Quinazoline substituted, hydration

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

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 neutral species of substituted quinazolines are predominantly anhydrous. The ratio of the hydrated to the anhydrous neutral species... 

In principle, if an estimate could be made of K, the equilibrium concentration ratio of hydrated to anhydrous cations, relation (15) would enable the approximate pA of the anhydrous species to be calculated. Although such an estimate may be derivable from absorption spectral data, no such calculation appears to have been reported. Conversely, if an upper estimate of pA is made from the (pAa)eqm value for the corresponding, appropriately methyl-substituted base, Eq. (15) can be used to furnish a lower limit to the extent of hydration in the cation. Taking quinazoline as an example ... 

Heterocyclic structures analogous to the intermediate complex result from azinium derivatives and amines, hydroxide or alkoxides, or Grignard reagents from quinazoline and orgahometallics, cyanide, bisulfite, etc. from various heterocycles with amide ion, metal hydrides,or lithium alkyls from A-acylazinium compounds and cyanide ion (Reissert compounds) many other examples are known. Factors favorable to nucleophilic addition rather than substitution reactions have been discussed by Albert, who has studied examples of easy covalent hydration of heterocycles. 

Heating a mixture of 6,7,8,9-tetrahydro-ll//-pyrido[2,l-b]quinazolin-ll-one (7) and acetyl and benzoyl chlorides, acetic anhydride, and vinyl acetate under reflux gave 6-condensation products (123), whereas reactions with ethyl chloroacetate, ethyl dichloroacetate, and chloral hydrate afforded 6-substituted products (124) (86MI7). 6,7,8,9-Tetrahydro-ll//-pyrido[2,l-b]quinazolin-l 1-one (7) and acetic anhydride, heated under reflux for 36 h, gave compound 123 (X = OAc, R = Me or X = Me, R = OAc, 18%) and its 6-acetyl derivative (124, R = COMe) in 31% yield (87JHC175 91JHC2071). 

Cyano-3-methyl-5,6-dihydro-l//-pyrido[l,2-a]quinazoline-l,6-dione and its 5-substituted derivatives were prepared from 2-cyano-3-methylpyrido[l,2-a][3,l]benzoxazin-6-one with ammonium acetate at 200°C for 4 h, with hy-droxylamine hydrochloride and (thio)ureas in a boiling mixture of pyridine and ethanol for 4-7 h, with hydrazine hydrate, phenylhydrazide, primary aliphatic and (hetero)aromatic amines in boiling ethanol for 3-6 h (93CCC1953). 

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 pK of quinazoline, as commonly measured, is 3.51 this represents mainly the equilibrium between the two most stable species, namely, the hydrated cation and the anhydrous neutral species. The true anhydrous pKa (i.e., for the instantaneous equilibrium between anhydrous cation and anhydrous neutral species) was obtained25 for quinazoline, twelve substituted quinazolines, and triazanaphthalenes in the rapid-reaction apparatus just described. The true anhydrous pKa of quinazoline turned out to be 1.95. The true hydrated pKa of quinazoline has already been reported26 as 7.77, the slower rate of hydration permitting its determination in the usual rapid-reaction apparatus. Thus, in general, three pKa values exist for each hydrating base, and the equilibrium between the totally hydrated species furnishes the strongest basic properties. 

In this way, it was found that quinazoline (neutral species) has one hydrated molecule for every 5500 anhydrous ones. Altogether twenty-eight variously substituted quinazolines were examined,27 and the ratio was seen to vary from 10-2 to 10-5. It was concluded that (—1) substituents favor hydration, and, in general, the relative effects of various substituents on the ratio was very similar to that which they had earlier been found to exert on the cations, although much less intense. 

Quinazoline (11.16) nitrates in the 6-position, and because theoretical calculations predict 8- > 6-substitution (the 5- and 7-positions are each conjugatively deactivated by both nitrogens), it has been assumed that reaction must involve the hydrated quinazolinium cation (11.93) (47JOC405 49JCS1367). However, these calculations may not take sufficient account of inductive deactivation of the 8-position the deficiency of the calculations in this respect will be particularly marked if no auxiliary inductive parameter is used for the bridgehead carbon between the 1- and 8-positions. 

Bromination of 4-(3/T)-quinazoline (11.109, R = H), its 3-methyl derivative (11.109, R = Me), and 1,4-dihydro-l,3-dimethyl-4-oxoquinazoli-nium perchlorate (11.110) occurred in each case at the 6-position, no 8-substitution being observed (though the 6-bromo compounds were slowly converted into the 6,8-dibromo derivatives). At pH <2, all three compounds exist predominantly as cations at pH 0.29 the relative rates for the Me2, Me, and H derivatives were 4.68 1.54 1. The mechanisms are thought to involve attack of bromine on covalent hydrates (76JOC838). 

The alteration of nucleophilic reactivity by the intervention of covalent hydration and analogous nucleophilic additions needs to be borne in mind for many polyazanaphthalenes. Covalent hydration has been observed in several bicyclic azines besides pteridine and quinazoline (Section IV, B) and is related to nucleophilic substitution in activation and in proceeding through the same first stage as 8 Ar2 reactions. The Bucherer interconversion of naphthols and naphthylamines involves exchange of oxygen and nitrogen substituents in a covalent adduct produced by bisulfite ion. ... 

The pAj value for anhydrous quinazoline obtained using a rapid reaction apparatus is 1.95 at 20°C, as compared to the equilibrium pAf, value of 3.51 and to the pA, value of 7.77 for the hydrated species. The equilibrium pK value obtained by potentiometric titration or by spectrophotometry is a composite value arising from equilibrium between a stable hydrated cation and a stable anhydrous neutral species. Quinazoline in aqueous solution is a much stronger base (pAT = 3.51) than pyrimidine (pAT = 1.31) because its cation is stabilized as a covalent 3,4-hydrate. Most quinazoline derivatives in which the cation is capable of hydration are stronger bases than the corresponding pyrimidines. Substituents at the 4-position interfere with the covalent addition of water making the pK. values of 4-substituted quinazolines comparable with the pAf, values of the corresponding 4-substitiited pyrimidines (e.g., 4-methylquinazoline has pK 2.52, as compared to pK of 2.0 for 4-methylpyrimidine). The pAT values of several substituted quinazolines have been compiled. ... 

Oxidation of quinazoline with various oxidizing agents, e.g. hydrogen peroxide, chromic oxide, peracetic acid, or monoperoxyphthalic acid, affords quinazolin-4(3//)-one in high yield. The reactive species is in fact the hydrated cation which is formed from quinazoline in the presence of even a trace of water and which is readily oxidized to the respective oxo compound (cf. p 161). 2-Substituted quinazolines react similarly, whereas when a substituent is present at C4, the hydrated cation is not readily formed and the more sensitive substituent is oxidized. 

A number of 2-substituted 3,4-dihydroquiiiazolines, prepared in situ by Raney nickel desulfurization of the corresponding quinazoline-4(3//)-thiones 3, undergo alumina-catalyzed hydration across the C—N double bond followed by ring opening, leading to substituted acetamide derivatives 4 in approximately 7% yield. ... 

In a systematic study, the kinetics of the reversible addition of water to substituted quinazolines and the ratios of hydrated to anhydrous neutral species of 28 quinazolines have been determined. ... 

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