Indol: Diferenzas entre revisións
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Revisión como estaba o 4 de outubro de 2014 ás 17:35
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Indol | |
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Indol | |
Outros nomes 2,3-benzopirrol, ketol, | |
Identificadores | |
Número CAS | 120-72-9 |
PubChem | 798 |
ChemSpider | 776 |
UNII | 8724FJW4M5 |
KEGG | C00463 |
ChEBI | CHEBI:16881 |
ChEMBL | CHEMBL15844 |
Número RTECS | NL2450000 |
Imaxes 3D Jmol | Image 1 |
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| |
Propiedades | |
Fórmula molecular | C8H7N |
Masa molecular | 117,15 g/mol |
Aspecto | Sólido branco |
Densidade | 1,1747 g/cm3, sólido |
Punto de fusión | 52–54 °C |
Punto de ebulición | 253–254°C (526 K) |
Solubilidade en auga | 0,19 g/100 ml (20 °C) Soluble en auga quente |
Acidez (pKa) | 16,2 (21,0 en DMSO) |
Basicidade (pKb) | 17,6 |
Estrutura | |
Estrutura cristalina | Pna21 |
Forma da molécula | Plana |
Momento dipolar | 2,11 D en benceno |
Perigosidade | |
MSDS | [1] |
Declaracións R/S | R: 21/22-37/38-41-50/53 S: 26-36/37/39-60-61 |
Punto de inflamabilidade | 121 °C; 250 °F; 394 K |
Compostos relacionados | |
compostos aromáticos relacionados |
benceno, benzofurano, carbazol, carbolina, indeno, indolina, isatina, metilindol, oxindol, pirrol, excatol |
Se non se indica outra cousa, os datos están tomados en condicións estándar de 25 °C e 100 kPa. |
O indol é un composto orgánico heterocíclico aromático. Ten unha estrutura bicíclica, constituída por un anel hexagonal de benceno fusionado cun anel pentagonal pirrol que contén nitróxeno. O indol está amplamente distribuído nos ambientes naturais, xa que poden producilo diversas bacterias. Como molécula de sinalización celular o indol regula varios aspectos a fisioloxía bacteriana, como a formación de esporas, estabilidade dos plásmidos, resistencia aos fármacos, formación de biopelículas, e a virulencia.[1] Un importante derivado do indol é o aminoácido triptófano, o cal é o precursor do neurotransmisor serotonina.[2]
Propiedades xerais e distribución
Indole is a solid at room temperature. Indole can be produced by bacteria as a degradation product of the amino acid tryptophan. It occurs naturally in human feces and has an intense fecal odor. At very low concentrations, however, it has a flowery smell,[3] and is a constituent of many flower scents (such as orange blossoms) and perfumes. It also occurs in coal tar.
The corresponding substituent is called indolyl.
Indole undergoes electrophilic substitution, mainly at position 3. Substituted indoles are structural elements of (and for some compounds the synthetic precursors for) the tryptophan-derived tryptamine alkaloids like the neurotransmitter serotonin, and melatonin. Other indolic compounds include the plant hormone auxin (indolyl-3-acetic acid, IAA), tryptophol, the anti-inflammatory drug indomethacin, the betablocker pindolol, and the naturally occurring hallucinogen dimethyltryptamine.
The name indole is a portmanteau of the words indigo and oleum, since indole was first isolated by treatment of the indigo dye with oleum.
Historia
Indole chemistry began to develop with the study of the dye indigo. Indigo can be converted to isatin and then to oxindole. Then, in 1866, Adolf von Baeyer reduced oxindole to indole using zinc dust.[4] In 1869, he proposed a formula for indole (left).[5]
Certain indole derivatives were important dyestuffs until the end of the 19th century. In the 1930s, interest in indole intensified when it became known that the indole nucleus is present in many important alkaloids, as well as in tryptophan and auxins, and it remains an active area of research today.[6]
Distribución na natureza
Indole is biosynthesized via anthranilate.[2] It condenses with serine via Michael addition of indole to PLP-aminoacrylate.
Indole is a major constituent of coal-tar, and the 220–260 °C distillation fraction is the main industrial source of the material.
Rutas sintéticas
Indole and its derivatives can also be synthesized by a variety of methods.[7][8][9]
The main industrial routes start from aniline via vapor-phase reaction with ethylene glycol in the presence of catalysts:
In general, reactions are conducted between 200 and 500 °C. Yields can be as high as 60%. Other precursors to indole include formyltoluidine, 2-ethylaniline, and 2-(2-nitrophenyl)ethanol, all of which undergo cyclizations.[10] Many other methods have been developed that are applicable.
Síntese do indol de Leimgruber-Batcho
- Artigo principal: Leimgruber-Batcho indole synthesis.
The Leimgruber-Batcho indole synthesis is an efficient method of synthesizing indole and substituted indoles. Originally disclosed in a patent in 1976, this method is high-yielding and can generate substituted indoles. This method is especially popular in the pharmaceutical industry, where many pharmaceutical drugs are made up of specifically substituted indoles.
Síntese do indol de Fischer
- Artigo principal: Fischer indole synthesis.
One of the oldest and most reliable methods for synthesizing substituted indoles is the Fischer indole synthesis, developed in 1883 by Emil Fischer. Although the synthesis of indole itself is problematic using the Fischer indole synthesis, it is often used to generate indoles substituted in the 2- and/or 3-positions. Indole can still be synthesized, however, using the Fischer indole synthesis by reacting phenylhydrazine with pyruvic acid followed by decarboxylation of the formed indole-2-carboxylic acid. This has also been accomplished in a one-pot synthesis using microwave irradiation.[11]
Outras reaccións formadoras de indol
- Bartoli indole synthesis
- Bischler-Möhlau indole synthesis
- Fukuyama indole synthesis
- Gassman indole synthesis
- Hemetsberger indole synthesis
- Larock indole synthesis
- Madelung synthesis
- Nenitzescu indole synthesis
- Reissert indole synthesis
- Baeyer-Emmerling indole synthesis
- In the Diels-Reese reaction [12][13] dimethyl acetylenedicarboxylate reacts with diphenylhydrazine to an adduct, which in xylene gives dimethyl indole-2,3-dicarboxylate and aniline. With other solvents, other products are formed: with glacial acetic acid a pyrazolone, and with pyridine a quinoline.
Reaccións químicas do indol
Basicidade
Unlike most amines, indole is not basic. The bonding situation is completely analogous to that in pyrrole. Very strong acids such as hydrochloric acid are required to protonate indole. The protonated form has an pKa of −3.6. The sensitivity of many indolic compounds (e.g., tryptamines) under acidic conditions is caused by this protonation.
Substitución electrofílica
The most reactive position on indole for electrophilic aromatic substitution is C-3, which is 1013 times more reactive than benzene. For example, it is alkylated by phosphorylated serine in the biosynthesis of the amino acid tryptophan (see figure above). Vilsmeier-Haack formylation of indole[14] will take place at room temperature exclusively at C-3. Since the pyrrollic ring is the most reactive portion of indole, electrophilic substitution of the carbocyclic (benzene) ring can take place only after N-1, C-2, and C-3 are substituted.
Gramine, a useful synthetic intermediate, is produced via a Mannich reaction of indole with dimethylamine and formaldehyde. It is the precursor to indole acetic acid and synthetic tryptophan.
Acidez nitróxeno-H e complexos anión indol organometálicos
The N-H center has a pKa of 21 in DMSO, so that very strong bases such as sodium hydride or butyl lithium and water-free conditions are required for complete deprotonation. The resulting alkali metal derivatives can react in two ways. The more ionic salts such as the sodium or potassium compounds tend to react with electrophiles at nitrogen-1, whereas the more covalent magnesium compounds (indole Grignard reagents) and (especially) zinc complexes tend to react at carbon-3 (see figure below). In analogous fashion, polar aprotic solvents such as DMF and DMSO tend to favour attack at the nitrogen, whereas nonpolar solvents such as toluene favour C-3 attack.[15]
Acidez do carbono e litiación C-2
After the N-H proton, the hydrogen at C-2 is the next most acidic proton on indole. Reaction of N-protected indoles with butyl lithium or lithium diisopropylamide results in lithiation exclusively at the C-2 position. This strong nucleophile can then be used as such with other electrophiles.
Bergman and Venemalm developed a technique for lithiating the 2-position of unsubstituted indole.[16]
Alan Katritzky also developed a technique for lithiating the 2-position of unsubstituted indole.[17]
Oxidación do indol
Due to the electron-rich nature of indole, it is easily oxidized. Simple oxidants such as N-bromosuccinimide will selectively oxidize indole 1 to oxindole (4 and 5).
Cycloadicións do indol
Only the C-2 to C-3 pi-bond of indole is capable of cycloaddition reactions. Intramolecular variants are often higher-yielding than intermolecular cycloadditions. For example, Padwa et al.[18] have developed this Diels-Alder reaction to form advanced strychnine intermediates. In this case, the 2-aminofuran is the diene, whereas the indole is the dienophile. Indoles also undergo intramolecular [2+3] and [2+2] cycloadditions.
Despite mediocre yields, intermolecular cycloadditions of indole derivatives have been well documented.[19][20][21] One example is the Pictet-Spengler reaction between tryptophan derivatives and aldehydes.[22] The Pictet-Spengler reaction of indole derivatives, such as tryptophan, leads to a mixture of diastereomers as products. The formation of multiple products reduces the chemical yield of the desired product.
Aplicacións
Natural jasmine oil, used in the perfume industry, contains around 2.5% of indole. Since 1 kilogram of the natural oil requires processing several million jasmine blossoms and costs around $10,000, indole (among other things) is used in the manufacture of synthetic jasmine oil (which costs around $10/kg).
Notas
- ↑ Lee, Jin-Hyung; Lee, Jintae (2010). "Indole as an intercellular signal in microbial communities". FEMS Microbiology Reviews. ISSN 0168-6445. doi:10.1111/j.1574-6976.2009.00204.x.
- ↑ 2,0 2,1 Modelo:Lehninger4th
- ↑ http://www.leffingwell.com/olfact5.htm
- ↑ Baeyer, A. (1866). "Ueber die Reduction aromatischer Verbindungen mittelst Zinkstaub". Ann. 140 (3): 295. doi:10.1002/jlac.18661400306.
- ↑ Baeyer, A.; Emmerling, A. (1869). "Synthese des Indols". Chemische Berichte 2: 679. doi:10.1002/cber.186900201268.
- ↑ R. B. Van Order, H. G. Lindwall (1942). "Indole". Chem. Rev. 30: 69–96. doi:10.1021/cr60095a004.
- ↑ Gribble G. W. (2000). "Recent developments in indole ring synthesis—methodology and applications". J. Chem. Soc. Perkin Trans. 1 (7): 1045. doi:10.1039/a909834h.
- ↑ Cacchi, S.; Fabrizi, G. (2005). "Synthesis and Functionalization of Indoles Through Palladium-catalyzed Reactions". Chem. Rev. 105 (7): 2873. PMID 16011327. doi:10.1021/cr040639b.
- ↑ Humphrey, G. R.; Kuethe, J. T. (2006). "Practical Methodologies for the Synthesis of Indoles". Chem. Rev. 106 (7): 2875. PMID 16836303. doi:10.1021/cr0505270.
- ↑ Gerd Collin and Hartmut Höke “Indole” Ullmann's Encyclopedia of Industrial Chemistry 2002, Wiley-VCH, Weinheim. doi 10.1002/14356007.a14_167.
- ↑ Bratulescu, George (2008). "A new and efficient one-pot synthesis of indoles". Tetrahedron Letters 49 (6): 984. doi:10.1016/j.tetlet.2007.12.015.
- ↑ Diels, Otto; Reese, Johannes (1934). "Synthesen in der hydroaromatischen Reihe. XX. Über die Anlagerung von Acetylen-dicarbonsäureester an Hydrazobenzol". Ann. 511: 168. doi:10.1002/jlac.19345110114.
- ↑ Ernest H. Huntress, Joseph Bornstein, and William M. Hearon (1956). "An Extension of the Diels-Reese Reaction". J. Am. Chem. Soc. 78 (10): 2225. doi:10.1021/ja01591a055.
- ↑ James, P. N.; Snyder, H. R. (1959). "Indole-3-aldehyde". Organic Syntheses 39: 30.
- ↑ Heaney, H.; Ley, S. V. (1974). "1-Benzylindole". Organic Syntheses 54: 58.
- ↑ Bergman, J.; Venemalm, L. (1992). "Efficient synthesis of 2-chloro-, 2-bromo-, and 2-iodoindole". J. Org. Chem. 57 (8): 2495. doi:10.1021/jo00034a058.
- ↑ Alan R. Katritzky, Jianqing Li, Christian V. Stevens (1995). "Facile Synthesis of 2-Substituted Indoles and Indolo[3,2-b]carbazoles from 2-(Benzotriazol-1-ylmethyl)indole". J. Org. Chem. 60 (11): 3401–3404. doi:10.1021/jo00116a026.
- ↑ Lynch, S. M. ; Bur, S. K.; Padwa, A. (2002). "Intramolecular Amidofuran Cycloadditions across an Indole π-Bond: An Efficient Approach to the Aspidosperma and Strychnos ABCE Core". Org. Lett. 4 (26): 4643. PMID 12489950. doi:10.1021/ol027024q.
- ↑ Use {{Cita publicación periódica}} no canto deste marcador. Pode indicar a referencia DOI no parámetro
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- ↑ Gremmen, C.; Willemse, B.; Wanner, M. J.; Koomen, G.-J. (2000). "Enantiopure Tetrahydro-β-carbolines via Pictet-Spengler Reactions with N-Sulfinyl Tryptamines". Org. Lett. 2 (13): 1955–1958. doi:10.1021/ol006034t.
- ↑ a) The intermolecular Pictet-Spengler condensation with chiral carbonyl derivatives in the stereoselective syntheses of optically-active isoquinoline and indole alkaloids Enrique L. Larghi, Marcela Amongero, Andrea B. J. Bracca, and Teodoro S. Kaufman Arkivoc (RL-1554K) pp 98-153 2005 (Online Review); b) Teodoro S. Kaufman “Synthesis of Optically-Active Isoquinoline and Indole Alkaloids Employing the Pictet-Spengler Condensation with Removable Chiral Auxiliaries Bound to Nitrogen”. in “New Methods for the Asymmetric Synthesis of Nitrogen Heterocycles”; Ed.: J. L. Vicario. ISBN 81-7736-278-X. Research SignPost, Trivandrum, India. 2005. Chapter 4, pp. 99-147.
- ↑ Bonnet, D.; Ganesan, A. (2002). "Solid-Phase Synthesis of Tetrahydro-β-carbolinehydantoins via the N-Acyliminium Pictet-Spengler Reaction and Cyclative Cleavage". J. Comb. Chem. 4 (6): 546–548. doi:10.1021/cc020026h.
- Referencias xerais
- Indoles Part One, W. J. Houlihan (ed.), Wiley Interscience, New York, 1972.
- Sundberg, R. J. (1996). Indoles. San Diego: Academic Press. ISBN 0-12-676945-1.
- Joule, J. A.; Mills, K. (2000). Heterocyclic Chemistry. Oxford, UK: Blackwell Science. ISBN 0-632-05453-0.
- Joule, J., In Science of Synthesis, Thomas, E. J., Ed.; Thieme: Stuttgart, (2000); Vol. 10, p. 361. ISBN 3-13-112241-2 (GTV); ISBN 0-86577-949-X (TNY).
- Schoenherr, H.; Leighton, J. L. Direct and Highly Enantioselective Iso-Pictet-Spengler Reactions with alpha-Ketoamides: Access to Underexplored Indole Core Structures. Org. Lett. 2012, 14, 2610.
Véxase tamén
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Ligazóns externas
Commons ten máis contidos multimedia sobre: Indol |
- Síntese de indois (panorma xeral de métodos recentes)
- Síntese e propiedades dos indois en chemsynthesis.com