Atom-efficient direct amidation by thermo-mechanochemistry

07 June 2023, Version 1
This content is a preprint and has not undergone peer review at the time of posting.

Abstract

Direct amide bond formation involving carboxylic acids and amines predominantly involves solution-based reactions with coupling reagents and catalysts that result in poor sustainability performance. Here, we present a conceptually different approach, which includes simultaneous mechanical and thermal activation. Such an approach enables direct and quantitative conversion to amides starting from carboxylic acids and amines and avoids using activators and additives. As a model reaction, we studied the thermo-mechanochemical condensation of benzoic acid and p-toluidine, which gave N-(p-tolyl)benzamide almost quantitatively in gram-scale. We show that crystalline supramolecular arrangements between reactants act as intermediates that precede the formation of amides. The applicability of the methodology was demonstrated by a quantitative synthesis of moclobemide, a valuable active pharmaceutical ingredient. Finally, the sustainability assessment by green chemistry metrics highlights the atom-efficiency of our methodology.

Keywords

mechanochemistry
high-temperature ball milling
direct amidation
amide bond formation
moclobemide
active pharmaceutical ingredient

Supplementary materials

Title
Description
Actions
Title
Atom-efficient direct amidation by thermo-mechanochemistry
Description
Supplementary material.
Actions

Comments

Comments are not moderated before they are posted, but they can be removed by the site moderators if they are found to be in contravention of our Commenting Policy [opens in a new tab] - please read this policy before you post. Comments should be used for scholarly discussion of the content in question. You can find more information about how to use the commenting feature here [opens in a new tab] .
This site is protected by reCAPTCHA and the Google Privacy Policy [opens in a new tab] and Terms of Service [opens in a new tab] apply.