Covalent hydration equilibria

An understanding of covalent hydration is essential for all who work with heteroaromatic compounds containing doubly bonded nitrogen atoms. As chemists become more aware of the circumstances in which hydration occurs, and the means for detecting it, many new examples will probably be discovered and many puzzling discrepancies solved. Many of the values for ionization constants and ultraviolet spectra which are in the literature refer to partly hydrated equilibrium mixtures and should be replaced by values for the pure substances. 

Some of the scatter within the groups is undoubtedly due to differences in bond order and also to whether or not the nitrogens are located in the same ring. Nevertheless, some striking exceptions are apparent in which the pA values are much higher than expected. These include quinazoline, 1,3,5-, 1,3,7-, 1,3,8-, and 1,4,6-triazanaph-thalene, pteridine, and 1,4,5,8-tetraazanaphthalene. In all these cases, covalent hydration of the cation has been shown to occur, so the measured pA values are, in fact, equilibrium values involving both hydrated and anhydrous species. The hydrated species are, without... 

For an organic base, X, which can undergo covalent hydration, the corresponding equilibrium constants are... 

Very few values are known for anhydrous organic bases which can undergo covalent hydration, so that, in general, and for such systems cannot be calculated using Eqs. (12) and (13). However, in cases where the pA of the hydrated species can be measured, Eq. (14) can be used to obtain an approximate estimate of K, the equilibrium ratio of hydrated to anhydrous neutral molecules. This treatment has been applied to quinazoline, the nitroquinazolines, and some triazanaphthalenes. 

Tables V and VI contain all the equilibrium constants so far reported for nitrogen-containing heterocycles that undergo reversible covalent hydration. Table V comprises equilibria involving hydration in cations and neutral molecules, and Table VI deals with systems of neutral molecules and anions.

Dihydroxypteridine was expected to undergo hydration but, a priori, it was difficult to decide whether covalent hydration would occur across the 3,4- or the 7,8-position, or both. Kinetic and spectroscopic evidence now indicate that addition of water occurs much more rapidly across the 3,4-positions (and, hence, that the energy of activation must be less for this site), but the 7,8-water-adduct is thermodynamically the more stable. With time, the concentration of the species hydrated in the 3,4-position reaches a maximum (about 64% of the total concentration). Thereafter, it falls steadily and the concentration of the 7,8-adduct rises until, at equilibrium, the latter accounts for 92% of the total and the 3,4-adduct for only 7.6%. In 2,6-dihydroxy-4-methylpteridine, the methyl group drastically reduces the extent of water addition to the 3,4-position but does not significantly affect 7,8-addition, so that, spectroscopically, only a first-order conversion of anhydrous molecule into the 7,8-water-adduct is observed. ... 

The rate-acidity profile for pyrimidin-2-one indicated reaction on the free base but since the derived second-order rate coefficient is 104 times greater than that for 2-pyridone, and the acidity dependence in the H0 region was also greater, the slope of log kt versus —H0 plot being 0.45, cf. 0.15 for 2-pyridone reaction was, therefore, postulated as occurring via a covalent hydrate, hydration taking place at the 4 position. Methyl substitution increased the rate as expected and N-methyl substitution produced a larger effect than 4,6-dimethyl substitution and this may be due to alteration of the amount of covalent hydration at equilibrium. The data... 

Rate and equilibrium constant data, including substituent and isotope effects, for the reaction of [Pt(bpy)2]2+ with hydroxide, are all consistent with, and interpreted in terms of, reversible addition of the hydroxide to the coordinated 2,2 -bipyridyl (397). Equilibrium constants for addition of hydroxide to a series of platinum(II)-diimine cations [Pt(diimine)2]2+, the diimines being 2,2 -bipyridyl, 2,2 -bipyrazine, 3,3 -bipyridazine, and 2,2 -bipyrimidine, suggest that hydroxide adds at the 6 position of the coordinated ligand (398). Support for this covalent hydration mechanism for hydroxide attack at coordinated diimines comes from crystal structure determinations of binuclear mixed valence copper(I)/copper(II) complexes of 2-hydroxylated 1,10-phenanthroline and 2,2 -bipyridyl (399). 

For the 3-pyridyl derivative 62 (R = 3-Py), it was demonstrated [83ACS(B)617] that the open-chain tautomer 62A or its form protonated on the pyridine nitrogen predominates at high and low solution pH, whereas the equilibrium concentration of the pyrrolinium ion 62C reaches a maximum (53%) at pH 7. The covalent hydrations of compound 62 (R = 3-Py) and 3,4,5,6-tetrahydro-2,3 -bipyridine (anabaseine) were more thoroughly investigated by Zoltewicz (89JOC4462) and all equilibrium constants were measured. 

A fused benzene ring has little effect on the pKa values in the cases of quinoxaline (ca. 0.6) and cinnoline (2.6). Quinazoline has an apparent pAfa of 3.3 which makes it a much stronger base than pyrimidine, but this is due to covalent hydration of the quinazolinium cation (see Section 3.2.1.6.3) the true anhydrous pK.d for equilibrium between the anhydrous cation and anhydrous neutral species of quinazoline is 1.95 (76AHC(20)128). 

Insertion of a methyl group at the site where nucleophilic attack occurs during hydration considerably hinders the reaction and lowers the percentage of covalently hydrated species at equilibrium. Covalent hydrates are converted by mild oxidation into oxo compounds. 

Those dihydro compounds which carry a leaving group attached to their single. vp -hybridized carbon atom exist in equilibrium with the corresponding aromatic compounds (e.g. the pseudobases 467= 468 see Section 3.2.1.6.3.iv). Another similar example is that of the covalently hydrated cations of neutral azines (see Section 3.2.1.6.3). A somewhat less obvious example is the acid-catalyzed cleavage (469) — (470) with the loss of MeC02H. 

Pyridoxal phosphate exists in an equilibrium between the aldehyde and its covalent hydrate (as in Eq. 13-1). The aldehyde has a yellow color and absorbs at 390 nm (Fig. 14-9), while the hydrate absorbs at nearly the same position as does PMP. The absorption bands of Schiff bases of PLP are shifted even further to longer wavelengths, with N-protonated forms absorbing at 415-430 nm. Forms with an unprotonated C = N group absorb at shorter wavelengths.149 240... 

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. 

Pteridine in liquid ammonia at - 40° gives a mixture of the mono- and bisammonates (213 and 214) which consists of 60% 214 and 40% 213 at equilibrium.358 Higher temperatures more heavily favor the bis-adduct at equilibrium. Substituted pteridines behave similarly. These results are exactly analogous to the formation of mono- and bis-covalent hydrates by the pteridine cation in aqueous acid.359... 

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