Equilibrium Constants for Pseudobase Formation

For the equilibrium between the quaternary heterocyclic cation (Q+) and the corresponding pseudobase (QOH), 

KR4 is related to the association constant K of Eq. (1) through the ionic product of water Kw by K = KR+/KW. Although the symbol KROH has occasionally been used instead of Kku the latter is preferable since it stresses the similarity of the heterocyclic cation-pseudobase equilibrium and the carbonium ion-carbinol equilibrium for which KR+ was originally introduced by Deno et al,71 

Equation (2) stresses the acid-base nature of the cation-pseudobase equilibrium and the pK + value, which is analogous to the pKa value for a Br nsted acid, denotes the pH at which the heterocyclic cation and pseudobase are present at equal concentrations. Experimental techniques for the spectrophotometric or potentiometric determination of pK values for pseudobase formation are identical to the methods for determination of pKa values for Br nsted acids.72 

In Tables 126,37- 1,43,46,56,73-115 and n 57.90.9.4,..6-.34 pKr+ values currently available for heterocyclic cations are listed in order of increasing complexity of the heterocyclic system. Aromatic and nonaromatic heterocyclic cations are considered separately in Tables I and II, respectively. Only data for strictly aqueous solutions or for aqueous solvents containing small proportions of nonnucleophilic organic solvents are included in Tables I and II. A number of data reported for aqueous alcoholic solutions are discussed separately in Section VI,A. Equilibrium constants in such media can only be considered as apparent constants since no allowance is made for the existence of the pseudobases in these solutions as mixtures of the corresponding hydroxide and alkoxide adducts. The presence of an organic solvent is sometimes necessary to promote sufficiently the solubility of the pseudobase for pXR+ determination. In such cases, interpretation of data relative to strictly aqueous solutions is more straightforward if nonnucleophilic cosolvents such as acetonitrile and dioxane, are chosen in preference to alcohols. 

The temperature dependence of pKR + has been reported92 for three heteroaromatic cations over the range 15°-55°. The use of pKR to assess 

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It should be noted that, in principle, correlation equations such as (3)-(7) for the influence of N-substituents on the equilibrium constants for pseudobase formation should allow the estimation of the extent of covalent hydration of the parent nitrogen heterocycle in aqueous solution. Thus using a = 0.49 for H and the appropriate correlation equation, pKR+ for pseudobase formation from the N-protonated parent heterocycle can be estimated. 

The fluorescence spectra of chelerythrine, nitidine, and sanguinarine in different solvents have been shown to be dependent on the pH of the solution and to allow the determination of the equilibrium constant for the formation of the pseudobases.531 A salt of chelidonine with 5-carboxymethyl-2-thio-l,3-thiazan-4-one has been prepared.532 The intercalative binding of sanguinarine533 and the anti-tumour activities of chelidonine JV-oxide534 and of nitidine535 have been studied. 

While quantitative measurements of pseudobase formation in aqueous alcoholic solutions may be used as indications of the relative susceptibilities to nucleophilic attack for closely related cations,9,53,75,218 such data are not directly comparable with equilibrium and rate data for pseudobase formation in either water or the pure alcohol (or even with data in aqueous alcoholic solutions of other compositions). Several workers218,257,261,262 have reported rate constants for hydroxide ion attack on heterocyclic cations in aqueous alcoholic solutions without any apparent attempt to consider the complications that arise in such media as a result of the competition between hydroxide and alkoxide ions as nucleophiles. The only attempt to measure the relative reactivities of hydroxide and alkoxide ions toward a heterocyclic cation appears to be the work of Gravitz and Jencks306 for the IV,0-trimethylenephthalimidium cation (158). In this study, product analysis indicated the relative proportions of hydroxide and alkoxide adduct... 

Beranek et ai.314 report a 600-fold enhancement in equilibrium constant for methoxide addition to pyridinium cations in 1 1 dimethyl sulfoxide-methanol relative to methanol. These workers have also measured the rates of dissociation of the methoxide adducts of N-phenylpyridinium cations (163) in dimethyl sulfoxide-methanol mixtures and have used the observation that the relative rates of dissociation appear to be independent of dimethyl sulfoxide content of the solvent to extrapolate these data to pure methanol. The rates of dissociation for all substituents other than X = 3-N02 or 4-NOz are too rapid in 100% methanol to allow direct determination by stopped-flow spectrophotometry. The presence of dimethyl sulfoxide shifts the equilibrium toward the adduct both by enhancing the rate of methoxide addition and by decreasing the rate of adduct dissociation. These solvent effects on pseudobase formation are similar to those observed... 

It is unfortunate that there has been so little work devoted to quantitative measurements of cation-pseudobase equilibria in methanol and ethanol since these media have several advantages over water for the determination of the relative susceptibilities of heterocyclic cations to pseudobase formation. The enhanced stability of the pseudobase relative to the cation in alcohols compared to water is discussed earlier this phenomenon will permit the quantitative measurement of pseudobase formation in methanol (and especially ethanol) for many heterocyclic cations for which the equilibrium lies too far in favor of the cation in aqueous solution to allow a direct measurement of the equilibrium constant. Furthermore, the deprotonation of hydroxide pseudobases (Section V,B) and the occurrence of subsequent irreversible reactions (Sections V,C and D), which complicate measurements for pKR+ > 14 in aqueous solutions, are not problems in alcohol solutions. Data are now available for the preparation of buffer solutions in methanol over a wide range of acidities.309-312 An appropriate basicity function scale will be required for more basic solutions. The series of -(substituted phenyl)pyridinium cations (163) studied by Kavalek et al.i2 should be suitable for use as indicators in at least some of the basic region. The Hm and Jm basicity functions313 should not be assumed90 to apply to methoxide ion addition to heterocyclic cations because of the differently charged species involved in the indicators used to construct these scales. 

Equilibrium constants have been measured for the formation of the pseudobase 14 from the 1-methylquinoxalinium cation 13. The pseudobase is in equilibrium with a considerable amount of the covalent hydrate 15 formed by addition of water across the C-3, N-4bond. ... 

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