in cold DCM. Thus place the flask in the freezer -10 or -20°C for up to 24 h, then filter of the colorless precipitate, which is likely to be the urea. Make shure it's not your compound before you discard it.

The melting point of the urea is tabulated and provides fast identification.

thanks Dear Dr. Schmidt

I will try it tomorrow.

To complete Boris's answer, you could use other DCC derivatives (DIC or equivalent to DCC with tertiary amino group) more easy to eliminate by wash and more easy to manipulate and furthermore less toxic.

Thanks Dear Dr. Diolez

I used DIC but this compound is very toxic and I prefer to use DCC which is less toxic.

As you can see, in my profile picture there is a chemical compound in my hand. It's DIC

You should try EDC hydrochloride; a bit more expensive, but it can easily be removed by one acidic wash. everything else is going to stay the same.

Using EDCI instead of DCC, DMAP can be removed if it is washed with acid

EDC is hydrolyzed upon extraction, then an acidic workup to remove DMAP. Otherwise flash chromatography will do if your compound's structure is not similar to Pyridine or Quinoleine

I agree with Boris and Dinhvu. I did a lot of this kind of reaction before and I like DCC, there are white precipitate, DCU, the urea, if using DCM as solvent and most of it can be removed by filtration then just concentrated the filtrate and the residue applied to silica chromatography.

DMAP is water soluble and you can extract by washing of your compound with water. For DCC, I would like to suggest check solubility of your compound and DCC in organic solvents. You may find one of solvent in terms of solubility difference which could allow you to get pure compound.

Dear Shima,

I do not know what kind of ester you want to make but I believe that the traces you see are DCU.

-when your reaction is finished add 1-5 % (v/v) of the mixture AcOH: H2O (1:1) to quench unreacted DCC and stir for 0.5-1h. If you do not quench it will always slowly hydrolyse towards DCU and make problems. As mentioned above, after filtration concentrate the reaction mixture and try flash chromatography. If it does not work, try the method of Boris.

-As a last resort, after filtration try preparative reverse phase HPLC. This works perfect.

for details see:

https://www.researchgate.net/post/How_to_purify_polar_cyclic_peptides.

Good luck.

you can make an extraction with diluted HCl various times and saturated NaCl... after that you have to purify it with column chromatography with silica gel... I will assure you that will remove all the byproducts and impurities

if You have already used DCC and DMAP, and want to remove them, then after filtration of DCU, you can recystallize your product, at least I have got pure product without trace of DCU in NMR spectra. of course, you have to be ready, that you will lose some of your product.

I agree Dr. Stanimir Popovic method. DCU can dissolve in dichloromethane. I dilute the reaction solution by hexane, and then remove the most of DCU by filtration.

As far as I know, DCC is converted into DCU after amidation ( a research which I did long time ago) and I think this applies to esterification. DCU is soluble in methanol, ethanol, chloroform, acetone. It is worthy to try one of these to get rid of DCU. Otherwise, the polymers are made in solution & DCU will precipitate & thus it is removed by suction filtration.

I think what you see in the NMR spectrum is DCU. It's possible that the ester has the same Rf of DCU and after the column you always find the NMR signal of DC cycles. Try to change solvents for the column and you'll achieve the pure ester without DCU (with CHCl3 100% the DCU remaned attached at the column).

Use cold acetone to precipitate it.

If you use excess DCC, add some oxalic acid after the reaction; it converts DCC to DCU, also forming H2O, CO and CO2; this reaction is very fast, 30 min is usually enough. For DMAP, as said above, washing with water or dilute acid should do the job.

You might want to consider using polyDMAP, a resin form of DMAP as your catalyst. When the reaction is complete, you can just filter it out of the product without losing product due to hydrolysis from an acid wash. PolyDMAP used to be available from Reilly chemicals. I don't know if it still is.

That's really a headache problem. To avoid this, we can use EDC, which is water soluble and you can extract it by washing.

If your ester is not having amine function, Wash with dil HCl (may be 2-5%) to the MDC layer to get rid of DMAP. or else if your ester is low in boiling point, you can do the fractional distillation to get pure compound

Wash with dilute NH3 to remove DCC...

with DCC

Keep the solution after extraction with ether or DMC in an ice bath for a half hour

urea precipitates and filter the cold

That is indeed difficult to fully remove the byproduct DCU. If your aimed product is Ethyl acetate or diethyl ether soluble , i suggest you redisove the crude products using EA or Et2O. The precipiates should be DCU. You can remove it by centrifugation or filter paper. Using EA/Hehane eluent would be better if you run silica gel column.

The best way to aviod this is using EDC to run your reaction.

Like others have mentioned, DMAP is easy to remove by washing the crude mixture with 2N HCl, unless your product is basic in nature (in fact, since you usually use the catalytic amount of DMAP in combination with Et3N, acidic wash is a part of the standard work-up procedure).

Speaking of DCC/DCU contamination, I think that the bigger problem is the removing of N-acyl urea, the notorious by-product of almost any carbodiimide mediated esterifications. This by-product is much harder to remove than DCC or DCU because it is is usually very close in properties to your desired compound. You may consider using other esterification protocol.

As Anthony Burke noted the use of cold acetone gives good results. Cold ethylacetate can be used also.

As pointed out by Vladimir, apart from DCU after acidic wash, N-acyl urea gives usually the main headache. Could you use chromatography (normal or reversed phase) to purify your product? Additionally, crystallization from polar solvents can do the job as well.

Dear All. Thank you

All of your comments are great and helpful for me.

Hi Shima,

i) Option A: Use precipitation by dissolving in DCM/Hexane

ii) Option B: Use solid supported coupling agents

SHIMA

was a pleasure helping friends hugs Brazil

Some or all of the following should work. In some hard cases I followed all 7 steps!

1 After reaction, remove DCU ppt by filtration.

2 Evaporate and redissolve in small volume DCM

3 Remove any undissolved solid by filtration.

4 Wash with 10% cold AcOH followed by satd. NaHCO3.

5 Dry (MgSO4) and evaporate.

6 If necessary, dissolve in small volume MeCN, leave 8h at -20 C and filter.

7 Flash chromatography (SiO2 and DCM) followed by crystallization.

Neises B, Steglich W, van Ree T (1981) SA J Chem 34(2), 58-59

And even then, you may still see 2 small cyclohexyl humps in the NMR!

Dissolve your stuff in cold EtOAc and filter through a short plug of silica. This worked well for me.

We have found that the small amount of DCU observed in the NMR is really the n-acyl urea, a minor rearrangement impurity that accompanies the ester product. Does anyone know the best conditions to minimize the formation of this side reaction?

You may try adding HOBT/HOAT, although you may not be able to suppress N-acyl urea formation completely. Chromatography can be used to remove the N-acyl urea by-product, but it is not always easy (partially due to the poor solubility of N-acyl urea in common organic solvents).

Better yet, use different coupling reagent - for example, oxyma/comu: Aldrichinica Acta, 2003, vol 46, No 1, p.21-40. These reagents are also good in preventing racemization, if this is the issue.

Addition of acetic acid and water, and stirring for a while to convert the diiimide to urea which could be removed as ppt by filtration in low polar solvent e.g. hexane;

Use acid washing to remove DMAP;

and finally a chromatography is normally needed.

I used this rout to synthesis am amide, i was straggling too.. I tried to use recrystallization using DCM/ Petroleum ether But it did not work , Then i used  column chromatography using Pertoleum ether / ethyl acetate 8:2 and then flushed by ethyl acetate and eventually i got a pure product.

Filter the reaction mixture through a medium frit, rinsing with a minimal amount of reaction solvent, then work up. Depending one runs reaction in dioxane, THF, DMF, dichloromethane, etc., but urea is mostly insoluble in most solvents and this is a good way to get rid of it (the rest can be flashed away pretty straightforwardly). If it is too soluble, one can concentrate the reaction mixture first and take it up in ether, then filter and rinse.

To remove DMAP, you can extract with 1 M HCl.   DCC and the urea DCU are more difficult. There are reports of dissolving the crude reaction in DCM and cooling to -78.  DCU will crystallize out.   Best way is to do a column or avoid DCC and use EDCI

Dialysis is one of the best method to remove unreacted DCC/DMAP.

If the material is polymer, then dissolve the polymer in THF (limited amount, just right viscosity) and precipitate in cold diethyl ether (4 oC) (THF:Ether = 1:20). Your polymer will precipitate out and the DCC and the DCU will be going into Ether. Decant the solvents and dry and check the NMR. Mostly impurities will go or traces will be still there. If you found the traces, just repeat one more time. You will get pure product. You may do this process for non-polymeric material, but may loose lot of compound. 

I do not know what is your reaction. Most of DCU was removed by diluting the reaction mixture with hexane and then filtration. After the organic phase was concentrated, the residue was dissolved in hexane again. The remained DCU will precipitate, and filtrate again.

How to separate an imidazole terminated amide pdt (which possesses cationic amide part and anionic halide part) from a mixture of extra EDC, HOBT, by pdt urea and 3-(2-carboxyethyl)-1-methyl-1H-imidazol-3-ium bromide soluble in a aqueous layer in an acid-amine coupling reaction?

Just like the previous people have said, acid wash with 1 M HCl will ensure the removal of the cat. DMAP during the product work-up if your target product is stable in acidic medium. But, this can be done after  filtering the reaction mixture through celite which removes massive amount of the insoluble DCU by-product. However, to avoid the residual DCC when the reaction is completed, it is usually advisable to use within 1 equivalent of DCC as the excess has no role in the general reaction knowing fully well that DCC is basically used for activating the equivalent carboxylic group before the nucleophic attack on the carbonyl carbon by the alcohol.

Probably my system was not like your, but I have wahsed it with a cold 98% Ethanol (5-7C) , and its work .

I think you can go for water soluble byproduct producing coupling reagents like EDC, DIC, 1-hydroxybenzotriazole. other wise use acidic solution to remove the contaminated byproduct. if your compound is sensitive to acid, then dilute the acid and repeat the extraction several times. The below link will give an idea about the coupling reagents and their byprodut.

https://www.peptide.com/coupling-reagents-i-414.html

Hope it will help you solve your issue.... othe wise you have to go for flash column, it will help you to separate the byproducts.

Couple of questions I have to ask you, Shima:

How many equivalents of DCC and DMAP did you use? In most cases, DMAP is used as nucleophilic catalyst (tiny amount) and so shouldn't be a problem.

As for the DCC, it is converted into dicyclohexyl urea (DCU) at the end of the reaction if a maximum of two equivalents were used. DCU removal is quite easy. Filtering the reaction mixture through a pad of celite and rinsing with minimal amount of the reaction solvent will get rid of most of it. You could concentrate the reaction mixture first and take it up in ether, then filter, if it is too soluble.

Finally, you could devolve the crude product in EtOAc and put it in fridge to precipitate the last bit of the DCU.