PK.d values

Besides the well-known lower basicity of ethanol, these data illustrate the greater acidity of benzoxazolium compared with benzothiazolium. The relative pK.d values of the quaternary salts obtained in acetonitrile when treated with tetrabutvlammonium hydroxide are 18.3 and 17.6, respectively (25). Those of 2-methyl 4-phenyl thiazolium and 2.4-dimethyl thiazolium are 20.5 and 21.8 under the same conditions (25). 

Correlations between pK,d values and the equilibrium constants for the formation of iodine complexes with imidazoles suggest that the charge transfer complexes are of the /j-type involving donation of the unshared electron pair at N-3. For examples of K and pK3 values are imidazole, 202, 6.95 1-methylimidazole, 333, 7.33 4-phenylimidazole, 152, 6.10 4,5-diphenylimidazole, 141, 5.90 (83BSB923). 

From an acid-base titration curve, we can deduce the quantities and pK.d values of acidic and basic substances in a mixture. In medicinal chemistry, the pATa and lipophilicity of a candidate drug predict how easily it will cross cell membranes. We saw in Chapter 10 that from pKa and pH, we can compute the charge of a polyprotic acid. Usually, the more highly charged a drug, the harder it is to cross a cell membrane. In this chapter, we learn how to predict the shapes of titration curves and how to find end points with electrodes or indicators. 

The pK.d values of TV-methyltrifluoromethanesulfonamide (TfNHMe = 7.5) and TV-meth-yltoluenesulfonamide (TosNHMe= 11.7) have been examined and it was found that these sulfonamides are applicable to the Mitsunobu reaction conditions. 80 A modified Mitsunobu reaction has been used for the synthesis of A7"-alkyl amino acid esters 81,82 this method is only applicable to amino acid esters and not to the free acids. Thus, TV-Tos amino acid esters are condensed with MeOH, EtOH, or iPrOH in the presence of TPP and DEAD. The Tos group is deprotected by sodium in liquid ammonia or with sodium amalgam. 83 The deprotection of the Tos group has also been achieved electrochemically under mild conditions and in good yields. 84 ... 

Some amino acids have side chains that bear acidic or basic groups. As Table 27.3 indicates, these amino acids are characterized by three pK.d values. The third pKd reflects the nature of the side chain. Acidic amino acids (aspartic and glutamic acid) have acidic side chains basic amino acids (lysine, arginine, and histidine) have basic side chains. 

NMR studies have been carried out on Schiff bases derived from pyridoxal phosphate and amino acids, since they have been proposed as intermediates in many important biological reactions such as transamination, decarboxylation, etc.90 The pK.d values of a series of Schiff bases derived from pyridoxal phosphate and a-amino adds, most of which are fluorinated (Figure 11), have been derived from H and19F titration curves.91 The imine N atom was found to be more basic and more sensitive to the electron-withdrawing effect of fluorine than the pyridine N atom. Pyridoxal and its phosphate derivative are shown in Figure 12a. The Schiff base formation by condensation of both with octopamine (Figure 12b) in water or methanol solution was studied by 13C NMR. The enolimine form is favoured in methanol, while the ketoamine form predominates in water.92... 

Table XIII shows the strengths measured by Hammett indicators with pK.d values ranging from —5.6 to — 14.5. As described above, dried H3PW 204o possesses superacidity (127). The order of the acid strengths agrees with that...

Protonation represents the simplest electrophilic reaction. Contrary to azulene (pKa = — 1.7)237 most pseudoazulene systems are relatively strong bases. The pK.d values are listed in Table V. Numerous pseudoazulenes can be obtained from their quaternary salts by the action of sodium acetate (see... 

If Ke signifies the concentrations of enol and keto tautomers in a carboxylic acid, then pfCE is the difference between the pKa values of the a-protons of the keto tautomer and the hydroxyl group of the enol tautomer. pfCE, however, is also the difference in pfCa values between the a-protons and the proton of the carbonyl group of the carbonyl-protonated acid, that is deemed to be decisive (Gerlt, 1991) for the kinetics of abstraction of a proton, rather than the pfQ value of the substrate in solution. The pki of mandelic acid (15.4) links the pka of the a-proton of the keto tautomer (22.0) with the pK.d value of the enol tautomer (6.6). The pk, value also links the pka value of the a-proton with that of the carbonyl-bound proton of the protonated mandelic acid. If the pka value of the carbonyl-bound proton of the protonated mandelic acid is assumed to be about -8.0 then the pfQ value of the a-proton is about 7.4. This value matches well with the pka -values of Lys and His residues which have been assigned recently in the active center of mandelate race-mase, so electrophilic catalysis alone is able to explain the catalytic power of mandelate racemase. 

The partial and selective functionalization allows the design and synthesis of a large variety of receptors for ions and neutral molecules bearing mixed functionalities. Especially in calix[4]arenes, the significant differences in the pK.d values of the phenolic OH groups allow their stepwise deprotonation and hence their selective functionalization. 

Moving further to the left along the Periodic Table in seeking the central atom of the substituent, i.e. the one by which the substituent is anchored to the heterocyclic nucleus, we expect to find that nucleus overwhelmingly in the pyridine form. Generally this turns out to be true (76AHC(Sl)7i>. Measurements of pK.d values have been made in aqueous solution of model systems such as (234) (233) and (233) (235), from which KT may be... 

The log D value at a single pH is often influenced by ion partitioning, especially at neutral pH where log D may be used in quantitative structure-permeation relationships. Therefore, the lipophilicity profile may be essential to interpreting PK... 

The basicity of the donors, which is proportional to the p/ a values, becomes a measure of the relative donor strength. Thus, diglyme (pK.d 4) is a weak donor, while Bu3PO (pKa 0) is a strong donor. 

A fused benzene ring has little effect on the pKa values in the cases of quinoxaline (ca. 0.6) and cinnoline (2.6). Quinazoline has an apparent pAfa of 3.3 which makes it a much stronger base than pyrimidine, but this is due to covalent hydration of the quinazolinium cation (see Section 3.2.1.6.3) the true anhydrous pK.d for equilibrium between the anhydrous cation and anhydrous neutral species of quinazoline is 1.95 (76AHC(20)128). 

For pyrrole, furan and thiophene the pKd values of their 2,5-di-t-butyl derivatives are - 1.01, — 10.01 and - 10.16, respectively. In each case protonation occurs at position 2. The basestrengthening effect of alkyl substitution is clearly apparent by comparison of pyrrole and its alkyl derivatives, e.g. /V-methylpyrrole has a pKd for a-protonation of — 2.9 and 2,3,4,5-tetramethylpyrrole has a pK.d of +3.7. In general, protonation of a-alkylpyrroles occurs at the a-position whereas [3-alkylpyrroles are protonated at the adjacent a-position. As expected, electron-withdrawing groups are base-weakening thus A-phenylpyrrole is reported to have a pKa of — 5.8. 

When the volume of titrant is Ve, pH = pK.d for the acid HA (neglecting activity coefficients). From an experimental titration curve, you can find the approximate value of pKa by reading the pH when Fb = Ve, where Vh is the volume of added base. (To find the true value of prequires activity coefficients.)... 

This model is wrong for two reasons. Log % absorption values are used instead of rate constants, and differences p fa—pH are used to model the p7+, /p EI dependence of the colonic absorption (valid only if pH < pK ). The correct p/+/pl I correction procedure was applied by Scherrer and Howard [74] (Eq. (39)). They performed a nonlinear transformation of the percentage values (log %ABS) to absorption rate constants (log fcabs) and converted the log P values into log D values (distribution values between -octanol and an aqueous buffer of a certain pH value, nowadays most often called log Papp) by Eqs. (36) and (37) ... 

Fitch, C.A., Karp, D.A., Lee, K.K., Stites, W.E., Lattman, E.E., Garcia-Moreno, E.B. Experimental pK(a) values of buried residues Analysis with continuum methods and role of water penetration. Biophys. J. 2002, 82,3289-304. 

Only those pK values that have not been used to calculate ffji values are acceptable in the set. Sufficient data are extant for two such sets. The data are given in Table 31, the correlations in Table 30 (sets 9,10). The results obtained are highly signiHcant (99.9% CL) and would undoubtedly have given even better results had the data been determined in the same laboratories under exactly the same conditions. It is also encouraging to compare the D values obtained from correlation by Equation 98 with those obtained from correlation with Equation 88... 

In the defining equation for the partition coefficient it was noted that the concentration terms referred to the concentration of the same species. This can have significance for the measurement of log P if some interaction (for example, dimerization) occurs predominantly in one phase, but is probably of most significance if the molecule contains an ionizable group. Since P refers to one species it is necessary to suppress ionization by the use of a suitable pH for the aqueous phase. An alternative is to measure a distribution coefficient, D, which involves the concentrations of both ionized and un-ionized species, and apply a correction factor based on the pK values of the group(s) involved. Yet another alternative is to use log D values themselves as a hydrophobic descriptor, although this may suffer from the disadvantage that it includes electronic information. 

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