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

Abstract

Aromatic 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 re-

Improved synthesis of antiplasmodial 4-aminoacridines and 4,9-diaminoacridines

“…The rate and regioselectivity of this reaction is strongly dependent on acridine substituents, and the presence of the nitro group in the C-4 position of 6 signicantly increases its reactivity, which results in the formation of multiple by-products. 10,11 For this reason, our rst optimization attempt consisted in rst reducing 6 into 6,9-dichloro-2-methoxy-4aminoacridine, by use of SnCl 2 , and then perform the S N Ar reaction. However, 6,9-dichloro-2-methoxy-4-aminoacridine failed to undergo the desired S N Ar, probably due to the electron-donating effect of the amine group in C-4.…”

“…The reactivity of these positions is obviously modulated by the electrondonating or withdrawing properties of the substituents on the phenyl rings of the acridine scaffold. 6,10,11 The N-10 position is the main nucleophilic site of the acridine core, in which Nalkylations can easily occur, with the formation of acridinium salts under strongly acidic conditions. On the other hand, due to the strong electron deciency caused by the pyridinic nitrogen on the C-9 position, this is the most electrophilic site of the acridine system, allowing for nucleophilic reactions to take place there.…”

Nucleophilic aromatic substitution in chlorinated aromatic systems with a glutathione thiolate model

“…Experimental evidence generally points to a two‐step process, which is dependent upon nucleophile, leaving group, and the presence of electron‐withdrawing substituents . In contrast, ab initio and semiempirical theoretical treatments reveal both two‐step and single‐step mechanisms …”