||Calculations of pK Differences between Structurally Similar Compounds.
Rashin, A. A. ;
Rabinowitz, J. R. ;
Bandelder., J. R. ;
||Health Effects Research Lab., Research Triangle Park, NC. ;Mount Sinai School of Medicine, New York.;National Science Foundation, Washington, DC.
Nuclear binding energy ;
Molecular structure ;
Competitive binding ;
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An attempt is made to find out whether accurate calculations of pK differences in series of biologically active compounds are feasible. The computational method used employs a combination of quantum mechanical calculations of the vacuum proton affinities, and a new method for calculation of hydration energies based on a continuum representation of the solvent. Application of the method to the calculations of pK differences between congeners of imidazolium shown that experimental values of such differences can be computationally predicted within one pK unit for pairs of congeners differing in the hydrogen to methyl substitution or in the position of the same substituent in the molecule. However, calculated values deviate from the experimental ones by more than four pK units for the pairs of congeners differing in the substitution of the hydrogen or methyl group to chloro- or nitro- group. The deviations from experimental values found for the substitutions may be attributed to errors in the calculated proton affinities in vacuum that do not cancel for substitutions involving groups with very different chemical properties.