High-throughput DoE synthesis of chalcones and pyrazolines for fluorescent sensing

Abstract

Pyrazolines are attractive scaffolds for fluorescent sensors due to their unique photophysical properties and the ease of their synthesis from chalcone precursors. While both chalcones and pyrazolines have been widely explored, a systematic optimization of their synthesis using design of experiments (DoE) has yet to be reported. Here, we apply a data-driven DoE strategy, evaluating multiple variables across more than 105 datapoints, to establish highly optimized conditions for the Claisen-Schmidt condensation of chalcones and their subsequent conversion to pyrazolines. These conditions enabled the gram-scale preparation of a structurally diverse library of 27 chalcones by direct recrystallization, which were subsequently transformed into 11 pyrazolines. High-throughput screening of this library revealed pyrazoline P10 with unusual “turn on” fluorescence at 590 nm in the presence of Zn2+ only. This integrated DoE–HTS workflow demonstrates a powerful approach for accelerating sensor discovery.