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Theoretical study of some heterocyclic amines with applications to the chemistry of 9‐amino‐1,2,3,4‐tetrahydroacridine
Author(s) -
Pop Emil,
Brewster Marcus E.,
Kaminski J. J.,
Bodor Nicholas
Publication year - 1989
Publication title -
international journal of quantum chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.484
H-Index - 105
eISSN - 1097-461X
pISSN - 0020-7608
DOI - 10.1002/qua.560350208
Subject(s) - chemistry , protonation , steric effects , heterocyclic amine , pyridinium , pyridine , ring (chemistry) , amine gas treating , dibasic acid , computational chemistry , morpholine , chemical stability , molecule , lone pair , aromatic amine , medicinal chemistry , organic chemistry , ion
9‐Amino‐1,2,3,4‐tetrahydroacridine ( THA ), a potent cholinesterase inhibitor, was recently used in the treatment of Alzheimer's disease. On attempting to prepare a dihydropyridine ⇆ pyridinium salt‐based redox chemical delivery system ( CDS ) to enhance brain delivery of THA , several of the practical synthetic challenges were examined by using a theoretical MO approach. The structures, reactivities and stability of THA , derivatives of THA and a model compound, 4‐aminopyridine, a simple dibasic heterocyclic amine, were studied in the framework of the AM ‐1 approximation. The study included the possible protonated forms of THA and 4‐aminopyridine. The calculated heats of formation showed that ring nitrogen protonated forms are more stable for both THA and 4‐aminopyridine. The calculated heats of formation showed that ring nitrogen protonated forms are more stable for both THA and 4‐aminopyridine, consistent with experimental results. Electron delocalization is responsible for the remarkable stability of these molecules and for the observed lack of reactivity of the amino group, both in the basic and protonated forms. The site of N ‐alkylation of the 9‐nicotinamide derivative of THA (an intermediate in the synthesis of THA ‐ CDS ) is controlled by electronic, thermodynamic, and steric factors.