Know Stereochemical Aspects of Nucleophilic Substitution Reactions

Stereochemical Aspects of Nucleophilic Substitution Reactions: Nucleophiles are nucleus seeking electron-rich species. Therefore, they attack the electron-deficient part positive centre of the substrate molecule. A nucleophilic substitution reaction is a reaction in which a replacement of a nucleophile occurs by an already existing nucleophile in a molecule. Haloalkanes are substrates in these reactions. Let’s learn the stereochemical aspects of nucleophilic substitution reactions.

Nucleophilic Substitution Reactions in Haloalkanes

In haloalkanes, the \({\rm{C – X}}\) bond is polar due to the electronegativity difference between carbon and halogen atoms. The difference in electronegativity develops a slight positive charge over the carbon atom and a slight negative charge over the halide atom. The nucleophile attacks the positively charged carbon atom bonded to halogen in a nucleophilic substitution reaction involving haloalkanes. The halogen atom bearing the negative charge departs as a halide ion. Since a nucleophile initiates this substitution reaction, it is called a nucleophilic substitution reaction.

There are groups like cyanides and nitrites that possess two nucleophilic centres. Such groups are called ambident nucleophiles. The cyanide group acts as an ambident nucleophile because it links through two centres through carbon atoms resulting in alkyl cyanides and through nitrogen atoms leading to isocyanides.  It is a hybrid of two contributing structures and therefore can act as a nucleophile in two different ways \([{}^ – {\rm{C}} \equiv {\rm{N}} \leftrightarrow :{\rm{C}} = {{\rm{N}}^ – }]\). Similarly, nitrite ion, \({\rm{NO}}_2^ – \) also represents an ambident nucleophile with two centres of linkage \(\left[ {{}^ – {\rm{O}} – {\rm{N}} = {\rm{O}}} \right]\). The linkage through oxygen results in alkyl nitrites, while the linkage through nitrogen atoms leads to nitroalkanes.

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Mechanism

The nucleophilic substitution reaction proceeds by two different mechanisms, these are-

(a) Substitution Nucleophilic Bimolecular \(\left( {{{\rm{S}}_{\rm{N}}}{\rm{2}}} \right)\):

A Substitution nucleophilic bimolecular \(\left( {{{\rm{S}}_{\rm{N}}}{\rm{2}}} \right)\) reaction is a second-order reaction in which the rate of the reaction depends upon the concentration of both the reacting species, i.e. the substrate and the nucleophile.

For example, The reaction between \({\rm{C}}{{\rm{H}}_3}{\rm{Cl}}\) and hydroxide ion to yield methanol and chloride ion follows a second-order kinetic.

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In this reaction, the incoming nucleophile, the halide ion, interacts with the alkyl halide substrate. The carbon-halide bond in alkyl halide breaks, forming a new bond between carbon and the attacking nucleophile. These two processes take place in a single step simultaneously with no intermediate formation. As the reaction proceeds, the bond between the incoming nucleophile and the carbon atom starts forming and the bond between the carbon atom and leaving group weakens. As the nucleophile approaches the substrate, the three carbon-hydrogen bonds start to move away from the attacking nucleophile till the nucleophile attaches to carbon and leaving group leaves the carbon. This results in the inversion of configuration, and the product formed has an inverted configuration than the original substrate. In the transition state, all the three \({\rm{C}} – {\rm{H}}\) bonds are in the same plane, and the attacking and leaving nucleophiles are partially attached to the carbon. The carbon atom is simultaneously bonded to five atoms.

The order of reactivity of alkyl halides through \({{\rm{S}}_{\rm{N}}}{\rm{2}}\) mechanism is as follows:

Primary halide > Secondary halide > Tertiary halide.

Tertiary halides are the least reactive because three bulky groups hinder the approach of the incoming nucleophile.

(b) Substitution Nucleophilic Unimolecular \(\left( {{{\rm{S}}_{\rm{N}}}{\rm{1}}} \right)\)

The substitution nucleophilic unimolecular \({{\rm{S}}_{\rm{N}}}{\rm{1}}\) reaction follows the first-order kinetics, i.e., the reaction rate depends upon the concentration of only one reactant, the alkyl halide substrate. These reactions are generally carried out in polar protic solvents such as water, alcohol, acetic acid, etc.

For example, the reaction between tert-butyl bromide and hydroxide ion follows a \({{\rm{S}}_{\rm{N}}}{\rm{1}}\) reaction to yield tert-butyl alcohol. The reaction rate depends upon the concentration of only one reactant, which is tert- butyl bromide.

The reaction follows a \({{\rm{S}}_{\rm{N}}}{\rm{1}}\) mechanism that occurs in two steps.

Step 1: Formation of a carbocation

The polarised \({\rm{ C – Br}}\) bond undergoes slow cleavage to produce a carbocation and a bromide ion.

Step 2: Attack by the nucleophile

The incoming nucleophile then attacks the carbocation formed in step 1.

Step I is a slow, reversible and rate-determining step of the reaction involving the \({\rm{ C – Br}}\) bond breakage. Hence, the reaction rate depends only on the concentration of alkyl halide and not on the hydroxide ion concentration. Besides, the stability of the carbocation also determines the rate of the reaction. The greater the stability of carbocation, the greater its ease of formation from an alkyl halide, and the faster will be the reaction rate.

The order of reactivity of alkyl halides through \({{\rm{S}}_{\rm{N}}}{\rm{1}}\) mechanism is as follows:

Tertiary halide > Secondary halide > Primary halide.

To summarise:

For a given alkyl group, the reactivity of the halide, \({\rm{R – X}}\), follows the same order in both the mechanisms \({\rm{R}} – {\rm{I}} > {\rm{R}} – {\rm{Br}} > {\rm{R}} – {\rm{Cl}} > > {\rm{R}} – {\rm{F}}\)

Stereochemical Aspects of Nucleophilic Substitution Reactions

Optical Activity

A plane polarised light is produced by passing ordinary light through the Nicol prism.

The plane of plane polarised light rotates when it is passed through the solutions of certain compounds known as optically active compounds. A polarimeter measures the angle by which the plane polarised light is rotated. Suppose the compound rotates the plane of plane polarised light in the clockwise direction. In that case, it is called dextrorotatory or the \({\rm{d}}\)-form indicated by placing a positive \({\rm{( + )}}\) sign before the degree of rotation. Suppose the light is rotated in the anticlockwise direction. In that case, the compound is said to be laevorotatory or the \({\rm{l}}\)-form indicated by a negative \({\rm{( – )}}\) sign before the degree of rotation. Such \({\rm{( + )}}\) and \({\rm{( – )}}\) isomers of a compound are called optical isomers, and the phenomenon is termed optical isomerism.

Chirality

Everyday objects such as a sphere, cube, and cone are all identical to their mirror images and superimposed. However, the mirror image of our right hand is not superimposable on our left hand.

The objects that are non-superimposable on their mirror image (like a pair of hands) are called chiral, and the phenomenon is known as chirality. Chiral molecules are optically active. The objects that are superimposable on their mirror images are called achiral. The achiral molecules are optically inactive.

For example- Propan-\(2\)-ol and its mirror image are superimposable on each other.

However, the mirror images of butane-\(2\)-ol are non-superimposable on each other.

Molecular Asymmetry

The carbon atom is tetravalent, i.e. its valency is four. The spatial arrangement of these four groups around the central carbon is tetrahedral. If all the four groups attached to that carbon are different, the molecule’s mirror image is not superimposed (overlapped) on the molecule; such carbon is called asymmetric carbon or stereo centre. The resulting molecule would lack symmetry and is referred to as an asymmetric molecule. The asymmetry of the molecule and the non-superimposability of mirror images are responsible for the optical activity in such organic compounds.

In the above example, Propan-\(2\)-ol has two \( – {\rm{C}}{{\rm{H}}_3}\) groups hence is a symmetrical molecule. However, in butan-\(2\)-ol all the substituents are different and hence is an asymmetrical molecule.

Racemisation

When the mirror image of a compound is non-superimposable on each other, then the stereoisomers are known as enantiomers.

Enantiomers possess identical physical properties, namely, boiling point, melting point, refractive index, etc. They only differ with respect to the rotation of plane polarised light. If one of the enantiomers is dextrorotatory, the other will be laevorotatory.

A racemic mixture or racemic modification is a mixture containing two enantiomers in equal proportions. This mixture results in zero optical rotation. This is because the rotation due to one isomer will be cancelled by the rotation due to the other isomer. A racemic mixture is represented by prefixing dl or \(( \pm )\) before the name of the compound. For example, \(( \pm )\) butan-\(2\)-ol. The process of conversion of enantiomer into a racemic mixture is known as racemisation.

Retention and Inversion

The replacement of \({\rm{X}}\) by \({\rm{Y}}\) in the following reaction occurs in three ways as shown below-

If \({\rm{(A)}}\) is the only compound obtained, the retention of configuration occurs.

If \({\rm{(B)}}\) is the only compound obtained, the inversion of configuration occurs.

If \({\rm{A}}\) and \({\rm{B}}\) are obtained in equal amounts, then the process is called racemisation, and the product is optically inactive.

\({{\rm{S}}_{\rm{N}}}{\rm{1}}\) and \({{\rm{S}}_{\rm{N}}}{\rm{2}}\) Mechanisms of Optically Active Alkyl Halides

1. \({{\rm{S}}_{\rm{N}}}{\rm{2}}\) reactions of optically active halides are accompanied by inversion of configuration, i.e., the product has an inverted configuration compared to the reactant. This is because the nucleophile attaches itself to the side opposite to that of the halogen atom.

For example- When \(( – )2\)-bromooctane reacts with sodium hydroxide, \(( + )\)-octan-\(2\)-ol is formed. The nucleophile \( – {\rm{OH}}\) group, is the opposite of that of the bromide ion in the original molecule.

2. \({{\rm{S}}_{\rm{N}}}{\rm{1}}\) reaction of optically active halides is accompanied by racemisation. This is because the carbon atom of the carbocation formed in the slow step of the reaction is sp \(2\) hybridised. It is planar and achiral. The attack of the nucleophile may be accomplished from either side of the plane of the carbocation. This results in a mixture of products in which one of the products retains the configuration of the original optically active alkyl halide (the \( – {\rm{OH}}\) attaching on the same position as halide ion), and the other inverts the configuration of the original optically active alkyl halide (the \( – {\rm{OH}}\) attaching on the side opposite to halide ion).

This is illustrated by the hydrolysis of optically active \(2\)-bromobutane, which results in the formation of \(( \pm )\)-butan-\(2\)-ol.

Summary

The reactions in which a nucleophile replaces an already existing nucleophile in a molecule is known as substitution nucleophilic reactions. Two types of nucleophilic substitution reaction take place-\({{\rm{S}}_{\rm{N}}}{\rm{1}}\) and \({{\rm{S}}_{\rm{N}}}{\rm{2}}\). The former follows first-order kinetics, whereas the latter follows second-order kinetics. Both types depend on the concentration and approach of the incoming nucleophile. A compound can either be superimposable or non-superimposable on its mirror image. The ability to rotate the polarised light and its superimposability together contribute to the optical activity of the organic compound. In this article, we learnt about the types of nucleophilic substitution reaction, chirality, molecular symmetry, optical activity and racemisation of optically active compounds.

Frequently Asked Questions

Q.1. What is meant by nucleophilic substitution reaction?
Ans: Nucleophilic substitution reactions are a class of reactions in which an electron-rich nucleophile attacks a positively charged electrophile to replace a leaving group.

Q.2. What are the types of nucleophilic reactions?
Ans: There are two main types of nucleophilic substitution reactions – \({{\rm{S}}_{\rm{N}}}{\rm{1}}\) reaction and \({{\rm{S}}_{\rm{N}}}{\rm{2}}\) reaction.

Q.3. What is the difference between enantiomers and diastereomers?
Ans: Enantiomers are chiral molecules that are not superimposable on each other’s mirror images. Diastereomers are the stereoisomers of non-superimposable and non-mirror images of each other.

Q.4. What is the stereochemical aspect of \({{\rm{S}}_{\rm{N}}}{\rm{2}}\) reaction?
Ans: In an \({{\rm{S}}_{\rm{N}}}{\rm{2}}\) reaction, the product formed has inverted configuration as compared to that of the substrate. The nucleophile attacks the electrophilic centre on the side that is opposite to the leaving group. During a backside attack, the stereochemistry at the carbon atom changes.

Q.5. What is the difference between electrophilic substitution and nucleophilic substitution?
Ans: Electrophilic substitutions involve the displacement of a functional group by an electrophile (generally a hydrogen atom). Nucleophilic substitutions involve the attack of a nucleophile on a positively charged (or partially positively charged) atom or group. Nucleophiles are electron-rich species that can donate an electron pair.

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