Spontaneous\nCatalytic Paal–Knorr Reactions\nfor <i>N</i>‑Substituted Pyrrole Synthesis by Microdroplet\nChemistry

It is well recognized in recent studies\nthat water molecules\nat\nthe gas–liquid interface of microdroplets spontaneously dissociate\ninto hydronium and hydroxide and form superacids/superbases and reactive\nspecies (hydrated electrons, hydroxide radicals, hydrogen peroxide,\nwater radical cations/anions, etc.) due to the 10<sup>9</sup> V m<sup>–1</sup> electric field. In contrast to extensive interest\nin spontaneous redox reactions by the reactive species in microdroplet\nstudies, limited attention has been attracted by gram-scale organic\nsynthesis catalyzed by the spontaneously formed superacids/superbases.\nThis study demonstrates spontaneous organic catalysis of the superacids\nfor Paal–Knorr reactions, one of the most classic pathways\nto construct <i>N</i>-substituted pyrroles with biologically\nand pharmaceutically important roles. Paal–Knorr reactions\ncan proceed well with no external catalysts in isopropanol microdroplets\nwithin 10 min at room temperature. Sixteen <i>N</i>-substituted\npyrroles were synthesized using the microdroplet method with 83–99%\nyields, several orders of magnitude reaction acceleration (a typical\nrate acceleration factor of 1.18 × 10<sup>3</sup> based on the\nratio of the rate constants), and a scale-up rate of 5.50 g h<sup>–1</sup>. By avoiding external catalysts, thermal irradiation,\nlong reaction times, and problematic solvents required by conventional\nPaal–Knorr methods, the microdroplet method was a green, efficient,\nand attractive alternative for the construction of pyrroles and their\nderivatives.