Improving Product Quantification in High-Throughput Experimentation via Petasis Reaction

• Ken Tran, Biochemistry, University of Delaware

• Jessica Sampson, Chemistry and Biochemistry, University of Delaware

High-throughput Experimentation (HTE) is a laboratory approach that enables multiple reactions to be performed in parallel, significantly accelerating data generation. In recent decades, HTE has seen increasing application in the pharmaceutical industry due to its versatility in addressing key chemical questions, such as functional group compatibilities and structure–activity relationships (SAR) studies, which are central to drug design. When HTE reactions yield novel compounds, proper characterization is critical. Quantitative NMR (qNMR) is commonly used to estimate reaction yield by comparing the signal intensity of a product peak to that of an internal standard. However, without structural confirmation, qNMR can be unreliable, as it may quantify peaks from impurities rather than the intended product. To improve confidence in product quantification from running HTE, we developed a workflow to isolate and characterize novel compounds from the uncatalyzed thermal Petasis reaction. The separation was performed on a normal-phase Solid Phase Extraction (SPE) to wash off impurities and collect product fractions. These were then concentrated and analyzed by ¹H-NMR, allowing direct comparison with crude qNMR spectra to verify product peak identity. This step ensures that the qNMR data are accurate and enhances their reliability. While this workflow may not achieve complete purification, it yields sufficient material for NMR analysis, which is very important for the rapid generation of high-quality data, especially when coupled with automation platforms. We further validated this workflow using the photoredox Petasis reaction, demonstrating its potential applicability across diverse reaction types. This approach can benefit drug discovery significantly by enabling a faster and more reliable reaction assessment, making it a valuable tool for early‑stage pharmaceutical research.