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I am interested in creating an amide of stearic acid. I thought that simply mixing both of them in some solvent, heating the solution, and using a vacuum pump to distill the liberated water (to drive the reaction forward) would be enough.

But a bit of research showed that this synthesis is normally done with acyl chlorides derivatives or methyl ester derivatives or other more elaborate methods.

Without access to those tools, is it still possible for me to produce a good yield of amide, using only a fatty acid, a primary or secondary amine, a solvent, and heating & vacuum?

(Secondary optional question: If I use ethanolamine, what will be formed preferentially, the amino-ester or the hydroxy-amide?)

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  • $\begingroup$ What is "some solvent", and how do you separate solvent & water after boiling it off? There is a special piece of glassware to do this with e.g. toluene, another one with chloroform, but you don't have such equipment, right? $\endgroup$
    – Karl
    Mar 19, 2021 at 12:23
  • $\begingroup$ And, please: Your "secondary, optional question" must come before the other one. What reaction exactly do you want to do?? Ethanolamine is not just an amine. Methylamine, diethylamine, triethylamine, those are, and they're diverse enough already. $\endgroup$
    – Karl
    Mar 19, 2021 at 12:31
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    $\begingroup$ To answer your second question - which should really be a separate question - the amino group is by far the better nucelophile so you'll get the amide. $\endgroup$
    – Waylander
    Mar 19, 2021 at 13:18

1 Answer 1

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It can be done but it is not a good reaction. From Lundberg et al. [1]:

Formally, the amide bond is formed through the condensation of a carboxylic acid and an amine with the release of one equivalent of water. This reaction has been considered challenging due to the competing acid–base reaction, which occurs when the amine and the carboxylic acid are mixed. Although the amide bond can be formed from the corresponding ammonium carboxylate salt upon heating, this reaction has generally been considered to be of limited preparative value. Furthermore, the high activation barrier for the direct coupling of a carboxylic acid and an amine can only be overcome using forcing reaction conditions.

Use of borate ester catalysis under Dean–Stark conditions has recently been reported to give good yields without resorting to acyl activation groups [2].

References

  1. Lundberg, H.; Tinnis, F.; Selander, N.; Adolfsson, H. Catalytic Amide Formation from Non-Activated Carboxylic Acids and Amines. Chem. Soc. Rev. 2014, 43 (8), 2714–2742. DOI: 10.1039/C3CS60345H. (PDF)
  2. Sabatini, M. T.; Boulton, L. T.; Sheppard, T. D. Borate Esters: Simple Catalysts for the Sustainable Synthesis of Complex Amides. Sci. Adv. 2017, 3 (9), e1701028. DOI: 10.1126/sciadv.1701028.
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