Substitution reaction

An early method of preparing phenol (the Dow process) involved the reaction of chlorobenzene with a concentrated sodium hydroxide solution at temperatures above 350 ºC. The chief products are phenol and diphenyl ether (see below). This apparent nucleophilic substitution reaction is surprising, since aryl halides are generally incapable of reacting by either an S_N1 or S_N2 pathway.

C6H5–Cl  +  NaOH solution

350 ºC

C6H5–OH  +  C6H5–O–C6H5  +  NaCl

The presence of electron-withdrawing groups (such as nitro) ortho and para to the chlorine substantially enhance the rate of substitution, as shown in the set of equations presented on the left below. To explain this, a third mechanism for nucleophilic substitution has been proposed. This two-step mechanism is characterized by initial addition of the nucleophile (hydroxide ion or water) to the aromatic ring, followed by loss of a halide anion from the negatively charged intermediate. This is illustrated by clicking the "Show Mechanism" button next to the diagram. The sites over which the negative charge is delocalized are colored blue, and the ability of nitro, and other electron withdrawing, groups to stabilize adjacent negative charge accounts for their rate enhancing influence at the ortho and para locations.
Three additional examples of aryl halide nucleophilic substitution are presented on the right. Only the 2- and 4-chloropyridine isomers undergo rapid substitution, the 3-chloro isomer is relatively unreactive. Nitrogen nucleophiles will also react, as evidenced by the use of Sanger's reagent for the derivatization of amino acids. The resulting N-2,4-dinitrophenyl derivatives are bright yellow crystalline compounds that facilitated analysis of peptides and proteins, a subject for which Frederick Sanger received one of his two Nobel Prizes in chemistry.

Additional Examples

Such addition-elimination processes generally occur at sp² or sp hybridized carbon atoms, in contrast to S_N1 and S_N2 reactions. When applied to aromatic halides, as in the present discussion, this mechanism is called S_NAr. Some distinguishing features of the three common nucleophilic substitution mechanisms are summarized in the following table.

مواضيع ذات صلة

Organic compounds are more soluble in water as ions

Heterocyclic aromatic compounds

Hückel’s rule tells us if compounds are aromatic

Molecular orbitals and aromaticity

The π molecular orbitals of other conjugated cyclic hydrocarbons

Benzene has six π molecular orbitals

Varying the number of electrons

Heats of hydrogenation of benzene and cyclooctatetraene

? What makes benzene special

Aromaticity

Conjugation and reactivity: looking forward to Chapter 10

The amide group