Pyrimidine positional reactivity

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. 

The pyridine family of heteroaromatie nitrogen compounds is reactive toward nueleophilie substitution at the C-2 and C-4 positions. The nitrogen atom serves to aetivate the ring toward nueleophilie attack by stabilizing the addition intermediate. This kind of substitution reaction is especially important in the ehemistiy of pyrimidines. 

The halogen atom in benz-chloro substituted quinazolines is very stable (as in chlorobenzene), whereas the halogen atoms in positions 2 and 4 show the enhanced reactivity observed with halogen atoms on carbon atoms placed a and y to heterocyclic ring nitrogens. The chlorine atom in position 4 is more reactive than in position 2, and this property has been used to introduce two different substituents in the pyrimidine ring. ... 

With unsymmetrical diketones the orientation of the reaction is again controlled by the reaction of the most reactive carbonyl group with the 5-position of the pyrimidine ring. Thus, benzoyl acetone and 6-aminouraoil gave 5-methyd-7-phenylpyrido[2,3-d]pyrimidine-2,4-(lH,3iI)-dione (71), in preference to the 5-phenyl isomer (72). ... 

All these methods demonstrate that the 2-positions of pyridine, pyrimidine, and other azines are the most electron deficient in the ground state. However, considerably greater chemical reactivity toward nucleophiles at the 4-position is often observed in syntheses and is supported by kinetic studies. Electron deficiency in the ground state is related to the ability to stabilize the pair of electrons donated by the nucleophile in the transition state. However, it is not so directly related that it can explain the relative reactivity at different ring-positions. Certain factors which appear to affect positional selectivity are discussed in Section II, B. 

In other heterocycles such as pyrimidine (48), the reactive positions are either between two centers of high eleetron density, the 2-position, or opposite one and adjaeent to the other sueh eenter, the 4-position. 

The replacement of a heterocyclic hydroxyl group (generally in the 0X0 form, Section II,E, 2,e) with thioxo or chloro groups by phosphorus pentasulfide or phosphorus oxychloride presumably proceeds through nucleophilic substitution (frequently acid-catalyzed, 21 and 86) of thiophosphoryloxy and dichlorophosphoryloxy intermediates. The 4-position in pyrimidine is more reactive than the 2-position and, at low temperature, this type of thionation of pyrimidine-2,4-diones is specific for the 4-position. In as-triazine... 

Alkylthio, arylthio, and thioxo. The thioxo group in pyrimidine-2,4-dithione can be displaced by amines, ammonia, and amine acetates, and this amination is specific for the 4-position in pyrimidines and quinazolines. 2-Substitution fails even when a 5-substituent (cf. 134) sterically prevents reaction of a secondary amine at the 4-position. Acid hydrolysis of pyrimidine-2,4-dithione is selective at the 4-position. 2-Amination of 2-thiobarbituric acid and its /S-methyl derivative has been reported. Under more basic conditions, anionization of thioxo compounds decreases the reactivity 2-thiouracil is less reactive toward hot alkali than is the iS-methyl analog. Hydrazine has been reported to replace (95°, 6 hr, 65% 3deld) the 2-thioxo group in 5-hexyl-6-methyl-2-thiouracil. Ortho and para mercapto- or thio- azines are actually in the thione form. ... 

Statements in the hterature on the reactivity of the ring-positions in monocyclic azines are conflicting. Reactivity is said to be greater at the position ortho (or alpha) than at the position para (or gamma) to an azine nitrogen 2-> 4-position in pyridine and pyrimidine and 3-> 5-position in as-triazine. By others, the... 

The 2- and 4-chloro derivatives readily react with sodium methoxide in methanol at reflux (and probably at 25°) to yield 2-methoxy- and 4-methoxy-pyrimidine. The high order of reactivity of the 4-position is evident from the fact that 4-methoxy-2-chloropyrimidine (299) is the sole product formed on treatment of 2,4-dichloropyrimidine in methanol with one mole of sodium methoxide at 25° cf. 

Brown has also predicted, from localization energy calculations, that pyrrole and glyoxaline should react with radicals mainly at the 2-position, whereas pyrazole should be most reactive at the 3-position. Browm and Heffernan s calculation that the orientation in pyrimidine substitution should be 4 > 2 > 5 is in agreement with the results from the p-nitrophenylation of pyrimidine. ... 

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