Leaving groups in substitution reactions

Although fluorine is known to be a rather poor leaving group in substitution reactions, some examples have been reported for the replacement of fluorine by N-nucleophiles. Here, substitution can proceed with amines,1 -3 amides,4 amidines,5-6 hydrazines3-7 or azides.8-9 Nitriles in the presence of nitrosyl hexafluorophosphate replace fluorine in alkyl fluorides, in a Ritter-like reaction, to form tV-alkylnitrilium species, which are hydrolyzed to amides.10... 

Sulfonates are common leaving groups in substitution reactions " however, solvolysis of triflates 16 with 2.2.2-trifluoroethanol 17 can lead to either C-O or S-C) bond formation. Consequently, a mixture of products containing minor amounts of the desired ether 18 and a 1 2 mixture of sulfonate 19 and the symmetrical ether 20 is obtained. 

The -R and -H in these compounds can t act as leaving groups in substitution reactions. 

The leaving groups commonly employed in E2 reactions are listed in Table 2.1. As you can see, they are essentially the same as those displaced in nucleophilic substitution reactions (see Part 2), with two exceptions. First, protonated alcohols are not listed as substrates RX in Table 2.1, because they usually react by the El mechanism (as we shall see later) rather than the E2 mechanism. Secondly, the trimethylammonium and dimethylsulfonium groups have limited importance as leaving groups in substitution reactions, although they are particularly important in elimination reactions. In fact, the reaction involving trimethylammonium is known, after its discoverer, as the Hofmann elimination... 

The structure and nomenclature of sulfonate esters (see 113, 114, or 115) are described in Chapter 20 (Section 20.11.2). It is also true that sulfonate esters are good leaving groups in the substitution reactions described in this chapter (see Section 11.2.4). Sulfonate esters are prepared by the reaction of sulfonic acids with alcohols—much the way that carboxylic acid esters are prepared from carboxylic acids and alcohols (described in Chapter 20, Section 20.11.2). More commonly, sulfonate esters are prepared by the reaction of a sulfonyl chloride (see 112) with an alcohol. This reaction is also described in Chapter 20. This section presents only a simple preview of that chemistry, with the goal of showing that it is easy to convert alcohols into sulfonate esters, which are then useful as leaving groups in substitution reactions. The formal mechanism of these reactions will be discussed in Chapter 20. 

A systematic study of the effects of solvent on the leaving group in substitution reactions at palladium(II) has been carried out. Rate and equilibrium constants were reported for reactions (1) and (2) in methanol. 

When complex organic systems have evolved in nature, they are frequently made by the combination of carboxy carbonyl groups and the heteroatoms of alcohols, amines, or thiols. Why The addition-elimination processes introduced in Chapter 19 provide mechanistic pathways of relatively low activation energy for the interconversion of variously substituted carboxylic acid derivatives, many of which play central roles in biology (Chapter 26). Chemists find these compounds similarly useful, as we shall see in this chapter, which deals with the chemistry of four major carboxylic acid derivatives halides, anhydrides, esters, and amides. Each has a substituent, L, that can function as a leaving group in substitution reactions. We already know, for instance, that displace-O... 

Effect on Reactivity. The leaving groups in elimination reactions are similar to those in nucleophilic substitution. The E2 eliminations have been performed with the following groups NRj, PR, SRj, OHR", SO2R, OSO2R,... 

The use of chiral leaving groups, e.g.. a camphorsulfonyl group, in substitution reactions with C-C bond formation was first reported in 19745. Since the leaving group is involved in the transition state of SN2 reactions, asymmetric induction is observed if a chiral leaving group is used. 

This last step is one of the rare examples in which the leaving group is OH. Generally, hydroxide is a poor leaving group in substitution (SN1 or SN2) or elimination (El or E2) reactions (see Section 8-7C). 

As substitution anchors, heterocycles with a reduced jt-electron density in the heterocyclic ring are used. The rate of hydrolysis or alcoholysis (i.e., the reaction with the cellulose anion) is influenced by the nature of the heterocyclic nucleus, the substituents, and the leaving groups. In the reaction with the cellulose anion, the substitution anchors listed in Figure 4.1 are bonded by ester linkages. In contrast, cellulose adds to the vinylsulfone anchor in a nucleophilic reaction, and an ether link is formed. 

The number of reactions in this chapter may seem overwhelming at first. The key to success is to remember that nucleophiles react with electrophiles. If you can identify the nucleophile or base and the electrophilic carbon (the one bonded to the leaving group) in each reaction and recall the factors that affect the competition between the two substitution mechanisms and the two elimination mechanisms, the material you have to learn will be much more manageable. 

The trichloromethyl group of 4-(trichloromethyl)quinazoline can be replaced by methoxy, hydroxy, aliphatic amino, and pyrrolidino groups to give quinazolines 1. From a preparative point of view, these nucleophilic aromatic substitution reactions are similar to the replacement of other more common leaving groups. In the reaction of 4-(trichloromethyl)quinazoline with a methoxide ion, in contrast to the usual aromatic substitution mechanism, a covalent solvation adduct was isolated as intermediate. Whereas 4-(trichloromethyl)quinazoline prefers to undergo aromatic substitution, 4-(tribromomethyl)quinazoline prefers aliphatic substitution. 2-Methyl-4-(tribromomcthyl)quinazoline affords 2-methylquinazolin-4(3/f)-one in 74% yield on treatment with sodium hypobromite in dioxane, probably via an aromatic substitution reaction of a tribromomethyl group. 

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