Issue 47, 2020

Accelerated microdroplet synthesis of benzimidazoles by nucleophilic addition to protonated carboxylic acids

Abstract

We report a metal-free novel route for the accelerated synthesis of benzimidazole and its derivatives in the ambient atmosphere. The synthetic procedure involves 1,2-aromatic diamines and alkyl or aryl carboxylic acids reacting in electrostatically charged microdroplets generated using a nano-electrospray (nESI) ion source. The reactions are accelerated by orders of magnitude in comparison to the bulk. No other acid, base or catalyst is used. Online analysis of the microdroplet accelerated reaction products is performed by mass spectrometry. We provide evidence for an acid catalyzed reaction mechanism based on identification of the intermediate arylamides. Their dehydration to give benzimidazoles occurs in a subsequent thermally enhanced step. It is suggested that the extraordinary acidity at the droplet surface allows the carboxylic acid to function as a C-centered electrophile. Comparisons of this methodology with data from thin film and bulk synthesis lead to the proposal of three key steps in the reaction: (i) formation of an unusual reagent (protonated carboxylic acid) because of the extraordinary conditions at the droplet interface, (ii) accelerated bimolecular reaction because of limited solvation at the interface and (iii) thermally assisted elimination of water. Eleven examples are shown as evidence of the scope of this chemistry. The accelerated synthesis has been scaled-up to establish the substituent-dependence and to isolate products for NMR characterization.

Graphical abstract: Accelerated microdroplet synthesis of benzimidazoles by nucleophilic addition to protonated carboxylic acids

Supplementary files

Article information

Article type
Edge Article
Submitted
30 abr 2020
Accepted
13 jul 2020
First published
14 jul 2020
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2020,11, 12686-12694

Accelerated microdroplet synthesis of benzimidazoles by nucleophilic addition to protonated carboxylic acids

P. Basuri, L. E. Gonzalez, N. M. Morato, T. Pradeep and R. G. Cooks, Chem. Sci., 2020, 11, 12686 DOI: 10.1039/D0SC02467H

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