Substitution Reaction - Definition, Types and Examples

In this article we will discuss about Substitution Reaction. Here we will learn definition, types and examples of Substitution Reaction. 

Key words: Substitution reactions, Leaving group, Nucleophile, Electrophile, Free radical, Electrophilic Substitution, Free Radical Substitution and Nucleophilic Substitution.

What is Substitution Reaction?

A substitution reaction is a chemical reaction where on one group is replaced by another group. Generally substitution reaction takes place where there is polar carbon-heteroatom bond present in the molecule. The atom or group which is replaced in the reaction is known as leaving group and the product formed is called as substitution product. The group or atom which replaces the leaving group is can be nucleophile, electrophile or a free radical.

Figure 1: Substitution Reaction

Substitutions reactions are classified based on the group which replaces the leaving group. Hence substitution reactions are classified as Electrophilic Substitution, Free Radical Substitution and Nucleophilic Substitution. The electrophilic substitution reactions are of two types, Electrophilic Aromatic Substitution and Electrophilic Aliphatic Substitution. The nucleophilic substitution reactions are further classified as Nucleophilic Aliphatic Substitution, Nucleophilic Acyl Substitution and Nucleophilic Aromatic Substitution.

Figure 2: Classification of Substitution Reactions

1.        Electrophilic Substitution Reactions

An electrophilic substitution reaction is chemical reaction in which leaving group is replaced by an electrophile. This reaction is observed in the compound which contains electron rich carbon-carbon double bond. The electrophile is an electron deficient species which is formed in the reaction. The elctrophile accepts the pair of electron from carbon-carbon double bond form new carbocation intermediate. Finally the leaving group get cleaved to form stable molecule.

Figure 3: Electrophilic substitution reaction

Based upon type of substrate molecule there are two types of electrophilic substitutions reactions are found namely; Electrophilic Aromatic Substitution Reaction and Electrophilic Aliphatic Substitution Reaction.

1.1    Electrophilic Aromatic Substitution Reaction

In electrophilic aromatic substitution reaction the substrate is an aromatic compound and electrophile is replaces a hydrogen atom from the aromatic ring. For example, halogenation of benzene compound is electrophilic aromatic substitution reaction.

Figure 4: Bromination of Benzene

In this case first step is generation of an electrophile. Here Br₂ donate pair of electron to FeBr₃ to form electrophilic complex. Then second step is addition of electrophile on to aromatic ring to form carbocation intermediate. Then the last step is deprotonation and regeneration of acid catalyst.

Figure 5: Mechanism of Bromination of Benzene

Other examples of electrophilic aromatic substitution are nitration of benzene and sulphonation of benzene.

Figure 6: Examples of electrophilic aromatic substitution

1.2    Electrophilic Aliphatic Substitution Reaction

In electrophilic aliphatic substitution reaction the substrate is an aliphatic compound and electrophile replaces hydrogen atom from the molecule. For example, ketone halogenation in basic condition is an electrophilic aliphatic substitution reaction.

Figure 7: Alpha bromination of ketone

 In this reaction first step is formation enolate from ketone. Then the enolate attack on the bromine electrophile to form carbon-bromine bond.

2.        Free Radical Substitution Reactions

Free radical substitution reaction consists of replacement of leaving group by free radical. This reaction has three steps which are shown below.

Initiation: Generation of radical.

Propogation: Formation of new intermediate radicals.

Termination: This is final step in which stable molecule is forms and reaction stops.

Halogenation of alkane in presence of halogen gas and light is an example of free radical substitution reaction. 

Figure 8: Haloganation of Alkane

In this reaction is first step is initiation in which bromine radical is formed from bromine gas in presence light. Then bromine radical takes a hydrogen atom from alkane to form HBr and new alkyl radical. This step is known as propogation. The last step is termination where another bromine radical and alkyl radical combines to form alkyl halide.

Figure 9: Mechanism of Haloganation of Alkane

3.        Nucleophilic Substitution Reactions

The nucleophilic substitution reaction consists of replacement of leaving group by nucleophile. There are three types of nucleophilic substitution can be found in organic chemistry these are; Nucleophilic aliphatic substitution, Nucleophilic acyl substitution and Nucleophilic aromatic substitution.

3.1    Nucleophilic Aliphatic Substitution

The nucleophilic aliphatic substation reaction is can be seen in aliphatic molecules. In general alkyl halides shows this type of reactions. Based upon molecularity of the reaction there are two types nucleophilic aliphatic substitution reactions present in nature namely Unimolecular Substitution Reaction (S_N1) and Bimolecular Substitution Reaction (S_N2)

3.1.1        Unimolecular Substitution Reaction (S_N1)

This is two step reaction in which first step is formation of carbocation intermediate takes place. In second step a nucleophile attacks on the carbocation to produce substitution compound. Tertiary alkyl halides and allyl halides favours this type of substitution. Also there is requirement of weak nucleophile to attack on the carbocation.  For example, reaction of tert-butyl bromide with methanol is a unimolecular substitution reaction. The rate of the reaction is depending upon concentration of alkyl bromide. In this reaction first step is heterolytic cleavage of carbon-halogen bond to form tertiary butyl carbocation intermediate. Then methanol molecule attack on the carbocation to form substitution product.

Figure 10: Unimolecular Substitution Reaction (S_N1)

3.1.2        Bimolecular Substitution Reaction (S_N2)

This is one step reaction in which a strong nucleophile attack on tetrahedral carbon to replace the leaving group. Primary and secondary alkyl halides are prone to show S_N2 reaction. The rate of the reaction is depending upon the concentration of both nucleophile and alkyl halide. For example, reaction of isopropyl iodide with sodium ethoxide produces substitution product. In this reaction iodine is a leaving group and ethoxide is a nucleophile. 

Figure 11: Bimolecular Substitution Reaction (S_N2)

3.2    Nucleophilic Acyl Substitution

This type of reaction is shown by acyl derivative like acyl chloride and anhydride. In this reaction a strong nucleophile attacks on the acyl carbon to form tetrahedral intermediate. Then the next step is removal of leaving group to give neutral molecule.

Reaction of acyl chloride and methyl amine to form amide compound is an example of nucleophilic acyl substitution reaction. In this reaction first step is addition of methyl amine (nucleophile) on to carbonyl carbon to produce charged species. Then in second step removal of chloride ion takes place. Finally deprotonation of amine nitrogen gives formation of amide product.

Figure 13: Nucleophilic Acyl Substitution

3.3    Nucleophilic Aromatic Substitution

In this reaction the leaving group is present on the aromatic ring. There are three types of substitution reaction can be found in this category of reactions.

3.3.1        Addition elimination reaction (S_NAr)

Here in the first step a nucleophile add to the electron deficient aromatic ring to form anionic intermediate. Then in second step elimination of leaving group takes place to form stable aromatic ring. The main requirement of the reaction is that the aromatic ring must contain one or more electron withdrawing group.  

Figure 14: S_NAr (addition-elimination) Mechanism

For example, reaction of 1-chloro-2-nitrobenzene with sodium hydroxide under heating condition gives 2-nitrophenol. Here the mechanism of the reaction is S_NAr. In the first step hydroxide ion add to the electron deficient ring to form anionic intermediate. And the second step is elimination of leaving group to form aromatic ring.

Figure 15: Reaction of 1-chloro-2-nitrobenzene with sodium hydroxide

3.2.2      Aromatic  S_N1 Mechanism

In aromatic S_N1 reaction first step is formation of carbocation intermediate takes place. The second step consists of addition of nucleophile occurs to give substitution product. This reaction is similar to aliphatic S_N1 reaction.

Figure 16: Aromatic S_N1 Mechanism

For example; reaction of diazonium salt with sulphuric acid gives substitution product by aromatic S_N1 mechanism. In this reaction nitrogen gas releases as leaving group to form arenium ion. Then the sulphuric acid acts as nucleophile and attack on arenium ion to give substitution product.

Figure 17: Reaction of diazonium salt with sulphuric acid

3.3.3        Benzyne Mechanism

Benzyne mechanism is similar to E2 elimination reaction. According to this mechanism a strong nucleophile abstract a proton which is adjacent to leaving group. Simultaneously the leaving group cleaves from the substrate molecule to form triple bond species it is known as benzyne intermediate. Then the nucleophile attack on electron deficient benzyne to form another anionic intermediate. Finally protonation of anionic species gives stable compound. 

Figure 18: Benzyne Mechanism

Reaction of chlorobenzene with sodium amide (NaNH₂) /liq. NH₃ proceeds through benzyne intermediate followed by addition of nucleophile (NH₂) delivers substitution product.

Figure 19: Reaction of chlorobenzene with sodium amide (NaNH₂) /liq. NH₃

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See Also

1. Reaction Mechanism
2. Reactive Intermediates
3. Organic Synthesis