Spectrophotometric determination and computational evaluation of the rates of hydrolysis of 9-amino-substituted acridines.
Aminoacridines have a long history in the drug and dye industries and display a wide range of biological and physical properties. Despite the historical relevance of 9-aminoacridines, there have been few studies investigating their stability. 9-Aminoacridines are known to hydrolyze at the C9-N15 bond, yielding acridones. In this study, the pH-dependent hydrolysis rates of a series of 9-substituted aminoacridines are investigated. In addition, ground-state physical properties of the compounds are determined using ab initio quantum mechanics calculations to gain insight into the forces that drive hydrolysis. An analysis of the bond orders, bond dissociation energies, and conformational energies show that the rate of hydrolysis depends on two main factors: delocalization across the C9-N15 bond and steric effects. The computational results are applied to explain the change in experimental rates of hydrolysis going from primary to secondary and to tertiary substituted 9-aminoacridines. In the case of tertiary substituted amines, the calculations indicate the C9-N15 bond is forced into a more gauche-like conformation, greatly diminishing delocalization (as shown by reductions in bond orders and bond energy), which leads to rapid hydrolysis. A model of intramolecular hydrogen bonding is also presented, which explains the increased rate of hydrolysis observed for highly substituted compounds under acidic conditions.
Department of Medicinal Chemistry and Center for Drug Design, University of Minnesota Supercomputer Institute, University of Minnesota, Minneapolis, Minnesota 55455, USA.
John R
JR
Goodell
Bengt
B
Svensson
David M
DM
Ferguson
D000166:Acridines / Q000138:chemical synthesis; D054831:Acridones; D000609:Aminoacridines / Q000737:chemistry*; D003198:Computer Simulation; D006860:Hydrogen Bonding; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D007700:Kinetics; D008956:Models, Chemical; D015394:Molecular Structure; D011789:Quantum Theory; D013057:Spectrum Analysis
D000166:Acridines; D054831:Acridones; D000609:Aminoacridines; C041300:acridone