Bases, pKa

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

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... 

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. 

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.]...

Another advantage of PB based pKa calculations is that effects of electrolytes are readily accounted for in the PB equation. The Coulombic contribution in conjunction with salt dependence to the abnormally depressed pAVs of histidine in staphylococcal nuclease has been experimentally tested [56], Recently, the methodology used in the PB calculations (Eqs. 10-11 and 10-12) has been combined with the generalized Born (GB) implicit solvent model [94] to offer pKa predictions at a reduced computational cost [52],... 

Several remedies have been suggested for improving the PB based pKa prediction methods. Most of them are based on strategies that combine conformational flexibility with the PB calculation. You and Bashford included multiple conformers by systematically scanning the side chain torsion angles [107], Alexov and Gunner used Monte-Carlo protocol to sample positions of hydroxyl and other polar protons [1], This method, referred to as the multi-conformation continuum electrostatic (MCCE), was later extended to include rotamers for residues that have strong electrostatic... 

The exact reverse of the above is seen with aniline (13), which is a very weak base (pKa = 4-62) compared with ammonia (pKa = 9-25) or cyclohexylamine (pKa = 10-68). In aniline the nitrogen atom is again bonded to an sp2 hybridised carbon atom but, more significantly, the unshared electron pair on nitrogen can interact with the delocalised 7r orbitals of the nucleus ... 

The aniline molecule is thus stabilised with respect to the anilinium cation, and it is therefore energetically unprofitable for aniline to take up a proton it thus functions as a base with the utmost reluctance (p Ka = 4 62, compared with cyclohexylamine, pKa = 10-68).Thebase-weakening effect is naturally more pronounced when further phenyl groups are introduced on the nitrogen atom thus diphenylamine, Ph2NH, is an extremely weak base (pKa = 0-8), while triphenylamine, Ph3N, is by ordinary standards not basic at all. 

Complexes between amines and phenols in apolar solvents56 were extensively investigated by several techniques. The equilibrium between molecular complexes and ions was recently investigated57 by 1H NMR techniques for the complexes between phenols and /V./V-dirncthylaniline. The constant of the proton transfer equilibrium (K of equilibrium 7) increases on increasing ApKa (= pKa of protonated base —pKa of phenol) in water, and when the solutions are cooled. 

Acting as a base pKa of H3O+ Here, we need to consider the pK for ionization of the conjugate acid ... 

This is a lipophilic weak base (pKa 4), which crosses cell membranes easily at physiological pH. It is a prodrug, which at the acidic intracellular pH in the gastric parietal cell converts to the active sulfenamide form, which is lipophobic and so is trapped and preferentially concentrated in the parietal cells. Omeprazole is highly protein-bound. Hepatic metabolism is rapid, with a plasma half-life of 0.5-1.5 h, but because of covalent binding to the H-1-/K-1- ATPase enzyme, the duration of action exceeds 24 h. 

Total Fluid Blood Concentration Ratios for Pyrimethamine (base, pKa 7.0)1... 

The proton pump inhibitors are lipophilic weak bases (pKa 4-5) and after intestinal absorption diffuse readily across lipid membranes into acidified compartments (eg, the parietal cell canaliculus). The prodrug rapidly becomes protonated within the canaliculus and is concentrated more than 1000-fold by Henderson-Hasselbalch trapping (see Chapter 1). There, it rapidly undergoes a molecular conversion to the active form, a reactive thiophilic sulfenamide cation, which forms a covalent disulfide bond with the H +, K+ ATPase, irreversibly inactivating the enzyme. 

Acid Buffering base PKa Acid Buffering base PKa... 

Notes A very strong base (pKa = 21.1) with poor nucleophilicity due to steric effects. This makes it a useful organic base for reactions sensitive to most other Lewis bases. 

Isoxazolidines display the properties consistent with their cyclic hydroxylamine structure. Thus, isoxazolidines behave as nucleophiles and thus can be alkylated or acylated. Isoxazolidines are also strong bases (pKa 5.05), and undergo reactions such as quatemization, hydrogenolysis, oxidation, thermolysis, photolysis, decomposition by bases, etc. (84CHEC(6)i, 9iHC(49)i). 

The imidazole ring is present in a number of biologically important molecules as exemplified by the amino acid histidine. It can serve as a general base (pKa = 7.1) or a ligand for various metals (e.g., Zn, etc.) in biological systems. Furthermore, the chemistry of imidazole is prevalent in protein and DNA biomolecules in the form of histidine or adenine/guanine, respectively. 

To circumvent problems of nucleophilicity, lithium diisopropylamide (LDA), potassium hexamethyldisilylamide (KHMDS), and KH are often employed for proton removal since they are very strong bases (pKa > 35) but relatively poor nucleophiles. Hence they remove protons from acidic C-H bonds but normally do not attack carbonyl groups or other electrophilic centers. 

Sakmar, T. P., Franke, R. R., and Khorana, H. G. (1991). The role of the retinylidene schiff base counterion in rhodopsin in determining wavelength absorbance and schiff base pKa. Proc. Natl. Acad. Sci. USA 88, 3079-3083. 

At this point, we had to conclude that the wrong slope must have a mysterious reason outside our calculation methods, either in the experimental pKa scale or in the theoretical interpretation of pKa, although both alternatives seem equally strange and unlikely. Nevertheless, from a practical point of view, Eq. (10.3) is the most widely applicable and most accurate quantum chemically based pKa equation presently available, and it may be of great practical value in predicting the dissociation constants of... 

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