Anchoring Stealth Amine Biomarkers via Coupled Chemical Activation for Surface Immobilization

Abstract

Detection of low-activity tertiary amine-containing biomarkers such as N,N-dimethyltryptamine remains a significant challenge due to the inherent electrochemical inertness of the functional groups. Thus, we demonstrate an integrated functionalization strategy combining selective chemical activation with surface-confined transamidation chemistry to enable the comprehensive chemical activation of the analyte and selective binding to modified gold surfaces. This step facilitates an effective surface immobilization strategy that selectively converts inert indole-based tertiary amines into reactive, surface-bondable derivatives suitable for potential electronic biosensing applications. Our approach integrates the selective oxidation of tertiary amines to N-oxides, followed by the Polonovski activation to form reactive tertiary amides in solution. This stage is further coupled with the covalent immobilization of the activated amides onto an −NH2-terminated self-assembled monolayer via transition-metal-free transamidation surface chemistry. Surface analysis revealed modified topology and properties. The high grafting density of the adsorbed layer, along with the corresponding elemental analyses, confirms the successful immobilization of the activated derivatives in contrast to nonactivated molecules. This surface reactivity triggering demonstrates the transformation of chemically inert tertiary amines in an important class of drugs into surface-bound reactive species with high selectivity in surface adsorption, establishing a foundation toward label-free selective binding for real-time bioelectronic monitoring for health diagnostic and forensic applications.