Substitution, nucleophilic other mechanisms

The relative importance of the potential catalytic mechanisms depends on pH, which also determines the concentration of the other participating species such as water, hydronium ion, and hydroxide ion. At low pH, the general acid catalysis mechanism dominates, and comparison with analogous systems in which the intramolecular proton transfer is not available suggests that the intramolecular catalysis results in a 25- to 100-fold rate enhancement At neutral pH, the intramolecular general base catalysis mechanism begins to operate. It is estimated that the catalytic effect for this mechanism is a factor of about 10. Although the nucleophilic catalysis mechanism was not observed in the parent compound, it occurred in certain substituted derivatives. 

It is quite reasonable to expect the bimolecular two-stage mechanism Sj Ar ) to predominate in most aromatic nucleophilic substitutions of activated substrates. However, only in rare instances is there adequate evidence to rule out the simultaneous occurrence or predominance of other mechanisms. The true significance of the alternative mechanisms in azines needs to be determined by trapping the intermediates or by applying modem separation and characterization methods to the identification of at least the major portion of the products, especially in kinetic studies. 

Some of the reactions in this chapter operate by still other mechanisms, among them an addition-elimination mechanism (see 13-15). A new mechanism has been reported in aromatic chemistry, a reductively activated polar nucleophilic aromatic substitution. The reaction of phenoxide with p-dinitrobenzene in DMF shows radical features that cannot be attributed to a radical anion, and it is not Srn2. The new designation was proposed to account for these results. 

The diazonium group can be replaced by a number of groups. Some of these are nucleophilic substitutions, with SnI mechanisms (p. 853), but others are free-radical reactions and are treated in Chapter 14. The solvent in all these reactions is usually... 

According to this mechanism, there is a first-order dependence on both the concentration of [ A B] and B, and the reaction is called an SN2 process (substitution, nucleophilic, second-order). Although many nucleophilic substitution reactions follow one of these simple rate laws, many others do not. More complex rate laws such as... 

The basic classification of nucleophilic substitutions is founded on the consideration that when a new metal complex is formed through the breaking of a coordination bond with the first ligand (or water) and the formation of a new coordination bond with the second ligand, the rupture and formation of the two bonds can occur to a greater or lesser extent in a synchronons manner. When the mpture and the formation of the bonds occur in a synchronous way, the mechanism is called substitution nucleophilic bimolecular (in symbols Sn2). On the other extreme, when the rupture of the first bond precedes the formation of the new one, the mechanism is called substitution nucleophilic unimolecular (in symbols SnI). Mechanisms Sn2 and SnI are only limiting cases, and an entire range of intermediate situations exists. 

The diazonium group can be replaced by a number of groups.222 Some of these are nucleophilic substitutions, with SnI mechanisms (p. 644), but others are free-radical reactions and are treated in Chapter 14. The solvent in all these reactions is usually water. With other solvents it has beeen shown that the SnI mechanism is favored by solvents of low nucleo-philicity, while those of high nucleophilicity favor free-radical mechanisms.222 (For formation of diazonium ions, see 2-49.) The N2 group can be replaced by Cl, Br. and CN, by a nucleophilic mechanism (see OS IV, 182). but the Sandmeyer reaction is much more useful (4-25 and 4-28). As mentioned on p. 651 it must be kept in mind that the N2 group can activate the removal of another group on the ring. 

Dehydroheteroarenes like (10) and (11) have also been proposed as intermediates in nucleophilic substitution.23-25 Some of these reactions were evaluated uncritically and operation of other mechanisms like addition-elimination (AE) and ring opening-ring closure (ANRORC) can now be demonstrated in many such cases. Nevertheless, there is conclusive evidence for heteroaryne intermediacy in some reactions of heterocyclic halides. From the preparative point of view, nucleophilic coupling of such intermediates has found only limited applications.26-28 Reactive intermediates with an additional formal bond between nonadjacent atoms, like (12) and (13), have also been postulated but again hold little synthetic interest. 

The same mechanism is true for nucleophilic substitutions of other carboxylic acid derivatives with neutral nucleophiles (Following fig.). In practice, acids or bases are generally added to improve yields. 

With other nucleophiles (overview Figure 5.52) aryldiazonium salts react according to other mechanisms to form substitution products. These substitutions are possible because cer-... 

With other nucleophiles (Figures 5.42-5.45) aryldiazonium salts react according to other mechanisms to form substitution products. These substitutions are possible because certain nucleophiles reduce aryldiazonium salts to form radicals Ar—N=N-. These radicals lose molecular nitrogen. A highly reactive aryl radical remains, which then reacts directly or indirectly with the nucleophile. 

Nucleophilic aromatic substitutions have been studied in detail. Either of two mechanisms may be involved, depending on the reactants. One mechanism is similar to the electrophilic aromatic substitution mechanism, except that nucleophiles and carban-ions are involved rather than electrophiles and carbocations. The other mechanism involves benzyne, an interesting and unusual reactive intermediate. 

This is a nucleophilic acyl substitution reaction whose mechanism is similar to others we have studied. 

It is hard to believe, however, that a coordinatively and electronically saturated iron atom in (7T-C5lI,)Fe(CO)2Br can associate with nucleophiles via additional bridge bonds. Besides which it is known that halogen is not active under conditions of substitution 217). Probably the first step of reaction (49) involves dissociation (either CO and Br may be eliminated), so that a generated intermediate then reacts with a substrate. As a result the ligand transfer via an intermediate does not differ from other mechanisms proposed. 

There are two mechanisms for nucleophilic aromatic substitution. Both occur in two important steps. In one mechanism, an addition is followed by an elimination. In the other mechanism, an elimination is followed by an addition. 

The other mechanism involves 3-55 as the nucleophile in the S, 2 displacement at the highly reactive chloro-substituted carbon a to the carbonyl. The remaining anion, 3-58, reacts with the carbonyl group to give 3-57. 

Other cases in which second-order kinetics seemed to require an associative mechanism have subsequently been found to have a conjugate base mechanism (called S ICB, for substitution, nucleophilic, unimolecular, conjugate base in Ingold s notation ). These reactions depend on amine, ammine, or aqua ligands that can lose protons to form amido or hydroxo species that are then more likely to lose one of the other ligands. If the structure allows it, the ligand Irons to the amido or hydroxo group is frequently the one lost. 

The relative extent of dialkylation depends on the electrophilicity of RX (and the nucleophilicity of AR ) when a realtively fast SET (AE i/2 < 0.5 V) is the primary reaction. Other mechanisms may also satisfactorily explain the distribution of products. For instance, adduct formation between the alkyl radical and the mediator (acting as a radical trap) is possible and must be considered in such a case, further reduction of AR may take place, either by electron transfer or by abstraction of a hydrogen atom from the solvent. However, let us keep in mind that radical anions or dianions may act as nucleophiles, since a partial inversion of configuration of some optically active secondary RX compounds has been found [222] after workup under experimental conditions similar or identical to those of the electrolyses. Table 8 exemplifies alkylation reactions following a SET. The reaction scheme may be complicated by the fact that reduced forms of the mediator may act as a reducing nucleophile toward RX. The SET may then be assumed as the rate-determining step in aliphatic nucleophilic substitutions [223], and/or R generated in solution may be added to an electrophilic mediator, such as an activated ketone [224]. 

Now let us turn to the other mechanism by which nucleophilic aliphatic substitution can take place. 

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