Computation of the influence of chemical substitution on the p K a of pyridine using semiempirical and ab initio methods

Abstract

The physical properties of chemicals are strongly in¯uenced by their protonation state, aecting, for example, solubility or hydrogen-bonding characteristics. The ability to accurately calculate protonation states in the form of pK a s is, therefore, desirable. Calculations of pK a changes in a series of substituted pyridines are presented. Computations were performed using both ab initio and semiempirical approaches, including free energies of solvation via reaction-®eld models. The selected methods are readily accessible with respect to both software and computational feasibility. Comparison of calculated and experimental pK a s shows the experimental trends to be reasonably reproduced by the computations with root-mean-square dierences ranging from 1.22 to 4.14 pK a units. Of the theoretical methods applied the best agreement occurred using the secondorder Mùller±Plesset/6-31G(d)/isodensity surface polarized continuum solvation model, while the more computationally accessible Austin model 1/Solvent model 2 (SM2) approach yielded results similar to the ab initio methods. Analysis of component contributions to the calculated pK a s indicates the largest source of error to be associated with the free energies of solvation of the protonated species followed by the gas-phase protonation energies; while the latter may be improved via the use of higher levels of theory, enhancements in the former require improvements in the solvation models. The inclusion of alternate minimum in the computation of pK a s is also indicated to contribute to dierences between experimental and calculated pK a values.

Human Aldehyde Dehydrogenase Catalytic Activity and Structural Interactions with Coenzyme Analogs

“…Results presented in Table 7 show guanine to be the most favorably solvated purine followed by hypoxanthine with adenine and N-1,N 6 -ethenoadenine being the least favorably solvated. Note that the 0.4 kcal/mol difference in solvation of adenine and N-1,N 6 -ethenoadenine is probably not significant based on limitations in the applied reaction field model (49). The ordering of the free energies of solvation in Table 7 corresponds well with the K m values for all three isozymes.…”

“…While the present calculations exclude energetic contributions associated with geometry and vibrational contributions, those terms are expected to be small and similar based on the cyclic nature of the studied compounds. In addition, differences in free energies of solvation are expected to be more reliable than the absolute values (49).…”

Accurate pKa Determination for a Heterogeneous Group of Organic Molecules

“…A recent theoretical study by MacKerell Jr. and co-workers [58] exploited QC computations combined with differently parameterized reaction field methods to evaluate pK a shifts of substituted pyridines relative to pyridine. But, for none of these methods did the computed pKa values of substituted pyridines agree with experiments to better than one pKa unit.…”

Influence of Sequential Guanidinium Methylation on the Energetics of the Guanidinium···Guanine Dimer and Guanidinium···Guanine···Cytosine Trimer: Implications for the Control of Protein···DNA Interactions by Arginine Methyltransferases

“…Relative (methylated)EG acidities were calculated using the methods of Chen and MacKerell 38. Briefly, Born-Haber cycles for the deprotonation of the methylated-EGs and EG were constructed as depicted in Scheme 2.…”