Naphthyridines covalent hydration

The first paper on the addition of water to the C=N bond in naphthyridines (covalent hydration) appeared in 1963,9 but it was not until 1976 that the first report concerning covalent amination of naphthyridines using potassium amide in liquid ammonia was published.10... 

Covalent hydration has been demonstrated in the following families of compounds 1,6-naphthyridines, quinazolines, quinazoline. 3-oxides, four families of l,3,x-triazanapththalenes, both l,4,x-triazanaphthalenes, pteridines and some other tetraazanaphthalenes, and 8-azapurines these compounds are discussed in that order. In general, for any particular compound (e.g. 6-hydroxypteridine) the highest ratio of the hydrated to the anhydrous species follows the order cation > neutral species > anion. In some cases, however, anion formation is possible only when the species are hydrated, e.g. pteridine cf. 21 and N-methyl-hydroxypteridines (Section III, E, 1, d). Table V in ref. 10 should be consulted for the extent of hydration in the substances discussed here. 

In all the examples studied, the difference in the free energy between the anhydrous and hydrated species is 4 kcal/mole or less. ° Both electron deficiency and resonance stabilization are necessary for covalent hydration to be measurable. The necessity for electron deficiency is clearly shown in the following examples. The cation of 1,4,5-triazanaphthalene is anhydrous, but the cation of 1,4,5,8-tetraazanaphthalene is predominantly hydrated. 1,6-Naphthyridine cation is anhydrous, whereas the cations of the 3- and 8-nitro derivatives are predominantly hydrated. Also, the percentages of the hydrated form in the neutral species of 2-hydroxy-1,3-diaza-, 1,3,8-... 

Tlie pKa values of 3-iiitro-l,6-iiaphthyridiiie (pAT = 2.32) and 8-iiitro-l,6-iiaphthyridiiie (pAT = 2.59) were reported (63JCS4237). In contrast to 3-nitro-l,5-naphthyridine cation (166a), the cations of 3-nitro-l,6-naphthyri-dine and 8-nitro-l,6-naphthyridine form in aqueous solution covalent hydrates. Tire most likely structures for the hydrated cations are presented as 167A/167B and 168A/168B, respectively (63JCS4237). 

Covalent hydration in the naphthyridines has been considered in comprehensive reviews.l60 161 Although no evidence could be obtained for covalent hydration in the neutral species or cations of 1,5-, 1,6-, 1,7-, and 1,8-naphthyridine, the 3-nitro- and 8-nitro-l,6-naph-thyridine cations readily undergo hydration. 3-Nitro-l,5-naph-thyridine, on the other hand, is not hydrated. 

The added electron deficiency at positions 2 and 5 in the nitro-1,6-naphthyridines together with the resonance stabilization of the hydrated cations (150<—>151 152<—>153) is thus required for covalent hydration. The 3-nitro-1,5-naphthyridine satisfies the first require-... 

Extensive studies have shown that covalent amination is a more general phenomenon than covalent hydration systems that are not able to undergo covalent hydration may easily undergo covalent amination. The 1,X- and 2,X-naphthyridines illustrate this phenomenon clearly. Whereas all parent naphthyridines do not give covalent fT-adducts with water (in basic as well as in acidic mediums), addition of the amide ions easily takes place using potassium amide in liquid ammonia, and the corresponding fT-adducts easily formed. 

For the same reasons as discussed for the 3-nitro-1,8-naphthyridines, addition at C-4 is strongly promoted. If position 4 is occupied, no addition takes place 4-amino-3-nitro-l,6- and -1,5-naphthyridine do not undergo addition at C-2 when subjected to treatment with liquid ammonia. It is interesting that 46a does not undergo covalent hydration in neutral nor in acidic medium.9... 

Naphthyridines. Part II. Covalent Hydration, Electron-deficiency, and Resonance Stabilization in 1,6-Naphthyridines. 

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