Amino acid–functionalized magnetic Fe3O4 nanocatalysts in aldol addition reactions: a systematic study using full factorial experimental design

Abstract Aldol reactions constitute one of the most fundamental carbon–carbon bond-forming transformations in organic synthesis and play a crucial role in the preparation of value-added chemical intermediates. In this study, magnetic Fe 3 O 4 nanocatalysts functionalized with two different amino acids were synthesized and evaluated as efficient heterogeneous catalysts for aldol addition reactions. The prepared nanocatalysts were comprehensively characterized by X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), and BET surface area analysis, confirming successful surface functionalization and preservation of the magnetic core structure.The catalytic performance of the amino acid-functionalized Fe 3 O 4 nanocatalysts was investigated in model aldol reactions involving cyclohexanone and 4-n-propylcyclohexanone with various aromatic aldehydes. A full factorial experimental design was employed to systematically evaluate the effects of catalyst type and reaction parameters on yield and selectivity, enabling the identification of significant main effects and interaction-driven substrate–catalyst matching behavior. Statistical analysis revealed that catalyst identity and ketone–catalyst interactions play a dominant role in governing reaction efficiency.Under optimized conditions, a series of β-hydroxy ketones were obtained in high isolated yields, including three previously unreported compounds. The magnetic nanocatalysts could be readily recovered using an external magnetic field and reused over multiple reaction cycles with only a minor decrease in catalytic activity. Overall, this study demonstrates that amino acid-functionalized magnetic Fe 3 O 4 nanocatalysts, combined with a structured Design of Experiments approach, provide an effective and reliable platform for the synthesis of aldol-type chemical intermediates.