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Topic: Urea Linkage  (Read 3901 times)

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Offline Greek

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Urea Linkage
« on: June 15, 2013, 11:19:34 AM »
Hello everyone, what do you think would be the best workup for an isocyanate reaction with an amino acid containing an amine? I saw in literature that you have to deprotonate the amino acid first, and then add it to the dissolved isocyanate which is in acetone. Does this sound like the best way to proceed?

Also, are these types of reactions basically one step since isocyanates are so reactive? Or do you think I will have a hard time in clean up? Any advice will be appreciated.

Thanks!

Offline Doc Oc

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Re: Urea Linkage
« Reply #1 on: June 16, 2013, 10:00:14 PM »
You don't need to deprotonate the amino acid first, that would require a pretty strong base.  If you just add the amine to the isocyanate, the amine will react with it and form an ammonium.  This is easy to deprotonate with a milder base like pyridine or triethylamine.  I've generally dissolved the amino acid in solvent with a base, then added that to a solution of the isocyanate.  Cleanups are usually pretty easy, a liquid/liquid extraction is generally enough.

Offline Greek

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Re: Urea Linkage
« Reply #2 on: June 17, 2013, 01:08:32 PM »
Thanks so much for your reply Doc Oc! I think I may be a little slow at understanding what you meant. Are you recommending that I just add the amino acid in with pyridine or triethylamine and mix it in with the isocyanate solution since you mentioned that you don't have to deprotonate the amino acid first?

Also, this may be a dumb thing to ask, but would Sodium Bicarbonate work to dissolve the amino acid and add that solution to the isocyanate solution? This is generally what we have been doing in our lab for an amino acid coupling, but I dont know if it will work with this reaction. Thanks again for your advice!

Offline Doc Oc

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Re: Urea Linkage
« Reply #3 on: June 20, 2013, 06:50:42 PM »
Yes, you can just add it all together at once.  It's commonly taught that the first thing you do is the deprotonation, then the anion attacks the nucleophile.  In many systems this isn't the case, especially with amines.  Amines are so reactive that they usually donate their lone pair first, creating an ammonium cation.  This then gets deprotonated by your base.  Essentially, it works in reverse of what is often taught in organic chemistry courses.

Sodium bicarbonate is too weak of a base.  If you're going to use it here you'd want sodium carbonate.  However, the solubility of it in organic solvents is pretty limited, so you'd have to use a solvent like DMF, which is a pain in the ass to get rid of at the end.  Just use pyridine or triethylamine in dichloromethane.  If you're nervous about it try it at a very small scale to see if you get product.  Then if it works you can scale it up.  But I did an isocyanate to urea synthesis just a couple weeks ago using these conditions and it worked fine.

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