3. 3
The diazines – pyridazine, pyrimidine and pyrazine – show many similarities
to pyridines with respect to their reactivities, but to an exaggerated degree. In
particular, the presence of two nitrogens, both as imines, results in increased
electron defi ciency at carbon and hence an increased susceptibility to
nucleophilic addition but an increased resistance to electrophilic attack
4. 4
there has been emphasis on the study of amino- and oxy-pyrimidines (uracil, thymine
and cytosine) due to their importance as constituents of the nucleic acids DNA and
RNA (see pages 163–164), where they occur in nucleotide polymers. These three
pyrimidines, and their nucleosides, can be isolated from some natural sources, but
they are readily available in quantity via fermentation (with or without further
chemical modifi cation) or direct chemical synthesis – uracil in particular, as would
be expected for this simple compound, is very cheap
It should be noted that 2- and 4-amino-pyrimidines exist as the amino tautomers; 2-
and 4-oxy-pyrimidines exist as carbonyl tautomers. These tautomeric preferences
are essential for their role in DNA, where hydrogen bonding holds the two chains of
the double helix together
6. 6
these pyrimidine bases and their nucleosides and nucleotides generally do not
have a great deal of biological signifi cance outside of their participation in
nucleic acids. However, an exception is uridine di/triphosphate, which has a
key role in glucose metabolism and the biosynthesis of glycogen. Pyrazines
have widespread natural occurrences, in low concentrations (see Food and
Drink, page 186), but pyridazines are rare in nature
7. 7
The inductive and mesomeric effects of the second nitrogen lead to a considerable
reduction in the basicity of the parent diazines relative to pyridine (pKaH 5.2). However,
secondary effects result in a different order of basicity between the individual diazines
than would be predicted based simply on induction. In particular, destabilising
interactions between the adjacent nitrogen lone pairs in pyridazine lead to a relatively
higher basicity. Only in very strong acid can a proton be added to both nitrogens, giving
doubly protonated salts.
The diazines react with alkyl halides to give quaternary salts, although somewhat less
readily than does pyridine. Pyridazine is the most reactive. Steric hindrance by
substituents adjacent to ring nitrogens generally governs regioselectivity.
Electrophilic addition to nitrogen
8. 8
The diazines react with alkyl halides to give quaternary salts, although
somewhat less readily than does pyridine. Pyridazine is the most reactive.
Steric hindrance by substituents adjacent to ring nitrogens generally governs
regioselectivity
9. 9
All three diazines react with peracids to give N-oxides, but less acidic
conditions are required for pyrimidine, due to the susceptibility of
pyrimidine N-oxide to acid-catalysed decomposition.
10. 10
Direct electrophilic attack at carbon in simple diazines is unusual. Pyrimidine can be
brominated under conditions similar to those required for pyridine, reaction
occurring at the 5-position – the only position that is not or to nitrogen and
therefore equivalent to a -position in pyridine – in fact it is the only such position in
any diazine. Chlorination of 2-methylpyrazine occurs under such mild conditions
that some mechanism other than a classical aromatic electrophilic substitution must
be involved: addition of chlorine across the 3,4-imine unit, initiated by electro philic
attack on nitrogen, then loss of hydrogen chloride, is the most likely sequence
Electrophilic substitution at carbon
11. 11
The amino-diazines, benefi ting from activation by the electron-releasing
substituent, generally undergo electrophilic substitution under normal conditions.
Oxy-diazines are similarly activated for electrophilic substitution but this probably
owes more to the enamine-like system present in the keto-tautomer, which allows
electron donation from the ring nitrogen. With two activating groups, even mild
electrophiles can bring about substitution.
12. 12
N-Oxides are also useful substrates for electrophilic substitution, another
parallel to the chemistry of pyridines.
