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Aryl halide

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In organic chemistry, an aryl halide (also known as haloarene) is an aromatic compound in which one or more hydrogen atoms, directly bonded to an aromatic ring are replaced by a halide. Haloarenes are different from haloalkanes because they exhibit many differences in methods of preparation and properties. The most important members are the aryl chlorides, but the class of compounds is so broad that there are many derivatives and applications.

Classification according to halide

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Aryl fluorides

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Aryl fluorides are used as synthetic intermediates, e.g. for the preparation of pharmaceuticals, pesticides, and liquid crystals.[1] The conversion of diazonium salts is a well established route to aryl fluorides. Thus, anilines are precursors to aryl fluorides. In the classic Schiemann reaction, tetrafluoroborate is the fluoride donor:

[C6H5N+2]BF−4 → C6H5F + N2 + BF3

In some cases, the fluoride salt is used:

[C6H5N+2]F− → C6H5F + N2

Many commercial aryl fluorides are produced from aryl chlorides by the Halex process. The method is often used for aryl chlorides also bearing electron-withdrawing groups. Illustrative is the synthesis of 2-fluoronitrobenzene from 2-nitrochlorobenzene:[2]

O2NC6H4Cl + KF → O2NC6H4F + KCl

Aryl chlorides

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Aryl chlorides are the aryl halides produced on the largest scale commercially: 150,000 tons/y in the US alone (1994). Production levels are decreasing owing to environmental concerns. Chlorobenzenes are used mainly as solvents.[3]

Friedel-Crafts halogenation or "direct chlorination" is the main synthesis route. Lewis acids, e.g. iron(III) chloride, catalyze the reactions. The most abundantly produced aryl halide, chlorobenzene, is produced by this route:[4]

C6H6 + Cl2 → C6H5Cl + HCl

Monochlorination of benzene is accompanied by formation of the dichlorobenzene derivatives.[3] Arenes with electron donating groups react with halogens even in the absence of Lewis acids. For example, phenols and anilines react quickly with chlorine and bromine water to give multihalogenated products. Many detailed laboratory procedures are available.[5] For alkylbenzene derivatives, e.g. toluene, the alkyl positions tend to be halogenated by free radical conditions, whereas ring halogenation is favored in the presence of Lewis acids.[6] The decolouration of bromine water by electron-rich arenes is used in the bromine test.

 
Reaction between benzene and halogen to form an halogenobenzene

The oxychlorination of benzene has been well investigated, motivated by the avoidance of HCl as a coproduct in the direct halogenation:[3]

4 C6H6 + 4 HCl + O2 → 4 C6H5Cl + H2O

This technology is not widely used however.

The Gatterman reaction can also be used to convert diazonium salts to chlorobenzenes using copper-based reagents. Owing to high cost of diazonium salts, this method is reserved for specialty chlorides.

Aryl bromides

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The main aryl bromides produced commercially are tetrabromophthalic anhydride, decabromodiphenyl ether, and tetrabromobisphenol-A. These materials are used as flame retardants. They are produced by direct bromination of phenols and aryl ethers. Phthalic anhydride is poorly reactive toward bromine, necessitating the use of acidic media.

The Gatterman reaction can also be used to convert diazonium salts to bromobenzenes using using copper-based reagents. Owing to high cost of diazonium salts, this method is reserved for specialty bromides.

Aryl iodides

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Synthetic aryl iodides are used as X-ray contrast agents, but otherwise these compounds are not produced on a large scale. Aryl iodides are "easy" substrates for many reactions such as cross-coupling reactions and conversion to Grignard reagents, but they are much more expensive than the lighter, less reactive aryl chlorides and bromides.

Aryl iodides can be prepared by treating diazonium salts with iodide salts.[7] Electron-rich arenes such as anilines and dimethoxy derivatives react directly with iodine.[8]

Aryl lithium and aryl Grignard reagents react with iodine to give the aryl halide:

ArLi + I2 → ArI + LiI

This method is applicable to the preparation of all aryl halides. One limitation is that most, but not all,[9] aryl lithium and Grignard reagents are produced from aryl halides.

Classification according to aryl group

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Halobenzenes and halobenzene derivatives

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Main article: Halobenzene

Although the term aryl halide includes halogenated derivatives of any aromatic compound, it commonly refers to halobenzenes, which are specifically halogenated derivatives of benzene. Groups of halobenzenes include fluorobenzenes, chlorobenzenes, bromobenzenes, and iodobenzenes, as well as mixed halobenzenes containing at least two different types of halogens bonded to the same benzene ring. There are also many halobenzene derivatives.

Halopyridines

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Halopyridines are based on the aromatic compound pyridine.[10] This includes chloropyridines and bromopyridines. Chloropyridines are important intermediates to pharmaceuticals and agrochemicals.

Halogenated naphthalenes

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Halogenated naphthalenes are based on naphthalene. Polychlorinated naphthalenes were used extensively from the 1930s to 1950s in cable and capacitor production, due to their insulating, hydrophobic, and flame retardant properties, but they have since been phased out for this use due to toxicity, environmental persistence, and introduction of new materials.[3]

Aryl halides in nature

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The thyroid hormones triiodothyronine (T3) and thyroxine (T4) are aryl iodides. A tetraiodide, T4 is biosynthesised by electrophilic iodination of tyrosine derivative.[11] Synthetic T4 is one of the most heavily prescribed medicines in the U.S.[12]

Many chlorinated and brominated aromatic compounds are produced by marine organisms. The chloride and bromide in ocean waters are the source of the halogens. Various peroxidase enzymes (e.g., bromoperoxidase) catalyze the reactions. Numerous are derivatives of electron-rich rings found in tyrosine, tryptophan, and various pyrroles. Some of these natural aryl halides exhibit useful medicinal properties.[13][14]

 
Vancomycin, an important antibiotic, is an aryl chloride isolated from soil fungi.
 
The chemical structure of 6,6′-dibromoindigo, the main component of Tyrian Purple.
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The C-X distances for aryl halides follow the expected trend. These distances for fluorobenzene, chlorobenzene, bromobenzene, and methyl 4-iodobenzoate are 135.6(4), 173.90(23), 189.8(1), and 209.9 pm, respectively.[15]

Reactions

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Substitution

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Unlike typical alkyl halides, aryl halides typically do not participate in conventional substitution reactions. Aryl halides with electron-withdrawing groups in the ortho and para positions, can undergo SNAr reactions. For example, 2,4-dinitrochlorobenzene reacts in basic solution to give a phenol.

Unlike in most other substitution reactions, fluoride is the best leaving group, and iodide the worst.[16] A 2018 paper indicates that this situation may actually be rather common, occurring in systems that were previously assumed to proceed via SNAr mechanisms.[17]

Benzyne

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Aryl halides often react via the intermediacy of benzynes. Chlorobenzene and sodium amide react in liquid ammonia to give aniline by this pathway.

 

Organometallic reagent formation

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Aryl halides react with metals, generally lithium or magnesium, to give organometallic derivatives that function as sources of aryl anions. By the metal-halogen exchange reaction, aryl halides are converted to aryl lithium compounds. Illustrative is the preparation of phenyllithium from bromobenzene using n-butyllithium (n-BuLi):

C6H5Br + BuLi → C6H5Li + BuBr

Direct formation of Grignard reagents, by adding the magnesium to the aryl halide in an ethereal solution, works well if the aromatic ring is not significantly deactivated by electron-withdrawing groups.

 

Other reactions

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The halides can be displaced by strong nucleophiles via reactions involving radical anions. Alternatively aryl halides, especially the bromides and iodides, undergo oxidative addition, and thus are subject to Buchwald–Hartwig amination-type reactions.

Chlorobenzene was once the precursor to phenol, which is now made by oxidation of cumene. At high temperatures, aryl groups react with ammonia to give anilines.[3]

Biodegradation

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Rhodococcus phenolicus is a bacterium that degrades dichlorobenzene as sole carbon sources.[18]

Applications

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The aryl halides produced on the largest scale are chlorobenzene and the isomers of dichlorobenzene. One major but discontinued application was the use of chlorobenzene as a solvent for dispersing the herbicide Lasso. Overall, production of aryl chlorides (also naphthyl derivatives) has been declining since the 1980s, in part due to environmental concerns.[3] Triphenylphosphine is produced from chlorobenzene:

3 C6H5Cl + PCl3 + 6 Na → P(C6H5)3 + 6 NaCl

Aryl bromides are widely used as fire-retardants. The most prominent member is tetrabromobisphenol-A, which is prepared by direct bromination of the diphenol.[19]

References

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  1. ^ Shimizu, Masaki; Hiyama, Tamejiro (2005). "Modern Synthetic Methods for Fluorine-Substituted Target Molecules". Angewandte Chemie International Edition. 44 (2): 214–231. doi:10.1002/anie.200460441. PMID 15614922.
  2. ^ Siegemund, Günter; Schwertfeger, Werner; Feiring, Andrew; Smart, Bruce; Behr, Fred; Vogel, Herward; McKusick, Blaine (2002). "Fluorine Compounds, Organic". Ullmann's Encyclopedia of Industrial Chemistry. Weinheim: Wiley-VCH. doi:10.1002/14356007.a11_349. ISBN 978-3527306732..
  3. ^ a b c d e f Beck, U.; Löser, E. (2011). "Chlorinated Benzenes and Other Nucleus-Chlorinated Aromatic Hydrocarbons". Ullmann's Encyclopedia of Industrial Chemistry. doi:10.1002/14356007.o06_o03. ISBN 978-3527306732.
  4. ^ Peter Bernard, David De la Mare (1976). Electrophilic HalogenationReaction Pathways Involving Attack by Electrophilic Halogens on Unsaturated Compounds. Cambridge University Press. ISBN 9780521290142.
  5. ^ Atkinson, Edward R.; Murphy, Donald M.; Lufkin, James E. (1951). "dl-4,4′,6,6′-Tetrachlorodiphenic Acid". Organic Syntheses. 31: 96. doi:10.15227/orgsyn.031.0096.
  6. ^ Boyd, Robert W.; Morrison, Robert (1992). Organic chemistry. Englewood Cliffs, N.J: Prentice Hall. p. 947. ISBN 978-0-13-643669-0.
  7. ^ Lyday, Phyllis A.; Kaiho, Tatsuo (2015). "Iodine and Iodine Compounds". Ullmann's Encyclopedia of Industrial Chemistry. pp. 1–13. doi:10.1002/14356007.a14_381.pub2. ISBN 9783527306732.
  8. ^ Janssen, Donald E.; Wilson, C. V. (1956). "4-Iodoveratrole". Organic Syntheses. 36: 46. doi:10.15227/orgsyn.036.0046.
  9. ^ Snieckus, Victor (1990). "Directed ortho metalation. Tertiary amide and O-carbamate directors in synthetic strategies for polysubstituted aromatics". Chemical Reviews. 90 (6): 879–933. doi:10.1021/cr00104a001.
  10. ^ Siegemund, Günter; Schwertfeger, Werner; Feiring, Andrew; Smart, Bruce; Behr, Fred; Vogel, Herward; McKusick, Blaine (2000). "Pyridine and Pyridine Derivatives". Ullmann's Encyclopedia of Industrial Chemistry. Weinheim: Wiley-VCH. doi:10.1002/14356007.a22_399. ISBN 978-3527306732.
  11. ^ Mondal, Santanu; Raja, Karuppusamy; Schweizer, Ulrich; Mugesh, Govindasamy (2016). "Chemistry and Biology in the Biosynthesis and Action of Thyroid Hormones". Angewandte Chemie International Edition. 55 (27): 7606–7630. doi:10.1002/anie.201601116. PMID 27226395.
  12. ^ Brito, Juan P.; Ross, Joseph S.; El Kawkgi, Omar M.; Maraka, Spyridoula; Deng, Yihong; Shah, Nilay D.; Lipska, Kasia J. (2021). "Levothyroxine Use in the United States, 2008-2018". JAMA Internal Medicine. 181 (10): 1402–1405. doi:10.1001/jamainternmed.2021.2686. PMC 8218227. PMID 34152370.
  13. ^ Fujimori, Danica Galonić; Walsh, Christopher T. (2007). "What's New in Enzymatic Halogenations". Current Opinion in Chemical Biology. 11 (5): 553–60. doi:10.1016/j.cbpa.2007.08.002. PMC 2151916. PMID 17881282.
  14. ^ Gribble, Gordon W. (2004). "Natural Organohalogens: A New Frontier for Medicinal Agents?". Journal of Chemical Education. 81 (10): 1441. Bibcode:2004JChEd..81.1441G. doi:10.1021/ed081p1441.
  15. ^ Oberhammer, Heinz (2009). "The Structural Chemistry of Carbon-Halogen Bonds". PATai's Chemistry of Functional Groups. doi:10.1002/9780470682531.pat0002. ISBN 978-0-470-68253-1.
  16. ^ Ritter, Tobias; Hooker, Jacob M.; Neumann, Constanze N. (June 2016). "Concerted nucleophilic aromatic substitution with 19F− and 18F−". Nature. 534 (7607): 369–373. Bibcode:2016Natur.534..369N. doi:10.1038/nature17667. ISSN 1476-4687. PMC 4911285. PMID 27281221.
  17. ^ Jacobsen, Eric N.; Harrison A. Besser; Zeng, Yuwen; Kwan, Eugene E. (September 2018). "Concerted nucleophilic aromatic substitutions". Nature Chemistry. 10 (9): 917–923. Bibcode:2018NatCh..10..917K. doi:10.1038/s41557-018-0079-7. ISSN 1755-4349. PMC 6105541. PMID 30013193.
  18. ^ Rehfuss, Marc; Urban, James (2005). "Rhodococcus phenolicus sp. nov., a novel bioprocessor isolated actinomycete with the ability to degrade chlorobenzene, dichlorobenzene and phenol as sole carbon sources". Systematic and Applied Microbiology. 28 (8): 695–701. doi:10.1016/j.syapm.2005.05.011. PMID 16261859.
  19. ^ Ioffe, D.; Kampf, A. (2002). "Bromine, Organic Compounds". Kirk-Othmer Encyclopedia of Chemical Technology. doi:10.1002/0471238961.0218151325150606.a01. ISBN 978-0471238966.
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