Covalent hydrates

The spectra of protonated polyaza heterocycles are frequently complicated by the occurrence of covalent hydration. This is more common with polycyclic systems, e.g. pteridine. 

The UV spectra have been used in studies of protonation and related covalent hydration, structural assignments and tautomerism (see appropriate Sections), as well as in studies of bridgehead addition to 5-deazapterins (79MI21500, 78TL2271) and related 5-deazaflavin derivatives (80JA1092). 

In aqueous alkaline conditions with chloroacetic acid the pyrido[4,3- f]pyrimidinethione (80) undergoes facile ring opening, attributed to the resonance stabilization of a delocalized covalent hydrate dianion intermediate (81) (82). Pyrido[2,3- f]pyrimidine-4-thiones (and... 

The UV spectra of the [3,2-c] and [3,4-c] parent compounds, and that of the dihydro[4,3-c] derivative (302), have been measured (79T2027), as has that of the parent [2,3-d] analogue in a study of its possible covalent hydration (see Section 2.15.8.2) (68AJC1291). The UV spectra of the [2,3-d]-5,8-diones have also been studied (30BSF630, 33BSF151). 

Protonation of pyrido[2,3-d]pyridazine (pK 2.01) is believed to occur at position 1 as predicted by MO calculations (68AJC1291), although alkylation results (see below) cast doubt on this. Covalent hydration has not been observed in this series, nor in the slightly weaker [3,4-d] base (pX a 1.76), which probably protonates at N-6, though this is not certain. 

The NMR spectra of both the parent [2,3-f ] and [3,4-f ] pyridopyrazine systems have been analyzed (66JCS(C)999). Shift values are given in Table 3. These studies were extended to the phenomenon of covalent hydration in both systems (66JCS(C)999,79JHC301) (see Section 2.15.13.2), as well as the addition of other nucleophiles such as amide ion (79JHC301, 79JHC305). 

Relatively little work has been carried out on NMR spectra of jjyridopyrazines, but some have been utilized during studies of the covalent hydration (q.v.) of both parent bases (66JCS(C)999, 75AG356, 79JHC301) and their reaction with nucleophiles (79JHC305). 

Protonation of pyrido[2,3-f ]pyrazine occurs normally without covalent hydration, although the 2-hydroxy derivative did show such behaviour (63JCS5737). The pyrido[3,4-f)]pyrazine parent base does show the phenomenon, although the exact structure of the covalent hydrate seemed to be in doubt between protonated (392) and (397). The issue was resolved in favour of the former by NMR (79JHC301, 75AG356). The 3-hydroxy derivative also shows hydration effects, as does the 7-amino cation (63JCS5166). 

Studies on covalent hydration of N-heterocycles (67AG(E)919,76AHC(20)117) have revealed the diagnostic value of alkyl substituents in structural assignments due to their steric hindrance effects in addition reactions. C-Methyl substituents are therefore also considered as molecular probes to solve fine-structural problems in the pteridine field. The derivatives... 

Considering the four potential monohydroxypteridines, pteridin-4- and -7-one 56JCS3443) behave normally whereas pteridin-2- and -6-one (25) form covalent hydrates. The reversible hydration of nitrogen heterocycles was actually discovered with pteridin-6-one (52JCS1620),... 

The molecular features of covalent hydration are also present in the dihydroxy series, i.e., in pteridine-2,6-dione (30) and in pteridine-4,6-dione. The latter compound is hydrated only at the C(7)—N(8) double bond, whereas (30) forms two hydrated species, 7-hydroxy-7,8-dihydro- (29) and 4-hydroxy-3,4-dihydro-pteridin-2,6-dione (31) (equation 8). Structure (29) is thermodynamically the more stable substance (31) is formed more rapidly in solution but disappears slowly with time (63JCS5151). Insertion of a 4-methyl group greatly reduces the extent of 3,4- in favour of 7,8-hydration by a blocking effect . 

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... 

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 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... 

P3Timidines, and pyrido[4,3-< ]pyrimidines. The experimentally determined values have been used for studies of covalent hydration, structural assignments, - and tautomerism. -... 

Nuclear magnetic resonance spectra of all four parent compounds have been measured and analyzed.The powerful potentialities of NMR as a tool in the study of covalent hydration, tautomerism, or protonation have, however, as yet received no consideration for the pyridopyrimidines. NMR spectra have been used to distinguish between pyrido[3,2-d]pyrimidines. and isomeric N-bridgehead compounds such as pyrimido[l,2- ]pyrimidines and in several other structural assignments (cf. 74 and 75). 

In common with other fused pyrimidines, the pyridopyrimidines are susceptible to the nucleophilic addition of water across the 3,4-bond. This is the phenomenon of covalent hydration... 

The parent compounds undergo facile hydrolysis to aminoaldehydes subsequent to the covalent hydration and reversible ring-opening as described above for pyrido[4,3-d]pjrrimidines (Section IV, B). 2-(3-Pyridyl)pyTido[2,3-d]pyrimidine undergoes hydrolysis to yield 2-aminonicotinaldehyde and nicotinamide when treated with N—HCl under reflux for 3 hours. This mechanism also probably involves a covalent hydrate. 2-Methylpyrido[4,3-d]pyrimidin-4(3H)-one, although much more stable than the parent compound, is readily hydrolyzed with dilute acid, whereas the isomeric compounds from the other three systems are stable under such conditions. 

Oxidations of pyridopyrimidines are rare, but the covalent hydrates of the parent compounds undergo oxidation with hydrogen peroxide to yield the corresponding pyridopyrimidin-4(3 T)-ones. Dehydrogenation of dihydropyrido[2,3-(i]pyrimidines by means of palladized charcoal, rhodium on alumina, or 2,3-diehloro-5,6-dicyano-p-benzo-quinone (DDQ) to yield the aromatic derivatives have been reported. Thus, 7-amino-5,6-dihydro-1,3-diethylpyrido[2,3-d]-pyri-midine-2,4(lif,3f/)-dione (177) is aromatized (178) when treated with palladized charcoal in refluxing toluene for 24 hours. 

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