Leveraging 11 B NMR for Optimization of Boronic Acid–Diol Complexation: Insights for SERS-Based Diol Detection

Boronic acids (BAs) are well-known for their distinctive ability to form reversible, covalent bonds with 1,2- and 1,3-diols, making them valuable capture agents to facilitate detection of biologically relevant diols. While their integration with surface-enhanced Raman spectroscopy (SERS) holds promise for selective analyte localization, their applications beyond saccharide detection remain limited. This gap is largely due to the time-consuming optimization required to establish ideal diol-binding conditions. Herein, this work explores the use of 11 B NMR spectroscopy with SERS to efficiently optimize small-molecule BA capture agents for diol detection. Given the structural diversity of BA types, 11 B NMR offers an efficient method for rapidly assessing the BA p K a and binding affinity, which can be applied directly to enhance the performance of the SERS-based sensor. The diol reactivity of 4-mercaptophenylboronic acid and 2-aminopyrimidine-5-boronic acid was assessed with cis -1,2-cyclopentanediol and catechol as model diols across a wide range of pH conditions and concentrations. The 11 B NMR spectra provided both qualitative insight into complex structure and quantitative determination of binding affinity. SERS measurements confirmed that the highest binding affinity occurred at the pH values predicted by 11 B NMR. By coupling simple molecular-based characterization with complementary surface-based detection, this approach streamlines the development of BA-based biosensors to expand their applicability for sensitive and selective detection of other biologically relevant diols.