One-Step Formation of Pharmaceuticals Having a Phenylacetic Acid Core Using Water Microdroplets

The properties of water microdroplets strikingly differ from bulk water. Using room-temperature water microdroplets, we find that toluene can react with CO₂ to form phenylacetic acid in one step without any catalyst with negative high voltage applied at the sprayer source. The chemical components of these microdroplets are identified by mass spectrometry, and product structures are confirmed by tandem mass spectrometry. In this manner, we generate three drug molecules in a single step: 4-aminophenylacetic acid (epithelial peptide transporter PepT1 inhibitor), 3,4-dihydroxyphenylacetic acid (dopamine metabolite neurotransmitter), and phenylacetic acid (sodium salt form; treatment of urea cycle disorder). Mechanistic studies show that benzyl radicals formed from hydroxyl radicals at the water microdroplet interface drive these carboxylation reactions. This water microdroplet chemistry is general, allowing activation and subsequent carboxylation of aryl α-C-H groups.