PA.a values

The pA"a values of 49 derivatives of pyrazol-3-one were measured by poten-tiometric titration and their H NMR spectra were recorded in DMSO- fe- The experimental acidity order correlates for structurally similar compounds as do substituent constants and HMO electron densities (76JPR555). 

Fig. 3. The ethynyl group pA a values and

In general, the A -methyl derivative of a given compound absorbs at longer wavelengths than the O-methyl derivative. The intensity of a band which appears in aqueous solutions beyond the maximum absorption in alcohol and which is due to the absorption of the betainic species alone, is a measure of the tautomeric equilibrium. The pA"a value of the 2-methyl-hydroxyisoquinolinium chlorides increase in the order 4-hydroxy (4.93), 8-hydroxy (5.81), 6-hydroxy (6.02), 5-hydroxy (6.90), and 7-hydroxy (7.09 in water at 25 °C, respectively) (57JCS5010). Thus, 2-methyl-4-hydroxyisoqui-nolinium chloride is the strongest acid. The UV spectra of 2-methyl-isoquinolinium-5-olate (34) and 2-methyl-isoquinolinium-8-olate (39) were also presented (61BCJ533) and the formation of a quinoid structure of 2-methyl-isoquinolinium-6-olate (38) can also be detected by means of UV-spectroscopy. 

Therefore, the presence of halogens can lower the pA"a value of an alcohol to around 14. In other words, the presence of a halogen will make the compound more acidic. The following two alcohols provide an interesting comparison ... 

The pA a values of two classes of pyridinocrown ethers [9a] and [9b] with ring sizes varying from 15 to 33 ( = 2-8) have been measured in different solvents by Reinhoudt and his co-workers (Grootenhuis et al., 1984, 1986 van Staveren et al., 1988). The data are summarized in Table 6. 

As thermodynamic stability indexes for the hydrocarbon ions, pA R+ and pA a values [(4) and (5)] have been widely applied for the carbocation and carbanion, respectively, in solution. Here K + stands for the equilibrium constant for the reaction (6) of a carbocation and a water molecule stands for the equilibrium constant for the reaction (7) of a hydrocarbon with a water molecule to give the conjugate carbanion. The equilibrium constants are given by (8) and (9) for dilute aqueous solutions. Obviously, the reference system for the pKn+ scale is the corresponding alcohol, and... 

Table Some stable all-hydrocarbon anions derived from hydrocarbon acids with pA a values 7.

In turn, for the phosphonic acid diester 95, stereoselectivity of the native phosphodiesterase was enhanced by over three orders of magnitude by alteration of the pA a values of the leaving group phenol. Eor example, for X = C02Me, Y = H the stereoselectivity was 5000 higher than for X = NO2, Y = 2-F. ... 

The carbamate -NH- moiety present in asulam has acidic properties (e.g. the pA a value for asulam is 4.82). On the other hand, the -NH2 moiety present in sulfanilamide has a slightly alkaline character. Considering these properties, the partition of these analytes into an organic solvent should depend strongly on the pH value in the aqueous phase. 

Numbers used in the cycle AG° for addition of hydroxide to p-nitrophenyl sulfate, see above AG° for proton transfer from p-nitrophenyl sulfate to hydroxide, based on pA a values AG° for ionization of the monoanionic adduct of p-nitrophenyl sulfate, estimated by the method of Branch and Calvin, supplemented by the difference in pATa between sulfuric acid and p-nitrophenyl sulfate.)... 

This method estimates pA a values for oxygen acids from that of the reference molecule water (corrected for the number of acidic hydrogens) using terms... 

The Bronsted plots shown in Figs 4 and 5 assist in visualizing the data of the metal-catalyzed reactions which show definite evidence of a break where the rate constants are quite sensitive to phenols or alcohols with high (pA a values, but almost no sensitivity to the nature of the ROH groups with low (pA a values. In these cases there is no obvious discrepancy between aliphatic and aryl esters, so all... 

The pA a-values quoted for nucleophilic, basic or acidic groups are generally those measured in the course of the work cited, but values have been estimated in a few instances or taken from tables. A small error in pKt affects the calculated EM relatively little in most cases. 

Except where a more specific reference is given, pA a values quoted explicitly, or quoted implicitly through correlations, in this chapter have been taken from the following compilations ... 

FIGURE 4. (Top) plot of log k for the reactions of primary and secondary amine nucleophiles with picryl chloride against their pK3 values in aqueous solution at 25 °C. (Bottom) plot of log k for the reactions of a series of substituted quinuclidine ions with picryl chloride against the pA a values of the nucleophiles. In aqueous solution at 25 °C77. Reprinted with permission from Reference 77. Copyright (1992) American Chemical Society... 

Smdies of the thermal degradation of several aromatic acids have been reported. Phthalic acid (80), but not isophthalic acid (81) or terephthalic acid (82), decomposes via dehydration to its anhydride at 140-160 °C. However, (81) and (82) and benzoic acid are thermally stable below 200 °C. Dissociation constants of all 19 isomers of methyl-substimted benzoic acids (83) have been measured in methanol and DMSO. From the pA a values, the substiment effects of the methyl groups were calculated and tentatively divided into polar and steric effects. Also, in the case... 

The kinetics of the alkaline hydrolysis of 5-ethyl-l-methyl-5-phenyl-2-thioxo-4,6-(7//,5//,5//)-pyrimidinedione (2-thioprominal) (370) have been reported. Hammett plots of pA a values were linear for a series of Al-2f-benzoyl N, Ai -diethylthioureas (371). 3... 

It is perhaps worth mentioning that substitution of other groups for the C-methyl group in amidinium ions has an effect on their pA a-values, which is best correlated with Hammett s -constants (p = —1T98), and the same is true of C-substituted N-phenylami-dinium ions (p = —12-08) (Charton, 1965). This is in line with the suggestion made on page 286, that -constants are a measure of the inductive and mesomeric interactions of groups with a carbon in the sp state of hybridization. 

The range of pA a values that can be measured in water is determined by the ionization of water itself, i.e. —1.74 (the pA a of H3O+) to 15.74 (the pATa of H2O) see Box 4.1. Acids that are stronger than H3O+ simply protonate water, whereas bases that are stronger than HO remove protons from water. 

Finally, the zwitterion is not the major form for all amino acids. For both o-aminobenzoic acid (anthrani-lic acid) and p-aminobenzoic acid, the uncharged species is the more prevalent form whereas the zwitterion/uncharged ratio for m-aminobenzoic acid is about 2.31. This behavior arises primarily from the low pK values for the aromatic ring s amino group e.g., the pi i and pKi values for anthranUic acid are 2.05 and 4.95 and the pA"a value for the ester is only 2.09). 

Tr a composite delocalized electrical-effect parameter of the ctd type with rj equal to —2.98. It is derived from pA a values of substituted nitriles. 

It is accepted that the acmal nucleophile in the reactions of oximes with OPs is the oximate anion, Pyr+-CH=N-0 , and the availability of the unshared electrons on the a-N neighboring atom enhances reactions that involve nucleophilic displacements at tetravalent OP compounds (known also as the a-effect). In view of the fact that the concentration of the oximate ion depends on the oxime s pATa and on the reaction pH, and since the pKs also reflects the affinity of the oximate ion for the electrophile, such as tetra valent OP, the theoretical relationship between the pATa and the nucleophilicity parameter was analyzed by Wilson and Froede . They proposed that for each type of OP, at a given pH, there is an optimum pK value of an oxime nucleophile that will provide a maximal reaction rate. The dissociation constants of potent reactivators, such as 38-43 (with pA a values of 7.0-8.5), are close to this optimum pK, and can be calculated, at pH = 7.4, from pKg = — log[l//3 — 1] -h 7.4, where is the OP electrophile susceptibility factor, known as the Brpnsted coefficient. If the above relationship holds also for the reactivation kinetics of the tetravalent OP-AChE conjugate (see equation 20), it would be important to estimate the magnitude of the effect of changes in oxime pX a on the rate of reactivation, and to address two questions (a) How do changes in the dissociation constants of oximes affect the rate of reactivation (b) What is the impact of the /3 value, that ranges from 0.1 to 0.9 for the various OPs, on the relationship between the pKg, and the rate of reactivation To this end, Table 3 summarizes some theoretical calculations for the pK. ... 

What are the pA a value(s), partition coefficients, solubilities and stability of a drug substance under development ... 

Some weak acids and bases have more than one buffer range, for example phosphoric acid has three ionisable protons with three different pA"a values and can be used to prepare buffers to cover three different pH ranges. The ionic species involved in the ranges covered by phosphate buffer are ... 

---