Indeno(1,2,3-cd)pyrene

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The correct title of this article is Indeno[1,2,3-cd]pyrene. The substitution of any brackets is due to technical restrictions.
Indeno(1,2,3-cd)pyrene
Indeno(1,2,3-cd)pyrene 200.svg
Names
Other names
    • o-Phenylenepyrene
    • 1,10-(o-Phenylene)pyrene
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.005.359 OOjs UI icon edit-ltr-progressive.svg
EC Number
  • 205-893-2
KEGG
PubChem CID
RTECS number
  • NK9300000
UNII
UN number 3077
  • InChI=1S/C22H12/c1-2-7-17-16(6-1)18-11-10-14-9-8-13-4-3-5-15-12-19(17)22(18)21(14)20(13)15/h1-12H
    Key: SXQBHARYMNFBPS-UHFFFAOYSA-N
  • C1=CC=C2C(=C1)C3=C4C2=CC5=CC=CC6=C5C4=C(C=C6)C=C3
Properties
C22H12
Molar mass 276.338 g·mol−1
AppearanceYellow crystals [1]
Melting point 164 °C (327 °F; 437 K) [1]
Boiling point 536 °C (997 °F; 809 K) [1]
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Indeno[1,2,3-cd]pyrene is a polycyclic aromatic hydrocarbon (PAH), one of 16 PAHs generally measured in studies of environmental exposure and air pollution. Many compounds of this class are formed when burning coal, oil, gas, wood, household waste and tobacco, and can bind to or form small particles in the air. The compounds are known to have toxic, mutagenic and/or carcinogenic properties. Over 100 different PAHs have been identified in environmental samples. One of these 16 is Indeno[1,2,3-cd]pyrene (IP). IP is the combination of an indeno molecule and a pyrene molecule with a fluoranthene network. [2] In 1962, the National Cancer Institute reported that indeno[1,2,3-cd]pyrene has a slight tumor activity. [3] This was confirmed in 1973 by the IARC in mice testing. [4]

Contents

Production

In nature, IP is formed when burning coal, oil, gas, wood, household waste and tobacco. There are various pathways in which nature can produce PAHs, but the most important mechanism to form such compounds is based on hydrogen abstraction-acetylene addition (HACA). This is accepted as the major reaction route to form PAHs in combustion flames. [5]

When producing IP in the lab, there are two efficient synthetic approaches. The first one is by forming a reactive diazonium intermediate out of 2-(pyren-1-yl)aniline. When this intermediate is formed, it can react with a tethered polycyclic aromatic moiety at room temperature. This is done by an intramolecular aromatic substitution. [6] The reactivity of this reaction is controlled by the substrate concentration and its stoichiometry. tBuONO is used as a reagent (figure 1). [7] The second way to synthesize IP is with a one-pot synthesis. With 4-bromopyrene as starting material and by adding Pd3(dba)2, P(Cy)2 and BDU in DMF, the final product will form (figure 2). [8]

Chemical properties

Reactions with electrophiles

Indeno[1,2,3-cd]pyrene can undergo reaction with bromine or fluorine to 12-bromoindeno[1,2,3-cd]pyrene [9] and 2-fluoroindeno[1,2,3-cd]pyrene [10] respectively.

Nitration

The reaction with indeno[1,2,3-cd]pyrene can be performed using NHO3 in an acetyl nitrate solution. The reaction yielded IP-NO2 which was regioselective, the nitrate group being added mainly to the 12 position which is the same as the Friedel-Crafts acylation and bromination [2]

Physical properties

Indeno[1,2,3-cd]pyrene (IP) is classified as a polycyclic aromatic hydrocarbon (PAH) and appears as a yellow crystal. It contains five benzene rings and one cyclopentane, resulting in a planar molecule. There is no stereochemistry present in IP, but there are resonance structures due to benzene’s conjugated pi electrons. They can move freely within the cycling rings, providing stabilization energy. [11]

Ecological effect

Different studies have been conducted to investigate the ecological effects of several PAHs, including indeno(1,2,3-cd)pyrene. The International Agency for Research on Cancer (IARC) published results claiming that the compound is carcinogenic in several experimental animals. [12] Another research group studied phototoxic effects of the compound and they found these only at very high levels in a cell line of the rainbow trout. Since these levels can never be reached in water for indeno(1,2,3-cd)pyrene, even when it is maximally dissolved, it will not have any implications for aquatic animals. [13] It does not dissolve well because of its lipophilic and thus hydrophobic character. This is beneficial for the environment, as lipophilicity is inversely proportional to ecotoxicity because of this water solubility. Therefore this does not only prevent phototoxicity but also a large part of toxicity in general. [14] Some Swedish researchers have also conducted research into the PAH levels in sewage treatment plants in Sweden. They induced EROD activity, which is a measure for toxicity in chicken embryo livers, by incubating with PAH extracts from the sludge. Indeno(1,2,3-cd)pyrene, which was one of the researched PAHs in this paper, contributed together with 5 other selected PAHs to only a minor part of the EROD activity. Therefore, the indeno(1,2,3-cd)pyrene levels did induce some toxicity in the chicken embryo liver, but just a slight amount at its own in all probability. [15]

Mechanism

Indeno(1,2,3-cd)pyrene are among other PAHs considered as possible carcinogens to humans. [12] The PAH family consists of similar molecules and therefore they have a similar mechanism of causing cancer in vivo. The molecule is metabolized in the body by the cytochrome P450 system, resulting in metabolites containing nitro, quinone or hydroxyl groups. [16] This was in line with metabolites formed from other PAHs. [17] The nitro and quinone containing compound turned out to be cytotoxic or carcinogenic, while the hydroxyl containing metabolite did not show any toxicity or carcinogenicity. PAHs including indeno(1,2,3-cd)pyrene may be genotoxic. When PAHs are hydrolyzed, very reactive epoxide groups can be created at certain regions in the molecule where the molecule is extra reactive compared to the rest. These groups can ultimately form an adduct with the base of a nucleotide in the DNA. [18] DNA adducts with PAHs can disrupt the DNA replication or modify the DNA, by removing bases like adenine and guanine from the nucleotides. [19] This can in the end lead to cell death and the production of truncated or misfolded proteins.

Related Research Articles

Aromatic compounds are organic compounds also known as "mono- and polycyclic aromatic hydrocarbons". The parent member is benzene. Heteroarenes are closely related, since at least one carbon atom of CH group is replaced by one of the heteroatoms oxygen, nitrogen, or sulfur. Examples of non-benzene compounds with aromatic properties are furan, a heterocyclic compound with a five-membered ring that includes a single oxygen atom, and pyridine, a heterocyclic compound with a six-membered ring containing one nitrogen atom.

Carcinogen Substance, radionuclide, or radiation directly involved in causing cancer

A carcinogen is any substance, radionuclide, or radiation that promotes carcinogenesis, the formation of cancer. This may be due to the ability to damage the genome or to the disruption of cellular metabolic processes. Several radioactive substances are considered carcinogens, but their carcinogenic activity is attributed to the radiation, for example gamma rays and alpha particles, which they emit. Common examples of non-radioactive carcinogens are inhaled asbestos, certain dioxins, and tobacco smoke. Although the public generally associates carcinogenicity with synthetic chemicals, it is equally likely to arise from both natural and synthetic substances. Carcinogens are not necessarily immediately toxic; thus, their effect can be insidious.

Coal tar is a thick dark liquid which is a by-product of the production of coke and coal gas from coal. It has both medical and industrial uses. Medicinally it is a topical medication applied to skin to treat psoriasis and seborrheic dermatitis (dandruff). It may be used in combination with ultraviolet light therapy. Industrially it is a railroad tie preservative and used in the surfacing of roads. Coal tar was listed as a known human carcinogen in the first Report on Carcinogens from the U.S. Federal Government.

Mutagenesis is a process by which the genetic information of an organism is changed by the production of a mutation. It may occur spontaneously in nature, or as a result of exposure to mutagens. It can also be achieved experimentally using laboratory procedures. A mutagen is a mutation-causing agent, be it chemical or physical, which results in an increased rate of mutations in an organism's genetic code. In nature mutagenesis can lead to cancer and various heritable diseases, and it is also a driving force of evolution. Mutagenesis as a science was developed based on work done by Hermann Muller, Charlotte Auerbach and J. M. Robson in the first half of the 20th century.

Polycyclic aromatic hydrocarbon Hydrocarbon composed of multiple aromatic rings

A polycyclic aromatic hydrocarbon (PAH) is a hydrocarbon—a chemical compound containing only carbon and hydrogen—that is composed of multiple aromatic rings. The group is a major subset of the aromatic hydrocarbons. The simplest of such chemicals is naphthalene, having two aromatic rings, and the three-ring compounds are anthracene and phenanthrene. The terms polyaromatic hydrocarbon or polynuclear aromatic hydrocarbon are also used for this concept.

Benzo(<i>a</i>)pyrene Carcinogenic compound found in smoke and soot

Benzo[a]pyrene is a polycyclic aromatic hydrocarbon and the result of incomplete combustion of organic matter at temperatures between 300 °C (572 °F) and 600 °C (1,112 °F). The ubiquitous compound can be found in coal tar, tobacco smoke and many foods, especially grilled meats. The substance with the formula C20H12 is one of the benzopyrenes, formed by a benzene ring fused to pyrene. Its diol epoxide metabolites (more commonly known as BPDE) react with and bind to DNA, resulting in mutations and eventually cancer. It is listed as a Group 1 carcinogen by the IARC. In the 18th century a scrotal cancer of chimney sweepers, the chimney sweeps' carcinoma, was already known to be connected to soot.

Methylcholanthrene Chemical compound

Methylcholanthrene is a highly carcinogenic polycyclic aromatic hydrocarbon produced by burning organic compounds at very high temperatures. Methylcholanthrene is also known as 3-methylcholanthrene, 20-methylcholanthrene or the IUPAC name 3-methyl-1,2-dyhydrobenzo[j]aceanthrylene. The short notation often used is 3-MC or MCA. This compound forms pale yellow solid crystals when crystallized from benzene and ether. It has a melting point around 180 °C and its boiling point is around 280 °C at a pressure of 80 mmHg. Methylcholanthrene is used in laboratory studies of chemical carcinogenesis. It is an alkylated derivative of benz[a]anthracene and has a similar UV spectrum. The most common isomer is 3-methylcholanthrene, although the methyl group can occur in other places.

Pyrene Chemical compound

Pyrene is a polycyclic aromatic hydrocarbon (PAH) consisting of four fused benzene rings, resulting in a flat aromatic system. The chemical formula is C16H10. This yellow solid is the smallest peri-fused PAH. Pyrene forms during incomplete combustion of organic compounds.

Sudan I Chemical compound

Sudan I, is an organic compound, typically classified as an azo dye. It is an intensely orange-red solid that is added to colourise waxes, oils, petrol, solvents, and polishes. Sudan I has also been adopted for colouring various foodstuffs, especially curry powder and chili powder, although the use of Sudan I in foods is now banned in many countries, because Sudan I, Sudan III, and Sudan IV have been classified as category 3 carcinogens by the International Agency for Research on Cancer. Sudan I is still used in some orange-coloured smoke formulations and as a colouring for cotton refuse used in chemistry experiments.

Fluoranthene Chemical compound

Fluoranthene is a polycyclic aromatic hydrocarbon (PAH). The molecule can be viewed as the fusion of naphthalene and benzene unit connected by a five-membered ring. Although samples are often pale yellow, the compound is colorless. It is soluble in nonpolar organic solvents. It is a member of the class of PAHs known as non-alternant PAHs because it has rings other than those with six carbon atoms. It is a structural isomer of the alternant PAH pyrene. It is not as thermodynamically stable as pyrene. Its name is derived from its fluorescence under UV light.

DNA adduct Segment of DNA bound to a cancer-causing chemical

In molecular genetics, a DNA adduct is a segment of DNA bound to a cancer-causing chemical. This process could lead to the development of cancerous cells, or carcinogenesis. DNA adducts in scientific experiments are used as biomarkers of exposure. They are especially useful in quantifying an organism's exposure to a carcinogen. The presence of such an adduct indicates prior exposure to a potential carcinogen, but it does not necessarily indicate the presence of cancer in the subject animal.

Chrysene Chemical compound

Chrysene is a polycyclic aromatic hydrocarbon (PAH) with the molecular formula C
18H
12 that consists of four fused benzene rings. It is a natural constituent of coal tar, from which it was first isolated and characterized. It is also found in creosote at levels of 0.5–6 mg/kg.

<i>o</i>-Toluidine Aryl amine

o-Toluidine (ortho-toluidine) is an organic compound with the chemical formula CH3C6H4NH2. It is the most important of the three isomeric toluidines. It is a colorless liquid although commercial samples are often yellowish. It is a precursor to the herbicides metolachlor and acetochlor.

Benzopyrene

A benzopyrene is an organic compound with the formula C20H12. Structurally speaking, the colorless isomers of benzopyrene are pentacyclic hydrocarbons and are fusion products of pyrene and a phenylene group. Two isomeric species of benzopyrene are benzo[a]pyrene and the less common benzo[e]pyrene. They belong to the chemical class of polycyclic aromatic hydrocarbons.

Benzo(<i>j</i>)fluoranthene Chemical compound

Benzo[j]fluoranthene (BjF) is an organic compound with the chemical formula C20H12. Classified as a polycyclic aromatic hydrocarbon (PAH), it is a colourless solid that is poorly soluble in most solvents. Impure samples can appear off white. Closely related isomeric compounds include benzo[a]fluoranthene (BaF), bendo[b]fluoranthene (BbF), benzo[e]fluoranthene (BeF), and benzo[k]fluoranthene (BkF). BjF is present in fossil fuels and is released during incomplete combustion of organic matter. It has been traced in the smoke of cigarettes, exhaust from gasoline engines, emissions from the combustion of various types of coal and emissions from oil heating, as well as an impurity in some oils such as soybean oil.

Toxicodynamics, termed pharmacodynamics in pharmacology, describes the dynamic interactions of a toxicant with a biological target and its biological effects. A biological target, also known as the site of action, can be binding proteins, ion channels, DNA, or a variety of other receptors. When a toxicant enters an organism, it can interact with these receptors and produce structural or functional alterations. The mechanism of action of the toxicant, as determined by a toxicant’s chemical properties, will determine what receptors are targeted and the overall toxic effect at the cellular level and organismal level.

Dibenzopyrenes Chemical compound

Dibenzopyrenes are a group of high molecular weight polycyclic aromatic hydrocarbons with the molecular formula C24H14. There are five isomers of dibenzopyrene which differ by the arrangement of aromatic rings: dibenzo[a,e]pyrene, dibenzo[a,h]pyrene, dibenzo[a,i]pyrene, dibenzo[a,l]pyrene, and dibenzo[e,l]pyrene.

Benzo(<i>c</i>)fluorene Chemical compound

Benzo[c]fluorene is a polycyclic aromatic hydrocarbon (PAH) with mutagenic activity. It is a component of coal tar, cigarette smoke and smog and thought to be a major contributor to its carcinogenic properties. The mutagenicity of benzo[c]fluorene is mainly attributed to formation of metabolites that are reactive and capable of forming DNA adducts. According to the KEGG it is a group 3 carcinogen. Other names for benzo[c]fluorene are 7H-benzo[c]fluorene, 3,4-benzofluorene, and NSC 89264.

Glycidamide Chemical compound

Glycidamide is an organic compound with the formula H2NC(O)C2H3O. It is a colorless, oil. Structurally, it contains adjacent amides and epoxide functional groups. It is a bioactive, potentially toxic or even carcinogenic metabolite of acrylonitrile and acrylamide. It is a chiral molecule.

(+)-Benzo(<i>a</i>)pyrene-7,8-dihydrodiol-9,10-epoxide Cancer-causing agent derived from tobacco smoke

(+)-Benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide is an organic compound with molecular formula C20H14O3. It is a metabolite and derivative of benzo[a]pyrene (found in tobacco smoke) as a result of oxidation to include hydroxyl and epoxide functionalities. (+)-Benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide binds to the N2 atom of a guanine nucleobase in DNA, distorting the double helix structure by intercalation of the pyrene moiety between base pairs through π-stacking. The carcinogenic properties of tobacco smoking are attributed in part to this compound binding and inactivating the tumor suppression ability of certain genes, leading to genetic mutations and potentially to cancer.

References

  1. 1 2 3 "Indeno[1,2,3-cd]pyrene". PubChem.
  2. 1 2 Minabe M, Shibuya N. Nitration of indeno[1,2,3-cd]pyrene and mutagenic activities of related compounds. Chem. Res. Toxicol. 1989 Nov 1; 2(6); 357-358
  3. ↑ National Cancer Institute Monograph. 1st ed. National Cancer institute; 1962
  4. ↑ INDENO(1,2,3-cd)PYRENE. IPCS inchem. 1973; 3; 229
  5. ↑ V. V. Kislov, A. I. Sadovnikov, A. M. Mebel; Formation Mechanism of Polycyclic Aromatic Hydrocarbons beyond the Second Aromatic Ring; The Journal Of Physical Chemistry, 2013, number 117; p. 4794 - 4816.
  6. ↑ T. Chatterjee, D. S. Lee, E. J. Cho; Extended Study of Visible-Light-Induced Photocatalytic [4+2] Benzannulation: Synthesis of Polycyclic (Hetero)Aromatics; The Journal of Organic Chemistry, 2017, number 82; p 4369 - 4378
  7. ↑ Y. Choi, T. Chatterjee, J. Kim, J. S. Kim, E. J. Cho; Synthesis of cyclopenta-fused polycyclic aromatic hydrocarbons utilizing aryl-substituted anilines; Organic & Biomolecular Chemistry, 2016, number 14; p. 6804 - 6810.
  8. ↑ H. A. Wegner, H. Reisch, K. Rauch, A. Demeter, K. A. Zachariasse, A. de Meijere, L. T. Scott; Oligoindenopyrenes: A new Class of Polycyclic Aromatics; American Chemical Society, 10/21/2006; p. 9080 - 9087.
  9. ↑ Minabe M, Cho BP, Harvey RG. Polycyclic fluoranthene hydrocarbons. Part 4. Electrophilic substitution of polycyclic fluoranthene hydrocarbons. J. Am. Chem. Soc. 1989 May 1; 111(11); 3809-3812
  10. ↑ Rice JE, Czech A, Hussain N, LaVoie EJ. Synthesis of fluorinated dervatices of benzo[k]fluoranthene and indeno[1,2,3-cd]pyrene and 8,9-dihydro-8,9-epoxybenzo[k]fluoranthene. J. Org. Chem. 1988 April 1; 53(8); 1775-1779
  11. ↑ E. Dybing, P. E. Schwarze, P. Nafstad, K. Victorin, T. M. Penning; Chapter 7. Polycyclic Aromatic Hydrocarbons In Ambient Air and Cancer.
  12. 1 2 IARC. (1983). Indeno(1,2,3-cd)pyrene. 32, 373
  13. ↑ K Schirmer, A.G.J Chan, B.M Greenberg, D.G Dixon, N.C Bols. (1998). Ability of 16 priority PAHs to be photocytotoxic to a cell line from the rainbow trout gill. Toxicology, 127-1–3, 143-155.
  14. ↑ Line E. Sverdrup, Torben Nielsen, and Paul Henning Krogh. (2002) Soil Ecotoxicity of Polycyclic Aromatic Hydrocarbons in Relation to Soil Sorption, Lipophilicity, and Water Solubility. Environmental Science & Technology. 36 (11), 2429-2435
  15. ↑ Magnus Engwall, Björn Brunström, Carina Näf, Katarina Hjelm.(1999). Levels of dioxin-like compounds in sewage sludge determined with a bioassay based on erod induction in chicken embryo liver cultures. Chemosphere, 38-10, 2327-2343.
  16. ↑ Luo, Y., Li, S., She, Y. et al. (2015). Metabolic Transformation of Indeno[1,2,3-cd]pyrene and Toxicities of Its Metabolites. Bull Environ Contam Toxicol 94, 112–117.
  17. ↑ Luo, Y., Dai, J., Zhong, R., She, Y., Liu, R. and Wei, H. (2011), Production of polycyclic aromatic hydrocarbon metabolites from a peroxynitrite/iron(III) porphyrin biomimetic model and their mutagenicities. Environmental Toxicology and Chemistry, 30: 723-729.
  18. ↑ Baird, W. M.; Hooven, L. A.; Mahadevan, B. (2015). "Carcinogenic polycyclic aromatic hydrocarbon-DNA adducts and mechanism of action". Environmental and Molecular Mutagenesis. 45 (2–3): 106–114.
  19. ↑ Ramesh, A.; Walker, S. A.; Hood, D. B.; Guillén, M. D.; Schneider, K.; Weyand, E. H. (2004). "Bioavailability and risk assessment of orally ingested polycyclic aromatic hydrocarbons". International Journal of Toxicology. 23 (5): 301-333.
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