[CY231]

Hi everyone. I am trying to create an amide bond by coupling amino acid esters (such as ethyl glycinate) to maleic anhydride. The esters are isolated as HCl salts, so I need to deprotonate them with a base first. I am trying to figure out which base and solvent would be best. I am attempting to find the most cost effective method as well. I can't afford expensive coupling reagents right now, but I am not concerned about racemization of the amino acids during coupling. (Of course, that is not a problem with glycine, but I am planning to try other amino acids.) I am planning to try triethyl amine and diethyl ether or THF. I have THF, but currently do not have TEA or diethyl ether. I could also purchase something like MTBE. Any suggestions are appreciated, as I do not have extensive experience with synthesis.

[Babcock_Hall]

This is not an exact answer to your question (and I am not sure that I understand your application), but have you thought about using active ester coupling?  One makes a 4-nitrophenylester from an acid and 4-nitrophenol (using DCC) and then adds an amine to make the amide bond.  In our hands it is a slow reaction, but it does work.  One can follow its extent by quantitating the 4-nitrophenol that is produced.  With respect to your question, I would defer to the full-time synthesis people here, but triethylamine is relatively non-nucleophilic.

[CY231]

Thanks so much for your reply. I have considered coupling reagents, however I have $1400 to spend this year in total. That includes all supplies, reagents and glassware. I am really trying to save money. I don't think I really need the coupling reagents with this reaction since the anhydride should be reactive enough to get the addition on one side. If I wanted to add the amine to the other acid group, I would need to use coupling reagents, though.

Thanks again!

[phth]

Sounds like you don't understand what you're doing.  If you don't use a coupling reagent you will experience racemization.  There are a plethora of coupling reagents, and more than Babcock Hall can name.  Take his advice. If you are so worried about spending your money wisely, then you need to thoroughly research the topic that you need to accomplish.

[Dan]

CY231 are you trying to make maleimides?



or you do you want to stop halfway?



As for generating the amine free base, you can do this in situ with tertiary amine bases (with anhydrides that react only slowly with water you can even use aqueous bicarbonate with THF or 1,4-dioxane). Alternatively you can isolate the free base before coupling by extracting it from aqueous bicarbonate.

It seems to me that amide coupling reagents are not the best choice for coupling a diacid, especially if you want to stop half way and isolate the unsaturated acid product. In an amide coupling strategy, this would require the use of a monoacid followed by an additional hydrolysis step (which must be orthogonal to the ethyl ester at the other terminus); using an cyclic acid anhydride is more direct. The conditions required are likely similar to those employed for amino acid N-protection as carbamates (i.e. THF, water, bicarb) and should not cause racemisation, but I have not checked this. Racemisation normally occurs alpha to the carboxylic acid coupling partner via azlactone formation, which in this case is irrelevant (since the acid coupling partner is not the amino acid).

[CY231]

Exactly, Dan. Thanks. I do not expect racemization, but I was pointing out that I really don't care for my application at this time. I am trying to do some preliminary work for a grant (hopefully). Here is what I am trying to do, which is what you pointed out in your second example. I have synthesized some amino acid esters. Now I need the monoacid:



Thanks for your suggestions. I will try the extraction from bicarb. I was leaning toward that, but I am a little concerned about hydrolysis. I don't have any other organic folks here, so any advice is appreciated.

Donna

[Dan]

I will try the extraction from bicarb. I was leaning toward that, but I am a little concerned about hydrolysis.

No chance in bircarb at room temperature, it'll be fine.