Nucleophilic Substitution Reactions

Nucleophilic Substitution reactions are the characteristic reactions of aliphatic halogen compounds. In nucleophilic substitution reactions, nucleophiles will be the attacking agents. This type of reactions will occur in the compounds which are electron deficient in nature.

However, whatever the type of substitution reaction may be, it’s mechanism just like in case of elimination reactions happens in two ways.

• Unimolecular
• Bimolecular

The mechanism of action of each method will be as follows:

• Unimolecular substitution reactions:

As in case of elimination reactions, in unimolecular substitution reactions also, one atom or group will participate or involve at a time or in each step. This is also a multi-step reaction. The basic concept of the substitution reaction is one atom, group or molecule from the substrate or the starting material or molecule will be removed and be replaced or substituted by another atom, group or molecule.

For easy understanding, the atom, group or molecule that will be removed is called as leaving group and is abbreviated as LG in the explanation and the atom, group or molecule that substitutes the place is called as attacking agent and is abbreviated as AG.

Mechanism of unimolecular substitution reaction: As discussed, this is a multi-step reaction.

Step-1: Breaking the existing bond in attacking group (AG): Any compound will be a composition of an electron rich part and an electron deficient part or a more electronegative part and a less electronegative parts. So when it is broken, the high electronegative part will take the bond pair of electrons and forms into a negatively charged nucleophile (:Nu^–) and the other part will lose the electrons resulting in the formation of electrophile (E⁺).

Step-2: Breaking the existing bond in the substrate or starting molecule: In this step, the already existing bond between the leaving group (LG) and the rest of the starting material or the substrate will be broken resulting in the formation of charged molecules.

The charge develops on the substrate ion depends on the nature of the leaving group (LG). If the leaving group (LG) is highly electronegative in nature, the substrate a positive charge will be developed on the substrate molecule and if the leaving group (LG) is not electronegative in nature, then negative charge will be developed on the substrate.

If positive charge is developed on the substrate, then a negatively charged atom, group or molecule (nucleophile) will be the attacking agent and is called as the unimolecular nucleophilic substitution (S_N¹) reaction.

If negative charge is developed on the substrate, then a positively charged atom, group or molecule (electrophile) will be the attacking agent and the reaction is called as unimolecular electrophilic substitution (S_E¹) reaction.

Step-3: Formation of new bong between the attacking group (nucleophile/electrophile) and the substrate ion: In this step, the attacking group (AG) will attack on the substrate molecule and a new bond will be formed between the substrate ion and the attacking group (AG) resulting in the formation of the final product.

Note:

• In S_N¹ reaction, the rate determining step will be the first step.
• S_N¹ reaction follows 1^st order kinetics
• The stability of the carbon ion formed will decide the rate of the reaction. Hence, the rate of reaction is dependent on the order of stability of carbon ions which towards substitution reactions is 3⁰>2⁰>1⁰>CH₃X
• The effect of structure on reactivity in S_N¹ mechanism will be similar to that of E1 mechanism.
• As the reaction involves carbon ion intermediate, there is a possibility for carbon ion rearrangement.
• Bimolecular substitution reactions:

As discussed in elimination reactions, two atoms or groups will participate or involve at a time. It is a single step reaction. In bimolecular substitution reaction, there is formation of transition state, an unstable and intermediate state between the starting material and end product.

Mechanism of bimolecular substitution reaction: This is a single step mechanism. In this mechanism, unlike unimolecular substitution reaction, the breaking of existing bond and formation of new bond will occur simultaneously. In this process, the substrate will undergo through an unstable state called as transition state a state between starting material and the end product.

            Note:

• S_N² mechanism follows second order kinetics
• Rearrangements are not accompanied in S_N²
• The orientation of S_N² mechanism involves inversion of configuration. Which means that the attacking group will attach on the opposite direction to that of leaving group.
• This change in configuration in S_N² mechanism is called as Walden inversion. Hence, this mechanism is regioselective.

Factors affecting substitution reaction:

• Nature/Type of the substrate: This decides the formation of carbon ion. If the substrate is having more substituents on it, it will form carbon ion easily. That means tertiary carbon atom with leaving group will form carbon ion easily and readily than secondary, primary and methyl group. The more readily the formation of carbon ion, the faster the occurrence of unimolecular reaction. Hence, the order of reactivity of unimolecular substitution reactions is 3⁰>2⁰>1⁰>CH₃X. for bimolecular mechanism there is no need of formation of intermediate of carbon ion. Hence, that will be vice-versa and the order of reactivity will be 3⁰<2⁰<1⁰<CH₃X or CH₃X>1⁰>2⁰>3⁰.
• Leaving group: A good leaving group always favours unimolecular mechanism as it helps in the formation of carbon ion.
• Nature of the reagent: This decides the type of substitution reaction to occur i.e. nucleophilic or electrophilic. The stronger the reagent or attacking group is, the faster it will attack and favours the bimolecular mechanism. Weaker reagent favours unimolecular mechanism.
• Type of solvent: As polar protic solvents favour the formation of carbon ions, these always favour unimolecular mechanism whereas polar aprotic solvents favour bimolecular mechanism.

Unimolecular Vs Bimolecular

S.No.	SN1 reaction (Unimolecular)	SN2 reaction (Nimolecular)
1.	This is a unimolecular reaction	This is a bimolecular reaction
2.	This reaction occurs in two steps	This reaction is a single step reaction
3.	This reaction follows first order kinetics	This reaction follows second order kinetics
4.	This reaction occurs through the formation of a carbo cation intermediate	There is no formation of carbocation here, but there is formation of a transition state.
5.	Reactivity order is 30>20>10>CH3	Reactivity order is CH3>10>20>30
6.	This is not stereospecific reaction	The orientation of this reaction involves Walden inversion
7.	Polar protic solvent favours the reaction	Polar aprotic solvent favours the reaction
8.	Rearrangement may take place	No rearrangement as there is no intermediate formation
9.	Rate of reaction increases with increase in the concentration of the substance	Strong reagent influence reaction

Applications:

1. Substitution reactions are having very important role in biology. These reactions are useful in the production of neuro transmitters like dopamine, norepinephrine or noradrenaline, epinephrine or adrenaline, etc.
2. These reactions also play a critical role in the metabolism of carbohydrate and DNA/RNA nucleotide.
3. Substitution reactions are also having an important role in organic synthesis.

Substitution reactions play a very important role in synthesis of drug molecules or pharmacologically active substances.

Stereochemistry of Substitution Reactions:

Walden inversion:

2-bromooctane and 2-octanol both are chiral i.e., they have molecules that are not superimposable on their mirror images.

Also, these can exist as enantiomers and con show optical activity.

Optically active 2-octanol has been obtained by resolution of the racemic modification and form optically active 2-bromooctane.

Here (-)-bromide and (-)-alcohol have similar configurations.

Now, when (-)-2-bromooctane is allowed to react with sodium hydroxide under suitable conditions, the obtained product will be (+)-2-octanol.

Here we see that the ‘–OH’ group has not taken the position previously occupied by ‘-Br’; the alcohol obtained has a configuration opposite to that of bromide.

A reaction that yields a product whose configuration is opposite to that of the reactant and is said to proceed with inversion of configuration and is known as Walden inversion.

Mechanism:

Step 1: Nucleophilic attack from the opposite side of the leaving group

Step 2: Formation of a transition state

Step 3: Separation of the leaving group.