Chemical Forums
Chemistry Forums for Students => Organic Chemistry Forum => Topic started by: OrganicDan96 on June 08, 2018, 10:55:59 AM
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I am protesting a secondary amine with Fmoc-Cl, i had it stirring with DCM in the presence of potassium carbonate over night as it said but this morning the TLC showed no product, it should be done by now. what is going wrong and how could I get this to work? i have left it over the weekend but if nothing happens by Monday I will have to recover my starting material.
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Did you dry the potassium carbonate? If it was just sitting around in an opened bottle it probably has significant water content.
A solid bake in a vacuum overnight at 150°C+ should do the trick. Store it in a desiccator.
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Did you dry the potassium carbonate? If it was just sitting around in an opened bottle it probably has significant water content.
A solid bake in a vacuum overnight at 150°C+ should do the trick. Store it in a desiccator.
didn't do anything special but it said it was anhydrous, also i dried the DCM
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If the seal was previously opened then it probably wasn't very anhydrous anymore. Drying that salt is so simple, I do it to a big batch and just put it in the desiccator and use for a long time for everything.
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i'm not overly convinced that this was the problem because TLC showed a very bright spot that corresponds to Fmoc-Cl so there definitely is some in there.
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Hmm... I'm surprised that chloroformate can survive on a TLC plate. Are you sure that's not hydrolsis product? (carboxylate? alcohol?)
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Hmm... I'm surprised that chloroformate can survive on a TLC plate. Are you sure that's not hydrolsis product? (carboxylate? alcohol?)
its possible, the spot was very clean and round and quite high up on the plate, i would expect the alcohol or carboxylate to have quite a low Rf value in 4:1 hexane ethyl-acetate.
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I think the alcohol would run pretty well, Fmoc is rather greasy. I think I. Hydrolyzes into the alcohol and eliminates Co2
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I think the alcohol would run pretty well, Fmoc is rather greasy. I think I. Hydrolyzes into the alcohol and eliminates Co2
could it be possible that my product is under the alcohol spot and the reaction is working but not complete?
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Unlikely but you could run the column and take nmr.
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I never had succes with carbonates during acylation reactions. Try triethylamine instead
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I never had succes with carbonates during acylation reactions. Try triethylamine instead
that would deprotect the Fmoc protected amine at the end of the reaction wouldn't it?
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I don't understand your last response. There are two amines in our discussion. TEA won't react, it's tertiary...
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I don't understand your last response. There are two amines in our discussion. TEA won't react, it's tertiary...
Fmoc protected amines can be deprotected by amine bases the common conditions are 20% piperidine in DMF i just thought TEA would do the same
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Piperidine and TEA are quite different. Cyclic secondary amines are rather strong nucleophiles and bases. Also, you use 1.1 equivalents TEA, not the huge over equivalency of the piperidine deprotection.
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Oh, I didnt thought of that.. but piperidine is nucleophilic, TEA is not. You could try pyridine as well
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Oh, I didnt thought of that.. but piperidine is nucleophilic, TEA is not. You could try pyridine as well
Yeah pyridine might be good because it's pKa is lower than that of TEA
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Pyridine is a better nucleophile I believe.
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Tertiary amines shouldn't be too dangerous to Fmoc groups, as others have noted.
The method I've used to protect amines is to make a 1:1 mixture of THF/1M NaHCO3. The Fmoc survives this condition and if your product doesn't just precipitate out you can rotovap the organic off and then do an extraction with ether or ethyl acetate.
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Tertiary amines shouldn't be too dangerous to Fmoc groups, as others have noted.
The method I've used to protect amines is to make a 1:1 mixture of THF/1M NaHCO3. The Fmoc survives this condition and if your product doesn't just precipitate out you can rotovap the organic off and then do an extraction with ether or ethyl acetate.
My supervisor has told me not to use triethylamine as he thinks it would just deprotect the product. We have a THF still in the lab so i can gen dry THF easily. I have also put some potassium carbonate in the oven to dry like others noted. I i will take more care with dry conditions next time.
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I have not reviewed the FMOC deprotection literature, but diisopropylethylamine is even less nucleophilic than TEA is, unless I am mistaken.
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You could try grinding the K2CO3 in a pestle and mortar. In my experience this leads to MUCH higher rates than the more coarse granules out of the pot.
Also, have you tried biphasic conditions? A typically way to put a carbamate on amines is to stir with the chloroformate and aqueous K2CO3. It's always surprised me that the chloroformates don't rapidly hydrolyse under these conditions, but it works. The carbonate is only there to mop up the HCl you form in the reaction (a la Schotten-Baumann).
Is there any other reason the reaction might be slow? Hindered amine? Is the amine SM a salt, and if so are you adding an extra eq. of base?
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On water reactions are fascinating, there are some that seem preposterous that they work.
Here's a great example: the way you make benzoyl peroxide on the bench scale is by adding benzoyl chloride to 30% aqueous H2O2 with NaOH. On its face this should produce benzoic acid or at best benzoyl hydroperoxide, but instead you get a 50+% yield of benzoyl peroxide.
In a similar vein, here is aryl lithium chemistry done in air in glycerol http://onlinelibrary.wiley.com/doi/10.1002/chem.201705577/abstract
Interface chemistry is a tremendous untapped resource beyond just emulsion polymerizations.
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My supervisor has told me not to use triethylamine as he thinks it would just deprotect the product. We have a THF still in the lab so i can gen dry THF easily. I have also put some potassium carbonate in the oven to dry like others noted. I i will take more care with dry conditions next time.
I've not had a huge problem with tertiary amines removing Fmoc, but since I use a totally different method to do the protection I won't try to convince you.
As I said earlier, I do this reaction regularly with water as the solvent, so I don't know that keeping things rigorously dry is necessary.
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I have not reviewed the FMOC deprotection literature, but diisopropylethylamine is even less nucleophilic than TEA is, unless I am mistaken.
I could try that
Is there any other reason the reaction might be slow? Hindered amine? Is the amine SM a salt, and if so are you adding an extra eq. of base?
it is a bit hindered but not overly hindered, the procedure i am followed (not a literature procedure) worked over night with exactly the same substrate so i don't know why it didn't work (or was just too slow)
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TEA will certainly start to deprotect Fmoc. Avoid using it.