Hydrates, covalent, isolation

Perfluorobutane-2,3-dione (76.15), a reactive compound which sometimes shows unexpected properties, behaved predictably with o-phenylenediamine to give quinoxalines. The cyclizations proceeded at or below room temperature in good yields [3165]. Transmolecular covalent hydrates were isolated from the reaction of diaminouracils (76.16) with the fluorinated diketones [3166]. 3-Phenyl-l,l,I-trifluoropropane-2,3-dione also behaves normally to give 3-(4-tolyl)-2-trifluoromethylquinoxaline in 63% yield [3409]. 

Hammett equation, applied to azines, 217 Hetarynes, 121-143 contrasted with arynes, 125 Heteroaromatic compounds, covalent hydration of, 1-41 "pKa generalizations for, 48-61 Heterocyclic acids, pH-rate profile for, 67 Heterocyclic diazonium compounds, 241 Heptaazanaphthalenes, 393 Hexaazanaphthalenes, 393 Hippuroflavin, 80 Hydrated salts, isolation of, 16 Hydrates, alcoholates from, 16 isolation of, 16... 

There are some special cases where tetrahedral intermediates are unusually stable there are three phenomena which lead to this stability enhancement. The first is an unusually reactive carbonyl (or imine) compound which is very prone to addition. An example of such a compound is trichoroacetaldehyde or chloral, for which the covalent hydrate can be isolated. A simple way to recognize such compounds is to think of the carbonyl group as a (very) stabilized carbocation, bearing an substituent. 

Benzotriazine (8, R = H), for example, can be isolated as a reasonably stable, colorless crystalline solid, but it reacts rapidly in solution with water to give o-aminobenzaldehyde, presumably by initial covalent hydration to give 98, which decomposes to o-aminobenzaldehyde via the triazene 99. Reaction of 8, R = H, with other nucleophiles also occurs readily, while 4-substituted 1,2,3-benzo-triazines react similarly but more slowly, as expected, owing to a combination of steric and electronic effects. 

Similar 3-substituted pyridinium salts give stable solid isolable adducts on reaction with aliphatic amines such as piperidine (equation 109) (Table 16) (80T785). These adducts are stable in apolar solvents, but in water they rapidly dissociate into pyridinium ions and amines, and reactions occur by several pathways (Scheme 94). All may be considered to arise from the covalent hydrates (159) and (160) which are formed under the aqueous basic conditions. 

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). 

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. ... 

Section II3). It seems therefore that the compound originally formulated as the 3-methyl compound on the basis of covalent hydration studies is in fact the 2-methyl isomer 23. Only one product has been isolated from the reaction of 3,4-diaminopyridine and phenylglyoxal under a variety of conditions. As the isomer was obtained under weakly acidic conditions it was formulated as the 2-phenyl derivative 25 by analogy with the arguments used for the orientation of pyrido[2,3-h]pyrazines. 

The insertion of CO2 into discrete covalent polar M-OH bonds has long been investigated because as the reaction is related to the conversion of CO2 into its hydrated forms (anionic or coordinated HCOs" and the elusive acid H2CO3 which cannot be isolated as a pure compound), a reaction that plays a key role in CO2 elimination in humans and animals in the respiratory process. Such a reaction is relevant to the enzyme carbonic anhydrase (CA) which accelerates the reaction of hydration-dehydration of CO2, thus facilitating its uptake at the cellular level and its elimination in the lungs from where it is expelled [30]. Scheme 4.7 shows the mechanism of reaction of CO2 with the Zn-OH moiety, active center of CA. 

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