Nucleophilic substitution substrate structure

In the discussion of electrophilic aromatic substitution (Chapter 11) equal attention was paid to the effect of substrate structure on reactivity (activation or deactivation) and on orientation. The question of orientation was important because in a typical substitution there are four or five hydrogens that could serve as leaving groups. This type of question is much less important for aromatic nucleophilic substitution, since in most cases there is only one potential leaving group in a molecule. Therefore attention is largely focused on the reactivity of one molecule compared with another and not on the comparison of the reactivity of different positions within the same molecule. 

As mentioned earlier, Ding et al.15 captured a number of dichlorohetero-cyclic scaffolds where one chloro atom is prone to nucleophilic aromatic substitution onto resin-bound amine nucleophiles (Fig. 1). Even though it was demonstrated that in many cases the second chlorine may be substituted with SNAr reactions, it was pointed out that palladium-catalyzed reactions offer the most versatility in terms of substrate structure. When introducing amino, aryloxy, and aryl groups, Ding et al.15 reported Pd-catalyzed reactions as a way to overcome the lack of reactivity of chlorine at the purine C2 position and poorly reactive halides on other heterocycles (Fig. 10). 

As discussed in Sect. 3, the mechanism of Pd-catalyzed allylic substitutions is often highly complex, involving numerous intermediates and competing reaction pathways. Enantioseiection can occur early in the catalytic cycle, e.g., by enan-tioface discrimination in the substrate, or later in the nucleophilic addition step. There are reactions where the enantioselectivity-determining step changes when the substrate structure or the reaction conditions are altered. Therefore, the origin of enantioselectivity may vary from one case to another and no general mechanism of enantioseiection can be proposed. 

Examples of effects of substrate structure on the rates of nucleophilic substitution reactions have appeared in the preceding sections of this chapter. Additionally, some special effects will be covered in detail in succeeding sections. This section will emphasize the role steric effects can play in nucleophilic substitution reactions. 

The nature of the substrate structure, nucleophile, leaving group, and solvent polarity can all alter the mechanistic course of the substitution. 

Often substitution and elimination reactions occur simultaneously with the same set of reactants—a nucleophile and a substrate. One reaction type or the other may predominate, depending on the structure of the nucleophile, the structure of the substrate, and other reaction conditions. As with substitution reactions, there are two main mechanisms for elimination reactions, designated E2 and El. To learn how to control these reactions, we must first understand each mechanism. 

The reactivities of alkyl halides in nucleophilic substitution reactions depend on two important factors reaction conditions and substrate structure. The reactivities of several subsfrafe fypes will be examined under bofh Sj l and Sj. 2 reaction conditions in this experiment. 

As in these last examples, the descriptions of diastereoselective epoxidations were accompanied already by details on their subsequent use in ring fission reactions, we shall now switch to the various options of controlled regioselective and diastereoselective epoxide transformations. The nucleophilic opening of epoxides shows a strong dependence on substrate structure, nature of the nucleophile, and the catalyst involved, similarly to nucleophilic substitutions. Lastly, one has to consider the solvent and other details of the reaction conditions including the transition state conformation. 

Sulfonate esters are especially useful substrates in nucleophilic substitution reactions used in synthesis. They have a high level of reactivity, and, unlike alkyl halides, they can be prepared from alcohols by reactions that do not directly involve bonds to the carbon atom imdeigoing substitution. The latter aspect is particularly important in cases in which the stereochemical and structural integrity of the reactant must be maintained. Sulfonate esters are usually prepared by reaction of an alcohol with a sulfonyl halide in the presence of pyridine ... 

The reactivities of the substrate and the nucleophilic reagent change vyhen fluorine atoms are introduced into their structures This perturbation becomes more impor tant when the number of atoms of this element increases A striking example is the reactivity of alkyl halides S l and mechanisms operate when few fluorine atoms are incorporated in the aliphatic chain, but perfluoroalkyl halides are usually resistant to these classical processes However, formal substitution at carbon can arise from other mecharasms For example nucleophilic attack at chlorine, bromine, or iodine (halogenophilic reaction, occurring either by a direct electron-pair transfer or by two successive one-electron transfers) gives carbanions These intermediates can then decompose to carbenes or olefins, which react further (see equations 15 and 47) Single-electron transfer (SET) from the nucleophile to the halide can produce intermediate radicals that react by an SrnI process (see equation 57) When these chain mechanisms can occur, they allow reactions that were previously unknown Perfluoroalkylation, which used to be very rare, can now be accomplished by new methods (see for example equations 48-56, 65-70, 79, 107-108, 110, 113-135, 138-141, and 145-146)... 

Al, as shown in structure 3), the molecularity (1 or 2), and the ionic form of the substrate [A for conjugate acid RC(OH)OR and B for conjugate base RCOOR]. Note that alkyl-oxygen fission constitutes nucleophilic substitution and is therefore equivalent to the classification ... 

Regioselective nucleophilic substitution at the 5 position is proved to occur when 1-hydroxytryptophan and -tryptamine derivatives are treated with 85% HCOOH (99H1157). Truly amazing is the fact that only substrates carrying a C—C—N structure in the side chain at the 3 position can undergo this regioselective substitution. 

Acidic ether cleavages are typical nucleophilic substitution reactions, either SN1 or Sn2 depending on the structure of the substrate. Ethers with only primary and secondary alkyl groups react by an S 2 mechanism, in which or Br attacks the protonated ether at the less hindered site. This usually results in a selective cleavage into a single alcohol and a single alkyl halide. For example, ethyl isopropyl ether yields exclusively isopropyl alcohol and iodoethane on cleavage by HI because nucleophilic attack by iodide ion occurs at the less hindered primary site rather than at the more hindered secondary site. 

The problem of the thermally induced polymerization reaction of partially or completely substituted cyclophosphazenes has been considered in the past by several authors [355-357], and more recently by H. R. AUcock [358]. This is because of the ease of synthesizing these substrates, the possibihty of preparing structurally regulated poly(organophosphazenes), and the lack of any additional nucleophilic substitution processes on the poly(organophosphazenes) obtained by the ROP process of fully saturated trimers. 

Dimethylmalonate 75 coordinates to a Fe(CO)4 species, yielding a ferrate species 128. This coordinates the allylic substrate under decarbonylation and by nucleophilic attack at the double bond an allyliron-species 131 is generated which undergoes substitution of the ferrate 132 by a dimethylmalonte molecule 75. Although there is some evidence of this catalytically active ferrate 128, until now it could not be fully analytically characterized and therefore the structure presented above still remains a hypothesis. 

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