Pyrimidine

Pyrimidine is an aromatic heterocyclic organic compound similar to

pyridine.[3] One of the three diazines (six-membered heterocyclics
Pyrimidine
with two nitrogen atoms in the ring), it has the nitrogen atoms at
positions 1 and 3 in the ring.[4]:250 The other diazines are pyrazine
(nitrogen atoms at the 1 and 4 positions) and pyridazine (nitrogen
atoms at the 1 and 2 positions). In nucleic acids, three types of
nucleobases are pyrimidine derivatives: cytosine (C), thymine (T),
and uracil (U).

Contents
Occurrence and history
Nomenclature
Physical properties Names
Chemical properties Preferred IUPAC name
Synthesis Pyrimidine[1]
Reactions Systematic IUPAC name
1,3-Diazabenzene
Nucleotides
Other names
Theoretical aspects
1,3-Diazine
See also m-Diazine
References 1,3-Diazacyclohexa-1,3,5-triene
Identifiers

Occurrence and history CAS Number 289-95-2 (http://www.

commonchemistry.or
The pyrimidine ring system has wide g/ChemicalDetail.asp
occurrence in nature[5] as substituted and ring x?ref=289-95-2)
fused compounds and derivatives, including the 3D model Interactive image (htt
nucleotides cytosine, thymine and uracil, (JSmol)
ps://chemapps.stolaf.
thiamine (vitamin B1) and alloxan. It is also
found in many synthetic compounds such as edu/jmol/jmol.php?m
barbiturates and the HIV drug, zidovudine. odel=c1cncnc1)
Although pyrimidine derivatives such as uric ChEBI CHEBI:16898 (http
Pinner's 1885 acid and alloxan were known in the early 19th
s://www.ebi.ac.uk/ch
structure for century, a laboratory synthesis of a pyrimidine
ebi/searchId.do?cheb
pyrimidine was not carried out until 1879,[5] when
Grimaux reported the preparation of barbituric iId=16898)
acid from urea and malonic acid in the presence ChEMBL ChEMBL15562 (http
of phosphorus oxychloride.[6] The systematic study of pyrimidines s://www.ebi.ac.uk/ch
began[7] in 1884 with Pinner,[8] who synthesized derivatives by embldb/index.php/co
condensing ethyl acetoacetate with amidines. Pinner first proposed
the name “pyrimidin” in 1885.[9] The parent compound was first
prepared by Gabriel and Colman in 1900,[10] [11] by conversion of mpound/inspect/ChE
barbituric acid to 2,4,6-trichloropyrimidine followed by reduction MBL15562)
using zinc dust in hot water.
ChemSpider 8903 (http://www.che
mspider.com/Chemic
Nomenclature al-Structure.8903.ht
ml)
The nomenclature of pyrimidines is straightforward. However, like
other heterocyclics, tautomeric hydroxyl groups yield complications ECHA 100.005.479 (https://
since they exist primarily in the cyclic amide form. For example, 2- InfoCard echa.europa.eu/subs
hydroxypyrimidine is more properly named 2-pyrimidone. A partial tance-information/-/s
list of trivial names of various pyrimidines exists.[12]:5–6 ubstanceinfo/100.00
5.479)
Physical properties KEGG C00396 (https://www.
kegg.jp/entry/C0039
Physical properties are shown in the data box. A more extensive 6)
discussion, including spectra, can be found in Brown et
MeSH pyrimidine (https://w
al.[12]:242–244
ww.nlm.nih.gov/cgi/m
esh/2014/MB_cgi?m
Chemical properties ode=&term=pyrimidin
e)
Per the classification by Albert[13]:56–62 six-membered heterocycles
PubChem 9260 (https://pubche
can be described as π-deficient. Substitution by electronegative CID
groups or additional nitrogen atoms in the ring significantly increase m.ncbi.nlm.nih.gov/c
the π-deficiency. These effects also decrease the basicity.[13]:437–439 ompound/9260)
CompTox DTXSID1051228 (htt
Like pyridines, in pyrimidines the π-electron density is decreased to Dashboard
an even greater extent. Therefore, electrophilic aromatic substitution ps://comptox.epa.go
(EPA)
is more difficult while nucleophilic aromatic substitution is v/dashboard/DTXSID
facilitated. An example of the last reaction type is the displacement 1051228)
of the amino group in 2-aminopyrimidine by chlorine[14] and its InChI
reverse.[15]
InChI=1S/C4H4N2/c1-2-5-4-6-3-1/h1-4H
Key: CZPWVGJYEJSRLH-UHFFFAOYSA-N
Electron lone pair availability (basicity) is decreased compared to
pyridine. Compared to pyridine, N-alkylation and N-oxidation are InChI=1/C4H4N2/c1-2-5-4-6-3-1/h1-4H
more difficult. The pKa value for protonated pyrimidine is 1.23 Key: CZPWVGJYEJSRLH-UHFFFAOYAT
compared to 5.30 for pyridine. Protonation and other electrophilic
SMILES
additions will occur at only one nitrogen due to further deactivation
c1cncnc1
by the second nitrogen.[4]:250 The 2-, 4-, and 6- positions on the
pyrimidine ring are electron deficient analogous to those in pyridine Properties
and nitro- and dinitrobenzene. The 5-position is less electron Chemical C4H4N2
deficient and substituents there are quite stable. However, formula
electrophilic substitution is relatively facile at the 5-position, Molar mass 80.088 g mol−1
including nitration and halogenation.[12]:4–8
Density 1.016 g cm−3
Reduction in resonance stabilization of pyrimidines may lead to Melting point 20 to 22 °C (68 to
addition and ring cleavage reactions rather than substitutions. One 72 °F; 293 to 295 K)
such manifestation is observed in the Dimroth rearrangement.
Boiling point 123 to 124 °C (253 to
255 °F; 396 to 397 K)
Solubility in Miscible (25°C)
Pyrimidine is also found in meteorites, but scientists still do not water
know its origin. Pyrimidine also photolytically decomposes into Acidity (pKa) 1.10[2] (protonated
uracil under ultraviolet light.[16] pyrimidine)
Except where otherwise noted, data
Synthesis are given for materials in their
standard state (at 25 °C [77 °F],
100 kPa).
As is often the case with parent heterocyclic ring systems, the
synthesis of pyrimidine is not that common and is usually performed verify (what is ?)
by removing functional groups from derivatives. Primary syntheses Infobox references
in quantity involving formamide have been reported.[12]:241–242

As a class, pyrimidines are typically synthesized by the principal synthesis involving cyclization of β-
dicarbonyl compounds with N–C–N compounds. Reaction of the former with amidines to give 2-substituted
pyrimidines, with urea to give 2-pyrimidinones, and guanidines to give 2-aminopyrimidines are
typical.[12]:149–239

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[17] or the synthesis of 4-methylpyrimidine with 4,4-dimethoxy-2-butanone and formamide.[18]

A novel method is by reaction of N-vinyl and N-aryl amides with carbonitriles under electrophilic activation
of the amide with 2-chloro-pyridine and trifluoromethanesulfonic anhydride:[19]

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.[4]:253–254

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.[12]:9–13

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.[12]:14–15
Free radical attack has been observed for pyrimidine and photochemical reactions have been observed for
substituted pyrimidines.[12]:15–16 Pyrimidine can be hydrogenated to give tetrahydropyrimidine.[12](pp17)

Nucleotides
Three nucleobases found in nucleic acids, cytosine (C), thymine
(T), and uracil (U), are pyrimidine derivatives:

Cytosine (C) Thymine (T) Uracil (U)

In DNA and RNA, these bases form hydrogen bonds with their
complementary purines. Thus, in DNA, the purines adenine (A)
and guanine (G) pair up with the pyrimidines thymine (T) and
cytosine (C), respectively.

In RNA, the complement of adenine (A) is uracil (U) instead of

thymine (T), so the pairs that form are adenine:uracil and
guanine:cytosine.

Very rarely, thymine can appear in RNA, or uracil in DNA, but

The pyrimidine nitrogen bases found in
when the other three major pyrimidine bases are represented,
DNA and RNA.
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.[20]

These hydrogen bonding modes are for classical Watson–Crick base pairing. Other hydrogen bonding
modes ("wobble pairings") 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.

Theoretical aspects
In March 2015, NASA Ames scientists reported that, for the first time, complex DNA and RNA organic
compounds of life, including uracil, cytosine and thymine, have been formed in the laboratory under outer
space conditions, using starting chemicals, such as pyrimidine, found in meteorites. Pyrimidine, like
polycyclic aromatic hydrocarbons (PAHs), the most carbon-rich chemical found in the universe, may have
been formed in red giants or in interstellar dust and gas clouds.[21][22][23]

See also
ANRORC mechanism Simple aromatic rings
Purine Transition
Pyrimidine metabolism Transversion
References
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Names 2013 (Blue Book). Cambridge: The Royal Society of Chemistry. 2014. p. 141.
doi:10.1039/9781849733069-FP001 (https://doi.org/10.1039%2F9781849733069-FP001).
ISBN 978-0-85404-182-4.
2. Brown, H. C.; et al. (1955). Baude, E. A.; F. C., Nachod (eds.). Determination of Organic
Structures by Physical Methods. New York, NY: Academic Press.
3. Gilchrist, Thomas Lonsdale (1997). Heterocyclic chemistry. New York: Longman. ISBN 978-0-
582-27843-1.
4. Joule, John A.; Mills, Keith, eds. (2010). Heterocyclic Chemistry (5th ed.). Oxford: Wiley.
ISBN 978-1-405-13300-5.
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(http://homepage.univie.ac.at/mario.barbatti/papers/pyrazine_pyrimidine/pyrimidine.pdf) (PDF).
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New York: Wiley. p. 235.
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p://visualiseur.bnf.fr/ark:/12148/bpt6k90702f/f761.image) [On the effect of acetylacetonate
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Fcber.190003303173).
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doi:10.1039/JR9510002323 (https://doi.org/10.1039%2FJR9510002323).
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tps://doi.org/10.15227%2Forgsyn.035.0034).; Collective Volume, 4, p. 182
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