Acidity constants pyridine derivatives

Tam, K. Y. Hadley, M. Patterson, W., Multiwavelength spectrophotometric determination of acid dissociation constants. Part IV. Water-insoluble pyridine derivatives, Talanta 49, 539-546 (1999). 

We can now make sensible guesses as to the order of rate constant for water replacement from coordination complexes of the metals tabulated. (With the formation of fused rings these relationships may no longer apply. Consider, for example, the slow reactions of metal ions with porphyrine derivatives (20) or with tetrasulfonated phthalocyanine, where the rate determining step in the incorporation of metal ion is the dissociation of the pyrrole N-H bond (164).) The reason for many earlier (mostly qualitative) observations on the behavior of complex ions can now be understood. The relative reaction rates of cations with the anion of thenoyltrifluoroacetone (113) and metal-aqua water exchange data from NMR studies (69) are much as expected. The rapid exchange of CN " with Hg(CN)4 2 or Zn(CN)4-2 or the very slow Hg(CN)+, Hg+2 isotopic exchange can be understood, when the dissociative rate constants are estimated. Reactions of the type M+a + L b = ML+(a "b) can be justifiably assumed rapid in the proposed mechanisms for the redox reactions of iron(III) with iodide (47) or thiosulfate (93) ions or when copper(II) reacts with cyanide ions (9). Finally relations between kinetic and thermodynamic parameters are shown by a variety of complex ions since the dissociation rate constant dominates the thermodynamic stability constant of the complex (127). A recently observed linear relation between the rate constant for dissociation of nickel complexes with a variety of pyridine bases and the acidity constant of the base arises from the constancy of the formation rate constant for these complexes (87). 

A simple case where the general a constants in Table 8.5 do not succeed in correlating acidity constants is when the acid or base function is in direct resonance with the substituent. This may occur in cases such as substituted phenols, anilines, and pyridines. For example, owing to resonance (see Fig. 8.4), a para nitro group decreases the pKa of phenol much more than would be predicted from the o para constant obtained from the dissociation of p-nitrobenzoic acid. In such resonance cases (another example would be the anilines), a special set of o values (denoted as oJpara) has been derived (Table 8.5) to try to account for both inductive and resonance... 

The apparent acid dissociation constants (p s)Ka) of two water-insoluble drugs, ibuprofen and quinine, were determined pH-metrically in ACN water, dimethyl-formamide water, DMSO water, 1,4-dioxane-water, ethanol water, ethylene glycol-water, methanol water, and tetrahydrofuran water mixtures. A glass electrode calibration procedure based on a four-parameter equation (pH = alpha-i- SpcH -i-jH[H+] -i-jOH[OH ]) was used to obtain pH readings based on the concentration scale (pcH). We have called this four-parameter method the Four-Plus technique. The Yasuda Shedlovsky extrapolation p s)K a + log [H2O] = A/epsllon -1- B) was used to derive acid dissociation constants in aqueous solution (pKa). It has been demonstrated that the pK a values extrapolated from such solvent-water mixtures are consistent with each other and with previously reported measurements. The suggested method has also been applied with success to determine the pKa values of two pyridine derivatives of pharmaceutical Interest. Spectrometric, ultraviolet (UV) ... 

Flexer, Hammett and Dingwall have determined the dissociation constants of several weak acids and bases by this method. Brown and co-workers have used a similar procedure for the determination of base strengths of pyridine derivatives. 

Reactives of Side-Chains of Monocyclic Thiophens. - The rate constants for the esterification of some 3-, 4-, and 5-substituted thiophen-2-carboxylic acids and of some 2- and 4-substituted thiophen-3-carboxylic acids with diazodiphenylmethane in methanol solution have been measured, and linear correlations gave information about the transmission of substituent effects. The rates of alkaline hydrolysis of ethyl thiophen-2-carboxylate in ethanol-water and DMSO-water media have been measured and compared with those of other heterocyclic esters. The kinetics of iodination of 2-acetylthiophen in methanol-water, using different carboxylate buffers, have been studied.Basicity constants have been measured for j3-(2-thienyl)-acrylamides and compared with those of the corresponding benzene and furan derivatives. The acidity constants of ( )-a-phenyl-j3-(2-thienyl)-acrylic acids and analogous furan-, selenophen-, and pyridine-substituted compounds have been measured, and have been rationalized by an equation involving separate contributions of polar, conjugative, and steric effects of the heterocycles. ... 

If the pH and the concentrations of HA (acid form) and A" (basic form) are known, pA o can be easily calculated. The ratio of [HA] to [A ] may be found spectrophoto-metrically if eha and ea- are known. These latter values can be determined after converting completely to A" or HA by adding excess acid or base. As an example, the dissociation constants of several weak acids and bases have been determined photometrically [18] the base strengths of pyridine derivatives have been determined using a similar procedure [19]. 

The protonation of polysubstituted pyridines (from di- to penta-) was also investigated for halogen (Cl or Br) derivatives (2007JMGM(26)740). The obtained acidity constants (plexperimental values. Additionally, the experimental pX values... 

Values of A5, AfT and A5° are given and a value of less than unity for the gradient of the free energy relationship [log(rate constant) as ordinate versus log(equilibrium constant)] implies an mechanism. The planar complexes [NiX2L2] (X = Cl, Br, I, or NCS L = pyridine derivative with methyl groups in the 2-and 6-position) are uniquely inert to substitution and are not even attacked by strong mineral acids.This lack of reactivity is attributed to steric hindrance. 

Solvation of Pb(CH3)4 in solution increases along the series of solvents cyclohexane < 1,2-dimethoxyethane dioxane = hexamethylphosphoric acid triamide < pyridine < tetrahydrothiophene < triethylamine < tetrahydrofuran < triethylphosphane < N,N,N, N -tetramethylethylenediamine = acetone < dimethylformamide < dimethyl sulfoxide as derived from the increase of the NMR coupling constants J( H, Pb). Coordination of only one solvent molecule and trigonal bipyramidal geometry of the complexes was supposed [8]. For studies of the dispersion interaction of Pb(CH3)4 and various solvents, see [9, 28]. For a correlation of the ionization potential and the solvation energy of Pb(CH3)4 and other tetraorganometal compounds in acetonitrile, see [36]. 

In a study designed to investigate the effect of the presence on a ligand of one or more protons on the mechanism of complex formation with nickel(n), Wilkins and co-workers have published a list of 13 rate constants for derivatives of imidazole, 2,2 -bipyridine, and 1,10-phenanthroline and for cysteine, penicillamine, chelidamic acids, and pyridine-2-aldoxime. As expected, if the proton is far removed from potential reaction sites it has little effect but if it blocks a binding position, as in bipyH+ and particularly phenH+, it has a much lar r effect on kt. Frequently, however, the effect of the proton appears to be merely to reduce Kos (and therefore kt) by increasing the positive charge on the ligand (cf Table 8). 

Table 3 Negative logarithms of the acidity constants (eq. 3) of some monoprotonated purine nucleobase (NB) derivatives and logarithms of the stability constants (eq. 2) of the corresponding Cd(NB) and Cd(NB - H) complexes as determined by potentiometric pH titration in aqueous solution at 25°C and / = 0.5 M (entries 1 - 7) or 0.1 M (entries 8 - 10) (NaNOs), together with data for 1-methylimidazole (IMIm) or pyridine (Py) derivatives (see Figure 5) .

The methods outlined, of course, are readily applicable to a wide variety of substituted heterocycles like the carboxyl, hydroxy and mercapto derivatives of pyridines, pyridine 1-oxides, pyrroles, etc. The application to amines and to diaza compounds such as pyrimidine, where the two centers are basic, is obvious except that now 23 takes the role of the neutral compound, 21 and 22 the roles of the tautomeric first conjugate bases, and 20 the role of the second conjugate base. Extensions to molecules with more than two acidic or basic centers, such as aminonicotinic acid, pyrimidinecarboxylic acids, etc., are obvious although they tend to become algebraically cumbersome, involving (for three centers) three measurable Kg s, four Ay s, and fifteen ideal dissociation constants (A ), a total of twenty-two constants of which seven are independent. 

Compared with esters, acid halides and anhydrides are more reactive and are hydrolyzed more readily. It is interesting to note that there is a substantial lifetime for these acid derivatives in aqueous media. Acid halides dissolved in PhCl or in PhBr shaken at a constant rate with water shows that hydrolysis occurs at the boundary between the two liquid phases.35 The reaction of benzoyl chloride (PhCOCl) and benzoate ion with pyridine A-oxide (PNO) as the inverse phase-transfer catalyst yields both the substitution product (benzoic anhydride) and the... 

The DSP approach nicely answers the controversial question about which substituent parameters should be employed to correlate pKa data for 4-substituted pyridinium ions. Statistically, the best correlation is given by Eq. (9), which has values to measure the resonance contribution of a substituent, a result in keeping with chemical intuition. This correlation is statistically superior to a Hammett treatment, where both resonance and inductive effects of a group are combined into a single parameter, p or ap.53,54 Moreover, now it is possible to rationalize why a simple Hammett treatment using ap works so well. Equation (9) reveals that the protonation equilibrium is much more sensitive to an inductive effect (p, — 5.15) than to a resonance effect (p = 2.69). Hence, substituent parameters, such as erp, which are derived from a consideration of the dissociation constants for benzoic acids where resonance contributions are small serve as a useful approximation. The inductive effect is said to have a larger influence on pKa values for pyridinium ions than for benzoic acids because the distance between the substituent and the reactive site is shorter in the pyridine series.53... 

The effective correlation times for an approximately isotropic motion, tr, ranged from 40.3 ps in methanol to 100.7 ps in acetic acid for 5a, and from 61.6 ps to 180.1 ps for 5b in the same solvents. Neither solvent viscosity nor dielectric constant bore any direct relationship to the correlation times found from the overall motion, and attempts to correlate relaxation data with parameters (other than dielectric constant) that reflect solvent polarity, such as Kosover Z-values, Win-stein y-values, and the like, were unsuccessful.90 Based on the maximum allowed error of 13% in the tr values derived from the propagation of the experimental error in the measured T, values, the rate of the overall motion for either 5a or 5b in these solvents followed the order methanol N,N-dimethylformamide d2o < pyridine < dimethyl sulfoxide. This sequence appears to reflect both the solvent viscosity and the molecular weight of the solvated species. On this basis, and assuming that each hydroxyl group is hydrogen-bonded to two molecules of the solvent,137 the molecular weights of the solvated species are as follows in methanol 256, N,N-dimethylformamide 364, water 144, pyridine 496, and dimethyl sulfoxide 312. 

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