Dependence of the Reactivity of Acridine on Its Substituents: A Computational and Kinetic Study

Abstract

AbstractAromatic nucleophilic substitution on the C9 carbon of acridine plays an important role in multiple biological and medicinal applications. The rate of the key reaction is strongly dependent on the environment and acridine substituents. In this study, the factors influencing the reaction mechanism were studied theoretically and verified experimentally for simplified systems. Density functional theory was used for the computations. The activation energy of a model derivative was determined experimentally from a kinetic study. Also, the relative reactivities of selected compounds were verified by a competition experiment. The theoretical predictions correlate well with the observations. The computed reaction path confirms that the thiol group attacks the aromatic core activated by the nitrogen heteroatom and replaces halogen or amino substituents via a well‐defined Meisenheimer transition state. The reaction barrier is strongly influenced by both the solvent and substituents on the aromatic system. A multistep mechanism is proposed for the reaction of aminoacridine in which the aqueous solvent participates in the reaction. Strong correlations between reaction energies and geometrical parameters were observed and can be used to rationalize the design of acridine drugs as well as to avoid lengthy computations of the transition states.