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Pyrimidine (; ) is an
aromatic In chemistry, aromaticity is a chemical property of cyclic ( ring-shaped), ''typically'' planar (flat) molecular structures with pi bonds in resonance (those containing delocalized electrons) that gives increased stability compared to satur ...
, heterocyclic,
organic compound In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen or carbon-carbon bonds. Due to carbon's ability to catenate (form chains with other carbon atoms), millions of organic compounds are known. Th ...
similar to
pyridine Pyridine is a basic heterocyclic organic compound with the chemical formula . It is structurally related to benzene, with one methine group replaced by a nitrogen atom. It is a highly flammable, weakly alkaline, water-miscible liquid w ...
(). One of the three diazines (six-membered heterocyclics with two
nitrogen Nitrogen is the chemical element with the symbol N and atomic number 7. Nitrogen is a nonmetal and the lightest member of group 15 of the periodic table, often called the pnictogens. It is a common element in the universe, estimated at se ...
atoms in the ring), it has nitrogen atoms at positions 1 and 3 in the ring. 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 Nucleobases, also known as ''nitrogenous bases'' or often simply ''bases'', are nitrogen-containing biological compounds that form nucleosides, which, in turn, are components of nucleotides, with all of these monomers constituting the bas ...
are pyrimidine
derivative In mathematics, the derivative of a function of a real variable measures the sensitivity to change of the function value (output value) with respect to a change in its argument (input value). Derivatives are a fundamental tool of calculus. ...
s:
cytosine Cytosine () ( symbol C or Cyt) is one of the four nucleobases found in DNA and RNA, along with adenine, guanine, and thymine ( uracil in RNA). It is a pyrimidine derivative, with a heterocyclic aromatic ring and two substituents attached ( ...
(C),
thymine Thymine () ( symbol T or Thy) is one of the four nucleobases in the nucleic acid of DNA that are represented by the letters G–C–A–T. The others are adenine, guanine, and cytosine. Thymine is also known as 5-methyluracil, a pyrimidin ...
(T), and
uracil Uracil () (symbol U or Ura) is one of the four nucleobases in the nucleic acid RNA. The others are adenine (A), cytosine (C), and guanine (G). In RNA, uracil binds to adenine via two hydrogen bonds. In DNA, the uracil nucleobase is replaced b ...
(U).


Occurrence and history

The pyrimidine ring system has wide occurrence in nature as substituted and ring fused compounds and derivatives, including the nucleotides
cytosine Cytosine () ( symbol C or Cyt) is one of the four nucleobases found in DNA and RNA, along with adenine, guanine, and thymine ( uracil in RNA). It is a pyrimidine derivative, with a heterocyclic aromatic ring and two substituents attached ( ...
,
thymine Thymine () ( symbol T or Thy) is one of the four nucleobases in the nucleic acid of DNA that are represented by the letters G–C–A–T. The others are adenine, guanine, and cytosine. Thymine is also known as 5-methyluracil, a pyrimidin ...
and
uracil Uracil () (symbol U or Ura) is one of the four nucleobases in the nucleic acid RNA. The others are adenine (A), cytosine (C), and guanine (G). In RNA, uracil binds to adenine via two hydrogen bonds. In DNA, the uracil nucleobase is replaced b ...
,
thiamine Thiamine, also known as thiamin and vitamin B1, is a vitamin, an essential micronutrient, that cannot be made in the body. It is found in food and commercially synthesized to be a dietary supplement or medication. Phosphorylated forms of thi ...
(vitamin B1) and
alloxan Alloxan, sometimes referred to as ''alloxan hydrate'', is the name of the organic compound with the formula OC(N(H)CO)2C(OH)2. It is classified as a derivative of pyrimidine. The anhydrous derivative OC(N(H)CO)2CO is also known, as well as a dim ...
. It is also found in many synthetic compounds such as
barbiturate Barbiturates are a class of depressant drugs that are chemically derived from barbituric acid. They are effective when used medically as anxiolytics, hypnotics, and anticonvulsants, but have physical and psychological addiction potential a ...
s and the HIV drug, zidovudine. Although pyrimidine derivatives such as 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
urea Urea, also known as carbamide, is an organic compound with chemical formula . This amide has two amino groups (–) joined by a carbonyl functional group (–C(=O)–). It is thus the simplest amide of carbamic acid. Urea serves an important ...
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 The organic compound ethyl acetoacetate (EAA) is the ethyl ester of acetoacetic acid. It is a colorless liquid. It is widely used as a chemical intermediate in the production of a wide variety of compounds. It is used as a flavoring for food. ...
with amidines. Pinner first proposed the name “pyrimidin” in 1885. The parent compound was first prepared by
Gabriel In Abrahamic religions (Judaism, Christianity and Islam), Gabriel (); Greek: grc, Γαβριήλ, translit=Gabriḗl, label=none; Latin: ''Gabriel''; Coptic: cop, Ⲅⲁⲃⲣⲓⲏⲗ, translit=Gabriêl, label=none; Amharic: am, ገብ� ...
and Colman in 1900, by conversion of barbituric acid to 2,4,6-trichloropyrimidine followed by reduction using
zinc Zinc is a chemical element with the symbol Zn and atomic number 30. Zinc is a slightly brittle metal at room temperature and has a shiny-greyish appearance when oxidation is removed. It is the first element in group 12 (IIB) of the periodi ...
dust in hot water.


Nomenclature

The nomenclature of pyrimidines is straightforward. However, like other heterocyclics,
tautomer Tautomers () are structural isomers (constitutional isomers) of chemical compounds that readily interconvert. The chemical reaction interconverting the two is called tautomerization. This conversion commonly results from the relocation of a hy ...
ic
hydroxyl In chemistry, a hydroxy or hydroxyl group is a functional group with the chemical formula and composed of one oxygen atom covalently bonded to one hydrogen atom. In organic chemistry, alcohols and carboxylic acids contain one or more hydrox ...
groups yield complications since they exist primarily in the cyclic
amide In organic chemistry, an amide, also known as an organic amide or a carboxamide, is a compound with the general formula , where R, R', and R″ represent organic groups or hydrogen atoms. The amide group is called a peptide bond when it i ...
form. For example, 2-hydroxypyrimidine is more properly named 2-pyrimidone. 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 heterocycles 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 Chlorine is a chemical element with the symbol Cl and atomic number 17. The second-lightest of the halogens, it appears between fluorine and bromine in the periodic table and its properties are mostly intermediate between them. Chlorine i ...
and its reverse. Electron
lone pair In chemistry, a lone pair refers to a pair of valence electrons that are not shared with another atom in a covalent bondIUPAC '' Gold Book'' definition''lone (electron) pair''/ref> and is sometimes called an unshared pair or non-bonding pair. L ...
availability (
basicity In chemistry, there are three definitions in common use of the word base, known as Arrhenius bases, Brønsted bases, and Lewis bases. All definitions agree that bases are substances that react with acids, as originally proposed by G.-F. R ...
) is decreased compared to pyridine. Compared to pyridine, ''N''-alkylation and ''N''-oxidation are more difficult. The p''K''a 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 substituents 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
meteorite A meteorite is a solid piece of debris from an object, such as a comet, asteroid, or meteoroid, that originates in outer space and survives its passage through the atmosphere to reach the surface of a planet or moon. When the original object ...
s, but scientists still do not know its origin. Pyrimidine also photolytically decomposes into
uracil Uracil () (symbol U or Ura) is one of the four nucleobases in the nucleic acid RNA. The others are adenine (A), cytosine (C), and guanine (G). In RNA, uracil binds to adenine via two hydrogen bonds. In DNA, the uracil nucleobase is replaced b ...
under
ultraviolet Ultraviolet (UV) is a form of electromagnetic radiation with wavelength from 10 nm (with a corresponding frequency around 30  PHz) to 400 nm (750  THz), shorter than that of visible light, but longer than X-rays. UV radiation ...
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 β-di carbonyl compounds with N–C–N compounds. Reaction of the former with amidines to give 2-substituted pyrimidines, with
urea Urea, also known as carbamide, is an organic compound with chemical formula . This amide has two amino groups (–) joined by a carbonyl functional group (–C(=O)–). It is thus the simplest amide of carbamic acid. Urea serves an important ...
to give 2- pyrimidinones, and guanidines to give 2- aminopyrimidines are typical. Pyrimidines can be prepared via the Biginelli reaction and other multicomponent reactions. Many other methods rely on
condensation Condensation is the change of the state of matter from the gas phase into the liquid phase, and is the reverse of vaporization. The word most often refers to the water cycle. It can also be defined as the change in the state of water vapo ...
of carbonyls with diamines for instance the synthesis of 2-thio-6-methyluracil from thiourea and
ethyl acetoacetate The organic compound ethyl acetoacetate (EAA) is the ethyl ester of acetoacetic acid. It is a colorless liquid. It is widely used as a chemical intermediate in the production of a wide variety of compounds. It is used as a flavoring for food. ...
or the synthesis of 4-methylpyrimidine with 4,4-dimethoxy-2-butanone and formamide. A novel method is by reaction of ''N''-vinyl and ''N''-aryl
amide In organic chemistry, an amide, also known as an organic amide or a carboxamide, is a compound with the general formula , where R, R', and R″ represent organic groups or hydrogen atoms. The amide group is called a peptide bond when it i ...
s with carbonitriles under electrophilic activation of the amide with 2-chloro-pyridine and trifluoromethanesulfonic anhydride: : :Thymine :Patented 2013, the current method used for the manufacturing of thymine is done by dissolving the molecule Methyl methacrylate in a solvent of methanol. The solvent is to be maintained at a pH of 8.9-9.1by addition of a base like sodium hydroxide and a temperature of 0-10 degrees celsius. 30% Hydrogen peroxide is then added to the solution to act as an oxygen giver and form the molecule 2,3-epoxy-2-methyl methacrylate, and the solution is mixed for 2-20 hours at the maintained conditions. After this period, urea is dropped into the flask containing the solution and the solution is heated past the boiling point of the methanol and refluxed for 1-3 hours (boiled and fed back into the solution). After this period, the thymine should have formed in the solution. The solution is then concentrated by removing excess methanol through keeping the heat at 65 degrees celsius (slightly above boiling point of methanol) and allowing the methanol to vaporize out of the solution instead of reflux. The concentrated solution is then neutralized by adding hydrochloric acid, forming waste sodium chloride and the desired thymine crystals among the solution. The solution is temporarily warmed up to re- dissolve the crystals, then passed through a reverse osmosis filter to remove the sodium chloride formed and isolate the solution containing the thymine. This solution is then air-dried to yield pure thymine crystals in the form of a white powder.


Reactions

Because of the decreased basicity compared to pyridine, electrophilic substitution of pyrimidine is less facile.
Protonation In chemistry, protonation (or hydronation) is the adding of a proton (or hydron, or hydrogen cation), (H+) to an atom, molecule, or ion, forming a conjugate acid. (The complementary process, when a proton is removed from a Brønsted–Lowry acid ...
or
alkylation Alkylation is the transfer of an alkyl group from one molecule to another. The alkyl group may be transferred as an alkyl carbocation, a free radical, a carbanion, or a carbene (or their equivalents). Alkylating agents are reagents for effectin ...
typically takes place at only one of the ring nitrogen atoms. Mono-''N''-oxidation occurs by reaction with peracids.
Electrophilic In chemistry, an electrophile is a chemical species that forms bonds with nucleophiles by accepting an electron pair. Because electrophiles accept electrons, they are Lewis acids. Most electrophiles are positively charged, have an atom that carr ...
''C''-substitution of pyrimidine occurs at the 5-position, the least electron-deficient. Nitration, nitrosation, azo coupling,
halogen The halogens () are a group in the periodic table consisting of five or six chemically related elements: fluorine (F), chlorine (Cl), bromine (Br), iodine (I), astatine (At), and tennessine (Ts). In the modern IUPAC nomenclature, this grou ...
ation, 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 have 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.


Derivatives


Nucleotides

Three
nucleobase Nucleobases, also known as ''nitrogenous bases'' or often simply ''bases'', are nitrogen-containing biological compounds that form nucleosides, which, in turn, are components of nucleotides, with all of these monomers constituting the basi ...
s found in
nucleic acid Nucleic acids are biopolymers, macromolecules, essential to all known forms of life. They are composed of nucleotides, which are the monomers made of three components: a 5-carbon sugar, a phosphate group and a nitrogenous base. The two main ...
s,
cytosine Cytosine () ( symbol C or Cyt) is one of the four nucleobases found in DNA and RNA, along with adenine, guanine, and thymine ( uracil in RNA). It is a pyrimidine derivative, with a heterocyclic aromatic ring and two substituents attached ( ...
(C),
thymine Thymine () ( symbol T or Thy) is one of the four nucleobases in the nucleic acid of DNA that are represented by the letters G–C–A–T. The others are adenine, guanine, and cytosine. Thymine is also known as 5-methyluracil, a pyrimidin ...
(T), and
uracil Uracil () (symbol U or Ura) is one of the four nucleobases in the nucleic acid RNA. The others are adenine (A), cytosine (C), and guanine (G). In RNA, uracil binds to adenine via two hydrogen bonds. In DNA, the uracil nucleobase is replaced b ...
(U), are pyrimidine derivatives: : In DNA and RNA, these bases form
hydrogen bond In chemistry, a hydrogen bond (or H-bond) is a primarily electrostatic force of attraction between a hydrogen (H) atom which is covalently bound to a more electronegative "donor" atom or group (Dn), and another electronegative atom bearing a l ...
s with their complementary
purine Purine is a heterocyclic aromatic organic compound that consists of two rings ( pyrimidine and imidazole) fused together. It is water-soluble. Purine also gives its name to the wider class of molecules, purines, which include substituted purines ...
s. Thus, in DNA, the purines
adenine Adenine () ( symbol A or Ade) is a nucleobase (a purine derivative). It is one of the four nucleobases in the nucleic acid of DNA that are represented by the letters G–C–A–T. The three others are guanine, cytosine and thymine. Its deriv ...
(A) and
guanine Guanine () ( symbol G or Gua) is one of the four main nucleobases found in the nucleic acids DNA and RNA, the others being adenine, cytosine, and thymine ( uracil in RNA). In DNA, guanine is paired with cytosine. The guanine nucleoside is ...
(G) pair up with the pyrimidines thymine (T) and cytosine (C), respectively. In RNA, the complement of
adenine Adenine () ( symbol A or Ade) is a nucleobase (a purine derivative). It is one of the four nucleobases in the nucleic acid of DNA that are represented by the letters G–C–A–T. The three others are guanine, cytosine and thymine. Its deriv ...
(A) is
uracil Uracil () (symbol U or Ura) is one of the four nucleobases in the nucleic acid RNA. The others are adenine (A), cytosine (C), and guanine (G). In RNA, uracil binds to adenine via two hydrogen bonds. In DNA, the uracil nucleobase is replaced b ...
(U) instead of
thymine Thymine () ( symbol T or Thy) is one of the four nucleobases in the nucleic acid of DNA that are represented by the letters G–C–A–T. The others are adenine, guanine, and cytosine. Thymine is also known as 5-methyluracil, a pyrimidin ...
(T), so the pairs that form are
adenine Adenine () ( symbol A or Ade) is a nucleobase (a purine derivative). It is one of the four nucleobases in the nucleic acid of DNA that are represented by the letters G–C–A–T. The three others are guanine, cytosine and thymine. Its deriv ...
:
uracil Uracil () (symbol U or Ura) is one of the four nucleobases in the nucleic acid RNA. The others are adenine (A), cytosine (C), and guanine (G). In RNA, uracil binds to adenine via two hydrogen bonds. In DNA, the uracil nucleobase is replaced b ...
and
guanine Guanine () ( symbol G or Gua) is one of the four main nucleobases found in the nucleic acids DNA and RNA, the others being adenine, cytosine, and thymine ( uracil in RNA). In DNA, guanine is paired with cytosine. The guanine nucleoside is ...
:
cytosine Cytosine () ( symbol C or Cyt) is one of the four nucleobases found in DNA and RNA, along with adenine, guanine, and thymine ( uracil in RNA). It is a pyrimidine derivative, with a heterocyclic aromatic ring and two substituents attached ( ...
. Very rarely, thymine can appear in RNA, or uracil in DNA, but when the other three major pyrimidine bases are represented, 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 pair A base pair (bp) is a fundamental unit of double-stranded nucleic acids consisting of two nucleobases bound to each other by hydrogen bonds. They form the building blocks of the DNA double helix and contribute to the folded structure of both D ...
ing. 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 compound In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen or carbon-carbon bonds. Due to carbon's ability to catenate (form chains with other carbon atoms), millions of organic compounds are known. Th ...
s of
life Life is a quality that distinguishes matter that has biological processes, such as signaling and self-sustaining processes, from that which does not, and is defined by the capacity for growth, reaction to stimuli, metabolism, energy ...
, including
uracil Uracil () (symbol U or Ura) is one of the four nucleobases in the nucleic acid RNA. The others are adenine (A), cytosine (C), and guanine (G). In RNA, uracil binds to adenine via two hydrogen bonds. In DNA, the uracil nucleobase is replaced b ...
,
cytosine Cytosine () ( symbol C or Cyt) is one of the four nucleobases found in DNA and RNA, along with adenine, guanine, and thymine ( uracil in RNA). It is a pyrimidine derivative, with a heterocyclic aromatic ring and two substituents attached ( ...
and
thymine Thymine () ( symbol T or Thy) is one of the four nucleobases in the nucleic acid of DNA that are represented by the letters G–C–A–T. The others are adenine, guanine, and cytosine. Thymine is also known as 5-methyluracil, a pyrimidin ...
, have been formed in the laboratory under
outer space Outer space, commonly shortened to space, is the expanse that exists beyond Earth and its atmosphere and between celestial bodies. Outer space is not completely empty—it is a near-perfect vacuum containing a low density of particles, pred ...
conditions, using starting chemicals, such as pyrimidine, found in
meteorite A meteorite is a solid piece of debris from an object, such as a comet, asteroid, or meteoroid, that originates in outer space and survives its passage through the atmosphere to reach the surface of a planet or moon. When the original object ...
s. Pyrimidine, like polycyclic aromatic hydrocarbons (PAHs), the most carbon-rich chemical found in the
universe The universe is all of space and time and their contents, including planets, stars, galaxies, and all other forms of matter and energy. The Big Bang theory is the prevailing cosmological description of the development of the univers ...
, may have been formed in red giants or in
interstellar dust Cosmic dust, also called extraterrestrial dust, star dust or space dust, is dust which exists in outer space, or has fallen on Earth. Most cosmic dust particles measure between a few molecules and 0.1 mm (100 micrometers). Larger particles are c ...
and gas clouds., also published as


Prebiotic synthesis of pyrimidine nucleotides

In order to understand how
life Life is a quality that distinguishes matter that has biological processes, such as signaling and self-sustaining processes, from that which does not, and is defined by the capacity for growth, reaction to stimuli, metabolism, energy ...
arose, knowledge is required of the chemical pathways that permit formation of the key building blocks of life under plausible prebiotic conditions. The RNA world hypothesis holds that in the primordial soup there existed free-floating
ribonucleotide In biochemistry, a ribonucleotide is a nucleotide containing ribose as its pentose component. It is considered a molecular precursor of nucleic acids. Nucleotides are the basic building blocks of DNA and RNA. Ribonucleotides themselves are basic ...
s, the fundamental molecules that combine in series to form RNA. Complex molecules such as RNA must have emerged from relatively small molecules whose reactivity was governed by physico-chemical processes. RNA is composed of pyrimidine and
purine Purine is a heterocyclic aromatic organic compound that consists of two rings ( pyrimidine and imidazole) fused together. It is water-soluble. Purine also gives its name to the wider class of molecules, purines, which include substituted purines ...
nucleotides, both of which are necessary for reliable information transfer, and thus natural selection and Darwinian
evolution Evolution is change in the heritable characteristics of biological populations over successive generations. These characteristics are the expressions of genes, which are passed on from parent to offspring during reproduction. Variation ...
. Becker et al. showed how pyrimidine nucleosides can be synthesized from small molecules and
ribose Ribose is a simple sugar and carbohydrate with molecular formula C5H10O5 and the linear-form composition H−(C=O)−(CHOH)4−H. The naturally-occurring form, , is a component of the ribonucleotides from which RNA is built, and so this com ...
, driven solely by wet-dry cycles.Becker S, Feldmann J, Wiedemann S, Okamura H, Schneider C, Iwan K, Crisp A, Rossa M, Amatov T, Carell T. Unified prebiotically plausible synthesis of pyrimidine and purine RNA ribonucleotides. Science. 2019 Oct 4;366(6461):76-82. doi: 10.1126/science.aax2747. PMID 31604305 Purine nucleosides can be synthesized by a similar pathway. 5’-mono-and diphosphates also form selectively from phosphate-containing minerals, allowing concurrent formation of polyribonucleotides with both the pyrimidine and purine bases. Thus a reaction network towards the pyrimidine and purine RNA building blocks can be established starting from simple atmospheric or volcanic molecules.


See also

* ANRORC mechanism *
Purine Purine is a heterocyclic aromatic organic compound that consists of two rings ( pyrimidine and imidazole) fused together. It is water-soluble. Purine also gives its name to the wider class of molecules, purines, which include substituted purines ...
* Pyrimidine metabolism * Simple aromatic rings * Transition * Transversion


References

{{Authority control Biomolecules Aromatic bases Simple aromatic rings