Nucleophilic Substitution Reaction – Definition, Types, Examples

NUCLEOPHILIC SUBSTITUTION

Chemistry is the study of matter and its interaction with other matter and energy present around it. In our daily life, we can observe several chemical changes happening around us, such as photosynthesis, rusting of iron, burning of fire, cleaning action of soaps and detergents, digestion of food, etc. In the literature of chemistry, we understand the behavior and mechanism of these chemical changes with the help of chemical reactions. By understanding the reaction mechanism, we can successfully understand the fundamental interplay of electrons, atoms, and molecules that make these chemical changes possible. In organic chemistry, we come across a particular class of chemical reactions called “nucleophilic substitution reactions.” A substitution reaction involves the direct replacement of an atom or a group in the organic molecule by another atom or group without causing any effect on other parts of the molecules. A nucleophilic substitution reaction is one in which one nucleophile replaces another from a stable organic molecule. But what is a nucleophile? Well, the suffix -phile is derived from the Greek word “philos,” which means loving, and hence, nucleophiles are the electron-rich atom or group that is attracted toward the positive region of the molecule; in other words, a nucleus loving atom or group of atoms. To understand this phenomenon in terms of chemistry, let’s take a look at the following reaction:

{Nu :}^{-} +  R—LG→ R—Nu + {LG:}^{-}

Here, Nu : represents a nucleophile with an electron pair (:) that attacks a substrate (R—LG), in which R represents an aliphatic or aromatic (less often) carbon chain containing {sp}^{3} hybridized carbon atom at α-position and LG represents a leaving group. Chemists determine if a substrate will go under a nucleophilic substitution reaction by looking for the leaving group. For example, weak bases with strong conjugate acids are good leaving groups. They tend to float around as an anion, on their own, in a solution. Halides, sulphonates, and other elements that have highly negative pKa values (strong conjugate acids) are considered as good leaving groups. On the contrary, if the leaving group is a strong base, such as hydroxide, hydride, etc., it will not be able to exist on its own in the solution, and therefore, the substrate will not go under nucleophilic substitution. It’s important to note that this is often but not always the case because, in organic chemistry, variables such as stereochemistry can change how we generally expect molecules to behave. Particularly, nucleophilic substitution reactions are classified into two mechanisms, {S}_{N}{1} mechanism and {S}_{N}{2} mechanism. Depending on the substrate, nucleophile, and leaving group, chemists determine the likelihood of either mechanism that a particular reaction would follow.

Types of Nucleophilic Substitution Reaction

Substitution Nucleophilic Unimolecular Reaction ( {S}_{N}{1} Mechanism)

As it is clear from the name that in {S}_{N}{1} mechanism, S stands for substitution, N stands for nucleophilic, and “1” stands for unimolecular, which represents the kinetic order of the reaction, i.e., the rate of the reaction. The reason we call {S}_{N}{1} reactions unimolecular because the overall rate of the reaction depends only on the substrate molecule. The mechanism of this reaction is a two-step process: the formation of carbonation and the nucleophilic attack. The longer it takes to form the carbonation, the slower is the rate of reaction. Let’s try to understand the mechanism with the help of the following reaction:

REACTION1

 

In step I, the polarised C—Cl bond undergoes slow cleavage to produce a carbocation and a chloride ion. The carbocation thus formed is then attacked by nucleophile in step II  to complete the substitution reaction. Since the nucleophile is a neutral molecule (i.e. a solvent) a third step is required to complete the reaction. When the solvent is water, the intermediate is an oxonium ion. In step III, the deprotonation of oxonium ion will take place. Here, water will act as a base-forming the alcohol and a hydronium ion. If we plot the {S}_{N}{1} reaction on an energy diagram, we can see that it takes a lot of activation energy for the formation of carbocation, and therefore, the first step is the slower and rate-determining step. On the other hand, the activation energies for nucleophilic attack and deprotonation are relatively small.

SN1_ED

If we take a look at the stereochemistry of this reaction, we can see that carbocations contain sp 2 hybridized orbitals and thus have planar structures. {S}_{N}{1} mechanisms proceed via a carbocation intermediate, so a nucleophile attack is equally possible from either side of the plane. Therefore, a pure, optically active alkyl halide undergoing an {S}_{N}{1} substitution reaction will generate a racemic mixture as a product. If the groups around the central carbon are chiral, unlike the three methyl groups in our previous example, a mixture of two different stereoisomers can form as a product.

Substitution Nucleophilic Bimolecular Reaction ( {S}_{N}{2} Mechanism)

In {S}_{N}{2} reaction mechanism, the rate of the reaction depends both on the substrate and the nucleophile; therefore, the name substitution nucleophilic bimolecular reaction. The primary difference between {S}_{N}{1} and {S}_{N}{2} reaction mechanism is the absence of carbocation intermediate formation in the later. The {S}_{N}{2} mechanism begins with an electron pair of the nucleophile attacking the back lobe of the leaving group, or in other words, the partially electron-deficient site of the substrate molecule. Carbon in the resulting complex is trigonal bipyramidal in shape. With the loss of the leaving group, the carbon atom again assumes a pyramidal shape; however, its configuration is inverted. Let’s try to understand the mechanism with the help of the following reaction:

 

Sn2-mechanism

As we can see in the above reaction the substrate goes under a transition state by forming a pentacoordinate carbon complex, containing both the nucleophile and the substrate. It is also important to notice that the nucleophile must always attack from the side opposite the side that contains the leaving group. This occurs because the nucleophilic attack is always on the back lobe (antibonding orbital) of the carbon atom acting as the nucleus. {S}_{N}{2} mechanisms always proceed via rearward attack of the nucleophile on the substrate. This process results in the inversion of the relative configuration, going from starting material to product. This inversion is often called the Walden inversion. The energy diagram plot for the {S}_{N}{2} reaction proceeds through a transition state, which corresponds to the highest energy in the energy diagram. The transition state has a partially formed bond between carbon and the incoming nucleophile, and a partial bond between carbon and the leaving group (indicating simultaneous cleavage of the bond between carbon and the leaving group I). The negative charge on the nucleophile is dispersed or shared equally by both the nucleophile and the leaving group and is denoted as {δ}{-} on both -OH and -Br.

EDrxn2. JPEG

Difference Between {S}_{N}{1} and {S}_{N}{2} Reaction Mechanism 

Although {S}_{N}{1} and {S}_{N}{2} reaction mechanism may look almost similar to each other, there are few key differences that one should keep in mind while predicting a reaction pathway for a particular reaction.

Sn 1 Reaction MechanismSn 2 Reaction Mechanism
These reactions are unimolecular with the rate of reaction solely depending upon the substrate, i.e.,
Rate = k[R-LG]
These reactions are bimolecular with the rate of reaction depending upon both the substrate and nucleophile, i.e.,
Rate = k[R-LG][Nu]
These reactions usually generate a racemic mixture as a productThese reactions usually leads to the stereochemical inversion of configuration of the substrate.
These reactions are generallyn carried out in polar protic solvents such as water, alcohol, acetic acid, etc. Solvents of low polarity favour this reaction mechanismThese reactions do not depend on solvent as such, they require the presence of nucleophile
This reaction mechanism involves an intermediate state, i.e., the formation of carbocation.This reaction mechanism involves a transition state, i.e., the formation of pentacoordinate carbon complex
Most of the tertiary carbon compounds favour Sn 1 reaction mechanism.Most of the primary and secondary carbon compounds undergo Sn 2 reaction mechanism; however, some of secondary carbon compounds may favour Sn 1 reaction mechanism.

Examples of Nucleophilic Substitution Reaction

Here are a few examples of aromatic, aliphatic, and acyl compounds that go under nucleophilic substitution reaction.

Nucleophilic-Substitution-Examples

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