Azapurines, hydration

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. 

This does not exclude the possibility that hydration occurs too rapidly to be detected with existing apparatus. Special point is given to this conclusion by a recent survey of 8-azapurines.The abnormal... 

Hydroxy-8-azapurine was shown by rapid-reaction techniques (see Section II, E) to be anhydrous in the anion and hydrated in the neutral species. The hydration reaction has a half-time of about 0.5 second, which is too rapid for exact measurements with existing apparatus. The cation of 2-amino-8-azapurine was shown to have an anomalous value and ultraviolet spectrum, although its 6-methyl derivative is quite normal. Hydration in this case proved to be too fast to register in the rapid-reaction apparatus. 

To test whether we could accurately calculate the fold-difference of ADA inhibitory potency between purine riboside (8) and analogues of purine riboside, we selected 8-azapurine riboside (9) for our studies. Compound 9 was reported to be a 400-fold more potent ADA inhibitor relative to 8 despite differing from 8 only by the replacement of C8 with a nitrogen (Figure 8).19 The molecular reason for this enhancement in potency was not determined, but could be due either to enhanced hydration or enhanced ADA binding affinity of the hydrated species or both. To determine the reason,... 

Figure 8. Purine riboside/8-azapurine riboside and corresponding hydrates...

An alternative explanation for the 400-fold improvement in inhibitory potency exhibited by 8-azapurine riboside (9) is that the 8-aza analogue hydrates to a much larger extent than purine riboside (8). Calculation of the relative hydration free energy difference between 9-methylpurine and 8-aza-... 

Apparently the first published use of PMR to study hydration was the report that the proton in the 4-position of quinazoline moved upfield (t 0.63 — 3.58) after the molecule was converted into the cation by aqueous acid.10 Normally a downfield shift would be expected on ionization, and this reversal of direction afforded a further and convincing proof of the covalent character of hydration, as well as demonstrating the value of this technique in determining the position of hydration. Contemporaneous application of PMR to the hydration of 8-azapurine (6) cations established the scope and value of this technique.11... 

Equilibrium ratios for the hydrated-anhydrous cationic species of 8-azapurine (6) and its 2-methyl and 2-amino derivatives were similarly determined, and also for the neutral species of 2-amino-8-azapurine and 8-azapurin-2-one, the latter being substantially hydrated as the neutral... 

To summarize the cations of 8-azapurine and its 7- and 8-methyl derivatives are almost completely hydrated at equilibrium, whereas that of the 9-methyl isomer shows little evidence of hydration. None of the corresponding neutral species is appreciably hydrated.13... 

First-order rate constants for hydration and dehydration at 20° were obtained11 for 8-azapurine and its 2-methyl-, 2-amino-, and 2-oxo-derivatives in the pH range 2-7. Strong acceleration of hydration was observed in the cation. 

Azapurine (6) is the parent of a series in which most members with a free 6-position undergo 1,6-hydration (see Table I, and pp. 120, 128). No shift of the position of the added water molecule has ever been... 

Albert, A., 4-Amino-1,2,3-triazoles, 40, 129 The Chemistry of 8-Azapurines( 1,2,3-Triazolo[4,5-d]pyrimidines), 39, 117 Annelation of a Pyrimidine Ring to an Existing Ring, 32, 1 Covalent Hydration in Nitrogen Heterocycles, 20, 117. 

Penta-azaindenes (8-Azapurines). Part I. Covalent Hydration. Syntheses and Reactions. 

The ionization of 8-azapurines, which has not previously been reviewed, is complicated in many cases by covalent hydration, a phenomenon discovered by the present author in the pteridine and quinazoline series in 1952, and twice reviewed in this series. - This occurrence of covalent hydration, which does not exist to any detectable degree in the purine series, - indicates the increased n deficiency conferred by the additional doubly bonded 8-nitrogen atom. 

Ultraviolet and H-NMR measurements supported these assignments. The UV absorption of 6- and 9-methyl-8-azapurine cations (which do not undergo detectable hydration) give the same values in anhydrous trifluoro-acetic acid as they do in dilute hydrochloric acid. By contrast, the cations of 8-azapurine and its 1-, 2-, 7-, and 8-methyl derivatives have different UV spectra in these two solvents (a large shift of to shorter wavelengths occurs in the presence of water ). This shift indicated conversion of a double bond to a single bond by hydration. Similarly the H-NMR spectrum of the anhydrous cation showed peaks at S 9.60 and 10.69 (for H-6 and H-2, respectively), whereas corresponding peaks for the hydrated cation (in DjO, DCl) were at d 6.81 and 8.54, respectively. ... 

The rapid-reaction method was used in reverse to obtain the true pK, of hydrated 7-methyl-8-azapurine, which was 4.05 (cf. 1.92 for the value obtained by slow potentiometry). By contrast, the change from equilibrium titration to rapid-reaction technique raised the pAT, of 8-methyl-8-azapurine much less (from 3.18 to 4.2), which signifies much greater hydration (about 10%) in the neutral species. All of these hydrations were found to be first-order reactions, with 0.5 varying from < 1 to 150 sec. 

Prevention of hydration by the presence of a methyl group in the 6 position has been traced to a combination of both steric and electronic factors most other substituents in the 6 position diminish hydration. It is not known why a methyl group in the 9 position of 8-azapurine decreases hydration. Substituents in the 2 position of 8-azapurines favor 1,6 hydration if they are mesomeric donors (-1- M) e.g., NHj or O those that are inductive acceptors (—1) (e.g., SMe) oppose hydration by lowering the polarization of the 1,6 bond ° (cf. the similar responses of the 2 position in quinazolines ). The hydration of 8-azapurin-2-one stands apart from the above examples by being manifested mainly in the neutral species the hydration of 8-azapu-rine-2-thione is barely detectable. 

It is thought that purines owe their maximum in the 260-nm region to a polarized electronic transition in the direction C-2 — C-4, and 8-azapu-rines should behave similarly. However those ionic species of 8-azapurine that are subject to hydration exhibit (when compared to purines) a spectral shift of about 15-75 nm (to lower wavelengths) without loss of intensity. 3.4.45,48... 

Other points of interest, illustrated in Table III, are the hydration of the cation of 2-amino-8-azapurine and the spectra of some 1,6- hydro-azapu-rines. The spectra of substituted l,6-dihydro-6-imino-l-methyl-8-azapu-rines (15) are similar to those of the isomeric 6-methylamino-8-azapurines to which they are readily converted, but only the latter show coupling (5 Hz) between protons of HNCH3... 

The oxidation of 8-azapurines to 8-azapurin-6-ones is derived from the preexisting 1,6 hydration (Section II,B). Thus the parent substance, set aside with 1 equiv of30%hydrogen peroxide in sulfuric acid(25°C,4days)gave 8-azapurin-6-one in 65% yield, and 2-amino-8-azapurine similarly fur-... 

The absence of covalent hydration [65AHC(4)1 76AHC(20)117] enables the ionization constants and UV spectra of 1,2,3-triazoles to be interpreted more readily than those of 8-azapurines (1,2,3-triazolopyrimidines), which exhibit this phenomenon strongly [86AHC(39)117]. Table I presents the... 

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