Nucleophilic Substitution Reaction

Nucleophilic Substitution Reaction is a type of organic reaction in which a nucleophile replaces a leaving group in a molecule. This reaction is similar to the displacement reaction, where a more reactive element displaces a less reactive element in a solution.

In this article, we will discuss about Nucleophilic Substitution Reaction, its mechanism, characteristics, and examples.

What is Nucleophilic Substitution Reaction?

Nucleophilic Substitution Reaction is a type of organic reaction in which an electron-rich nucleophile replaces a leaving group in a molecule. This substitution typically occurs at an atom with a partial positive charge, such as a carbon atom in an alkyl group. The nucleophile, an electron-rich species, donates a pair of electrons to the electrophilic atom, leading to the formation of a new compound.

The group that takes an electron pair and is displaced from the carbon is known as the leaving group and the molecule on which substitution takes place is known as substrate.

The general form of a nucleophilic substitution reaction can be represented as follows:

Nu⁻ + R-X → Nu-R + X⁻

Nu^– represents the nucleophile, R-X is the substrate molecule where R is usually an alkyl or aryl group, and X is the leaving group, and Nu-R is the product formed.

Nucleophilic Substitution Reaction Definition

Nucleophilic substitution is a type of organic reaction in which a nucleophile (a species with an electron-rich center) reacts with a substrate by replacing a leaving group.

The nucleophile donates a pair of electrons to form a new bond with the substrate, resulting in the substitution of one group or atom by another.

Examples of Nucleophilic Substitution Reaction

Nucleophilic substitution reactions can occur with various nucleophiles and leaving groups, leading to different products and reaction mechanisms. The specific conditions and reagents used will influence the outcome of the reaction. Below are a few examples, where nucleophilic substitution reactions occur in a variety of organic and inorganic chemical reactions, depending on the specific compounds involved.

CH₃ – Br + OH → CH₃OH + Br^–

C₂H₅ – Br + NH₃ → C₂H₅ – NH₂ + NH₄Br

CH₃CO-OH + CH₃OH → CH₃CO-O-CH₃ + H₂O

Read More, Electrophiles and Nucleophile

Nucleophilicity

Nucleophilicity is the ability of a species to donate a pair of electrons to an electrophilic center, leading to the formation of a new chemical bond. It is a kinetic term which tells at what rate the nucleophile attacks the substrates .It is associated with the strength of a nucleophile in nucleophilic substitution reactions.

The key factors influencing the nucleophilicity are :

• Electron Density: Nucleophilicity increases with higher electron density. Example: Acetate (CH₃COO^– ion is better nucleophile than formate ion (HCOO^–) because CH₃ is an electron releasing group, which increases the electron density of oxygen.

• Charge: Negatively charged species are usually better nucleophiles than their neutral counterparts. This is because the negative charge indicates a surplus of electrons available for donation. Ex : OH^– is a better nucleophile than H₂O.

• Electronegativity: Nucleophilicity tends to increase as electronegativity decreases. Elements or molecules with lower electronegativity are more likely to donate electrons readily. Ex : SH^– is a better nucleophile than OH^–

• Steric Hindrance: Steric hindrance refers to the interference of bulky groups around the reaction site. Nucleophiles with less steric hindrance are generally more effective because they can approach the electrophilic center more easily. Ex: Tertiary alkoxide (3 degree) ions are weaker nucleophiles than secondary (2 degree) and primary alkoxide (1 degree) ions due to steric hindrance.

• Polar Solvent Effects: The nature of the solvent can influence nucleophilicity. Polar aprotic solvents (like acetone, dimethyl sulfoxide) typically enhance nucleophilicity, while polar protic solvents (like water, alcohols) can reduce nucleophilicity due to solvation effects.

• Leaving Capacity of the Leaving Group : The rate of the reaction depends on the nucleophilicity of the incoming nucleophile and the leaving capacity of the leaving group . The high the leaving capacity of the leaving group, faster is the reaction The only criteria for deciding the leaving capacities is that weaker bases are good leaving group. Order of Leaving Capacity is: F^– < Cl^–< Br^–< I^– (among halogens)

Order of Nucleophilicity

The general order of nucleophilicity can vary depending on the specific solvent used because the nature of the solvent influences the reactivity of nucleophiles.

Nucleophilicity in Polar Protic Solvents: In polar protic solvents, which are capable of forming hydrogen bonds, nucleophiles may be solvated by the solvent molecules. This solvation can affect the availability of the nucleophile for reaction. The general order of nucleophilicity in polar protic solvents is given as:

F^– < Cl^–< Br^–< I^–

This trend is known as the nucleophilicity trend across the halide ions in polar protic solvents. Larger and more polarizable ions, such as iodide are less affected by solvation and are generally more nucleophilic in polar protic solvents.

Nucleophilicity in Polar Aprotic Solvents: In polar aprotic solvents, which do not have acidic protons for hydrogen bonding, solvation effects are minimized. As a result, nucleophiles in polar aprotic solvents may exhibit different reactivity patterns. The general order of nucleophilicity in polar aprotic solvents is given as:

I^– < Br^– < Cl^– < F^–

In polar aprotic solvents, smaller and more electronegative nucleophiles, such as fluoride are often more nucleophilic.

Basicity and Nucleophilicity

Basicity and nucleophilicity are related concepts in organic chemistry, both involving the donation of electrons. However, they refer to different aspects of chemical reactivity.

Basicity is the ability of a species to donate a pair of electrons to a proton (H⁺). Basicity is relevant to acid-base reactions, where a proton is transferred between the species. The focus is on the donation of electrons to a proton.

Nucleophilicity is the ability of a species to donate a pair of electrons to an electrophilic center (except hydrogen), leading to the formation of a new chemical bond. It is associated with the strength of a nucleophile in nucleophilic substitution reactions.

Mechanisms of Nucleophilic Substitution Reaction

Nucleophilic substitution is a fundamental reaction in organic chemistry where an electron-rich nucleophile replaces a leaving group in a molecule. The rate of nucleophilic substitution reactions not only depends on the nucleophiles and leaving group but it also depends on the mechanism by which the reaction has taken place.

There are two main types of nucleophilic substitution reactions i.e.

• S_N1 (substitution nucleophilic unimolecular)
• S_N2 (substitution nucleophilic bimolecular)

S_N1 Mechanism

Nucleophilic Substitution Unimolecular (S_N1) reaction is a type of nucleophilic substitution reaction where the rate-determining step involves only one molecule. The key features of the S_N1 mechanism include the formation of a reactive intermediate (carbocation) and subsequent attack by a nucleophile.

This mechanism take place in two steps i.e.

• Formation of carbocation by the removal of leaving group
• Attack of nucleophiles on carbocation

The steps involved in an S_N1 reaction are:

Formation of Carbocation: The reaction begins with the removal of leaving group first from substrate molecule (often an alkyl halide), resulting in the formation of a carbocation and a leaving group.

The leaving group departs with its pair of electrons, leaving a positively charged carbon atom (carbocation) behind. This step is the slow step therefore it is a rate-determining step of the reaction.

R-X → R⁺ + X^–

Nucleophilic Attack: Nucleophile attacks the positively charged carbon atom to form the final product. The nucleophile can attack the carbocation from either side, leading to the formation of two enantiomers for the compound.

R⁺ + Nu^– → R-Nu

Final Reaction can be given as:

R-X + Nu^– → Nu-R + X⁻

The rate of S_N1 mechanism depends only on the leaving tendency of the leaving group. For different substrates, the rate of S_N1 mechanism depends on the stability of carbocation formed. Therefore, the order of reactivity of 1°, 2°, 3° alkyl halides is given as: 3° > 2° > 1° ( in terms of stability of carbocation).

S_N2 Mechanism

S_N2 (Substitution Nucleophilic Bimolecular) mechanism is a type of nucleophilic substitution reaction in organic chemistry in which a nucleophile attacks a substrate, and at the same time, a leaving group departs. It is a single step process unlike S_N1 Mechanism. It involves the simultaneous attack of a nucleophile and the departure of a leaving group.

It follows second order kinetics as two species are involved in the rate determining step of the reaction. The key features of the S_N2 mechanism are:

Bimolecular Reaction: The rate-determining step involves the simultaneous interaction of two molecules—the substrate and the nucleophile. The nucleophile attacks the substrate while the leaving group departs.

Nucleophile Attacks from the Backside: The nucleophile approaches the substrate from the side opposite to the leaving group (backside attack). This is because attacking from the front side would lead to steric hindrance with the leaving group.

Inversion of Configuration: Due to the backside attack, the configuration at the reaction center is inverted during the course of the reaction. If the substrate has a chiral center, the product will have the opposite stereochemistry.

The overall reaction for an S_N2 mechanism can be represented as:

R-X + Nu^– → Nu-R + X⁻

Order of Reactivity of Alkyl Halide under S_N2 reaction is 3° < 2° < 1°

Difference Between S_N1 and S_N2 reaction

S_N1 (Substitution Nucleophilic Unimolecular) and S_N2 (Substitution Nucleophilic Bimolecular) are two different mechanisms of nucleophilic substitution reactions in organic chemistry. The key difference between them is given below:

SN1 Reaction	SN2 Reaction
It is a two-step mechanism.	It is a one-step mechanism.
No partial bond is formed with the carbon during this reaction.	Carbon forms a partial bond with the nucleophile and the leaving group
Rate-determining step includes formation of the carbocation and substrate ionization.	The nucleophilic attack and leaving group departure occur simultaneously in the rate-determining step.
Nucleophilic attack can occur from either side, leading to racemization of product.	The nucleophile attacks from the backside of the leaving group, resulting in inverted product.
It follows a first-order kinetic mechanism.	It follows a second-order kinetic mechanism.

Factors Affecting Nucleophilic Substitution Reaction

Several factors influence the nucleophilic substitution reactions .The factors affecting these reactions can vary depending on the specific mechanism involved and these factors are:

• Concentration of Reactants: Higher concentrations of both the nucleophile and the substrate generally increase the rate of nucleophilic substitution reactions for S_N2 but for S_N1 it depends only on concentration of substrate.
• Stereochemistry: S_N2 reactions lead to inversion of stereochemistry while S_N1 reactions may lead to racemization.
• Nature of Leaving Group: The leaving group’s ability to stabilize negative charge affects the rate of the reaction.
• Substrate Structure: Tertiary substrates favor S_N1 reactions because the stability of the carbocation intermediate is increased whereas primary substrates favor S_N2 reactions because the nucleophile can easily access the carbon center without steric hindrance.
• Solvent Effects: Polar solvents stabilize ions and promote S_N1 reactions. Protic solvents, such as water or alcohols, are often used whereas Aprotic solvents, such as acetone or dimethyl sulfoxide (DMSO), are preferred for S_N2 reactions. These solvents do not solvate ions, minimizing ion-pairing effects.

Characteristics of Nucleophilic Substitution Reaction

Nucleophilic substitution is a type of organic reaction where a nucleophile displaces a leaving group from a substrate. The characteristics of nucleophilic substitution reactions include:

• Nucleophile Attack: A nucleophile attacks an electrophile leading to the substitution of one group by another.
• Leaving Group: The substrate contains a leaving group that can be displaced by the nucleophile. The leaving group is usually a weak base or a stable ion.
• Reaction Mechanism: Nucleophilic substitution reactions can proceed through either an S_N1 (substitution nucleophilic unimolecular) or S_N2 (substitution nucleophilic bimolecular) mechanism.
• Stereochemistry: In S_N2 reactions, the stereochemistry is often inverted due to the backside attack of the nucleophile. In S_N1 reactions, the stereochemistry can be racemized due to the formation of a planar carbocation.
• Rate of Reaction: The rate of nucleophilic substitution reactions is influenced by the concentration of the nucleophile and the substrate. In S_N1 reactions, the leaving group departure is the slow step, while in S_N2 reactions, the nucleophile attack is the rate-determining step.

Nucleophilic Substitution Reaction of Haloalkanes and Haloarenes

Haloalkanes and Haloarenes both undergoes nucleophilic substitution reactions but haloalkanes react more readily than haloarenes. This is because haloalkanes are more polar than haloarenes. The reaction of haloalkanes and haloarenes is described below:

Nucleophilic Substitution Reaction of Haloalkanes

Nucleophilic substitution reactions of haloalkanes (alkyl halides) are a common class of organic reactions. These reactions involve the replacement of a halogen atom (usually chlorine, bromine, or iodine) in a haloalkane with a nucleophile.

The specific reaction mechanism depends on the nature of the alkyl halide and the conditions of the reaction. The two main mechanisms are substitution nucleophilic unimolecular S_N1 and substitution nucleophilic bimolecular S_N2. The reaction is as follow:

R-X + Nu^– → Nu-R + X⁻

where

• R-X is the haloalkane (alkyl halide) ,
• Nu^– is the nucleophile ,
• X⁻ is the leaving group (halide ion).

Nucleophilic Substitution Reaction of Haloarenes

Haloarenes are a class of organic compounds that consist of an aromatic ring (arene) in which one or more hydrogen atoms are replaced by halogen atoms. In nucleophilic substitution reaction of haloarenes, the nucleophile replaces the halogen atom, which then leaves as a halide ion. 

In this reaction, the halogen atom is known as the leaving group. However, haloarenes are less reactive when compared to haloalkanes in nucleophilic substitution reactions.

Read More,

• Substitution Reaction
• Mechanism of SN1 Reactions
• Electrophilic Substitution Reaction

Nucleophilic Substitution Reaction: FAQs

What is Substitution Reaction?

Substitution reactions are fundamental chemical reactions in chemistry, and they involve the exchange of one atom or group of atoms (functional group) with another in a molecule.

What are Conditions of Nucleophilic Substitution Reaction?

Following are the general conditions and factors that can influence nucleophilic substitution reactions:

• Substrate Structure
• Nucleophile Strength
• Solvent
• Steric Hindrance
• Nature of Leaving Group

Is Nucleophilic Substitution S_N1 or S_N2?

Nucleophilic substitution reactions can follow either the S_N1 (substitution nucleophilic unimolecular) mechanism or the S_N2 (substitution nucleophilic bimolecular) mechanism, and the specific mechanism depends on the reaction conditions and the nature of the substrate.

What is Electrophilic and Nucleophilic Substitution Reaction?

Electrophilic and nucleophilic substitution reactions are two types of organic reactions involving the replacement of one group (or atom) with another in a molecule. These reactions are characterized by the participation of electrophiles and nucleophiles.

• In electrophilic substitution reactions, an electrophile (an electron-seeking species) replaces another atom or group in a molecule.
• In nucleophilic substitution reactions, a nucleophile (an electron-rich species) replaces another atom or group in a molecule.

What are Factors Influencing Rate of Nucleophilic Substitution Reactions?

Several factors affect the rate of nucleophilic substitution reactions, including the nature of the substrate, nucleophile strength, leaving group ability, steric hindrance, solvent effects, temperature, and concentration of reactants.

What is Role of a Nucleophile in a Nucleophilic Substitution Reaction?

A nucleophile is a species that donates an electron pair to form a new bond with an electron-deficient atom. In nucleophilic substitution reactions, the nucleophile attacks the substrate, leading to the displacement of a leaving group. The nucleophile’s role is crucial in determining the outcome of the reaction and influencing factors such as reaction rate and stereospecificity.