Green chemistry in action: A brief investigation into aqueous phase synthesis

The growing demand for sustainable and environmentally benign chemical methodologies has positioned green chemistry as a central theme in modern synthetic science. This study provides a comprehensive review of aqueous-phase organic synthesis as a key strategy for advancing green chemistry principles in pharmaceutical and fine chemical production. An extensive literature survey of over 200 peer-reviewed articles published since the early 1990s was conducted using major scientific databases, including Web of Science, Scopus, SciFinder, PubMed, and Google Scholar, along with publications from leading publishers such as Elsevier, Wiley, and the American Chemical Society. The selected literature was critically analyzed with emphasis on water-mediated organic transformations, including Suzuki–Miyaura, Stille, and Heck cross-coupling reactions, nucleophilic aromatic substitution (S_NAr), aryl amination, C–H functionalization, peptide synthesis, enzyme-catalyzed transformations, and metal-catalyzed reactions. The reviewed studies consistently demonstrate that water serves as an inexpensive, non-toxic, and environmentally friendly reaction medium that can enhance reaction efficiency, reduce reliance on hazardous organic solvents, and support milder reaction conditions. For example, nickel-catalyzed cross-coupling reactions of aryl iodides and bromides with phenylboronic acids have been reported to afford biaryl products in high yields (91–97%) within short reaction times, with electron-deficient bromides achieving quantitative yields under optimized aqueous conditions. Despite these advantages, the widespread industrial adoption of aqueous-phase synthesis remains limited due to financial constraints, legacy manufacturing infrastructure, regulatory burdens, and limited stakeholder awareness. Overall, this review highlights both the significant potential and current limitations of water-based synthetic methodologies in sustainable pharmaceutical manufacturing, emphasizing the need for integrated technological and industrial strategies.