Metal catalysis nucleophilic substitution

Direct nucleophilic displacement of halide and sulfonate groups from aromatic rings is difficult, although the reaction can be useful in specific cases. These reactions can occur by either addition-elimination (Section 11.2.2) or elimination-addition (Section 11.2.3). Recently, there has been rapid development of metal ion catalysis, and old methods involving copper salts have been greatly improved. Palladium catalysts for nucleophilic substitutions have been developed and have led to better procedures. These reactions are discussed in Section 11.3. 

Catalysis of Nucleophilic Substitution Reactions. It has been known for many years that metal ions with a strong affinity for halogens will accelerate the reactions of alkyl halides with nucleophiles (Equation 3). It is assumed that the polarization of the carbon-halogen bond, as a consequence of coordination,... 

In homogeneous catalysis, one species can also coordinate to the metal before the other has left. The two situations (first dissociation, then coordination or first coordination, then dissociation) are similar to the SN1 and SN2 nucleophilic substitution mechanisms. Figure 3.4 illustrates these two cases, using as an example the reaction of the Ni(CO)4 complex with acetone (dimethyl ketone) in TH F. In the first case, a CO ligand dissociates from the complex, leaving a vacant position that is immediately filled by a solvent molecule. Then, the solvent is replaced by an acetone... 

Stabilization of enolate anions generated from abstraction of a proton a to a carboxylate Hydrolysis, phosphoryl group transfer via hydrolytic nucleophilic substitution Stabilization of diverse oxyanion intermediates via metal-assisted catalysis Schiff base dependent formation of an electron sink ... 

Among common carbon-carbon bond formation reactions involving carbanionic species, the nucleophilic substitution of alkyl halides with active methylene compounds in the presence of a base, e. g., malonic and acetoacetic ester syntheses, is one of the most well documented important methods in organic synthesis. Ketone enolates and protected ones such as vinyl silyl ethers are also versatile nucleophiles for the reaction with various electrophiles including alkyl halides. On the other hand, for the reaction of aryl halides with such nucleophiles to proceed, photostimulation or addition of transition metal catalysts or promoters is usually required, unless the halides are activated by strong electron-withdrawing substituents [7]. Of the metal species, palladium has proved to be especially useful, while copper may also be used in some reactions [81. Thus, aryl halides can react with a variety of substrates having acidic C-H bonds under palladium catalysis. 

An aryl halide can also be coupled to an amine using metal catalysis. The reaction represents an alternative to the classical methods for the synthesis of aryl amines, such as reduction of nitro groups and nucleophilic aromatic substitution (see Chapter 8). 

Metal ions can accelerate nucleophilic substitution reactions as well as bring about transformations which would not occur in their absence. Often the mechanism of catalysis is obscure. Copper salts are among the oldest and most useful.121,122)... 

Keywords C-Cl activation, Ar-Cl oxidative addition, Chloroarenes, Homogeneous catalysis with metal complexes, Reductive dechlorination, Aromatic nucleophilic substitution, Heck reaction, Homocoupling, Cross-coupling, Carbonylation... 

In the realm of homogeneous catalysis we often encounter examples of acid- and base-catalyzed hydration-dehydration and hydrolysis, metal-catalyzed hydrolysis and autoxidation, photocatalytic oxidation and reduction, metal-catalyzed electron transfer, acid-catalyzed decarboxylation, photocatalytic decarboxylation, metal-catalyzed free-radical chain reactions, acid-catalyzed nucleophilic substitutions, and enzymatic catalysis. 

The amino acid side chains in the active site of enzymes catalyze proton transfers and nucleophilic substitutions. Other reactions require a group of nonprotein cofactors, that is, metal cations and the coenzymes. Metal ions are effective electrophiles, and they help orient the substrate within the active site. In addition, certain metal cations mediate redox reactions. Coenzymes are organic molecules that have a variety of functions in enzyme catalysis. 

Nucleophilic aromatic substitution often requires metal catalysis, as described above. In contrast, alkyl halides undergo reactions with phosphines directly. Nevertheless, metal-catalyzed cross-couplings of these reactive electrophiles have been developed by activation of the nucleophile. 

Two-substituted pyridines feature a structural unit containing in many small molecule compounds, which are of interest for material and medicinal research. A common method for their preparation is the displacement of halogen in the corresponding 2-halopyridines by action of nucleophiles. As a rule, yields for these transformations of inactivated 2-halopyridines are known to be low, and in most cases they require metal catalysis and drastic reaction conditions, such as a high temperature. 

Microwave reactions have been successfully demonstrated for many different organic reactions including metal-mediated catalysis, cyclo-additions, heterocyclic chemistry, rearrangements, electrophilic and nucleophilic substitutions, and reduction. Many reactions work well in water, adding to the techniques green credentials [27]. 

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