Purine anion formation

For reasons discussed in Section VI, a survey of the purine series (29) is being made in this Department, but so far no example (including 2-hydroxy- and 8-trifluoromethyl-2-hydroxy-purine) of covalent hydration has come to light. An examination of ionization constants disclosed no apparent anomalies, although the interpretation is made more difficult by the ease of anion formation in the 9-position, which often competes with that from other anionic substituents. The only abnormal spectrum seems to be that of the anion of 2-mercaptopurine which is being further examined. 

In simple purines the imidazole ring is usually involved in anion formation. The strong resemblance shown between the spectrum of the anion (6) of 8-oxopurine and that of 7-methyl-8-oxopurine (7)... 

A more pronounced effect on the 77-electron structure is produced by N-alkylation than by C-substitution, replacing the ring nitrogen proton by alkyl groups restricts the number of anionic forms and of tautomeric structures. The alkylated purines can be stabilized toward base attack by anion formation, but if no proton is available then fission of one of the rings is likely. 

The instability of simple purine ribosides toward alkali88 89 can be related to the fairly strong electron-withdrawing power of the ribose moiety, which directs the nucleophile to the 8-carbon. Stabilization of a nucleoside can be achieved if anion formation is possible. This is seen with inosine (hypoxanthine-9-D-riboside) (39, R = H), which is... 

Replacement of halogen atoms by alkoxy groups may be hindered in N(7)- and N(9)-unsubstituted purines because of anion formation although this has been overcome to some extent by use of antimony chloride followed by the alcohol (71MI40904). Aryloxypurines have similarly been prepared from halogenopurines and hot alkaline phenol solutions. Since alkylation of oxopurines tends to lead almost exclusively to Af-alkyl derivatives (see Section 4.09.5.2.2(iv)), direct replacement of halogen atoms assumes special importance as a route to the alkoxypurine derivatives. 

The pyrimidine moiety of purines is 7t-electron deficient, whereas the imidazole ring is a Jt-electron excessive system. The direction of the dipole moment is altered by the introduction of substituents, by protoiiation, tautomerization or base pairing. The 7t-excessive character of the imidazole moiety of various purines makes it suitable for anion formation upon treatment with sodium hydride, potassium hydroxide, potassium carbonate or other reagents which are used during electrophilic reactions, such as alkylation or glycosylation. The nucleophilic attack on carbons occurs in the order C8 > C6 > C2. A number of purine syntheses use the displacement of existing substituents. 

Purines are constructed from a rr-electron-deficient pyrimidine moiety and a rr-excessive imidazole system. As the rr-electron excess of the imidazole moiety is strongly reduced by the t-deficient pyrimidine system the C8 atom becomes the most electron deficient site in the non-ionized molecule and a substituent at this position is normally displaced first by a nucleophile. The order of nucleophilic displacement reactions is C8 > C6 > C2. Anion formation at the imidazole nitrogen increases the electron density of the imidazole system. As a consequence, nucleophilic attack is now directed to the pyrimidine moiety with C6 as the most reactive position followed by C2 and C8. 

In 9-substituted purines, the relative reactivity of halides is 8 > 6 > 2, but strongly influenced by the presence of other substituents. In 9H-purines this is modified to 6 > 8 > 2, the demotion of the 8-position being associated with anion formation in the five-membered ring. Conversely, in acidic media the reactivity to nucleophilic displacement at C-8 is enhanced protonation of the five-membered ring facilitates the nucleophilic addition step." The relative reactivities of the 2- and 6-positions are nicely illustrated by the conditions required for the reaction of the respective chlorides with hydrazine, a relatively good nucleophile." It is worth noting the parallelism between the relative positional reactivity here with that in halo-pyrimidines where it is 4 > 2. 

Moorthy PN, Hayon E (1975) Free-radical intermediates produced from the one-electron reduction of purine, adenine and guanine derivatives in water. J Am Chem Soc 97 3345-3350 Mori M, Teshima S-l, Yoshimoto H, Fujita S-l, Taniguchi R, Hatta H, Nishimoto S-l (2001) OH Radical reaction of 5-substituted uracils pulse radiolysis and product studies of a common redox-ambivalent radical produced by elimination of the 5-substituents. J Phys Chem B 105 2070-2078 Morin B, Cadet J (1995) Chemical aspects of the benzophenone-photosensitized formation of two lysine - 2 -deoxyguanosine cross-links. J Am Chem Soc 117 12408-12415 Morita H, Kwiatkowski JS,TempczykA(1981) Electronic structures of uracil and its anions. Bull Chem Soc Jpn 54 1797-1801... 

It has recently been found that purine in its anionic form undergoes a Chichibabin reaction with potassium amide in liquid ammonia with formation of adenine as the sole product. 

The reaction of hydrated electrons formed by radiolysis with peroxydisulfate yields the sulfate radical anion SO4 which is a strong chemical oxidant (Eqx = 2.4 V/NHE) [50, 58]. The oxidation of both purine and pyrimidine nucleotides by S04 occurs with rate constants near the diffusion-controlled limit (2.1-4.1 x 10 M s ). Candeias and Steenken [58a] employed absorption spectroscopy to investigate acid-base properties of the guanosine cation radical formed by this technique. The cation radical has a pKa of 3.9, and is rapidly deprotonated at neutral pH to yield the neutral G(-H) . Both G+ and G(-H) have broad featureless absorption spectra with extinction coefffcients <2000 at wavelengths longer than 350 nm. This has hampered the use of transient absorption spectra to study their formation and decay. Candeias and Steenken [58b] have also studied the oxidation of di(deoxy)nucleoside phosphates which contain guanine and one of the other three nucleobases by SO4 , and observe only the formation of G+ under acidic conditions and G(-H) under neutral conditions. 

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