Acids/bases, pKa

Salicylate anion (weakest base pKa of conjugate acid, 3)... 

Experimental pKa data suggests that simple alkyl groups all affeet acid-base reactivity in roughly the same way. What is more, this universal alkyl effect is roughly equivalent to the effect of a hydrogen atom. For example, the difference in pKa between water and ethanol is approximately the same as that between formic acid and propanoic acid (see table at right). 

Predicting Acid-Base Reactions from pKa Values 53... 

Where do hydrocarbons lie on the acidity scale As the data in Table 8.1 show, both methane (pKa 60) and ethylene (plC, = 44) are very weak acids and thus do not react with any of the common bases. Acetylene, however, has piCa = 25 and can be deprotonated by the conjugate base of any acid whose pKa is greater than 25. Amide ion (NH2-), for example, the conjugate base of ammonia (pKa - 35), is often used to aeprotonate terminal aikynes. 

In the first instance, acidity influences the acid-base equilibria of the reactants. The amine is a Bronsted base. Aniline, a typical substrate, has pKa = 4.6, which means that the protonation shown in Scheme 3-11 is almost complete under normal conditions of diazotization (pH < 1). The base is definitely a much better reagent than the anilinium ion for nitrosation because the latter is an electrophilic substitution. One expects — simply on the basis of the equilibrium shown in Scheme 3-11 — that the rate of diazotization should decrease linearly with increasing acid concentration or, at higher acidities, with the Hammett acidity function h0 (for acidity functions see Rochester, 1970 Cox and Yates, 1983). 

Aminopyridines, aminopyridine oxides, and 3-aminoquinoline are obviously diazotized by analogous mechanisms. Kalatzis (1967 b) studied the diazotization of 4-aminopyridine over a very large range of acid concentrations (0.0025-5.0 m HC104). This compound is comparable to 2-aminothiazole in its acid-base properties the heterocyclic nitrogen is easily protonated at pH 10, whereas the amino group is a very weak base (pKa = -6.5). Therefore, the kinetics indicate that the (mono-protonated) 4-aminopyridinium ion reacts with the nitrosyl ion. The... 

FIGURE 10.17 As shown here for five conjugate acid-base pairs, the sum of the pKa of an acid (pink) and the p/Ch of its conjugate base (blue) is constant and equal to pKw, which is 14.00 at 25°C. 

The effect of temperature on acid or base pKa values cannot be reliably predicted [2, 17, 23]. For many nitrogenous bases, the pKa decreases by 0.1-0.3 for every 10 °C rise in temperature. For some carboxylic acids (e.g. acetic, benzoic, salicylic acids), the pKj remains essentially unchanged between 25 and 37°C. 

It follows that at half-neutralization pH - pKa, while at A = 1/11 the pH = pjFira - land at A = 10/11 the pH = pKa + 1 in fact this means that the whole titration takes place within 2 pH units, which agrees with the maximum pH range of acid-base colour indicators. 

This equation corresponds to today s general convention of expressing base strength also be means of pKa, where K is considered in the sense of the Bronsted acid-base theory as a protolysis constant of the following protolytic reactions for acids ... 

The above-mentioned results indicate the additive effect of protons. Actually, a catalytic process is formed by protonation of the metal-oxygen bond instead of silylation. 2,6-Lutidine hydrochloride or 2,4,6-collidine hydrochloride serves as a proton source in the Cp2TiCl2-catalyzed pinacol coupling of aromatic aldehydes in the presence of Mn as the stoichiometric reduc-tant [30]. Considering the pKa values, pyridinium hydrochlorides are likely to be an appropriate proton source. Protonation of the titanium-bound oxygen atom permits regeneration of the active catalyst. High diastereoselectivity is attained by this fast protonation. Furthermore, pyridine derivatives can be recovered simply by acid-base extraction or distillation. 

The pKa of a molecule, a charge-state-related parameter, is a descriptor of an acid-base equilibrium reaction [34,35]. Lipophilicity, often represented by the octanol-water partition coefficient Kp is a descriptor of a two-phase distribution equilibrium reaction [36]. So is solubility [37-39]. These three parameters are thermodynamic constants. On the other hand, permeability Pe is a rate coefficient, a kinetics parameter, most often posed in a first-order distribution reaction [40-42]. 

Figure 2.2 Log flux-pH profiles at dosing concentrations (a) ketoprofen (acid, pKa 3.98), dose 75 mg (b) verapamil (base, pKa 9.07), dose 180 mg (c) piroxicam (ampholyte, pKa 5.07, 2.33), dose 20 mg. The permeability and the concentration of the uncharged species are denoted Po and Co, respectively. [Avdeef, A., Curr. Topics Med. Chem., 1, 277-351 (2001). Reproduced with permission from Bentham Science Publishers, Ltd.]...

The preceding section can be further generalized, to properly account for absorption of nonionized molecules. The selection of the maximum Pe for HIA prediction implicitly recognized that only a fraction of the small intestine is available for the maximum absorption of acids (with pKa near 4) and bases (with pKa near 9). But when this approach is applied to nonionizable molecules, then the absorption may be underestimated, since absorption should be uniform across the whole intestinal tract. The remedy is to sum the two Pe values. This is roughly equivalent to... 

In an early work by Mertz and Pettitt, an open system was devised, in which an extended variable, representing the extent of protonation, was used to couple the system to a chemical potential reservoir [67], This method was demonstrated in the simulation of the acid-base reaction of acetic acid with water [67], Recently, PHMD methods based on continuous protonation states have been developed, in which a set of continuous titration coordinates, A, bound between 0 and 1, is propagated simultaneously with the conformational degrees of freedom in explicit or continuum solvent MD simulations. In the acidostat method developed by Borjesson and Hiinenberger for explicit solvent simulations [13], A. is relaxed towards the equilibrium value via a first-order coupling scheme in analogy to Berendsen s thermostat [10]. However, the theoretical basis for the equilibrium condition used in the derivation seems unclear [3], A test using the pKa calculation for several small amines did not yield HH titration behavior [13],... 

The carboxyl functions in the new structures are buried within the clefts in a manner that discourages the formation of the intermolecular hydrogen bonded dimers which are usually observed in the solution and solid phases. Unusual acid-base behavior is one consequence. In the smallest system 11 (represented by the benzene spacer) a tremendous difference in pKa s (6 units) can be observed for the two ionizations 14). 

General acid/base catalysis is less significant in natural fresh waters, although probably of some importance in special situations. This phenomenon can be described fairly well via the Bronsted law (relating rate constants to pKa and/or pKb of general acids and bases). Maximum rates of general acid/base catalysis can be deduced from a compound s specific acid/base hydrolysis behavior, and actual rates can be determined from relatively simple laboratory experiments (34). 

Equations have been published [16] which relate pKa and p0Ka values to partition coefficient (P) values for monoprotic acids and bases, and diprotic acids, bases and ampholytes. For example, P1 for a monoprotic acid is calculated from... 

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