Cross-coupling Reactions in Water: A Comprehensive Review

Abstract

Cross-coupling reactions are indispensable tools in the field of modern organic synthesis. However, they have traditionally relied on organic solvents and expensive transition-metal catalysts, both of which raise significant concerns regarding sustainability and environmental impact. This review highlights recent advances and emerging strategies for performing C-C cross-coupling reactions in water, emphasizing how these approaches align with the principles of green chemistry. Particular attention is given to key enabling technologies, including the development of water-soluble ligands, such as sulfonated phosphines, newly designed aminophosphines, and polyethylene glycol-based N-heterocyclic carbenes, which enhance catalyst compatibility with aqueous media. In addition, micellar catalysis has emerged as a powerful platform through the use of designer surfactants, enabling a wide range of transformations, including Suzuki-Miyaura, Sonogashira, Heck, and Negishi cross-couplings, to proceed efficiently in water. Heterogeneous catalytic systems and phase-transfer catalysis are also discussed as complementary strategies that facilitate cross-coupling reactions under aqueous conditions. The intrinsic advantages of water, including its non-toxic nature, low cost, abundance, and the unique hydrophobic effect that can accelerate chemical transformations, are critically evaluated alongside the remaining challenges, such as the limited solubility of organic substrates, catalyst deactivation, and the protodeboronation of boronic acids. Furthermore, mechanistic aspects unique to aqueous reaction media are examined together with industrial applications, including multi-kilogram-scale water-mediated cross-coupling processes developed by the pharmaceutical industry that demonstrate substantial reductions in waste generation and improvements in process efficiency. Finally, this review discusses current challenges, identifies future research directions, and highlights emerging trends, particularly the development of base-metal catalytic systems, which are expected to further expand the scope and sustainability of water-based C-C cross-coupling chemistry.