Leveraging ¹¹B 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 ¹¹B NMR spectroscopy with SERS to efficiently optimize small-molecule BA capture agents for diol detection. Given the structural diversity of BA types, ¹¹B NMR offers an efficient method for rapidly assessing the BA pK_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 ¹¹B 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 ¹¹B 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.