Synthesis of Aspirin at the Gas-Water Interface With Phenol and Carbon Dioxide.

We present a gas-water interfacial carboxylation of phenol into salicylic acid under ambient conditions, bypassing the high temperature and pressure required by the conventional Kolbe-Schmitt reaction. Phenol-containing microdroplets were sprayed with CO2 into a high-resolution mass spectrometer, where in situ analysis revealed a highly regioselective ortho-carboxylation pathway. To scale up the process, we transitioned from microdroplets to microbubbles, extending the gas-water contact time. Milligram-scale acetylsalicylic acid (aspirin) was synthesized from 500 mL of 10 ppm aqueous phenol solution under a CO2 atmosphere, upon the addition of acetic anhydride. This study highlights the unique reactivity of micron-scale gas-water interfaces, whether in droplets or bubbles, as effective media for the proof-of-concept conversion of dilute aqueous phenol and CO2 into pharmaceutically relevant products under ambient conditions.