Inorganic chemistry, anaryl halide (also known as a haloarene) is anaromatic compound in which one or more hydrogen atoms directly bonded to an aromatic ring are replaced by ahalide ion (such as fluorine F−, chlorine Cl−1,−3,−5, bromine Br−1, or iodine I−). Aryl halides are distinct fromhaloalkanes (alkyl halides) due to significant differences in their methods of preparation, chemical reactivity, and physical properties. The most common and important members of this class are aryl chlorides, but the group encompasses a wide range of derivatives with diverse applications in organic synthesis, pharmaceuticals, and materials science.
Aryl fluorides are used as synthetic intermediates, e.g. for the preparation of pharmaceuticals, pesticides, and liquid crystals.[1] The conversion ofdiazonium salts is a well established route to aryl fluorides. Thus, anilines are precursors to aryl fluorides. In the classicSchiemann reaction,tetrafluoroborate is the fluoride donor:
In some cases, the fluoride salt is used:
Many commercial aryl fluorides are produced from aryl chlorides by theHalex process. The method is often used for aryl chlorides also bearingelectron-withdrawing groups. Illustrative is the synthesis of2-fluoronitrobenzene from2-nitrochlorobenzene:[2]
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]
Monochlorination of benzene is accompanied by formation of thedichlorobenzene 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 byfree 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 thebromine test.
Theoxychlorination of benzene has been well investigated, motivated by the avoidance of HCl as a coproduct in the direct halogenation:[3]
This technology is not widely used however.
TheGatterman reaction can also be used to convert diazonium salts to chlorobenzenes using copper-based reagents. Owing to high cost ofdiazonium salts, this method is reserved for specialty chlorides.
The main aryl bromides produced commercially aretetrabromophthalic anhydride,decabromodiphenyl ether, andtetrabromobisphenol-A. These materials are used asflame retardants. They are produced by direct bromination ofphenols and aryl ethers.Phthalic anhydride is poorly reactive toward bromine, necessitating the use of acidic media.
TheGatterman reaction can also be used to convert diazonium salts to bromobenzenes using copper-based reagents. Owing to high cost ofdiazonium salts, this method is reserved for specialty bromides.
Synthetic aryl iodides are used asX-ray contrast agents, but otherwise these compounds are not produced on a large scale. Aryl iodides are "easy" substrates for many reactions such ascross-coupling reactions and conversion toGrignard 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 asanilines and dimethoxy derivatives react directly with iodine.[8]
Aryl lithium and arylGrignard reagents react with iodine to give the aryl halide:
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.
Although the termaryl halide includes halogenated derivatives of any aromatic compound, it commonly refers to halobenzenes, which are specifically halogenated derivatives ofbenzene. Groups of halobenzenes includefluorobenzenes,chlorobenzenes,bromobenzenes, andiodobenzenes, as well asmixed halobenzenes containing at least two different types of halogens bonded to the same benzene ring. There are also manyhalobenzene derivatives.
Halopyridines are based on the aromatic compoundpyridine.[10] This includeschloropyridines andbromopyridines. Chloropyridines are important intermediates to pharmaceuticals andagrochemicals.
Halogenated naphthalenes are based onnaphthalene.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]
Thethyroid hormonestriiodothyronine (T3) andthyroxine (T4) are aryl iodides. A tetraiodide, T4 isbiosynthesised 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. Chloride and bromide ions in ocean waters are the source of the halogens. Variousperoxidaseenzymes (e.g.,bromoperoxidase) catalyze the formation of these natural aryl chlorides and bromides. 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]
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 209.9pm, respectively.[15]
Unlike typical alkyl halides, aryl halides typically do not participate in conventional substitution reactions. Aryl halides with electron-withdrawing groups in theortho andpara positions, can undergoSNAr 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]
When treated with strong base, some aryl halides often react via the intermediacy ofbenzynes. Benzyne is an intermediate in the reaction of chlorobenzene with strongly basic reagents such aspotassium amide, even at −33 °C. It is also implicated in the conversion of chlorobenzene tophenol using sodium hydroxide, which requires high temperatures.[3][18]
Aryl halides react with metals, generallylithium ormagnesium, to give organometallic derivatives that function as sources of aryl anions. By themetal–halogen exchange reaction, aryl halides are converted to aryl lithium compounds. Illustrative is the preparation ofphenyllithium frombromobenzene usingn-butyllithium (n-BuLi):
Direct formation ofGrignard 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.
The halides can be displaced by strong nucleophiles via reactions involving radical anions. Alternatively aryl halides, especially the bromides and iodides, undergooxidative addition, and thus are subject toBuchwald–Hartwig amination-type reactions.
Rhodococcus phenolicus is a bacterium that degradesdichlorobenzene as sole carbon sources.[19]
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:
Some prominent herbicides are aryl chlorides.
Several chlorobenzene derivatives are used aspigments and dyes.[20]
Aryl bromides are widely used as fire-retardants. A prominent member istetrabromobisphenol-A, which is prepared by direct bromination of the diphenol.[21]
