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

ABSTRACT

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 CO ₂ 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 CO ₂ 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 CO ₂ into pharmaceutically relevant products under ambient conditions.