Factor 2—The Nucleophile

EXERCISE 9.6 In the compound below, circle the LGs that are benzylic or allylic  

PROBLEMS For each compound below, determine whether the LG leaving would form a resonance-stabilized carbocation. If you are not sure, try to draw resonance structures of the carbocation you would get if you pulled off the leaving group. 

In many cases we can determine from the substrate alone whether we will get S l or S m2. If w e have a l° substrate, then the reaction will go via an Sjm2 mechanism, with inversion of configuration. If you have a 3° substitute, then the reaction will go 

Weak nucleophiles are those that do not have a negative charge at all. They have lone pairs, and they use these lone pairs to attack the electrophilic site of the substrate. Examples are 

Each of these compounds has no charge. Students often forget that compounds like this can be nucleophiles. But since there is no charge, they are certainly very weak nucleophiles. 

The rate of an Sn2 process is dependent on the strength of the nucleophile. A strong nucleophile will speed up the rate of an Sn2 reaction, while a weak nucleophile will slow down the rate of an Sn2 reaction. In contrast, an SnI process is not affected by 

In summary, the nucleophile has the following effect on the competition between Sn2 and SnI  

Below are some strong and weak nucleophiles that we will encounter often  

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Nucleophilic addition to car bonyl groups sometimes leads to a mixture of stereoisomeric products. The direction of attack is often controlled by steiic factors, with the nucleophile approaching the carbonyl group at its less hindered face. Sodium borohydride reduction of 7,7-dirnethylbicyclo[2.2.1]heptan-2-one illustrates this point ... 

The behavior of methyl and halomethyl radicals in their reactions with the fluoro-olefms (Table 1.2), can thus be rationalized in terms of a more dominant role of polar factors and the nucleophilic or electrophilic character of the radicals involved." Methyl radicals are usually considered to be slightly nucleophilic, trifluoromcthyl and triehloroincthyl radicals arc electrophilic (Tabic 1,4). 

L. Hough and A. C. Richardson, Diethylsulphonyl-(2-0-methyl-a-D-arabopyranosyl)-methane and its behaviour with base, J. Chem. Soc., (1961) 5561-5563 The nucleophilic degradation of diethylsulphonylglycopyranosylmethane derivatives, ibid.. (1962) 1019— 1023 Conformational and electronic factors influencing the nucleophilic degradation of diethylsulphonylglycopyranosylmethane derivatives, ibid.. (1962) 1024-1032. 

There are four factors that impact the competition between the n2 mechanism and Sfgl (1) the substrate, (2) the nucleophile, (3) the leaving group, and (4) the solvent. 

The nucleophilicity of amine nitrogens is also differentiated by their environments. In 2,4,5,6-tetraaminopyrimidine the most basic 3-amino group can be selectively converted to a Schiff base. It is meta to both pyrimidine nitrogens and does not form a tautomeric imine as do the ortho- and /xira-amino groups. This factor is the basis of the commercial synthesis of triamterene. 

A second factor that can tip the balance m favor of substitution is weak basicity of the nucleophile Nucleophiles that are less basic than hydroxide react with both pri mary and secondary alkyl halides to give the product of nucleophilic substitution m high yield To illustrate cyanide ion is much less basic than hydroxide and reacts with 2 chlorooctane to give the corresponding alkyl cyanide as the major product... 

Many properties have an influence on nucleophilicity. Those considered to be most significant are (1) the solvation energy of the nucleophile (2) the strength of the bond being formed to carbon (3) the size of the nucleophile (4) flie electronegativity of the attacking atom and (5) the polarizability of the attacking atom. Let us consider how each of these factors affects nucleophilicity ... 

All these methods demonstrate that the 2-positions of pyridine, pyrimidine, and other azines are the most electron deficient in the ground state. However, considerably greater chemical reactivity toward nucleophiles at the 4-position is often observed in syntheses and is supported by kinetic studies. Electron deficiency in the ground state is related to the ability to stabilize the pair of electrons donated by the nucleophile in the transition state. However, it is not so directly related that it can explain the relative reactivity at different ring-positions. Certain factors which appear to affect positional selectivity are discussed in Section II, B. 

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