Aryl halides mechanism

Hartwig, J. F. Palladium-catalyzed amination of aryl halides. Mechanism and rational catalyst design. Synlett 1997, 329-340. 

Catalyzed Amination of Aryl Halides. Mechanism and Rational Catalyst Design. 

These reactions follow first-order kinetics and proceed with racemisalion if the reaction site is an optically active centre. For alkyl halides nucleophilic substitution proceeds easily primary halides favour Sn2 mechanisms and tertiary halides favour S 1 mechanisms. Aryl halides undergo nucleophilic substitution with difficulty and sometimes involve aryne intermediates. 

The o-keto ester 513 is formed from a bulky secondary alcohol using tricy-clohexylphosphine or triarylphosphine, but the selectivity is low[367-369]. Alkenyl bromides are less reactive than aryl halides for double carbonyla-tion[367], a-Keto amides are obtained from aryl and alkenyl bromides, but a-keto esters are not obtained by their carbonylation in alcohol[370]. A mechanism for the double carbonylation was proposed[371,372],... 

A key step in the reaction mechanism appears to be nucleophilic attack on the alkyl halide by the negatively charged copper atom but the details of the mechanism are not well understood Indeed there is probably more than one mechanism by which cuprates react with organic halogen compounds Vinyl halides and aryl halides are known to be very unreactive toward nucleophilic attack yet react with lithium dialkylcuprates... 

Aryl halides react too slowly to undergo substitution by the Sn2 mechanism with the sodium salt of diethyl malonate and so the phenyl substituent of phenobarbital cannot be introduced in the way that alkyl substituents can... 

The strength of their carbon-halogen bonds causes aryl halides to react very slowly in reactions in which carbon-halogen bond cleavage is rate determining as m nude ophilic substitution for example Later m this chapter we will see examples of such reactions that do take place at reasonable rates but proceed by mechanisms distinctly dif ferent from the classical S l and 8 2 pathways... 

Second order kinetics is usually interpreted m terms of a bimolecular rate determining step In this case then we look for a mechanism m which both the aryl halide and the nucleophile are involved m the slowest step Such a mechanism is described m the fol lowing section... 

The generally accepted mechanism for nucleophilic aromatic substitution m nitro substituted aryl halides illustrated for the reaction of p fluoromtrobenzene with sodium methoxide is outlined m Figure 23 3 It is a two step addition-elimination mechanism, m which addition of the nucleophile to the aryl halide is followed by elimination of the halide leaving group Figure 23 4 shows the structure of the key intermediate The mech anism is consistent with the following experimental observations... 

Other aryl halides that give stabilized anions can undergo nucleophilic aromatic substitution by the addition-elimination mechanism Two exam pies are hexafluorobenzene and 2 chloropyridme... 

In each of the following reactions an amine or a lithium amide derivative reacts with an aryl halide Give the structure of the expected product and specify the mechanism by which it is formed... 

The reaction between an alkoxide ion and an aryl halide can be used to prepare alkyl aryl ethers only when the aryl halide is one that reacts rapidly by the addition-elim mation mechanism of nucleophilic aromatic substitution (Section 23 6)... 

A second general reaction that proceeds by an SrnI mechanistic pattern involves aryl halides. Aryl halides undergo substitution by eertain nueleophiles by a ehain mechanism of the SrnI class.Many of the reactions are initiated photochemically, and most have been conducted in liquid ammonia solution. 

Elimination-addition mechanism (Section 23.8) Two-stage mechanism for nucleophilic aromatic substitution. In the first stage, an aryl halide undergoes elimination to form an aryne intermediate. In the second stage, nucleophilic addition to the aryne yields the product of the reaction. 

Aryl halides undergo substitution, although not through an Sn2 mechanism, but rather via a two-step addition-elimination mechanism. (An elimination-addition mechanism is also possible see Chapter 13, Problem 12.)... 

Available information on the mechanism of cyclocondensation is rather contradictory. According to one hypothesis, both the condensation of aryl halides with copper acetylides and the cyclization occur in the same copper complex (63JOC2163 63JOC3313). An alternative two-stage reaction route has also been considered condensation followed by cyclization (66JOC4071 69JA6464). However, there is no clear evidence for this assumption in the literature and information on the reaction of acetylenyl-substituted acids in conditions of acetylide synthesis is absent. 

The mechanism of action of the cyanation reaction is considered to progress as follows an oxidative addition reaction occurs between the aryl halide and a palladium(O) species to form an arylpalladium halide complex which then undergoes a ligand exchange reaction with CuCN thus transforming to an arylpalladium cyanide. Reductive elimination of the arylpalladium cyanide then gives the aryl cyanide. 

As we ve seen, aromatic substitution reactions usually occur by an electrophilic mechanism. Aryl halides that have electron-withdrawing substituents, however, can also undergo nucleophilic aromatic substitution. For example. 2,4,6-trinitrochlorobenzene reacts with aqueous NaOH at room temperature to give 2,4,6-trinitrophenol. The nucleophile OH- has substituted for Cl-. 

Nucleophilic substitutions on an aromatic ring proceed by the mechanism shown in Figure 16.17. The nucleophile first adds to the electron-deficient aryl halide, forming a resonance-stabilized negatively charged intermediate called a Meisenlieimer complex. Halide ion is then eliminated in the second step. 

The anion of DMSO undergoes a phenylation reaction with aryl halides under sunlight stimulation38. The presence of benzhydryl methyl sulfoxide (maximum yield 5%) in all runs, the sunlight activation, the order of reactivity of halobenzenes (I > Br > Cl), the inhibition of the reaction with oxygen, all hint at the SRN139-44 mechanism (Scheme 3). 

The possible mechanism for the reactions involving stoichiometric amount of preformed Ni(0) complexes is shown in Fig. 9.8. The first step of the mechanism involves the oxidative addition of aryl halides to Ni(0) to form aryl Ni(II) halides. Disproportion of two aryl Ni(II) species leads to a diaryl Ni(II) species and a Ni(II) halide. This diaryl Ni(II) species undergoes rapid reductive elimination to form the biaryl product. The generated Ni(0) species can reenter the catalytic cycle. 

Examples of the intermolecular C-P bond formation by means of radical phosphonation and phosphination have been achieved by reaction of aryl halides with trialkyl phosphites and chlorodiphenylphosphine, respectively, in the presence of (TMSlsSiH under standard radical conditions. The phosphonation reaction (Reaction 71) worked well either under UV irradiation at room temperature or in refluxing toluene. The radical phosphina-tion (Reaction 72) required pyridine in boiling benzene for 20 h. Phosphinated products were handled as phosphine sulfides. Scheme 15 shows the reaction mechanism for the phosphination procedure that involves in situ formation of tetraphenylbiphosphine. This approach has also been extended to the phosphination of alkyl halides and sequential radical cyclization/phosphination reaction. ... 

Aryl halides can be dehalogenated by Friedel-Crafts catalysts. Iodine is the most easily cleaved. Dechlorination is seldom performed and defluorination apparently never. The reaction is most successful when a reducing agent, say, Br or 1 is present to combine with the I" or Br coming off." Except for deiodination, the reaction is seldom used for preparative purposes. Migration of halogen is also found," both intramolecular and intermolecular." The mechanism is probably the reverse of that of 11-11." ... 

For aryl halides and sulfonates, even active ones, a unimolecular SnI mechanism (lUPAC Dn+An) is very rare it has only been observed for aryl triflates in which both ortho positions contain bulky groups (fe/T-butyl or SiRs). It is in reactions with diazonium salts that this mechanism is important ... 

Unactivated aryl halides can be converted to amines by the use of NaNH2, NaNHR, or NaNR2. With these reagents, the benzyne mechanism generally operates, so cine substitution is often found. Ring closure has been effected by this type of reaction,for example. 

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