Nucleophilic substitutions mechanistic considerations

Nucleophilic substitution reactions by solvolysis at a carbon atom with a leaving group, Eq. (1), are well enough understood that they are often used in introductory organic chemistry textbooks as an instructional foundation for mechanistic concepts. Information on how variables such as the structure, stereochemistry, the leaving group (LG), and the nucleophilicity of the solvent (SOH) control the reactivity is so extensive that prediction of results for new cases can be made with considerable confidence. 

Mechanistic interpretations of the copper-catalyzed aromatic nucleophilic substitution reactions remain unsettled even after half-a-century of debate [19, 20]. Possible pathways involve an S Ar reaction mediated by copper complexation to the pi-system (Scheme 4a), an electron transfer reaction followed by halide dissociation (Scheme 4b), four-centered c-bond metathesis reaction (Scheme 4c) and Cu(l) oxidative addition to the Ar-X bond, followed by the nucleophile exchange and reductive elimination in the resulting Cu(lll) system (Scheme 4d). There is presently a considerable body of experimental and theoretical data for and against each of the proposed mechanisms [21]. While the mechanistic studies were mostly related to the formation of C-C, C-O and C-N bonds, it is likely that the copper-catalyzed halogen exchange reactions follow a similar trend. 

This chapter is concerned with reactions that introduce or interchange substituent groups on aromatic rings. The most important group of such reactions are the electrophilic aromatic substitutions, but there are also significant reactions that take place by nucleophilic substitution mechanisms, and still others that involve radical mechanisms. Examples of synthetically important reactions from each group will be discussed. Electrophilic aromatic substitution has also been studied in great detail from the point of view of reaction mechanism and structure-reactivity relationships these mechanistic studies received considerable attention in Part A, Chapter 9. In this chapter, the synthetic aspects of electrophilic aromatic substitutions will be emphasized. 

A type of reaction of considerable mechanistic interest in the kinetics of electrochemical and solvolytic reactions is the reduction of alkyl halides RX where a nucleophilic substitution type of reaction occurs with the electrode acting as the nucleophile. The anion X and the hydrocarbon RH are the main products. In some cases, organometallic intermediates are produced, e.g., in the reduction of alkyl iodides or bromides at Pb. Here the process which leads to lead tetraalkyls is of considerable commercial significance. 

Scheme 13 Mechanistic considerations for nucleophilic substitution cyclizations...

The photochemical nucleophile-olefin combination aromatic substitution (photo-NOCAS) reaction received considerable attention from many groups not only because of its synthetic value because the yields of nucleophile-olefm-arene (1 1 1) adducts can be high but also because of interesting mechanistic details (Scheme 48). 

For the remainder of this section on square planar substitution reactions, we will confine our attention to those proceeding by a nucleophilic path. We turn now to consideration of the mechanistic details of these reactions. 

Three examples of Sn2 (substitution, nucleophilic, bimolecular) reactions are shown in Scheme 11.5. These are simple reactions from a mechanistic standpoint. They are concerted, and there is very little that can go wrong when considering the proper electron-pushing notation. These reactions fit our paradigm for predicting reactivity, because they are combinations of nucleophiles and electrophiles, whose reactivity can be predicted solely based upon electrostatic considerations. The specific reaction shown in Scheme 11.5 B is an example of the Menschutkin reaction, defined as the reaction between an amine nucleophile and an alkyl halide. Scheme 11.5 C shows the second step of the enolate alkylation reaction we described in Section 11.3. 

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