Nucleophiles and Leaving Groups

In this chapter, the basic principle of arrow pushing was introduced in the context of organic reactions driven by homolytic cleavage, heterolytic cleavage, or concerted mechanisms. Furthermore, the concept of polarity was introduced using heteroatoms and common organic functional groups. This discussion led to the definitions of nucleophiles and 

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General-base catalysis can, as the name suggests, be accomplished by any adequately strong base, whereas very special demands are placed upon compounds acting as nucleophilic catalysts. The efficiency of these catalysts depends on three factors basicity, nucleophilicity, and leaving-group ability [166], Each of these characteristics is in turn the combined result of several attributes. 

These transition state properties have been modelled computationally at the HF/6-31G level.45 The transition state geometry and properties for the reaction of 7V-formyloxy-/V-methoxyformamide 40 with ammonia giving 69 (Scheme 13), is illustrated in Fig. 20. In the transition state the nucleophile and leaving group,... 

Intrinsic Nucleophilicity vs. Leaving Group Ability. As pointed out earlier, our definition of intrinsic nucleophilicity in terms of barriers to degenerate exchange reactions necessarily implies that nucleophilicity and leaving group ability are equivalent. This can be seen in either of two ways. First,... 

Nucleophiles and leaving groups reversible addition reactions... 

The different reactivities associated with nucleophiles and leaving groups is nicely exemplified in the synthesis of the analgesic drug paracetamol (USA acetaminophen) from 4-aminophenol. If 4-aminophenol is treated with an excess of acetic anhydride, aeetylation of both amino and phenol groups is observed, and the product is the diacetate. Paracetamol is the A-acetate of 4-aminophenol, so how might mono-acetylation be achieved There are two approaches. 

Lewis (1983) has posed the intriguing question What is the effect of simultaneous substitution on both nucleophile and leaving group on reactivity for an identity exchange process, such as (95) In other words, if we... 

If the carbocationic configuration [22] is dominant over [23] then the reaction will be enhanced by electron-withdrawing substituents, since [23] contains both nucleophile and leaving group in the free anionic form X . This will result in the observation of a positive p-value. Contrariwise, if the car-banion configuration [23] is dominant, then the reaction will be enhanced by electron-releasing substituents and a negative p-value will result. 

Nucleophilicity and leaving group ability 211 Effect of solvation on the gas-phase reaction 212 Mechanism of the gas-phase SN2 reaction 213 Potential energy surfaces for gas-phase SN2 reactions 214 Recent theoretical developments 218 Some examples of gas-phase SN2 reactions involving positive ions 220 Nucleophilic displacement reactions by negative ions in carbonyl systems 222 General features 222... 

A more complete picture of nucleophilicity and leaving group ability can be obtained from the data of Olmstead and Brauman (1977) and Tanaka et al. (1976). These results are compiled in Tables 4 and 5. 

The above model has been further explored to account for reaction efficiencies in terms of a scheme where nucleophilicities and leaving group abilities can be rationalized by a structure-reactivity pattern. Pellerite and Brau-man (1980, 1983) have proposed that the central energy barrier for an exothermic reaction (see Fig. 3) can be analysed in terms of a thermodynamic driving force, due to the exothermicity of the reaction, and an intrinsic energy barrier. The separation between these two components has been carried out by extending to SN2 reactions the theory developed by Marcus for electron transfer reactions in solutions (Marcus, 1964). While the validity of the Marcus theory to atom and group transfer is open to criticism, the basic assumption of the proposed model is that the intrinsic barrier of reaction (38)... 

Factors determining nucleophilicity and leaving group ability... 

The chemistry and stereochemistry of the reactions were extensively discussed in Chapter 8, sections El and E3. There is an in-line mechanism that generates a pentacovalent intermediate or transition state, with the attacking nucleophile and leaving group occupying the apical positions of the trigonal bipyramid. 

The nature of the solvent and the structures of the substrate, nucleophile, and leaving group all help determine whether a nucleophilic displacement proceeds by a unimolecular or bimolecular pathway. They also all affect the rate of reaction. 

In fact, most of the data that have accumulated since 1935 are qualitatively in accord with their predictions,19 but the predictions should not be used indis-criminately without considering the effect the solvent may have on nucleophile and leaving-group reactivity (see pp. 190-194). 

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