Solvent-Controlled Reaction Productivity and Mechanistic Pathways in the Multicomponent Synthesis of 2‑Amino-3-cyano‑4H‑pyrans.

In this work, we present a detailed mechanistic and solvent-effect study of the multicomponent synthesis of 2-amino-3-cyano-4H-pyran (ACP) derivatives catalyzed by a water-soluble imidazolium-functionalized polymer (PEI.IL)a synthetic enzyme (synzyme). Rather than focusing solely on synthetic scope, this study dissects how solvent properties and reaction equilibria govern reaction productivity and pathway selection in this multicomponent transformation. Solvent effects were quantitatively analyzed using the Kamlet-Abboud-Taft model, revealing that hydrogen-bond acidity (α), hydrogen-bond basicity (β), and dipolarity/polarizability (π*) play distinct and competing roles at different stages of the reaction. Control experiments, combined with systematic variation of reaction conditions, demonstrate that product formation proceeds predominantly through a pathway initiated by the reversible condensation between benzaldehyde and malononitrile, followed by enol-mediated a new C-C bond formation. Reaction productivity was treated as a thermodynamically oriented descriptor, allowing correlations between solvent effects, keto-enol equilibria, and overall efficiency to be established. The methodology affords a series of ACP derivatives in good to excellent yields under optimized conditions, with the catalyst remaining recyclable over multiple cycles without loss of activity. By integrating solvent-effect analysis, equilibrium considerations, and mechanistic control experiments, this work provides an experimentally grounded framework for understanding and optimizing multicomponent reactions beyond conventional yield-based approaches.