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Nucleophilic Aromatic Substitution Reaction

The substitution of nucleophilic species at aromatic substrate is called aromatic nucleophilic substitution reaction. It is not a usual reaction of aromatic compounds because there is difficulty for nucleophile to approach the benzene ring due to repulsion by the pi electron density of Benzene ring. Moreover, leaving group in this reaction is hydride ion which is highly unstable making the reaction less feasible. However, the reaction can be made feasible by 3 different ways depending upon this stability of intermediate and accordingly nucleophilic aromatic substitution reaction have three different types of mechanism.

1. Benzyne mechanism

This mechanism is applied to aromatic substrate that contains a leaving group with vacant ortho position(only hydrogen atom should be present at ortho position and no substituent group is present there) strong base is used and can also act as nucleophile and the intermediate involved in this reaction is benzyne or derivative of benzyne. i.e.

Cine Substitution:

If nucleophilic substitution occurs at different position with respect to the leaving group it is called cine substitution. For example, as a result of reaction between 2-bromo methoxybenzene and sodamide the product formed is 3-amino methoxy benzene. This is because Benzyne intermediate formed in this reaction is unsymmetrical and when the nucleophile approaches this intermediate two products should be obtained. But since, methoxy group is electron donating and so, it directs the incoming nucleophile at Meta position. Thus, 3-amino methoxybenzene obtained as a single product only. i.e.

Evidences for Benzyne Mechanism:

1. Isotopic Labeling:

We label the Ipso carbon(that contains the leaving group) with C-13 and then use strong base such as sodamide. Two products appear in the reaction mixture one with the nucleophile at ipsocarbon and other with the nucleophile at ortho carbon. It is possible when amide from sodamide act as a base and takes a proton ortho to the leaving group and makes the intermediate benzyne and then NH3 act as a nucleophile and attacks at the triple bond and give two products. This gives the evidence for the formation of some symmetrical intermediate which is Benzyne. i.e.

2. Diel’s-Alder Reaction:

If we add a diene such as cyclopentadiene in the reaction flask, benzyne acts as a dienophile and reacts with cyclopentadiene and gives the the stable Diels-Alder adduct that can be isolated at low temperature. This also gives the evidence for the formation of benzene as an intermediate in this reaction. i.e.

3. No Ortho Hydrogen Atom:

If the aromatic substrate used contains no ortho hydrogen atom, then reaction would not be possible because of no benzyne intermediate. This gives the evidence that benzyne intermediate formation is not possible for this reaction and thus, no nucleophilic aromatic substitution reaction. But if one substituent from the ortho position is removed then benzyne intermediate can from due to available ortho hydrogen atom and thus, nucleophilic aromatic substitution reaction is possible from both these reactions it is concluded that benzyne intermediate formation is necessary for such substrates to undergo nucleophilic aromatic substitution reaction so, ortho hydrogen atom must be needed for the generation of benzyne intermediate. i.e.

2. SN2 Mechanism:

In this mechanism, nucleophilic aromatic substitution reaction is catalysed by the presence of electron withdrawing group at ortho or para position and or at both positions. In this case, the reaction is catalysed because ipso carbon containing leaving group is more electrophilic in nature because of the electron withdrawing effect of ortho,para deactivating groups there. This mechanism is called SN2 as both the nucleophile and aromatic substrate are involved in rate determining step. i.e

However, the mechanism can be shifted from SN2 to SN1 depending upon the stability of intermediate. If the intermediate is more stable the mechanism shifts towards SN1. For example, In case of 2,4-dinitro halobenzene the rate of reaction is maximum for fluorinated substrate although C-F bond is is stronger than other C-X Bonds but fluorine is more electronegative and makes the intermediate more stable and thus, mechanism shifts towards SN1. i.e.

Rate of reaction depends upon the number of ortho, para electron withdrawing groups. Increasing the number of electron withdrawing groups increases the rate of nucleophilic aromatic substitution reaction as the ipso carbon with leaving group becomes even more electrophilic in nature. i.e.

Evidences of SN2 mechanism:

In 1902, Meisenheimer isolated the red colored solid crystalline intermediate from the reaction of 2,4,5-trinitro methoxybenzene with sodium ethoxide at low temperature. This gives the the evidences for the SN2 mechanism nucleophilic aromatic substitution reaction. i.e.

3. SN1 mechanism:

In case of diazonium salts, nitrogen is the leaving group. Since, nitrogen molecule is neutral. So, it leaves as a good leaving group in first step(slow reversible and rate determining step) and nucleophile attacks on the arenium ion in the second step to give the product.
Rate=k[ArN2+]
Since, diazonium salt is the only reactant involved in the rate equation(which is independent of the concentration of nucleophile)and hence, the mechanism is SN1. i.e.

Evidences for SN1 mechanism:

First step is slow, reversible and thus, rate determining step. If we label one of the nitrogen of diazonium compound as N-15, we will get two diazonium substrates; one with labelled nitrogen directly attached to the the aromatic nucleus and other with the nitrogen(other than the labelled nitrogen) directly attached to the aromatic nucleus. Formation of two diazonium compounds is possible because in first step N2(labeled)is detached and arenium ion is produced. As the first step is reversible, so N2(labeled)again attaches to the arenium ion and thus, it gives two diazonium compounds in the backward step. i.e.


Orientation and reactivity in aromatic nucleophilic substitution reaction:

Nucleophilic aromatic substitution reaction is favorable for deactivated aromatic substrates and heterocyclic aromatic compounds in which lone pair of atom is not involved in the pi electronic cloud of ring such as pyridine, quinoline, isoquinoline. In case of monocyclic aromatic compounds, the orientation of incoming nucleophile depends upon the nature of group that is already present at the ring.
If there is electron donating or activating group present at the ring the incoming nucleophile will come at Meta position as this position is not electron rich such as:

If there is electron withdrawing or deactivating group is already present at the ring, the incoming nucleophile will come at ortho or para position because these positions are more electrophilic in nature and incoming nucleophile will prefer to be at here. such as

In case of heterocyclic aromatic compounds, the incoming nucleophile will come at the position that is electron deficient or more electrophilic such as;

For More details of Nucleophilic aromatic substitution

More Relevant Topics on npodu:

Halogenation of Benzene and other Aromatics

Muhammad Asif

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