AbstractBACKGROUNDMandyphos‐Pd has been proven to be a good chiral extractant to enantioseparate 3‐chlorophenylglycine enantiomers with a separation factor of 2.64. However, this extractant is not suitable to enantioseparate other amino acids with separation factors of <2.0. The poor versatility has limited its practical application in chiral extraction.RESULTSMandyphos derivatives with different steric and electronic properties were synthesized and their enantioseparation properties toward amino acid and mandelic acid enantiomers were investigated. The results suggested that substituent groups with different steric properties affect the extraction properties, probably by adjusting the angles of tetra‐coordinated palladium complexes. And the substituent groups with different electronic properties affect the extraction properties mainly by adjusting the π‐π interactions/steric hindrance effects between Mandyphos‐Pd and substrates. After optimization, the highest separation factors for phenylalanine, homophenylalanine, 3‐chloro‐phenylglycine, 4‐nitro‐phenylalanine, mandelic acid and 2‐Cl‐mandelic acid were 2.10, 2.77, 3.51, 2.42, 2.24 and 5.19, respectively. The enantioseparation mechanisms revealed that the coordination interactions between metal ions and COO−/NH2, π‐π interactions or steric hindrance effects between aryls are the main forces acting in chiral recognition.CONCLUSIONThe enantioselectivities of the Mandyphos‐Pd complex are improved by introducing groups with suitable steric and electronic properties. Structural modification is a useful method to improve the enantioseparation efficiencies of chiral extractants. The results of this work will supply important theoretical guidance and reference for the design and modification of novel diphosphine ligands in future work. © 2024 Society of Chemical Industry (SCI).