Steric and Electronic Effects on Cu(OTf)2/(R)-VANOL-Catalyzed Alkynylation of Aromatic Aldehydes: A Structure Reactivity Study

A series of functionalized aromatic propargylic alcohols was synthesized through the alkynylation of substituted benzaldehydes with phenylacetylene using a Cu(OTf)2/(R)-VANOL catalytic system in CH2Cl2. The electronic and steric effects of aromatic substituents on reaction efficiency were investigated. Five aromatic propargylic alcohols (7-11), which, to the best of our knowledge, have not been previously reported, were obtained in 65.4-85.1% yields. The highest yield (85.1%) was achieved with the electron-donating n-butoxy substituent, whereas 2-chloro-6-fluorobenzaldehyde afforded the lowest yield (65.4%) due to steric hindrance from the ortho substituents. Density functional theory (DFT) calculations using Gaussian 09 were performed to evaluate substrate-dependent electronic and structural effects. Mulliken charges on the carbonyl atoms and Ar-C(=O) bond lengths showed that no single electronic descriptor accounted for the experimental yield trend, supporting the combined influence of electronic and steric effects on reaction efficiency. The synthesized compounds were characterized by IR, 1H NMR, 13C NMR, and HRMS (ESI). Molecular docking against sphingosine kinase 1 (SphK1; PDB ID: 3VZB) gave binding scores of -7.7 to -9.0 kcal/mol, with 1-(4-butoxyphenyl)-3-phenylprop-2-yn-1-ol exhibiting the strongest predicted interaction. Antimicrobial evaluation demonstrated antibacterial activity against the tested Gram-positive and Gram-negative bacteria, whereas no activity was observed against Candida albicans. These findings demonstrate the efficiency of the Cu(OTf)2/(R)-VANOL catalytic system and provide a basis for further investigation of the antibacterial properties of these aromatic propargylic alcohols.

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