[Stephen@NE]

Hi, all:

I am doing DCC/HOSu coupling using dichloromethane as a solvent at 0 deg C, however, I always have about a few hundred PPM level of cyclohexyl isocyanate byproduct and cannot be removed from followed purification process.  By checking on DCC purity, there is fairly little cyclohexyl isocyanate in the raw material. Please help me on what is the side reaction, how to avoid such side reaction, and how to remove the by-product. Thanks a million.

[Grundalizer]

What is a DCC/HOSu coupling?

[tmartin]

Are you doing this to couple peptides or to make an ester? (Just curious)  And HOSu... I forget some of my lesser used abbreviations... Su = succinamide, correct?

How do you quench this reaction?  That could perhaps eliminate this byproduct.  I think cyclohexyl isocyanate would react with water, giving a water soluble byproduct...although maybe it is more stable than I am giving credit, I've only used DCC a few times, but don't recall this issue.

Thinking about the mechanism, it would seem the byproduct should be a dicyclohexyl urea.  Does the reaction proceed smoothly (what is the yield, are you getting a lot of other byproducts)?  Sorry to answer your question with so many questions of my own  .

[stewie griffin]

In these coupling reactions, if the activated ester doesn't form fast enough then the DCC can react with your carboxylic acid to form an imide/urea type product. Perhaps HOSu isn't the best for your system? Maybe try HOBt or just plain old DMAP.

[movies]

I am no expert on peptide couplings, but I know most of my buddies who were experts preferred DIC instead of DCC because it was easier to remove the byproducts.  It might help in your case too.

[philmont702a]

What is your order of addition?  Can you give a little more information about your reaction?  I have done a number of DCC couplings, but always used DMAP to activate the reaction.  Does your reaction turn cloudy with the addition of the DCC?  We'll be able to help you a lot more with a bit more info on the reaction.  

With my reactions, I have not had to quench it, only filter off the insoluble precipitate (urea I believe) then flash it.  I have heard of the HOSu additive decreasing side reactions, but I have never used it. Is there a reason you're using HOSu?  Maybe try the reaction with just DCC/DMAP and your acid and nucleophile?  

[Stephen@NE]

Hi, all:

Thank you for your messages. I use DCC coupling to link peptide to PEG. First, PEG is end capped with carboxylic acid. Then PEG-carboxylic acid is dissolved in MeCl2 and hydroxysuccinimde is added to the solution. DCC is pumped into reaction system at 3 ml/min. After pumping DCC, the reaction is keeping at 0C for 20 hours. Reaction is then stopped by filtration and washing to remove unreacted DCC and urea byproduct. My product now is hydroxysuccinimde-activated PEG.

I observed cyclohexyl isocyanate by GC after DCC is started pumping into the system. Any idea about how cyclohexyl isocyanate is produced?

Thanks,