Aromatic Nucleophilic Substitution

Introduction:

Although most reactions of aromatic compounds occur by way of electrophilic aromatic substitution, aryl halides undergo a limited number of substitution reactions with strong nucleophiles

1) Ar-SN1 Reaction:

Organic compounds with a halogen atom attached to an aromatic carbon are very different from those compounds where the halogen is attached to an aliphatic compound.

While the aliphatic compounds readily undergo nucleophilic substitution and elimination reactions, the aromatic compounds resist nucleophilic substitution, only reacting under severe conditions or when strongly electron withdrawing groups are present ortho/para to the halogen.

Aryl halides, syntheses: Via Carbocation Intermediate

a) From Diazonium Salts

Ar-N2+ + CuCl → Ar-Cl

Ar-N2+ + CuBr → Ar-Br

Ar-N2+ + KI → Ar-I

Ar-N2+ + HBF4 → Ar-F

b) Halogenation

Ar-H + X2, Lewis acid → Ar-X + HX

X2 = Cl2, Br2

Lewis acid = FeCl3, AlCl3, BF3, Fe…

2) Ar-SN2 Reaction:

Aryl halides with strong electron-withdrawing groups (such as NO2) on the ortho or para positions react with nucleophiles to afford substitution products.

For example, treatment of p-chloronitrobenzene with hydroxide (–OH) affords p-nitrophenol by replacement of Cl by OH.

Nucleophilic aromatic substitution occurs with a variety of strong nucleophiles, including –OH, –OR, –NH2, –SR, and in some cases, neutral nucleophiles such as NH3 and RNH2.

The mechanism of these reactions has two steps:

- addition of the nucleophile to form a resonance-stabilized carbanion,

- followed by elimination of the halogen leaving group.

Mechanism:

Step 1:

a) Addition of the nucleophile (:Nu–) forms a resonance-stabilized carbanion with a new C– Nu bond—three resonance structures can be drawn.

b) Step [1] is rate-determining since the aromaticity of the benzene ring is lost.

Step 2:

a) Loss of the leaving group re-forms the aromatic ring. This step is fast because the aromaticity of the benzene ring is restored.

Example

2.1) Important criterian:

In nucleophilic aromatic substitution, the following trends in reactivity are observed.

a) Increasing the number of electron-withdrawing groups increases the reactivity of the aryl halide. Electron-withdrawing groups stabilize the intermediate carbanion, and by the Hammond postulate, lower the energy of the transition state that forms it.

b) Increasing the electronegativity of the halogen increases the reactivity of the aryl halide. A more electronegative halogen stabilizes the intermediate carbanion by an inductive effect, making aryl fluorides (ArF) much more reactive than other aryl halides, which contain less electronegative halogens.

2.2) If more than one Halogens on Aromatic ring then the reactivity is:

The location of the electron-withdrawing group greatly affects the rate of nucleophilic aromatic substitution.

When a (Electron withdrawing Group) nitro group is located ortho or para to the halogen , the negative charge of the intermediate carbanion can be delocalized onto the NO2 group, thus stabilizing it.

With a meta NO2 group, no such additional delocalization onto the NO2 group occurs.

Example

3) Nucleophilic Aromatic Substitution by Elimination–Addition via Benzyne

Aryl halides that do not contain an electron-withdrawing group generally do not react with nucleophiles.

Under extreme reaction conditions, however, nucleophilic aromatic substitution can occur with aryl halides.

For example, heating chlorobenzene with NaOH above 300 °C and 170 atmospheres of pressure affords phenol.

The mechanism proposed to explain this result involves formation of a benzyne intermediate (C6H4) by elimination–addition.

Mechanism:

Benzyne is a highly reactive, unstable intermediate formed by elimination of HX from an aryl halide.

a) Elimination of H and X from two adjacent carbons forms a reactive benzyne intermediate (Steps [1] and [2]).

b) Addition of the nucleophile (–OH in this case) and protonation form the substitution product (Steps [3] and [4]).

Formation of a benzyne intermediate explains why substituted aryl halides form mixtures of products.

Nucleophilic aromatic substitution by an elimination–addition mechanism affords substitution on the carbon directly bonded to the leaving group and the carbon adjacent to it.

As an example, treatment of p-chlorotoluene with NaNH2 forms para- and meta-substitution products.

This result is explained by the fact that nucleophilic attack on the benzyne intermediate may occur at either C3 to form m-methylaniline, or C4 to form p-methylaniline.

Mechanism:

Example

4) Hetero Atom in Ring:

Pyridine efficiently supports several nucleophilic substitutions, and is regarded as a good nucleophile

The reason for this is relatively lower electron density of the carbon atoms of the ring.

These reactions include substitutions with elimination of a hydride ion and elimination-additions with formation of an intermediate aryne configuration, and usually proceed at the 2- or 4-position.

4.1) Selectivity if more than one Halogen atom:

Due to more stability of the anion it will go to this position