Aryl chlorides reactivity

The concept of electron-rich P(f catalysts is based on the analogy between nucleophilic aromatic substitution (eq. (12a)) and Pd° insertion (cf. eq. (12b)) [42 c, d]. It had previously been applied in the carbonylation of aryl chlorides [38 a, b]. Related work by Milstein [42] and Basset [43] should be consulted. High-pressure conditions seem to enhance the aryl chloride reactivity, too [44]. Meanwhile, various other methods have been developed for the selective activation of aryl chlorides with defined Pd complexes as well as in situ systems (cf. Section 3.1.6.4). 

Chlorination is carried out m a manner similar to brommation and provides a ready route to chlorobenzene and related aryl chlorides Fluormation and lodmation of benzene and other arenes are rarely performed Fluorine is so reactive that its reaction with ben zene is difficult to control lodmation is very slow and has an unfavorable equilibrium constant Syntheses of aryl fluorides and aryl iodides are normally carried out by way of functional group transformations of arylammes these reactions will be described m Chapter 22... 

Arylamines are converted by diazotization with nitrous acid into arenediazonium salts, ArN2+ X-. The diazonio group can then be replaced by many other substituents in the Sandmeyer reaction to give a wide variety of substituted aromatic compounds. Aryl chlorides, bromides, iodides, and nitriles can be prepared from arenediazonium salts, as can arenes and phenols. In addition to their reactivity toward substitution reactions, diazonium salts undergo coupling with phenols and arylamines to give brightly colored azo dyes. 

The low reactivity of aryl chlorides is usually attributed to the strength of the C-Cl bond (bond dissociation energies for aryl-X Cl = 96 kcal/mol Br = 81 kcal/mol I = 65 kcal/mol). 

Aryl chlorides are not very reactive under normal Heck reaction conditions but reaction can be achieved by inclusion of tetraphenylphosphonium salts with Pd(OAc)2 or PdCl2 as the catalysts.138... 

Various phosphine ligands have been employed. Tm-(f-butyl)phosphine is an excellent ligand and is applicable to both vinyl and arylstannanes, including sterically hindered ones. Aryl chlorides are reactive under these conditions.195... 

Most of the synthetic applications to date have been based on empirical screening and comparison of ligand systems for effectiveness. A number of useful procedures have been developed. Aryl chlorides are generally less reactive than iodides and... 

The low catalytic reactivity of aryl chlorides in cross-coupling reactions is usually attributed to their reluctance towards oxidative addition to Pd(0). For a discussion, see V. V. Grushin and H. Alper, Chem. Rev., 94, 1047-1062 (1994), and reference therein. 

The order of reactivity of halides with magnesium is RI > RBr > RC1 (very few organomagnesium fluorides have been prepared), i) Aryl Grignard reagents are more easily prepared from aryl bromides and aryl iodides than from aryl chlorides, which react very sluggishly. 

Generally, monophosphine complexes can be generated by decomposition of suitable precursors, among which the most notable are palladacycles (Section 9.6.3.4.7). A spectacular example makes use of spontaneous disproportionation of a dimeric complex of Pd1 with very bulky ligands to give one of the most reactive catalytic systems known so far, which catalyzes the fast crosscoupling of arylboronic acids with aryl chlorides and hindered aryl bromides at room temperature (Equation (28)) 389... 

Commercially available Pd(PtBu3)2 is a unique, air-stable 14e Pd° complex, an excellent catalyst for cross-coupling reactions of aryl chlorides. The ability of P Bu3 to stabilize such a coordin-atively unsaturated, extremely reactive, and yet easily manageable form of Pd° is one of the most amazing and fruitful recent findings in Pd-based catalysis. The cross-coupling of arylzinc reagents with aryl or vinyl chlorides can be readily accomplished with as little as 0.03% of this catalyst. Both electron-rich and sterically hindered substrates are welcome in this protocol.404... 

Activated aryl chlorides, which are close in reactivity to unactivated aryl bromides, underwent reaction with the original P(o-tol)3-ligated catalyst.58 Nickel complexes, which catalyze classic C—C bond-forming cross-couplings of aryl chlorides, 9-64 also catalyzed aminations of aryl chlorides under mild conditions.65,66 However, the nickel-catalyzed chemistry generally occurred with lower turnover numbers and with a narrower substrate scope than the most efficient palladium-catalyzed reactions. 

Utilizing more reactive discrete palladium-N-heterocyclic carbene (NHC) complexes (for example, Pd(carb)2) or in situ generated palladium/imidazolium salt complexes (1 mol% ligand A), Caddick and coworkers were able to extend the rapid amination protocols described above to electron-rich aryl chlorides (Scheme 6.61) [128],... 

Recently, the groups of Fu and Buchwald have coupled aryl chlorides with arylboronic acids [34, 35]. The methodology may be amenable to large-scale synthesis because organic chlorides are less expensive and more readily available than other organic halides. Under conventional Suzuki conditions, chlorobenzene is virtually inert because of its reluctance to oxidatively add to Pd(0). However, in the presence of sterically hindered, electron-rich phosphine ligands [e.g., P(f-Bu)3 or tricyclohexylphosphine], enhanced reactivity is acquired presumably because the oxidative addition of an aryl chloride is more facile with a more electron-rich palladium complex. For... 

The use of reactive metal electrodes are also effective for the silylation of various organic halides and simple arenes [75]. For instance, Dunogues et al. reported that electrolysis of aryl chlorides in the presence of excess Me3SiCl in a one-compartment cell equipped with a sacrificial aluminum anode in 80 20 THF/HMPA gave the corresponding aryltrimethylsilanes (Scheme 36). When... 

Reactions of aryl halides with the reactive calcium required slightly higher temperatures, up to -30°C for aryl bromides and up to -20°C for aryl chlorides.1 2 3 4 5 Surprisingly, the active calcium reacted readily with fluorobenzene at room temperature to form the corresponding organocalcium reagent in near quantitative yield. 

It has been proposed that in this reaction CO2 reacts as an electrophile with [ArPd (PPh3)2] formed by reduction of the aryl-palladium(II) [102]. Aryl chlorides react too slowly with Pd° to enable an efficient carboxylation reaction. On the other hand aryl triflate and aryl bromide have similar reactivity. The synthesis of aryl carboxylic acids can then be obtained from phenols via the formation of the corresponding aryltriflate (Eq. 15) [29, 30] ... 

Because of their convenient preparation from palladium(II) salts and stable NHC-precursors (vide supra), paUadium(ll) complexes were first examined as potential catalysts for Heck-type reactions. Due to the high thermal stability, temperatures up to 150°C can be used to activate even less reactive substrates, like, e.g., aryl chlorides. Inunobilization of such catalysts has been shown recently (vide infra) ... 

The difference in the reactivity of benzylic versus aromatic halogens makes it possible to reduce the former ones preferentially. Lithium aluminum hydride replaced only the benzylic bromine by hydrogen in 2-bromomethyl-3-chloro-naphthalene (yield 75%) [540]. Sodium borohydride in diglyme reduces, as a rule, benzylic halides but not aromatic halides (except for some iodo derivatives) [505, 541]. Lithium aluminum hydride hydrogenolyzes benzyl halides and aryl bromides and iodides. Aryl chlorides and especially fluorides are quite resistant [540,542], However, in polyfluorinated aromatics, because of the very low electron density of the ring, even fluorine was replaced by hydrogen using lithium aluminum hydride [543]. 

A number of modified reaction conditions have been developed. One involves addition of silver salts, which activate the halide toward displacement.94 Use of sodium bicarbonate or sodium carbonate in the presence of a phase-transfer catalyst permits especially mild conditions to be used for many systems.95 Tetraalkylammonium salts often accelerate reaction.96 Solid-phase catalysts in which the palladium is complexed by polymer-bound phosphine groups have also been developed.97 Aryl chlorides are not very reactive under normal Heck reaction conditions, but reaction can be achieved by inclusion of triphenylphosphonium salts with Pd(OAc)2 or PdCl2 as the catalyst.98... 

Historically, one of the most important limitations of the Suzuki-Miyaura reaction was the poor reactivity of organic chlorides, attributed to the strength of the C-Cl bond. Aryl chlorides are very attractive halides due to their low cost and wider diversity of available compounds. Prior to 1998, reports of effective palladium-catalyzed Suzuki reactions of aryl chlorides were limited to activated substrates, and generally employing very high temperatures. In that year. 

Low reactive aryl chlorides are converted to the respective organomagnesium species in excellent yields through transition metal catalysis using 2 mol% FeCU (4-6, equation 3). Alternatively, a safe and reproducible method for activation of aryl chlorides or bromides 7 uses microwave irradiation (equation 4). In a synthesis of a novel HIV-1 protease inhibitor, microwave irradiation was essential to generate the starting arylmagnesium halide as well as to promote the subsequent Kumada coupling reaction. ... 

From the synthetic point of view, choice of the starting halide or sulfonate is usually based on availability. Reactivity and economy usually work antiparallel with bromides being the most frequently used substrates. The recent invention of highly active catalyst systems, on the other hand, broadened the applicability of aryl chlorides considerably in cross-coupling reactions.3... 

Lithium fluoride cannot displace less reactive halogens from aryl chlorides and bromides. However, a high-temperature reaction of lithium fluoride with bromoform gives a few percent exchange along with considerable side products.3 By passing a stream of methyl chloride in a lithium fluoride/sodium fluoride/potassium fluoride melt at 500 C a conversion rate of 42% to methyl fluoride in 85% yield is observed.4... 

---