Nucleophilic Substitution with Displacement of Good Leaving Groups

2 Nucleophilic Substitution with Displacement of Good Leaving Groups 

Fluorides are more reactive than the other hahdes, (cf. 3.3.2) for example 2-fluoropyridine can be converted into 2-dialkylamino-pyridines using hthium amides at room temperature. This could be compared with the 130 °C required to displace a-bromine using the potassium salt of pyrazole. Displacement of nitro can be made the means for the synthesis of a- and y-fluoro-pyridines. Of the five fluorines in pentafluoropyridine, the y-fluorine is displaced most rapidly.  

Replacements of halide by reaction with ammonia can be achieved at considerably lower temperatures than those illustrated, under 6-8 kbar pressure.  

The sulfonic acid substituent in 5-nitropyridine-2-sulfonic acid can be displaced by alcohols, amines or chloride.  

In some displacements, an alternative mechanism operates. For example the reaction of either 3- or 

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Nucleophilic substitution with displacement of good leaving groups... 

Aromatic rings are usually not good enough nucleophiles to react with alkyl halides. If Lewis acids are added to improve the electron sink, then electrophilic aromatic substitution occurs via the carbocation if it is more stable than secondary (an SnI viewed from the electrophile). With Lewis acids and methyl, primary, or secondary alkyl halides, electrophilic aromatic substitution usually occurs via direct displacement of the leaving group (an Sn2 viewed from the electrophile). 

Since acetylenic esters of any type, but especially ones with a good leaving group, like sulfonates, were unknown until recently [4], early substrates for nucleophilic acetylenic substitutions [Sn-A] were primarily the haloacetylenes 1 [2, 3, 5]. Unfortunately, product yields in these reactions tend to be moderate at best, usually because of competing reactions including displacement of RC C via direct attack on the halogen itself. 

Nucleophilic substitution of hydrogen Sn can also be combined with the displacement of a good leaving group as illustrated by the reaction of 3-phenyl-5-methoxy-l,2,4-triazine with resorcinol, proceeding via the intermediate o -adduct and affording benzofuro[2,3-e]-l,2,4-triazine according to the tandem Sn -Sn cyclization protocol (Scheme 57) [175]. 

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