The challenges of direct Claisen–Schmidt condensation in the synthesis of polyhydroxylated bischalcones: experimental results supported by DFT calculations

Abstract

The synthesis of chalcones commonly relies on the Claisen–Schmidt condensation, an attractive reaction owing to its operational simplicity and favorable atom economy. However, its application to acetophenones bearing multiple hydroxy substituents can be problematic, often requiring hydroxy protection and subsequent deprotection, thereby diminishing the sustainability advantages of the approach. In this work, density functional theory (DFT) calculations were performed at the CAM-B3LYP/6-311++G(d,p) level to provide a qualitative electronic rationale for the factors that may account for this limitation. The nucleophilic behavior of the starting species was examined under basic, acidic, and metal-assisted conditions, using molecular models both with and without the hydroxy groups to evaluate the hypothesis that competing nucleophilic sites could interfere with the desired condensation and hinder the reaction. The results indicated that strong basic conditions favor extensive phenol deprotonation, generating several competing nucleophiles. In this situation, the resulting phenolate species were more nucleophilic than the corresponding enolates, favoring undesired reaction pathways. Coordination of lithium or calcium to the two phenolate groups decreased their nucleophilicity but failed to suppress the unwanted reactivity of the remaining phenolate. In contrast, under acidic conditions, the enol species exhibited greater nucleophilic character than the phenolic groups, providing no support for the proposed competition between phenolates and enolates as the sole explanation for the unsuccessful reaction. Nevertheless, the acidic environment may facilitate isomerization of the bischalcone products, which could subsequently promote degradation and/or undesired cyclization processes. Taken together, experimental and computational results indicate that the failure of the reaction arises from multiple competing factors rather than from a single mechanistic limitation. Among the conditions investigated, the acid-mediated pathway appears to be the most promising starting point for further optimization of the synthesis of polyhydroxylated bischalcones.