Pyrimidine is an aromatic heterocyclic organic compound similar to pyridine.
One of the three diazines, it has the nitrogens at positions 1 and 3 in the ring.
The other diazines are pyrazine and pyridazine.
In nucleic acids, three types of nucleobases are pyrimidine derivatives: cytosine, thymine,
and uracil.
Occurrence and history
The pyrimidine ring system has wide occurrence in nature as substituted and ring fused compounds
and derivatives, including the nucleotides, thiamine and alloxan.
It is also found in many synthetic compounds such as barbiturates and the HIV drug, zidovudine.
Although pyrimidine derivatives such as uric acid and alloxan were known in the early 19th
century, a laboratory synthesis of a pyrimidine was not carried out until 1879, when Grimaux
reported the preparation of barbituric acid from Ivy urea and malonic acid in the presence
of phosphorus oxychloride.
The systematic study of pyrimidines began in 1884 with Pinner, who synthesized derivatives
by condensing ethyl acetoacetate with amidines.
Pinner first proposed the name “pyrimidin” in 1885.
The parent compound was first prepared by Gabriel & Colman in 1900, by conversion of
barbituric acid to 2,4,6-trichloropyrimidine followed by reduction using zinc dust in hot
water.
Nomenclature The nomenclature of pyrimidines is straightforward.
However, like other heterocyclics, tautomeric hydroxyl groups yield complications since
they exist primarily in the cyclic amide form.
For example, 2-hydroxypyrimidine is more properly named 2-pyrimidone [structures].
A partial list of trivial names of various pyrimidines exists.
Physical properties Physical properties are shown in the data
box.
A more extensive discussion, including spectra, can be found in Brown et al.
Chemical properties Per the classification by Albert six-membered
heterocyclics can be described as π-deficient.
Substitution by electronegative groups or additional nitrogen atoms in the ring significantly
increase the π-deficiency.
These effects also decrease the basicity.
Like pyridines, in pyrimidines the π-electron density is decreased to an even greater extent.
Therefore electrophilic aromatic substitution is more difficult while nucleophilic aromatic
substitution is facilitated.
An example of the last reaction type is the displacement of the amino group in 2-aminopyrimidine
by chlorine and its reverse.
Electron lone pair availability is decreased compared to pyridine.
Compared to pyridine, N-alkylation and N-oxidation are more difficult.
The pKa value for protonated pyrimidine is 1.23 compared to 5.30 for pyridine.
Protonation and other electrophilic additions will occur at only one nitrogen due to further
deactivation by the second nitrogen.
The 2-, 4-, and 6- positions on the pyrimidine ring are electron deficient analogous to those
in pyridine and nitro- and dinitrobenzene.
The 5-position is less electron deficient and substitutents there are quite stable.
However, electrophilic substitution is relatively facile at the 5-position, including nitration
and halogenation.
Reduction in resonance stabilization of pyrimidines may lead to addition and ring cleavage reactions
rather than substitutions.
One such manifestation is observed in the Dimroth rearrangement.
Pyrimidine is also found in meteorites, but scientists still do not know its origin.
Pyrimidine also photolytically decomposes into uracil under UV light.
Synthesis As is often the case with parent heterocyclic
ring systems, the synthesis of pyrimidine is not that common and is usually performed
by removing functional groups from derivatives.
Primary syntheses in quantity involving formamide have been reported.
As a class, pyrimidines are typically synthesized by the “Principal Synthesis” involving
cyclization of beta-dicarbonyl compounds with N-C-N compounds.
Reaction of the former with amidines to give 2-substituted pyrimidines, with urea to give
2-pyrimidiones, and guanidines to give 2-aminopyrimidines are typical.
Pyrimidines can be prepared via the Biginelli reaction.
Many other methods rely on condensation of carbonyls with diamines for instance the synthesis
of 2-Thio-6-methyluracil from thiourea and ethyl acetoacetate or the synthesis of 4-methylpyrimidine
with 4,4-dimethoxy-2-butanone and formamide.
A novel method is by reaction of certain amides with carbonitriles under electrophilic activation
of the amide with 2-chloro-pyridine and trifluoromethanesulfonic anhydride:
Reactions Because of the decreased basicity compared
to pyridine, electrophilic substitution of pyrimidine is less facile.
Protonation or alkylation typically takes place at only one of the ring nitrogen atoms.
Mono N-oxidation occurs by reaction with peracids.
Electrophilic C-substitution of pyrimidine occurs at the 5-position, the least electron
deficient.
Nitration, nitrosation, azo coupling, halogenation, sulfonation, formylation, hydroxymethylation,
and aminomethylation have been observed with substituted pyrimidines.
Nucleophilic C-substitution should be facilitated at the 2-, 4-, and 6-positions but there are
only a few examples.
Amination and hydroxylation has been observed for substituted pyrimidines.
Reactions with Grignard or alkyllithium reagents yield 4-alkyl- or 4-aryl pyrimidine after
aromatization.
Free radical attack has been observed for pyrimidine and photochemical reactions have
been observed for substituted pyrimidines.
Pyrimidine can be hydrogenated to give tetrahydropyrimidine.
Nucleotides
Three nucleobases found in nucleic acids, cytosine, thymine, and uracil, are pyrimidine
derivatives: In DNA and RNA, these bases form hydrogen
bonds with their complementary purines.
Thus, in DNA, the purines adenine and guanine pair up with the pyrimidines thymine and cytosine,
respectively.
In RNA, the complement of adenine is uracil instead of thymine, so the pairs that form
are adenine:uracil and guanine:cytosine.
Very rarely, thymine can appear in RNA, or uracil in DNA.
Other than the three major pyrimidine bases presented, some minor pyrimidine bases can
also occur in nucleic acids.
These minor pyrimidines are usually methylated versions of major ones and are postulated
to have regulatory functions.
These hydrogen bonding modes are for classical Watson-Crick base pairing.
Other hydrogen bonding modes are available in both DNA and RNA, although the additional
2'-hydroxyl group of RNA expands the configurations, through which RNA can form hydrogen bonds.
See also ANRORC mechanism
Pyrimidine metabolism Simple aromatic rings
References