Discovery of the Nucleophilic Substitution Reaction

Competition occurs throughout nature, in chemistry, competition often occurs between aiternative reaction pathways, such as in the substitution and eiimination reactions of aikyi haiides.cheryiAnnQuigiey/shutterstock 

Reactions of Alkyl Halides Nucleophilic Substitutions and Eliminations 

We saw in the preceding chapter that the carbon-halogen bond in an alkyl halide is polar and that the carbon atom is electron-poor. Thus, alkyl halides are electrophiles, and much of their chemistry involves polar reactions with nucleophiles and bases. Alkyl halides do one of two things when they react with a nucleophile/base, such as hydroxide ion either they undergo substitution of the X group by the nucleophile, or they undergo elimination of HX to yield an alkene. 

Why This Chapter Nucleophilic substitution and base-induced elimination are two of the most widely occurring and versatile reaction types in organic chemistry, both in the laboratory and in biological pathways. We ll look at them closely in this chapter to see how they occur, what their characteristics are, and how they can be used. We ll begin with substitution reactions. 

The discovery of the nucleophilic substitution reaction of alkyl halides dates back to work carried out in 1896 by the German chemist Paul Walden. Walden 

In 1896, the German chemist Paul Walden made a remarkable discovery. He found that the pure enantiomeric (+)- and (-)-malic acids could be intercon-veited through a series of simple substitution reactions. When Walden treated (-)-malic acid with PCl5, he isolated (4-)-chlorosuccinic acid. This, on treatment with wet Ag20, gave (+)-malic acid. Similarly, reaction of (+)-malic acid with 

Paul Walden (1863-1957) was born in Cesis, Latvia, to German parents who died while he was still a child. He received his Ph.D. in Leipzig, Germany, end returned to Russia as professor of chemistry at Riga Polytechnic (1882-1919). Following 

we refer to the transformations taking place in Walden s cycle as nucleophilic substitution reactions because each step involves the substitution of one nucleophile (chloride ion, Cl-, or hydroxide ion, HO-) by another. Nucleophilic substitution reactions are one of the most common and versatile reaction types in organic chemistry. 

Although this particular series of reactions involves nucleophilic substitution of an alkyl p-toluenesulfonate (called a tosylate) rather than an alkyl halide, exactly the same type of reaction is involved as that studied by Walden. For all practical purposes, the entire tosylate group acts as if it were simply a halogen substituent. In fact, when you see a tosylate substituent in a molecule, do a mental substitution and tell yourself that you re dealing with an alkyl halide. 

Thomson I. Click Organic Process to view an animation showing the stereochemistry of the Sn2 reaction. 

I rom this and nearly a dozen other series of siniilar reactions, workers concluded that the nucleophilic substitution reaction of a primary or secondary alkyl halide or tosylate always proceeds with inversion of configuration. (Tertiary alkyl halides and tosylates, as we ll see shortly, give different stereochemical results and react by a different mechanism.) 

What product would you expect from a nucleo ihilic substitution reaction of (f )-l-bromo-l-phenylethane with cyanide ion, C=K, as nucleophile Show the stereochemistry of both reactant and product, assuming that inversion of configuration occurs. 

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In recent years, the importance of aliphatic nitro compounds has greatly increased, due to the discovery of new selective transformations. These topics are discussed in the following chapters Stereoselective Henry reaction (chapter 3.3), Asymmetric Micheal additions (chapter 4.4), use of nitroalkenes as heterodienes in tandem [4+2]/[3+2] cycloadditions (chapter 8) and radical denitration (chapter 7.2). These reactions discovered in recent years constitute important tools in organic synthesis. They are discussed in more detail than the conventional reactions such as the Nef reaction, reduction to amines, synthesis of nitro sugars, alkylation and acylation (chapter 5). Concerning aromatic nitro chemistry, the preparation of substituted aromatic compounds via the SNAr reaction and nucleophilic aromatic substitution of hydrogen (VNS) are discussed (chapter 9). Preparation of heterocycles such as indoles, are covered (chapter 10). 

Miscellaneous PTC Reactions The field of PTC is constantly expanding toward the discovery of new enantioselective transformations. Indeed, more recent applications have demonstrated the capacity of chiral quaternary ammonium salts to catalyze a number of transformations, including the Neber rearrangement (Scheme 11.19a), ° the trifluoromethylation of carbonyl compounds (Scheme 11.19b), ° the Mannich reaction (Scheme 11.19c), and the nucleophilic aromatic substitution (SnAt)... 

Although ring-annulated and highly substituted borepins have been known for some time, simple 1-substituted borepins have only been thoroughly studied over the past decade. The discovery of a facile synthetic ronte to 1-snbstituted borepins through tin-boron exchange has much opened up the chemistry of these 7-membered boracycles. The chloro-substituted borepin (145) serves as a highly useful precursor to many other borepin derivatives via substitution reactions with nucleophiles (Scheme 20). In addition, several transition metal complexes of 1-borepins have been reported. 

In hypervalent sulfur compounds like (37) and (38), the apical bonds formed by the /r-orbitals are longer and more polar than the equatorial bonds. The special stability of many polycoordinated sulfur compounds is still concluded to be associated with the added orbital interaction with the energetically accessible 3J-orbitals. The discovery of sulfuranes has provided valuable insight into many nucleophilic substitution reactions on polycoordinate sulfur atoms and into ligand-coupling reactions which occur via a-sulfurane intermediates. 

Another catalytic application of chiral ketene enolates to [4 + 2]-type cydizations was the discovery of their use in the diastereoselective and enantioselective syntheses of disubstituted thiazinone. Nelson and coworkers described the cyclocondensations of acid chlorides and a-amido sulfones as effective surrogates for asymmetric Mannich addition reactions in the presence of catalytic system composed of O-TM S quinine lc or O-TMS quinidine Id (20mol%), LiC104, and DIPEA. These reactions provided chiral Mannich adducts masked as cis-4,5 -disubstituted thiazinone heterocycles S. It was noteworthy that the in situ formation of enolizable N-thioacyl imine electrophiles, which could be trapped by the nucleophilic ketene enolates, was crucial to the success of this reaction. As summarized in Table 10.2, the cinchona-catalyzed ketene-N-thioacyl-imine cycloadditions were generally effective for a variety of alkyl-substituted ketenes and aliphatic imine electrophiles (>95%ee, >95%cis trans) [12]. 

The ability of non-C2 symmetric ketones to promote a highly enantioselective dioxirane-mediated epoxidation was first effectively demonstrated by Shi in 1996 [114]. The fructose-derived ketone 44 was discovered to be particularly effective for the epoxidation of frans-olefins (Scheme 17 ). frans-Stilbene, for instance, was epoxidized in 95% ee using stoichiometric amounts of ketone 44, and even more impressive was the epoxidation of dialkyl-substituted substrates. This method was rendered catalytic (30 mol %) upon the discovery of a dramatic pH effect, whereby higher pH led to improved substrate conversion [115]. Higher pH was proposed to suppress decomposition pathways for ketone 44 while simultaneously increasing the nucleophilicity of Oxone. Shi s ketone system has recently been applied to the AE of enol esters and silyl enol ethers to provide access to enantio-enriched enol ester epoxides and a-hydroxy ketones [116]. Another recent improvement of Shi s fructose-derived epoxidation reaction is the development of inexpensive synthetic routes to access both enantiomers of this very promising ketone catalyst [117]. 

A variety of ring-fused systems have been prepared by reaction of pentafluoropyridine and various tetrafluoropyridine systems with difunctional nitrogen nucleophiles. For example, tetrahydropyrido[2,3-Z ]pyrazine and imidazopyridine systems can be prepared by reaction of pentafluoropyridine and appropriate tetrafluoropyridine systems with suitable diamines. The [5,6] and [6,6]-ring-fused systems are also useful substrates for further nucleophilic substitution processes and, consequently, act as versatile scaffolds for the construction of a range of functionalized annelated systems (Fig. 8.10). Of course, such scaffolds are of great interest to the life science industries where access to novel heterocyclic skeletal diversity is a major factor driving the discovery of new chemical entities in lead generation. 

The discovery of the new route to 4-ADPA and the elucidation of the mechanism of the reaction between aniline and nitrobenzene have been recognized throughout the scientific community as a breakthrough in the area of nucleophilic aromatic substitution chemistry, and hailed as a discovery of a new chemical reaction that can be implemented into innovative and environmentally safe chemical processes. 

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