I need to know what is the best technique for amide purification because when I use column chromatography, I lose a large amount of the amide product.
What amides, and what have you already tried? What column packings and solvents?
Amides tend to decompose under acidic and basic conditions, but their sensitivity to those conditions depends on the molecule; yours may be particularly sensitive.
Jack Silver Dear Silver, thanks for your reply. I am working on the synthesis of amide via the coupling of aldehydes and amines. I use different substrates, aromatic, aliphatic, and heterocyclic compounds. I tried to use the silica gel as a stationary phase and a mixture of hexane and ethyl acetate (2:1) as an eluent but every time I get a low yield of the product even if it is clear from 1HNMR that I have a quantitative yield.
Do you see the starting acid and amine elute from the column? (indicating decomposition)
Is the compound tailing as it elutes (compound eluting into many fractions with low concentration)?
Jack Silver Actually, I observed two things:
Firstly: After the first fraction elutes from the column which is the remaining aldehyde (one of the starting materials) and start to receive the second fraction which is the amide, I observe the presence of a pale spot (at the same position of starting aldehyde) with all amide fractions.
Second: Some times I notice the presence of other spots (very close to the start line) elute with the last amide fractions. I thought that one of them is the carboxylic acid which can be formed as a byproduct from aldehyde oxidation despite the absence of this carboxylic acid signals of HNMR spectrum.
You might try a little triethylamine in your mobile phase, assuming acidic silica is decomposing your compound. The column will take longer to equilibrate, and it is a little harder to evaporate the TEA.
Jack Silver what do you mean by this '' harder to evaporate''? evaporate from the whole system or it will be eluted with the fractions and then it will be difficult to get rid of?
And there is a specific ratio I have to use?
triethylamine (TEA) has a higher boiling point (89 °C) than hexane or ethyl acetate. It will evaporate, but take longer to evaporate than the other solvents.
Dear Amal, your interesting question was asked about half a year ago. Has your problem been solved by now? If it turns out that chromatographic purification reduces the yield of your target amides, you should try a more simple purification method such as distillation, sublimation, or recrystallization. Which one to choose depends on the volatility and solubility of the respective products. In the case of amides I assume that recrystallization is the method of choice. You could for example try polar solvents like ethanol, acetone, or acetonitrile. Especially that latter often gives very good results, and you can avoid the tedious chromatography. Just try to dissolve your product in a minimum amount of hot acetonitrile and let the solution slowly cool down to room temperature. Good luck with your work!
Frank T. Edelmann Dear Prof. Edelmann, Thank you very much for your recommendations, you are totally right about using recrystallization even I found out that 1,4-dioxane is one of the recommended solvents. But the issue in my case is that I am working on a small scale (1 mmole, wt. of the product = 200 mg approximately) in addition, some of the products are liquids. For this reason, I noticed that some of the literature avoid the mention of purification and just calculates the yield of the reaction from 1H NMR spectra using internal standards. From my side, I can say that the reverse phase column/flash chromatography, preparative TLC, or HPLC, especially in the case of amides containing aliphatic chains can also be used.
Hamid Reza Farhang Dear Hamid, thank you for your answer. Yes, I have already done but it was important for me to get a pure product and confirm the efficiency of my approach to be applied because H NMR sometimes is not so accurate especially if there are any byproducts.
Dear Amal, many thanks for your response and explanation. I'm well aware of the fact that many researchers in the field of synthetic organic chemistry nowadays avoid purification of their new compounds and just report yields calculated from the 1H NMR spectra. In my personal opinion this is a very bad habit and a rather unfortunate development. That way they never isolate any really pure compounds. I fully agree with you that even on a smaller scale a purification step should be carried out, either by recrystallization or some kind of chromatography (TLC or a short silica-packed column etc.). With best wishes, Frank Edelmann
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