Sources of Aryl Halides

Melting points and boiling points for some representative aryl halides are listed in Appendix 1. 

Compare the electronic charges at chlorine in chlorocy-clohexane and chlorobenzene on Learning By Modeling to verify that the C—Cl bond is more polar in chlorocyclohexane. 

Aryl halides resemble alkyl halides in many of their physical properties. All are practically insoluble in water and most are denser than water. 

Aryl halides are polar molecules but are less polar than alkyl halides. 

Since carbon is yp -hybridized in chlorobenzene, it is more electronegative than the sp -hybridized carbon of chlorocyclohexane. Consequently, the withdrawal of electron density away from carbon by chlorine is less pronounced in aryl halides than in alkyl halides, and the molecular dipole moment is smaller. 

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The diazonium salts 145 are another source of arylpalladium com-plexes[114]. They are the most reactive source of arylpalladium species and the reaction can be carried out at room temperature. In addition, they can be used for alkene insertion in the absence of a phosphine ligand using Pd2(dba)3 as a catalyst. This reaction consists of the indirect substitution reaction of an aromatic nitro group with an alkene. The use of diazonium salts is more convenient and synthetically useful than the use of aryl halides, because many aryl halides are prepared from diazonium salts. Diazotization of the aniline derivative 146 in aqueous solution and subsequent insertion of acrylate catalyzed by Pd(OAc)2 by the addition of MeOH are carried out as a one-pot reaction, affording the cinnamate 147 in good yield[115]. The A-nitroso-jV-arylacetamide 148 is prepared from acetanilides and used as another precursor of arylpalladium intermediate. It is more reactive than aryl iodides and bromides and reacts with alkenes at 40 °C without addition of a phosphine ligandfl 16]. 

Formate is an excellent hydride source for the hydrogenolysis of aryl halides[682]. Ammonium or triethylammonium formate[683] and sodium formate are mostly used[684,685]. Dechlorination of the chloroarene 806 is carried out with ammonium formate using Pd charcoal as a catalyst[686]. By the treatment of 2,4,6-trichloroamline with formate, the chlorine atom at the /iiara-position is preferentially removed[687]. The dehalogenation of 2,4-diha-loestrogene is achieved with formic acid, KI, and ascorbic acid[688]. 

Palladium-catalyzed aminations of aryl halides is now a well-documented process [86-88], Heo et al. showed that amino-substituted 2-pyridones 54 and 55 can be prepared in a two-step procedure via a microwave-assisted Buchwald-Hartwig amination reaction of 5- or 6-bromo-2-benzyloxypyri-dines 50 and 51 followed by a hydrogenolysis of the benzyl ether 52 and 53, as outlined in Fig. 9 [89]. The actual microwave-assisted Buchwald-Hartwig coupling was not performed directly at the 2-pyridone scaffold, but instead at the intermediate pyridine. Initially, the reaction was performed at 150 °C for 10 min with Pd2(dba)3 as the palladium source, which provided both the desired amino-pyridines (65% yield) as well as the debrominated pyridine. After improving the conditions, the best temperature and time to use proved... 

A set of aryl halides was reacted with carbonyl hydrazides and molybdenum hexacar-bonyl [Mo(CO)6] as a source of carbon monoxide, employing fluorous triphenylphos-phine (F-TPP) as ligand and the perfluorocarbon liquid FC-84 as a perfluorinated solvent (Scheme 7.87 see also Scheme 6.46c). 

Aryl and vinyl nitriles have been prepared very efficiently from the corresponding bromides by palladium-catalyzed reactions under microwaves. This energy source has been employed for the conversion of these nitriles into aryl and vinyl tetrazoles by cycloaddition reactions with sodium azide (Scheme 9.66). The direct transformation of aryl halides to the aryl tetrazoles in a one pot procedure could be accomplished both in solution and on a solid support [115], The reactions were complete in a few minutes, a reaction time considerably shorter than those previously reported for the thermal reactions. The cydoadditions were performed with sodium azide and ammonium chloride in DMF and, although no explosion occurred in the development of this work, the authors point out the necessity of taking adequate precautions against this eventuality. 

Wan, Y.Q., Alterman, M., Larhed, M. and Hallberg, A., Formamide as a combined ammonia synthon and carbon monoxide source in fast palladium-catalysed aminocarbonylations of aryl halides, /. Comb. Chem., 2003, 5, 82-84. 

A procedure has been developed for the palladium-catalysed a-arylation of amides by aryl bromides using the zinc enolates of the amides. The reaction works well with bromoarenes carrying a variety of ring substituents and with bromopyridine. In addition, the reaction has been shown to be effective with morpholine amides to give products which are precursors for aldehydes and ketones.39 A new method has been reported for the allylation of aryl halides using homoallyl alcohols as the allyl source the palladium-catalysed reaction, which may be both stereo- and regio-sepecific, uses a retro-allylation reaction to form a a-allyl(aryl)palladium intermediate.40... 

Based on mechanistic reasoning, the use of carbon monoxide or molybdenum hexacarbonyl as suitable CO sources necessitates of application of aryl halides. In addition, the effective concentration of CO in the reaction medium plays a crucial... 

If a Pd(II) source is used in the Heck reaction, it must be reduced to Pd(0) before entering the catalytic cycle. The initial oxidative addition of aryl halide to a Pd(0) catalyst affords... 

Nickel in its zerovalent state can also be used for the coupling of aryl halides to biphenyls and vinyl halides to 1,3-dienes. Bis(l,5-cyclooctadiene)nickel, Ni(COD)2, is the best source of zerovalent nickel for such couplings. 

Blaser and Spencer used aroyl halides in place of aryl halides, with aroyl chlorides being of specific interest as ubiquitous, relatively cheap compounds ( Blaser reaction ) [24], This latter reaction is normally conducted in aromatic solvents phosphines are not used here as catalyst ligands since they fully inhibit the reaction. In the same way, benzoic acid anhydrides can be used as the aryl source in combination with PdCl2 and catalytic amounts of NaBr [79]. In this reaction, one of the arenes is used in the coupling reaction by elimination of CO, whereas the other benzoate serves as the base. The benzoic acid thus formed can easily be recycled into the anhydride. The use of aryl and vinyl triflates according to Cacchi [25] and Stille [26] extends the scope of the Heck coupling to carbonyl compounds phenol derivatives act via triflate functionalization as synthetic equivalents of the aryl halides. The arylation of cyclic alkenes [27], electron-rich vinyl ethers [28], and allylic alcohols [29] is accessible through Heck reactions. Allylic alcohols yield C-C-saturated carbonyl compounds (aldehydes) for mechanistic reasons (y9-H elimination), as exemplified in eq. (6). 

In the presence of hydrogen sources and electron donors, the reaction mechanisms for photodechlorination of aryl halides may follow two general mechanisms, i.e., homolysis and electron transfer processes. In the homolysis process, C-Cl bond photolytic cleavage is the primary reaction, forming an aryl radical, which abstracts a hydrogen from the hydrogen source, and gives the product ArH. 

Instead of aryl halides, arenediazonium salts are also excellent arylating agents in the Suzuki coupling, although more hindered arylboronic acids did not react The reaction is catalysed by several sources of ligand-free palladium such as Pd(OAc)2, Pd2(dba)3 and Pd/C at room temperature in dioxane without any added base [98]. Use of potassium aryl trifluoroborate salts also allowed the introduction of more sterically hindered aryl groups [99]. 

Enolate Arylation Reactions. The direct coupling of aryl halides with enolates (or enolate equivalents) of ketones, esters, and amides is now well established. Malonic esters, cyanoacetates, and malononitrile can be arylated upon treatment with aryl halides in the presence of Pd(dba)2 and electron-rich phosphines or N-heterocyclic carbenes. Carbene ligands have also proven effective in promoting the a-arylation of protected amino acids. As a caveat to the use of Pd(dba)2, the arylation of azlactones in the presence of this palladium source and phosphines was less efficient than that with Pd(OAc)2. The dba ligands were found to react with azlactone substrates to form catalytically inactive palladium complexes. Diastereoselective enolate arylation has been achieved through the use of chiral auxiliaries appended to preformed enol silyl ethers (eq 23). The role of the zinc additive is not clear, however, it appears that discrete zinc enolates are not involved. 

Diazonium salts are the most reactive source of arylpalladium species and the reaction can be carried out at room temperature using Pd2(dba)3 as a catalyst in the absence of both phosphine ligand and base [44]. The reaction of diazonium salts means indirect substitution reaction of an amino group of anilines or aromatic nitro group with an alkene. The use of diazonium salts is synthetically more convenient than the use of aryl halides, because many aryl halides, particularly iodides, are prepared from diazonium salts. 

The source of palladium is often palladium(II) acetate [Pd(OAc)2l, but the active catalyst is Pd(0), which is formed under the reaction conditions. Only catalytic amounts of palladium are needed a typical molar ratio of aryl halide to Pd(OAc)2 is 100 1. 

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