PKa values calculated

Fig. 18.5. Correlation of simulated %HIA and experimental %HIA. The fraction absorbed was simulated using GastroPlus with input values of permeability, solubility, diffusivity, and pKa values calculated purely in silico.

Fig. 6.1-1 The pKa- values calculated from the data (open circles) and the straight line drawn through them by least-squares, extrapolated (thin colored line) to yield the infinite dilution value.

Overlapping ionization processes When, in titrations of these classes of compounds, it is observed that the pKa values (calculated by the methods already described) are of poor precision, it is very probable that the endpoint of the first equivalent is indefinite because the titration of one group has begun before that of the other is complete. When this occurs, the two ionization processes are said to overlap and the two pKg values will be found to be separated by less than 2 7 units of pKg. Speakman (1940) derived an equation which allows these pK values to be calculated. It can be written in the form... 

Earlier studies of 4-aminopyridine 1-oxide were less conclusive. The solid-state infrared spectrum could be interpreted to indicate the existence of both the imino structure and/or, more probably, the amino structure. Comparison of the actual pKa value of 4-aminopyridine 1-oxide wdth the value calculated using the Hammett equation was considered to indicate that the compound existed as such or as an equilibrium mixture with l-hydroxypyrid-4-onimine, the latter possibility being considered the less likely on the basis of resonance and bond energies/ Resonance energy and ultraviolet spectral considerations have been advanced to support the 4-aminopyridine 1-oxide structure/ The presence of an infrared absorption band at... 

The azolotriazines 294 were prepared (86KGS1137) by heating resorcinol with the corresponding nitroazole 293 in butanol. The pKa values of some nitropyrazolotriazinones have been calculated (84KGS697). Az-... 

Interestingly, comparison of the values of pAHB and the acidity constants pKa in a series of the same family of compounds, such as carbonyl compounds, amines, pyridines and sulphoxides, shows that a good correlation exists between p/CHB and pgiving straight lines in each series of compounds with parallel slopes. This enables one to calculate the difference of the several pKa values at the same p/CHB value, and vice versa. Thus, at p= 0, p/CHB values of various functional groups were determined and are shown in Table 13. 

Aalbers [49,50] calculated pKa-values from pH and conductivity measurements and concluded that the CMC increases with the EO degree and that the micelles of ether carboxylic acids are somewhat uncharged. 

As in Table 10.1, the experimental pKa values have more significant figures than shown here, and the K, values have been calculated from these better data. 

Scheme 7.25 shows the role of quinone methide energy on the cation-quinone methide equilibrium. A high pKa value for this equilibrium is expected if the energy of the quinone methide approaches that of the carbocation. To construct this cycle, we used the Ka values that we determined for the protonated ketone (pKa — —0.9) and quinone methide (pKa = 6.6). This pKa difference requires that the keto form be more stable than the quinone methide by — 10.2kcal/mol. We obtained the calculated energy difference of lO.lkcal/mol from Hartree-Fock calculations using 6-31G and STO-3G basis sets, inset of Scheme 7.25. 

The ionizability of compounds affects other parameters such as solubility, permeability, and ultimately oral bioavailability, so it may be important to track changes in the pka of new compounds. Calculated pka values can be used when planning the synthesis of new compounds, but it is also a good idea to confirm these values experimentally. An example where this strategy can be useful is in the search for bioisosteric replacements for a carboxylic acid group. 

Note that the distribution coefficient depends only on pH, pKa values, and P (not on concentration of sample species). Equation (4.7) is applicable to all lipophilicity calculations. Special cases, such as eq. 4.9, have been tabulated [275],... 

Niflumic acid, which has two pKa values, was studied both pH-metrically and spectroscopically using the shake-flask method [224]. The monoprotonated species can exist in two forms (1) zwitterion, XH 1 and (2) ordinary (uncharged) ampholyte, XH°. The ratio between the two forms (tautomeric ratio) was measured spectroscopically to be 17.4. On assuming that a negligible amount of zwitterion XH partitions into octanol, the calculated micro-log/1 for XH° was 5.1, quite a bit higher than the macro-log/1 3.9 determined pH-metrically in 0.15 M NaCl. It is noteworthy that the distribution coefficient D is the same regardless of whether the species are described with microconstants or macroconstants [275]. 

Since the pKa values of the compounds studied are reliably known (Table 6.1), it was possible to calculate the A shifts (Table 6.2). These shifts were used to calculate the corrected aqueous intrinsic solubilities So, also listed in Table 6.2. 

Although FEP is mostly useful for binding type of simulations rather than chemical reactions, it can be valuable for reduction potential and pKa calculations, which are of interest from many perspectives. For example, prediction of reliable pKa values of key groups can be used as a criterion for establishing a reliable microscopic model for complex systems. Technically, FEP calculation with QM/MM potentials is complicated by the fact that QM potentials are non-seperable [78], When the species subject to perturbation (A B) differ mainly in electronic structure but similar in nuclear connectivity (e.g., an oxidation-reduction pair), we find it is beneficial to use the same set of nuclear geometry for the two states [78], i.e., the coupling potential function has the form,... 

His residues at configurations sampled using the popular link-host-atom exclusion scheme changes the free energy derivatives by 8-9 kcal/mol despite that the QM/MM frontiers are far from the zinc-bound water. With this effect taken into account, the calculated pKa value for the zinc-bound water in the WT CAII is in encouraging agreement with experiment the value is 7.1 (5.4) for the 20 (25) A-inner-region simulations, as compared to the experimental value of around 7 [86],... 

Bashford D, Gerwert K (1992) Electrostatic calculations of the pKa values of ionizable groups in bacteriorhodopsin. J Mol Biol 224 473 186. 

Hardly surprisingly the tendency of alkanes to lose proton and form carbanions is not marked, as they possess no structural features that either promote acidity in their H atoms, or are calculated to stabilise the carbanion with respect to the undissociated alkane (cf. carboxylic acids, p. 55). Thus CH4 has been estimated to have a pKa value of 43, compared with 4.76 for MeC02H. The usual methods for determining pKa do not, of course, work so far down the acidity scale as this, and these estimates have been obtained from measurements on the iodide/organo-metallic equilibria ... 

Thermochemistry. Chen et al.168 combined the Kohn-Sham formalism with finite difference calculations of the reaction field potential. The effect of mobile ions into on the reaction field potential Poisson-Boltzman equation. The authors used the DFT(B88/P86)/SCRF method to study solvation energies, dipole moments of solvated molecules, and absolute pKa values for a variety of small organic molecules. The list of molecules studied with this approach was subsequently extended182. A simplified version, where the reaction field was calculated only at the end of the SCF cycle, was applied to study redox potentials of several iron-sulphur clusters181. 

The semi-empirical Yasuda-Shedlovsky technique of extrapolating a series of apparent pKa values obtained in several ratios of water/solvent to obtain an aqueous value is well established [32, 33], but three or more experiments are required and this adds significantly to assay times. A method of calculating aqueous pKas for various classes of organic acids and bases from single apparent pKa values obtained in water/solvent mixtures has been reported [34], and shows promise as a means of further speeding pKa measurement. 

Analysts like to make chemical measurements to the highest quality they can, and this is possible with modem instrumentation and good analytical practice. Chemical parameters are generally measured more accurately and reproducibly than parameters measured in biological systems, and the results are more reliable than values calculated by software from structure alone (e.g., calculated log P, pKa). Of all the information available to medicinal chemists, measured chemical parameters are probably the most reliable. With these thoughts in mind, it makes sense not to... 

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