Spontaneous Catalytic Paal–Knorr Reactions for <i>N</i>-Substituted Pyrrole Synthesis by Microdroplet Chemistry

It is well recognized in recent studies that water molecules at the gas–liquid interface of microdroplets spontaneously dissociate into hydronium and hydroxide and form superacids/superbases and reactive species (hydrated electrons, hydroxide radicals, hydrogen peroxide, water radical cations/anions, etc.) due to the 109 V m–1 electric field. In contrast to extensive interest in spontaneous redox reactions by the reactive species in microdroplet studies, limited attention has been attracted by gram-scale organic synthesis catalyzed by the spontaneously formed superacids/superbases. This study demonstrates spontaneous organic catalysis of the superacids for Paal–Knorr reactions, one of the most classic pathways to construct N-substituted pyrroles with biologically and pharmaceutically important roles. Paal–Knorr reactions can proceed well with no external catalysts in isopropanol microdroplets within 10 min at room temperature. Sixteen N-substituted pyrroles were synthesized using the microdroplet method with 83–99% yields, several orders of magnitude reaction acceleration (a typical rate acceleration factor of 1.18 × 103 based on the ratio of the rate constants), and a scale-up rate of 5.50 g h–1. By avoiding external catalysts, thermal irradiation, long reaction times, and problematic solvents required by conventional Paal–Knorr methods, the microdroplet method was a green, efficient, and attractive alternative for the construction of pyrroles and their derivatives.