Nucleophilic substitution in alkyl halides

Comparison of SnI and Sn2 Mechanisms of Nucleophilic Substitution in Alkyl Halides... 

In contrast to nucleophilic substitution in alkyl halides, where alkyl fluorides are exceedingly unreactive, aryl fluorides undergo nucleophilic substitution readily when the ring bears an o- or a p-nitro group. 

Nucleophilic substitutions in alkyl halides catalysed by polypode [116] under liquid-liquid phase-transfer conditions ... 

The well-known action of silver(i) salts on nucleophilic substitution in alkyl halides is another commonplace example of this effect. The silver ion interacts with the halide, thus weakening the carbon-halogen bond and enhancing the leaving ability of the halide... 

Nucleophilic Substitution in Alkyl Halides — S l vs S 2 Comparison Table 20-1... 

In contrast to nucleophilic substitution in alkyl halides, where alkyl fluorides are exceedingly unreactive, aryl fluorides undergo nucleophilic substitution when the ring bears an 0- or p-nitro group. The reaction of l-fluoro-2,4-dinitrobenzene, known as Sanger s reagent, with amino acids takes place readily at room temperature and is the basis of a method used in protein structure determination. 

Nitriles contain the —C=N functional group. We have already discussed the two main procedures by which they are prepared, namely, the nucleophilic substitution of alkyl halides by cyanide and the conversion of aldehydes and ketones to cyanohydrins. Table 20.6 reviews aspects of these reactions. Neither of the reactions in Table 20.6 is suitable for aryl nitriles (ArC N) these compounds are readily prepared by a reaction to be discussed in Chapter 22. 

Alkyl azides, prepared by nucleophilic substitution of alkyl halides by sodium azide, as shown in the first entry of Table 22.3, are reduced to alkylamines by a variety of reagents, including lithium aluminum hydride. 

A similar strategy in aqueous media has now been applied to the nucleophilic substitution of alkyl halides or tosylates using readily available alkali azides, thiocyanates or sulfinates under microwave irradiation. The approach afforded safe and efficient preparation of azides, thiocyanates and sulfones (Scheme 23) (Ju et al., personal communications). 

SN1 versus S There are two different mechanisms involved in the nucleophilic substitution of alkyl halides. When polar aprotic solvents are used, the SN2 mechanism is preferred. Primary alkyl halides react more quickly than secondary alkyl halides, with tertiary alkyl halides hardly reacting at all. Under protic solvent conditions with non-basic nucleophiles (e.g. dissolving the alkyl halide in water or alcohol), the SN1 mechanism is preferred and the order of reactivity is reversed. Tertiary alkyl halides are more reactive than secondary alkyl halides and primary alkyl halides do not react at all. 

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. 

Thus far we have concentrated on the starting material in nucleophilic substitution—the alkyl halide—and have not paid much attention to the product formed. Nucleophilic substitution reactions, and in particular Sn2 reactions, introduce a wide variety of different functional groups in molecules, depending on the nucleophile. For example, when OH, OR, and CN are used as nucleophiles, the products are alcohols (ROH), ethers (ROR), and nitriles (RCN). respectively. Table 7.8 lists some functional groups readily introduced using nucleophilic substitution. 

Alkynyl anions are useful in lengthening carbon chains. They react by nucleophilic substitution with alkyl halides. 

The two main mechanisms for nucleophilic substitution of alkyl halides are SN1 and SN2. These represent the extreme mechanisms of nucleophilic substitution, and some reactions involve mechanisms which lie somewhere in between the two. 

In addition to undergoing nucleophilic substitution reactions, alkyl halides undergo J8-elimination reactions The halogen is removed from one carbon and a proton is removed from an adjacent carbon. A double bond is formed between the two carbons from which the atoms are eliminated. Therefore, the product of an elimination reaction is an alkene. Removal of a proton and a halide ion is called dehydrohalogenation. There are two important jS-elimination reactions, El and E2. 

In the simple case of the aliphatic nucleophilic substitution of alkyl halides R-X in an aqueous organic two-phase system in the presence of catalytic amounts of a quaternary onium salt and an excess of a metal salt M+Y, the catalyst transfers the reacting... 

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... 

Both poly(vinylpyrrolidone) and poly(ethylene oxide) accelerate nucleophilic substitution of alkyl halides by phenoxide anions (60). These Williamson ether syntheses of phenyl alkyl ethers were up to 100 times faster when the ether syntheses were carried out in the presence of poly(vinylpyrrolidone) versus when they were performed using an equivalent amount of N-methylpyrroli-done. Poly(ethylene oxide) was as effective in these reactions as was 18-crown-6. Procedures for separating the products from the polymeric additives were not described. 

In Chapter 8, we noted that aryl halides are normally much less reactive toward nucleophilic substitution than alkyl halides. In the present chapter weTl see examples of novel, useful, and mechanistically interesting nucleophilic aromatic substitutions and explore the structural features responsible for these reactions. 

Substitution and Addition Reactions. All types of reactions between inorganic anions and organic partners can be executed under the PTC conditions. Nucleophilic aliphatic substitution in alkyl halides with cyanide anions to form nitriles was presented in the Introduction as a typical example of PTC on which the basic principles and characteristic features of this catalysis were discussed. 

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