Quinazoline hydration

Tetrahydro-l 1 //-pyrido[2,l-6]quinazoline hydrate (6 HzO) deteriorated during storage into its 11-oxo derivative (7), or in water at room temperature in the presence of air (85AJC1007). A mixture of the 7-methyl derivative of 6,7,8,9-tetrahydro-ll//-pyrido[2,l-b]quinazoline (6) and its 5,5a,6,7,8,9-hexahydro derivative partially oxidized on standing in air for 6 months to their 11-oxo derivatives (95AJC2023). 

The UV spectrum of quinazoline is less simple bands at 220, 267 and 311 all represent -rr - -rr transitions and a characteristic inflexion of low intensity at 330 nm represents the TT transition (63PMH(2)l). Quinazoline as cation (17) is 3,4-hydrated covalently, so... 

Quinazoline [253-82-7] M 130.2, m 48.0-48.5 , b 120-121 /17-18mm, pK, -4.51 (aq H2SO4, anhydrous dication), pK 2.01 (anhydrous monocation), pK3 4.3 (equilibrium with 3,4-hydrated species), PK4 12.1 (hydrated anion). Purified by passage through an activated alumina column in benzene or pet ether (b 40-60°). Distd under reduced pressure, sublimed under vacuum and crystd from pet ether. [Armarego 7 Chem 1170 1961.]... 

The present review describes recent advances in quinazoline chemistry, some of which are but modem applications of earlier methods, whereas others strike out on new, and sometimes surprising, pathways. The structure of the cation of the parent substance, quinazoline, has only recently been made clear, and it has become evident that covalent hydration is a phenomenon widely distributed throughout the quinazoline series. With this fact in mind, it seems better to set forth the newly found properties of quinazolines before proceeding to an account of advances in synthesis. 

The stabilizing influence in the hydrated cation is the amidinium resonance. If a solution of the cation is neutralized, a short-lived hydrated neutral molecule (4) (half-life 9 sec at pH 10) is obtained with an ultraviolet spectrum similar to that of the hydrated cation but shifted to longer wavelengths (5 m/ ). Supporting evidence can be derived from the anhydrous nature of the cation of 4-nitroiso-quinoline (pK 1.35), in which the nitro group has a similar electronic influence to that of the ring nitrogen atom N-I in quinazoline and where amidinium resonance is not possible. 

As yet no quinazoline has been discovered which has any appreciable amount (say, 1%) of hydrated species in the neutral molecule,but several quinazolines were shown to contain a mixture of anhydrous and hydrated species in the cations. Anhydrous neutral molecules and anhydrous cations have an ultraviolet absorption spectrum of the general type C (Fig. 3) and hydrated cations, the type... 

Fig, 3. Ultraviolet spectra of quinazoline cations in water. A, Typical hydrated cation B B, typical mixture of hydrated and anhydrous cation, and C, typical anhydrous cation. 

Percentage of Anhydrous Cation in the Mixture of Anhydrous AND Hydrated Cations of Substituted Quinazolines... 

The ionization constant of a typical heterocyclic compound (e.g., quinoline) designates the equilibrium involving a proton, a neutral molecule and its cation. With quinazoline, however, two distinct species (hydrated and anhydrous) are involved each of which is in equilibrium with its cation, and can be represented as in the reaction scheme, (7), (8), (3), and (4). 

The hydrated cation of quinazoline in dilute acid solution becomes dehydrated when the acidity of the solution is progressively increased. At Ho —4.3, the solution consists predominantly of the anhydrous cation with some anhydrous dication ( 7%). The ultraviolet spectrum of the anhydrous cation is similar to that of the neutral molecule (there is a small bathochromic shift) and it is also similar to that of quinazoline in anhydrous dichloroacetic acid. When the acid strength is further increased to Ho —9.4, the quinazoline dication is formed (pKa —5.5). 

The sole known example of electrophilic substitution in quinazoline is nitration. Quinazoline gives 6-nitroquinazoline with fuming nitric acid in concentrated sulfuric acid. No oxidation of the heterocyclic ring can occur under these conditions because the hydrated cation (see Section IIA>4) is not present. This substitution is in agreement with theoretical calculation [see (2) and reference 36]. 

No doubt the reactivity parallels the hydration pattern observed in benz-substituted quinazolines (see Section II,A,3). 

The reactivity of the methyl group in 4-methylcinnoline ethiodide indicates that the structure of this compound is 5, and this evidence has also been interpreted to mean that N-1 is the basic group in cinnolines. However, evidence of this type is only indicative since the formation of quaternary salts is subject to kinetic control, whereas protonation yields predominantly the thermodynamically more stable cation. The quinazoline cation has been shown to exist in the hydrated, resonance-stabilized form 6 7 by ultraviolet spectro-... 

The physical properties of the pyridopyrimidines closely resemble those of their nearest A-heteroeyclie neighbors the quinazolines and the pteridines. Thus, in common with the pteridines, the presence of groups capable of hydrogen-bonding markedly raises the melting point and lowers the solubility. - The acid dissociation constants (pif a values) and ultraviolet absorption spectra of all four parent pyridopyrimidines have been determined by Armarego in a comprehensive study of covalent hydration in these heterocyclic systems. The importance of these techniques in the study of covalent hydration, and... 

Heterocyclic compounds that have water bound covalently across a C=N bond behave as secondary alcohols. When subjected to very gentle oxidative conditions, they are converted into the corresponding 0x0 compounds. Potassium permanganate in 0. IN sodium hydroxide at room temperature has been used to oxidize 2- and 6-hydroxypteri-dine to 2,4- and 6,7-dihydroxypteridine, respectively. In contrast, 4-hydroxypteridine was not attacked by this reagent even at 100°. Hydrogen peroxide in acid solution was used to oxidize quinazoline quinazoline 3-oxide 1,3,5-, 1,3,7-, and 1,3,8-triazanaphthalene and pteridine (which hydrate across the 3,4-double bond in the... 

If one of the species is predominantly hydrated (e.g. the quinazoline cation then, by using the rapid-reaction apparatus and allowing... 

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