Covalent hydration kinetics

With pteridine (1) the covalent hydration is a complex matter since the general acid-base catalyzed reaction provides a good example of a kinetically controlled addition to the... 

E. Rapid-Reaction Technique Because this technique and the apparatus involved are considered in detail in the following review, only a qualitative discussion is given here. This is the most valuable method for the confirmation of covalent hydration because it can usually give conclusive results even when the percentage of the hydrated species is as low as 2%. It makes use of the facts that aU known examples of the formation or disappearance of the hydrated species followed first-order kinetics and that the rates are both acid- and base-catalyzed. It also depends on the usual state of affairs that the ratio of the hydrated to the anhydrous species, although pH independent (see Section II, A), is different in the three species, i.e. in the cation, neutral species, and anion. In principle, a solution of one... 

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. ... 

Covalent addition of solvent or of nucleophile prior to substitution will alter the reactivity characteristics of the substrate. Covalent addition of nucleophile after substitution will affect the kinetics in a way similar to the formation of 389. Covalent hydration and additions are especially likely to occur in bicyclic azines. (cf. Section IV,B,3,b).ii>i o>i i i4... 

Dimroth rearrangement probably starts with a covalent hydration catalyzed by acids or bases (Section II,B,3). According to Dukes et al. [72JCS(P2)1695] there is evidence from pKa values, kinetic measurements, and UV spectra that the alkaline hydrolysis of the amine 46 includes intermediate 47 (Scheme 22). 

Ring contractions of six- or seven-membered fused systems have sometimes been used to synthesize azapentalenes. Taylor et a/.158 found that triazolo[4,3-a]pyrazines (164) rearrange in acid to imidazotriazoles 165 following initial fission of the six-membered ring at the point shown (164). The kinetics,58b of this reaction have revealed the intermediacy of covalently hydrated species. 

Increasing numbers of nitrogen atoms increase not only the kinetic susceptibility toward attack but also the thermodynamic stability of the adducts. Reversible covalent hydration of C = N bonds has been observed in a number of heterocyclic compounds (76AHC(20)117). Pyrimidines with electron-withdrawing groups and most quinazolines show this phenomenon of covalent hydration . Thus, in aqueous solution the cation of 5-nitropyrimidine exists as (164) and quinazoline cation largely as (165). These cations possess amidinium cation resonance. The neutral pteridine molecule is covalently hydrated in aqueous solution. Solvent isotope effects on the equilibria of mono- (166) and dihydration (167) of neutral pteridine as followed by NMR are near unity (83JOC2280). The cation of 1,4,5,8-tetraazanaphthalene exists as a bis-covalent hydrate (168). 

The effect of substituents in the 5-, 6-, 7-, or 8-position of quinazo-line was summed up in the earlier review.38 In general, (—1) substituents promote hydration of the 3,4-bond by lowering the electron density on C-4. Later it was found that a (—1) substituent in the 2-position had the opposite effect. The addition of the negatively charged pole of a water molecule to C-4 is favored by the polarization of the 3,4-bond in this sense —C4 =N—4V But a (—1) group in the 2-position can oppose this polarization. In a study of twenty 2-substituted quinazolines,23 it was found that hydration was helped by (+1) substituents, not greatly affected by (+M), and much diminished by (—I) substituents. The pH rate profile (first-order kinetics) for the hydration of 2-aminoquinazoline, measured from pH 2 to 10, was parabolic,23 typical of molecules that undergo reverse covalent hydration.315... 

The rearrangement of the triazolo[4,3-c]pyrimidines, e.g., 24, to their [2,3-c) isomers has been hypothesized as going through a neutral covalent hydrate followed by ring fission.35 Kinetic evidence has been... 

A parallel study of aqueous bromination of pyrimidin-4(3//)-one and its /V-methyl derivatives also pointed to an addition-elimination process involving cationic intermediates. The kinetic results for these substrates differed from those of 39 (in which the pseudo bases dehydrate as neutral molecules) in that the intermediates dehydrated in cationic forms (79JOC3256). Again, the covalent hydrates, though present to only a minor extent (—0.0003%), were the reactive species in the bromination process. Pyrimidin-4(3//)-one, as its covalent hydrate, reacts 600 times faster than it does itself the rate enhancement is even greater O 104) for the 2-isomer, which exhibits a higher degree (—0.05%) of covalent hydration. 

Dihydro-2iT-thiazolo[2,3-c][l,2,4]triazine-3,4-dione rearranges in dilute base to give an unstable acid which decarboxylates on acidification of the sodium salt to give 5,6-dihydrothiazolo[2,3-c]-s-triazole (equation 68) (81CB1200). Kinetic evidence has been put forward in favor of covalently hydrated intermediates in the acid-catalyzed rearrangement of triazolo[4,3-a]pyrazines to 1H-imidazo[2,1 -c]-s-triazoles. The intermediate triazole has been isolated and characterized (equation 69) (72JCS(P2)4). 

Pteridine Studies. Part XXIV. Competitive Covalent Hydration of 2,6-Dihydroxypteridine Kinetics and Equilibria. 

The covalent addition of water to C=N in an N—0=N system to form a stable hydrate is rare in heterocyclic chemistry. Two examples are known in the quinazoline series, and these are 2-methyl- and 2-phenyltetra-zolo[l,5-c]quinazoline. In these compounds water addition across the 3,4 double bond is not possible because of ring fusion. When these were treated with hydroxides, the hydrates (7 R = Me and Ph) were isolated and characterized. - Undoubtedly such hydrates must be involved as intermediates in the syntheses or hydrolytic degradation of quinazolines in which the C-2, N-3 bond is made or broken. Indirect evidence that a 1,2-covalent hydrate was a necessary intermediate in the bromination of quinazolin-4-one came from judicious kinetic studies. The kinetic order, acidity dependence or rates, inverse dependence of rates on bromide ion, and the relative reactivities of quinazolin-4(3//)-one, 3-methylquinazolin-4-one and l,3-dimethyl-4-oxoquinazolinium perchlorate were consistent with a mechanism in which the rate-determining step was attack of molecular bromine on the 1,2-covalent hydrate, i.e., 8 -> 9. ... 

Is any reasonable mechanism consistent with the data The answer lies in an observation of a probable isotope effect in a coupled nonenzymic phenomenon. The double-isotope fractionation method does not enter into the analysis. The keto group of glyoxalate is actually present as a covalent hydrate to the extent of about 99% of the total glyoxalate concentration (27). However, the ketone is the form that will react in the enzymic process and the concentration of ketone determines the rate of reaction and binding to the enzyme. The equilibrium between ketone and hydrate is not catalyzed by the enzyme and as a result the isotope effect on this equilibrium will appear in the measured kinetic isotope effects. Of course, the extent of this equilibrium will not be affected by deutera-tion of the methyl group of acetyl-CoA. Therefore, the observed HVIK) is not an indication of kinetically significant carbon-carbon bond formation but of a preequilibrium hydration, a process that is independent of the enzyme. The value for HV/K) of 1.0037 is consistent with measured equilibrium isotope effects in related molecules (23). Therefore, the deuteration of acetyl-CoA has no effect on the observed kinetic because that value in fact is due to a preequilib-... 

Other Studies.— The kinetics and mechanisms of reactions of tptz (5) complexes of cobalt(ii), copper(ii), and nickel(u) with water and with hydroxide have been established and compared. Covalent hydrates are believed to be important intermediates in aquation of the [M(tptz)(OH2)3] + complexes. Kinetics of aquation of the anions [M(acac)a] (M = Co, Cr, or Ru) have been studied in pulse radiolysis experiments. All three steps were monitored for the cobalt(n) complex, but the first step for the chromium(ii) complex was too fast to follow and, predictably, all steps for the ruthenium(ir) complex were too slow to follow by this technique. The mechanism of acac loss is thought to involve equilibrium... 

The FCaq reduction of [Fe(phen)3] would generally be predicted as outer sphere in nature, but an inner-sphere mechanism has been proposed to explain a nonlinear Hammett plot obtained for substituted phenanthroline derivatives. Covalent hydration, that is, addition of H2O to the 2-position of the phenanthroline, is suggested to provide a hydroxo bridge for an inner-sphere mechanism but the evidence is not convincing. Kinetic evidence has been presented for an intermediate in the reduction of a variety of iron(III) complexes with donor ligands by [Fe(3,4,7,8-Me4phen)3] in acetonitrile. Both inner-sphere and outer-sphere pathways are found and the intermediate is thought to result from the former pathway. 

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