Fluorescent chemosensing of epinephrine by a bis-boronic molecular receptor in aqueous media: crystal structure, spectroscopic studies and visual detection

Abstract

Selective recognition and sensing of neurotransmitters in aqueous media using artificial receptors is an attractive but challenging goal in modern supramolecular chemistry. Despite advances in the development of optical receptors for some neurotransmitters, such as dopamine, limited efforts have been invested in developing receptors for epinephrine, a neurotransmitter of paramount importance and a widely used drug for heart attacks. Herein, a new fluorescent molecular receptor (referred to as 1) based on a 1,3-bis-benzimidazole-benzene derivative covalently linked to two phenyl boronic acids was synthesized, structurally characterized via single-crystal X-ray diffraction, and studied in-depth as a receptor for four catecholamine-based neurotransmitters as well as several nucleosides, monosaccharides and L-tyrosine in water at physiological pH. Receptor 1 is hydrostable and exhibits fluorescence emission at 408 nm, originated from intraligand (IL) [π–π*] transitions, as supported by TD-DFT calculations. The addition of epinephrine/norepinephrine at micromolar concentrations to an aqueous solution of 1 induces significant and rapid fluorescence changes, whereas in the presence of dopamine, L-DOPA, adenosine, guanosine, glucose, fructose, galactose, ribose and L-Tyr, only modest optical changes are observed. Bis-boronic receptor 1 was found to exhibit high affinity for epinephrine (K = 1.29 × 10⁵ M⁻¹), with good selectivity over other closely related neurotransmitters, including dopamine and L-DOPA. The affinity of epinephrine for 1 is an order of magnitude greater than that for norepinephrine. Such epinephrine affinity/selectivity for a molecular receptor is still rare. Spectroscopic techniques (fluorescence, ¹¹B NMR, fluorescence lifetimes), mass spectrometry, single-crystal X-ray diffraction, DFT calculations and atoms in molecules analysis revealed that epinephrine binds to 1 in a 1 : 2 (receptor : analyte) stoichiometry. This two-point recognition involves sp³ boronate–catechol condensation and multiple hydrogen bonds (OH⋯N and NH⋯N) between the aliphatic chain of epinephrine and the imidazole ring of 1, along with intermolecular interactions between the two epinephrine molecules in the resulting supramolecular structure. The efficient fluorescent response of 1 to epinephrine can be utilized in quantitative sensing of this bioanalyte in real pharmaceutical samples. Furthermore, a chromogenic sensing ensemble comprising 1 and the commercial dye Alizarin Red S was developed, in which epinephrine can be visually detected via an indicator displacement assay through a color change at micromolar concentrations.