| |||
| |||
| Names | |||
|---|---|---|---|
| Preferred IUPAC name Pyrimidine[1] | |||
| Systematic IUPAC name 1,3-Diazabenzene | |||
| Other names 1,3-Diazine m-Diazine | |||
| Identifiers | |||
| |||
3D model (JSmol) | |||
| 103894 | |||
| ChEBI | |||
| ChEMBL | |||
| ChemSpider |
| ||
| ECHA InfoCard | 100.005.479 | ||
| EC Number |
| ||
| 49324 | |||
| KEGG |
| ||
| MeSH | pyrimidine | ||
| UNII | |||
| |||
| |||
| Properties | |||
| C4H4N2 | |||
| Molar mass | 80.088 g mol−1 | ||
| Density | 1.016 g cm−3 | ||
| Melting point | 20 to 22 °C (68 to 72 °F; 293 to 295 K) | ||
| Boiling point | 123 to 124 °C (253 to 255 °F; 396 to 397 K) | ||
| Miscible (25°C) | |||
| Acidity (pKa) | 1.10[2] (protonated pyrimidine) | ||
| Hazards | |||
| GHS labelling:[1] | |||
  | |||
| Danger | |||
| H226,H318 | |||
| P210,P233,P240,P241,P242,P243,P264+P265,P280,P303+P361+P353,P305+P354+P338,P317,P370+P378,P403+P235,P501 | |||
Except where otherwise noted, data are given for materials in theirstandard state (at 25 °C [77 °F], 100 kPa). | |||
Pyrimidine (C4H4N2;/pɪˈrɪ.mɪˌdiːn,paɪˈrɪ.mɪˌdiːn/) is anaromatic,heterocyclic,organic compound similar topyridine (C5H5N).[3] One of the threediazines (six-membered heterocyclics with twonitrogen atoms in the ring), it has nitrogen atoms at positions 1 and 3 in the ring.[4]: 250 The other diazines arepyrazine (nitrogen atoms at the 1 and 4 positions) andpyridazine (nitrogen atoms at the 1 and 2 positions).
Innucleic acids, three types ofnucleobases are pyrimidinederivatives:cytosine (C),thymine (T), anduracil (U).
The pyrimidine ring system has wide occurrence in nature[5]as substituted and ring fused compounds and derivatives, including thenucleotidescytosine,thymine anduracil,thiamine (vitamin B1) andalloxan. It is also found in many synthetic compounds such asbarbiturates and the HIV drugzidovudine. 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,[5] when Grimaux reported the preparation ofbarbituric acid fromurea andmalonic acid in the presence ofphosphorus oxychloride.[6]The systematic study of pyrimidines began[7] in 1884 withPinner,[8]who synthesized derivatives by condensingethyl acetoacetate withamidines. Pinner first proposed the name “pyrimidin” in 1885.[9] The parent compound was first prepared byGabriel and Colman in 1900,[10][11]by conversion ofbarbituric acid to 2,4,6-trichloropyrimidine followed by reduction usingzinc dust in hot water.
The nomenclature of pyrimidines is straightforward. However, like other heterocyclics,tautomerichydroxyl groups yield complications since they exist primarily in the cyclicamide form. For example, 2-hydroxypyrimidine is more properly named 2-pyrimidone. A partial list of trivial names of various pyrimidines exists.[12]: 5–6
Physical properties are shown in the data box. A more extensive discussion, including spectra, can be found in Brownet al.[12]: 242–244
Per the classification byAlbert,[13]: 56–62 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.[13]: 437–439
Like pyridines, in pyrimidines the π-electron density is decreased to an even greater extent. Therefore,electrophilic aromatic substitution is more difficult whilenucleophilic aromatic substitution is facilitated. An example of the last reaction type is the displacement of theamino group in 2-aminopyrimidine bychlorine[14] and its reverse.[15]
Electronlone pair availability (basicity) is decreased compared to pyridine. Compared to pyridine,N-alkylation andN-oxidation are more difficult. ThepKa 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.[4]: 250 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, includingnitration and halogenation.[12]: 4–8
Reduction inresonance stabilization of pyrimidines may lead to addition and ring cleavage reactions rather than substitutions. One such manifestation is observed in theDimroth rearrangement.
Pyrimidine is also found inmeteorites, but scientists still do not know its origin. Pyrimidine alsophotolytically decomposes intouracil underultraviolet light.[16]
Pyrimidine biosynthesis creates derivatives —like orotate, thymine, cytosine, and uracil—de novo from carbamoyl phosphate and aspartate.
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 involvingformamide 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 withamidines to give 2-substituted pyrimidines, withurea to give 2-pyrimidinones, andguanidines to give 2-aminopyrimidines are typical.[12]: 149–239
Pyrimidines can be prepared via theBiginelli reaction and othermulticomponent reactions.[17] Many other methods rely oncondensation ofcarbonyls with diamines for instance the synthesis of 2-thio-6-methyluracil fromthiourea andethyl acetoacetate[18] or the synthesis of 4-methylpyrimidine with 4,4-dimethoxy-2-butanone andformamide.[19]
A novel method is by reaction ofN-vinyl andN-arylamides withcarbonitriles under electrophilic activation of the amide with 2-chloro-pyridine andtrifluoromethanesulfonic anhydride:[20]
Because of the decreased basicity compared to pyridine, electrophilic substitution of pyrimidine is less facile.Protonation oralkylation typically takes place at only one of the ring nitrogen atoms. Mono-N-oxidation occurs by reaction with peracids.[4]: 253–254
ElectrophilicC-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
NucleophilicC-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.[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]: 17
| Formula | Name | Structure | N1 | N3 | C2 | C4 | C5 | C6 |
|---|---|---|---|---|---|---|---|---|
| C4H4N2O | 2-Pyrimidone |  | -H | =O | -H | –H | –H | |
| C4H4N2O | 4-Pyrimidone | –H | -H | =O | –H | –H | ||
| C4H5N3O | cytosine | -H | =O | –NH2 | –H | –H | ||
| C4H4N2O2 | uracil | -H | –H | =O | =O | –H | –H | |
| C4H3FN2O2 | fluorouracil | -H | –H | =O | =O | –F | –H | |
| C5H6N2O2 | thymine | -H | –H | =O | =O | –CH3 | –H | |
| C4H4N2O3 | barbituric acid | -H | –H | =O | =O | –H | =O | |
| C5H4N2O4 | orotic acid | -H | –H | =O | =O | –H | -COOH |
Threenucleobases found innucleic acids,cytosine (C),thymine (T), anduracil (U), are pyrimidine derivatives:
 |  |  |
Cytosine (C) | Thymine (T) | Uracil (U) |
InDNA andRNA, these bases formhydrogen bonds with theircomplementarypurines. Thus, in DNA, thepurinesadenine (A) andguanine (G) pair up with the pyrimidines thymine (T) and cytosine (C), respectively.
InRNA, the complement ofadenine (A) isuracil (U) instead ofthymine (T), so the pairs that form areadenine:uracil andguanine:cytosine.
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 innucleic acids. These minor pyrimidines are usuallymethylated versions of major ones and are postulated to have regulatory functions.[21]
These hydrogen bonding modes are for classical Watson–Crickbase pairing. Other hydrogen bonding modes ("wobble pairings") are available in both DNA and RNA, although the additional 2′-hydroxyl group ofRNA expands the configurations, through which RNA can form hydrogen bonds.[22]
In March 2015,NASA Ames scientists reported that, for the first time, complexDNA andRNAorganic compounds oflife, includinguracil,cytosine andthymine, have been formed in the laboratory underouter space conditions, using starting chemicals, such as pyrimidine, found inmeteorites. Pyrimidine, likepolycyclic aromatic hydrocarbons (PAHs), the most carbon-rich chemical found in theuniverse, may have been formed inred giants or ininterstellar dust and gas clouds.[23][24][25]
In order to understand howlife arose, knowledge is required of the chemical pathways that permit formation of the key building blocks of life under plausibleprebiotic conditions. TheRNA world hypothesis holds that in theprimordial soup there existed free-floatingribonucleotides, the fundamental molecules that combine in series to formRNA. 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 andpurine nucleotides, both of which are necessary for reliable information transfer, and thus natural selection and Darwinianevolution. Becker et al. showed how pyrimidinenucleosides can be synthesized from small molecules andribose, driven solely by wet-dry cycles.[26] Purine nucleosides can be synthesized by a similar pathway. 5’-mono-and diphosphates also form selectively from phosphate-containing minerals, allowing concurrent formation ofpolyribonucleotides 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.
| International | |
|---|---|
| National | |
| Other | |
