For nucleophilic substitution

Conversion to p toluenesulfonate es ters (Section 8 14) Alcohols react with p toluenesulfonyl chloride to give p toluenesulfonate esters Sulfo nate esters are reactive substrates for nucleophilic substitution and elimma tion reactions The p toluenesulfo nate group is often abbreviated —OTs... 

Noticeably absent from Table 23 3 are nucleophilic substitutions We have so far seen no nucleophilic substitution reactions of aryl halides m this text Chlorobenzene for example is essentially inert to aqueous sodium hydroxide at room temperature Reac tion temperatures over 300°C are required for nucleophilic substitution to proceed at a reasonable rate... 

Substitution nucleophilic bimolecular (Sn2) mechanism (Sec tions 4 12 and 8 3) Concerted mechanism for nucleophilic substitution in which the nucleophile attacks carbon from the side opposite the bond to the leaving group and assists the departure of the leaving group... 

Substitution nucleophilic unimolecular(SNl) mechanism (Sec tions 4 9 and 8 8) Mechanism for nucleophilic substitution charactenzed by a two step process The first step is rate determining and is the ionization of an alkyl halide to a carbocation and a halide ion... 

The ionization mechanism for nucleophilic substitution proceeds by rate-determining heterolytic dissociation of the reactant to a tricoordinate carbocation (also sometimes referred to as a carbonium ion or carbenium ion f and the leaving group. This dissociation is followed by rapid combination of the highly electrophilic carbocation with a Lewis base (nucleophile) present in the medium. A two-dimensional potential energy diagram representing this process for a neutral reactant and anionic nucleophile is shown in Fig. 

Fig. S.l. Potential eneigy diagram for nucleophilic substitution by the ionization (S l) mechanism.

Fig. 5.7. Mote O Ferrall-Jencks diagtam showing concerted, ion-pair and stepwise mechanisms for nucleophilic substitution.

Trifluoromethanesulfonate (triflate) ion is an exceptionally good leaving grov. It can be used for nucleophilic substitution reactions on unreactive substrates. Acetolysis of cyclopropyl triflate, for example, occurs 10 times faster than acetolysis of cyclopropyl tosylate. Table 5.11 gives a conqiarison of the triftate group with some other common leaving groups. 

When a molecule that is a substrate for nucleophilic substitution also contains a group that can act as a nucleophile, it is often observed that the kinetics and stereochemistiy of nucleophilic substitution are strongly affected. The involvement of nearby nucleophilic substituents in a substitution process is called neighboring-group participation ... 

There are alternatives to the addition-elimination mechanism for nucleophilic substitution of acyl chlorides. Certain acyl chlorides are known to react with alcohols by a dissociative mechanism in which acylium ions are intermediates. This mechanism is observed with aroyl halides having electron-releasing substituents. Other acyl halides show reactivity indicative of mixed or borderline mechanisms. The existence of the SnI-like dissociative mechanism reflects the relative stability of acylium ions. 

Stereochemical course of the reaction. This kind of information was critical in the elucidation of the SnI and Sn2 pathways for nucleophilic substitution at saturated carbon. 

In cases where comparable data are available, the activation energy for nucleophilic substitution by anions such as methoxide ion is... 

Zahler and elaborated in a series of papers by Miller and co-workers and in Bunnett s publications, many of which are cited in Section I, D. It should be pointed out that the effects of substituents on nucleophilic substitutions show important differences from their effects on other reactions or on equilibria which involve competition for a lone-pair of electrons on another group or stabilization of negative charge on some atom of the reacting moiety. The cr-constants for nucleophilic substitutions differ from those determined in the latter work in that they show the response of the substituent to a strong demand for stabilization of negative charge on the substituent itself, especially by resonance. 

To derive the maximum amount of information about intranuclear and intemuclear activation for nucleophilic substitution of bicyclo-aromatics, the kinetic studies on quinolines and isoquinolines are related herein to those on halo-1- and -2-nitro-naphthalenes, and data on polyazanaphthalenes are compared with those on poly-nitronaphthalenes. The reactivity rules thereby deduced are based on such limited data, however, that they should be regarded as tentative and subject to confirmation or modification on the basis of further experimental study. In many cases, only a single reaction has been investigated. From the data in Tables IX to XVI, one can derive certain conclusions about the effects of the nucleophile, leaving group, other substituents, solvent, and comparison temperature, all of which are summarized at the end of this section. 

Ab initio calculations suggested that the oxygen-substituted compounds 40 and 41 should be much better candidates for nucleophilic substitution reactions that follow pathway b than the halo salts belonging to the 7a-7i family (Scheme 9). Tire properties of the CCls-substituted cation of 43 should reveal more similarities with those of 7a than with those of 40 and 41. 

Compound 40 has not yet been synthesized. However, there is a large body of synthetic data for nucleophilic substitution reactions with derivatives of 41 [synthesized from aliphatic and aromatic aldehydes, pyridine, and trimethylsilyl triflate (92S577)]. All of these experimental results reveal that the exclusive preference of pathway b is the most important feature of 41 (and also presumably of 40). 

The alkylation process possesses the advantages that (a) a wide range of cheap haloalkanes are available, and (b) the substitution reactions generally occur smoothly at reasonable temperatures. Furthermore, the halide salts formed can easily be converted into salts with other anions. Although this section will concentrate on the reactions between simple haloalkanes and the amine, more complex side chains may be added, as discussed later in this chapter. The quaternization of amines and phosphines with haloalkanes has been loiown for many years, but the development of ionic liquids has resulted in several recent developments in the experimental techniques used for the reaction. In general, the reaction may be carried out with chloroalkanes, bromoalkanes, and iodoalkanes, with the reaction conditions required becoming steadily more gentle in the order Cl Br I, as expected for nucleophilic substitution reactions. Fluoride salts cannot be formed in this manner. 

The reaction with 4-nitrophenol and pentafluorophenol in the presence of KF-18-crown-6 has been investigated. Pentafluorophenoxide anion was found to be a better leaving group [82JFC(20)439]. Alkali metal fluorides on graphite can act as catalysts for nucleophilic substitution of pentafluor-opyridine [90JFC(46)57]. 

Figure 5.39 Heterocyclic ring as activating group for nucleophilic substitutions.

Although phase-transfer catalysis has been most often used for nucleophilic substitutions, it is not confined to these reactions. Any reaction that needs an insoluble anion dissolved in an organic solvent can be accelerated by an appropriate phase transfer catalyst. We shall see some examples in later chapters. In fact, in principle, the method is not even limited to anions, and a small amount of work has been done in transferring cations, radicals, and molecules. The reverse type of phase-transfer catalysis has also been reported transport into the aqueous phase of a reactant that is soluble in organic solvents. ... 

This mechanism is exactly analogous to the allylic rearrangement mechanism for nucleophilic substitution (p. 421). The UV spectra of allylbenzene and 1-propenylbenzene in solutions containing NH2 are identical, which shows that the same carbanion is present in both cases, as required by this mechanism. The acid BH protonates the position that will give the more stable product, though the ratio of the two possible products can vary with the identity of BH". It has been shown that base-catalyzed double-bond shifts are partially intramolecular, at least in some cases. The intramolecularity has been ascribed to a conducted tour mechanism (p. 766) in which the base leads the proton from one carbanionic site to the other ... 

In these reactions, diazonium salts are cleaved to aryl radicals, in most cases with the assistance of copper salts. Reactions 14-17 and 14-18 may also be regarded as belonging to this category with respect to the attacking compound. For nucleophilic substitutions of diazonium salts, see 13-17-13-20. 

This mechanism is the same as the simple electrophilic one shown on page 970 except that the charges are reversed (lUPAC An- -Ae or A +Ah). When the alkene contains a good leaving group (as defined for nucleophilic substitution), substitution is a side reaction (this is nucleophilic substitution at a vinylic substrate, see p. 428). 

Phosphate esters have a variety of mechanistic paths for hydrolysis. Both C-O and P-0 cleavage are possible depending on the situation. A phosphate monoanion is a reasonable leaving group for nucleophilic substitution at carbon and so 8 2 or SnI reactions of neutral phosphate esters are well known. PO cleavage can occur by associative (by way of a pentacoordinate intermediate), dissociative (by way of a metaphosphate species), or concerted (avoiding both of these intermediates) mechanisms. 

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. 

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