Pi-Pi complexation of bupivacaine and analogues with aromatic receptors: Implications for overdose remediation

Evon Powell¹, Y-H Lee², Richard Partch¹, Donn Dennis³, Timothy Morey³, Manoj Varshney³

¹Department of Chemistry, Clarkson University, Potsdam, NY, USA; ²Department of Chemistry, Kyungwon University, Seoul, Korea; ³Department of Anesthesiology, University of Florida, Gainesville, FL, USA

Abstract: The interaction of the important but often overdosed local anesthetic bupivacaine, its structural analogs 2,6-dimethylaniline, and N-methyl-2,6-dimethylacetanilide, and cocaine, with several electron deficient aromatic moieties were studied primarily by proton NMR and UV-visible spectroscopy. In solution, the anesthetic, its analogs and cocaine are electron donors and form π-π charge transfer complexes with strong aromatic acceptors, as monitored by the upfield changes induced in the NMR chemical shifts (δ) and red-shifted UV-vis wavelength (λ_max) absorbance of the acceptors. The equilibrium binding constant, K, was determined from the 1H NMR charge transfer induced chemical shift changes and used to calculate the free energy (ΔG) for complex formation of three acceptor-donor pairs. HPLC results indicate that the concentrations of free bupivacaine, its analogs and of cocaine are reduced from solution via binding to aromatic-functionalized silica.

Keywords: bupivacaine, cocaine, charge transfer complex, NMR, drug overdose, selective toxin removal