Chemical Forums
Chemistry Forums for Students => Organic Chemistry Forum => Organic Chemistry Forum for Graduate Students and Professionals => Topic started by: Nescafe on August 07, 2014, 10:08:41 AM
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Hello,
I am trying to cycliz a molecule I have made to form a 7-member ring, on one end I have an amine and the other a carboxylic acid. thus far, I have tried a few coupling reagents with no luck. Any suggestions? the molecule is relatively flexible, prior to this step I did a global deprotection with HCl to remove the boc on the amine and tert-butyl group from the alcohol. I did not purify this step, maybe that is the issue?
Cheers,
Nescafe.
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Try heating it to above it's melting point.
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Formation of rings in the 7-12 range is notoriously finicky. Try running again with clean material and starting heating it up until it either works or decomposes. If it decomposes then you might have to rethink your strategy.
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when you say melt it, you mean without any sort of reagent? or do you mean place the SM (which has the amine and the caroxylic acid) and the reagent (let us say a coupling reagent) and melt them together?
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No reagents, just melt the compound.
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Very interesting suggestion, thank you, although, I only have 30mgs and it is an oil.... I am guessing just heat the crap out of it, maybe in a microwave vial?
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The object it to get it to cyclise by elimination of water. So uncontrolled heating will just destroy your material. Heat it to around 100°C and check if there is a new product there by TLC.
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Yamaguchi reaction? It's good for forming larger macrocycles, not sure about 7-rings... Also high dilution!
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I dont know, will it work when makink amide? Why dont you convert the carboxylic acid to more reactive intermediate like acyl chloride? Do I udnerstand corectly that you want to make 7-membered lactam with no other functional groups present in the molecule?
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Also, did you remember to add an extra equivalent of base? Since I'm assuming you got the HCl salt from the deprotection...
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Yamaguchi reaction? It's good for forming larger macrocycles, not sure about 7-rings... Also high dilution!
I dont think Yamaguchi will work because the amine on one end of the molecule could react with the reagent used which has an acid chloride on it. I have
H2N--------------COOH. Instead of the carboxylic acid reacting with the acid chloride reagent I fear the amine will do so. I think I will try heating it above melting point and see what happens
And Kriggy, yes, that is what I will be trying simultaneously and hope one avenue gives me result!
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I think first polymer forms inpalce of cyclisation
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Depends on condition. HIgh dilution might help. Using template ion migh help too but I think the ring is too small for it. I also hear that things like tosyl on amino group helps with cyclization. But I worked with bigger heterocyclic rings (15 membered N3O2 ring)
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Yamaguchi reaction? It's good for forming larger macrocycles, not sure about 7-rings... Also high dilution!
I dont think Yamaguchi will work because the amine on one end of the molecule could react with the reagent used which has an acid chloride on it. I have
H2N--------------COOH. Instead of the carboxylic acid reacting with the acid chloride reagent I fear the amine will do so. I think I will try heating it above melting point and see what happens
And Kriggy, yes, that is what I will be trying simultaneously and hope one avenue gives me result!
Fair point... what have you tried? I'm guessing standard peptide coupling reagents (DCC, DIC, EDC etc.) didnt work?
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I was actually unable to set anything up, I will try some of the suggestions and report back!
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After giving it some thought, melting it does not seem like the best choice as I anticipate it will just polymerize rather than cyclize. At the moment I am trying to generate the acid chloride under high dilution conditions.
Correct me if I am wrong but melting it would basically mean heating a concentrated sample (no solvent) so it will just polymerize
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I have quite often made lactams by this method, it works rather well.
Try some in a MPt tube and see what happens.
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I shall try it out then. Sorry, what is a MPt tube? I am guessing a melting tube but when I looked Sigma I could not find such an item.
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Just a melting point tube. Heat it to the MPt, leave it for 5 minutes, cool it and re-take the MPt. Then you will see if anything has happened.
https://www.youtube.com/watch?v=S-GGiTxjYo8 (https://www.youtube.com/watch?v=S-GGiTxjYo8)
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I will definitely give this a go and report back, quick question, so at the moment both the amine and the carboxylic acid functionality are protected with acid labile groups. I was thinking of doing a global deprotection with 0.1M HCl in dioxane, vac it off and then try melting. i can not do a work up since it will not leave my aqeous layer. Do I have any other options? I really want to try the melting idea.
If I neutralize with base I can not vac that off, can I just try melting with the base present? Also please keep in mind I have 30mg of this stuff :P
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The HCl salt will not cyclise. Try adding triethylamine , enough to neutralize the HCl salt.
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Neutralize with TEA and then try to melt with the TEA present?
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Yes
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You sir are a wizard!
That worked, not the cleanest reaction I have ever done but better than anything else I tried. There is a peak at 3.0-3.05 (it is in CDCl3) which is a broad singlet that integrates to 0.5, I just can not seem to figure out what it is. Granted my NMR sample was very concentrated but I am not sure if I dilute it if that will be cheating if it goes away or integrates to like 0.1. This compound needs to be at least 95% pure. I can try recolumning it but I barely have any left and it is hard to make. Any idea what it might be, I have no alcohols or anything of that sort in the SM, there is no SM left actually and it is one spot by UV. Stained with multiple things and nadaa so I am not sure where it is coming from. The solvent (CDCl3) is also relatively new.
Thanks!
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Does it exchange with D2O?