Imidazole quantum calculations

Semi-empirical LCAO calculations for all azoles, introducing cr-electrons, indicate that charges are weak except those on NH nitrogen atoms, and that the cr-dipolar moments are close to those of lone pairs. It is therefore inappropriate to take cr-polarity into account in the approximations used in 7r-calculations for these heterocycles. A number of other quantum mechanical calculations have been applied to reactions of imidazoles (80AHC 27)241), while the nucleophilic substitution reactions at C-2 of benzimidazoles, and diazo coupling at C-2 of uncondensed imidazoles have been discussed from theoretical points of view. 

Over the decade 1995-2005, ab initio quantum chemistry has become an important tool in studying imidazole derivatives. Two highly productive approaches are often utilized for the calculations the wave function-based methods (e.g., Hartree-Fock theory and second-order Moller-Plesset perturbation theory (MP2)) and the density functional theory (DFT) based methods (e.g., gradient-corrected (BLYP) and hybrid (B3LYP) methods). 

For molecular properties of complex systems, especially those in solution, ab initio quantum-chemical calculations may not be able to provide accurate results. For example, the acidity of imidazole in the gas phase can be calculated to provide equivalent or greater accuracy than that obtained experimentally however, the determination of its pK value... 

In the application of theoretical studies to the azole field many of these have attempted to achieve comparisons within the range of azole molecules. Thus, calculations of electron densities, dipole moments, and energies of formation give values that reflect the decrease in azole stability as the number of nitrogen atoms increase. ° Good correlations between a and total electron densities and and chemical shifts have been obtained. " Calculations (SCF) of n-electron distributions for the ground state of imidazole do not take into account the tautomeric equivalence of the 4-and 5-positions, but predict the order of electrophilic substitution as 5 > 2 > 4242,243 Various other quantum-mechanical calculations have... 

The effects on the 2-substituted compound of alkyl, aryl, and halogen substituents in the imidazole ring have also been examined, and although the rates for the 5-substituents were represented satisfactorily by quantum-mechanical calculations of 7c-electron densities for the imidazole neutral molecule predict the order of substitution as 5 > 4 > 2, but the tautomeric equivalence of the 4- and 5-positions is not taken into account. In addition, there are probably few occasions on which electrophilic substitution takes place with the neutral molecule the conjugate acid or conjugate base may be the reactive species. 

Quantum mechanical calculations on some imidazole and benzimidazole nucleosides do not predict the conformations observed in the crystal, the difference being attributed to stacking forces and intermolecular hydrogen bonds in the latter case. An ab initio molecular orbital study of adenosine has been reported. ... 

For the three classes of molecules for which detailed HiQSARs have been discussed here, viz., dibenzofurans, heteroaromatic and aromatic amines, and imidazole Cox-2 inhibitors, a hierarchical QSAR approach using a combination of topostructural, topochemical, 3D, and quantum chemical descriptors produced high quality models. Such models, based on purely calculated descriptors, can find application in the routine drug design process as shown in Fig. 11. 

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